Ovarian blood vessel occlusion as a surgical sterilization method in rats.

PubMed

Murakami, Eduardo; Sartori de Camargo, Laíza; Freitas Cardoso, Karym Christine de; Miguel, Marina Pacheco; Tavares, Denise Cláudia; Santos Honsho, Cristiane dos; Ferreira de Souza, Fabiana

2014-04-01

To evaluate the female sterilization by occlusion of the ovarian blood flow, using the rat as experimental model. Fifty-five females rats were divided into four groups: I (n=10), bilateral ovariectomy, euthanized at 60 or 90 days; II (n=5), opening the abdominal cavity, euthanized at 90 days; III (n=20), bilateral occlusion of the ovarian blood supply using titanium clips, euthanized at 60 or 90 days; and IV (n=20), bilateral occlusion of the ovarian blood supply using nylon thread, euthanized at 60 or 90 days. The estrous cycle was monitored by vaginal cytology. After euthanasia, the reproductive tissues were evaluated histologically. Ovarian atresia was identified macroscopically at 60 days after surgery in the rats in groups III and IV; however, most of the rats in group III maintained cyclicity. Histology of the tissues from group IV revealed that the ovarian tissue was replaced by dense fibrous connective tissue that was slightly vascularized and that intact follicles were absent by 90 days. Ovarian blood vessels occluded caused ischemia, leading to progressive tissue necrosis, and bilateral occlusion using a nylon ligature is a viable method for surgical sterilization.

The role of ovarian hormones in sexual reward states of the female rat.

PubMed

Parada, Mayte; Vargas, Erica Barbosa; Kyres, Maria; Burnside, Kimberly; Pfaus, James G

2012-09-01

To what extent does the reward value of sexual stimulation in females depend on ovarian hormones? The effects of estradiol benzoate (EB) and progesterone (P) were examined on the acquisition and expression of sexual reward induced by paced copulation and clitoral stimulation (CLS) in ovariectomized (OVX) rats. In experiment 1 we examined the expression of a pacing-induced conditioned place preference (CPP). Ovariectomized, hormone-primed rats were given experience with paced copulation associated with one side of a CPP apparatus. Changing hormonal status prior to the final CPP test did not alter pacing-induced CPP. However, subsequent partial extinction of CPP was observed only in rats primed with EB+P, a treatment previously shown to induce sexual desire and receptivity. In Experiment 2, significant CLS-induced CPP developed in ovariectomized rats regardless of hormone priming. Our results show that the expression of the sexual reward state induced by paced copulation, and CLS in particular, is independent of hormone priming. We propose that ovarian hormones sensitize sensory and motor pathways necessary for sexual behavior and stimulation to induce reward. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of thermal stimulation, applied to the hindpaw via a hot water bath, upon ovarian blood flow in anesthetized nonpregnant rats.

PubMed

Uchida, Sae; Hotta, Harumi; Hanada, Tomoko; Okuno, Yuka; Aikawa, Yoshihiro

2007-08-01

The effects of thermal stimulation, applied to the hindpaw via a hot bath set to either 40 degrees C (non-noxious) or 49 degrees C (noxious), upon ovarian blood flow were examined in nonpregnant anesthetized rats. Ovarian blood flow was measured using a laser Doppler flowmeter. Blood pressure was markedly increased following 49 degrees C stimulation. Ovarian blood flow, however, showed no obvious change during stimulation, although a small increase was observed after stimulation. Ovarian blood flow and blood pressure responses to 49 degrees C stimulation were abolished after hindlimb somatic nerves proximal to the stimuli were cut. Heat stimulation (49 degrees C) resulted in remarkable increases in both ovarian blood flow and blood pressure in rats in which the sympathetic nerves supplying the ovary were cut but the hindlimb somatic nerves remained intact. The efferent activity of the ovarian plexus nerve was increased during stimulation at 49 degrees C. Stimulation at 40 degrees C had no effect upon ovarian blood flow, blood pressure or ovarian plexus nerve activity. Electrical stimulation of the distal part of the severed ovarian plexus nerve resulted in a decrease in both the diameter of ovarian arterioles, observed using a digital video microscope, and ovarian blood flow.The present results demonstrate that noxious heat, but not non-noxious warm, stimulation of the hindpaw skin in anesthetized rats influences ovarian blood flow in a manner that is attributed to reflex responses in ovarian sympathetic nerve activity and blood pressure.

Hormone secretion by euthyroid and hypothyroid rat ovaries during the early stages of hCG-induced ovarian cyst development.

PubMed

Bruot, B C

1987-02-01

This study was undertaken to examine ovarian steroid production during the early stages of hCG-induced ovarian cyst formation in the hypothyroid rat. Rats were placed into two groups with one group made hypothyroid by adding thiouracil to their diet. After 10 days, each group was divided into two subgroups with one subgroup receiving daily injections of hCG for 2 days and the other subgroup receiving saline. On the morning of Day 13, ovaries were removed and incubated for 2 hr. No significant difference in progesterone secretion was observed. However, ovaries from hypothyroid, hCG-treated rats secreted significantly more testosterone and estradiol than ovaries from vehicle-treated, hypothyroid rats and euthyroid, hCG-treated rats. In a second experiment, ovaries from euthyroid and hypothyroid rats treated with hCG were incubated in medium supplemented with 100 nM androstenedione and 0 or 100 ng FSH/ml. FSH failed to affect progesterone, testosterone, and estradiol secretions by ovaries from euthyroid, hCG-treated rats. In contrast, FSH significantly enhanced testosterone and estradiol secretion by ovaries from hypothyroid, hCG-treated rats. These results support the hypothesis that increased levels of testosterone and estradiol secretion have a central role in the induction of polycystic ovaries by hCG in the hypothyroid rat.

Biological and histopathological investigations of moclobemide on injured ovarian tissue following induction of ischemia-reperfusion in rats.

PubMed

Ingec, Metin; Calik, Muhammet; Gundogdu, Cemal; Kurt, Ali; Yilmaz, Mehmet; Isaoglu, Unal; Salman, Suleyman; Akcay, Fatih; Suleyman, Halis

2012-04-01

The effects of moclobemide on damaged ovarian tissue induced by ischemia- reperfusion and damaged contralateral ovarian tissue were investigated in rats, biochemically and histologically. In this experimental study, 40 rats were equally divided into four groups: 10 mg/kg moclobemide, 20 mg/kg moclobemide, ischemia/reperfusion control, and intact control groups. A 2-2.5-cm-long vertical incision was made in the lower abdomen of each rat in order to reach the ovaries, after which a vascular clip was placed on the lower side of the right ovary of each animal in the two treatment groups and the ischemia-reperfusion control group, but not in the healthy (intact control) animal group. The purpose of this procedure was to create ischemia over the course of three hours, then the clips were unclamped to provide reperfusion for the next two hours. At the end of the two hours of reperfusion, all the animals were killed by high-dose anaesthesia and their ovaries were taken and subjected to histological and biochemical (malondialdehyde, nitric oxide, glutathione) studies. The obtained results showed that moclobemide suppressed nitric oxide and malondialdehyde production in the ischemia-reperfusion damage area, and prevented the decrease in endogenous antioxidant levels (glutathione) in the rat ovarian tissue. Moclobemide also prevented infiltration of leukocytes to the ovarian tissue. These results showed that moclobemide protected ovarian tissue against ischemiareperfusion injury. This study shows that moclobemide represses malondialdehyde and nitric oxide production in the rat ovarian tissue subjected to ischemia-reperfusion injury and keeps the endogenous antioxidant glutathione level from decreasing. Moclobemide also inhibits leukocytic migration into ovarian tissue following ischemia-reperfusion injury. From these results, it is suggested that moclobemide can be used in the treatment of ovarian ischemia-reperfusion injury.

Metabolomic changes in follicular fluid induced by soy isoflavones administered to rats from weaning until sexual maturity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Wenxiang; Zhang, Wenchang, E-mail: wenchang2002@sina.com; Liu, Jin

Female Wistar rats at 21 days of age were treated with one of three concentrations of soy isoflavones (SIF) (50, 100 or 200 mg/kg body weight, orally, once per day) from weaning until sexual maturity (3 months) in order to evaluate the influence of SIF on ovarian follicle development. After treatment, the serum sex hormone levels and enumeration of ovarian follicles of the ovary were measured. The metabolic profile of follicular fluid was determined using HPLC-MS. Principal component analysis (PCA) and partial least-squares-discriminant analysis (PLS-DA) was used to identify differences in metabolites and reveal useful toxic biomarkers. The results indicatedmore » that modest doses of SIF affect ovarian follicle development, as demonstrated by decreased serum estradiol levels and increases in both ovarian follicle atresia and corpora lutea number in the ovary. SIF treatment-related metabolic alterations in follicular fluid were also found in the PCA and PLS-DA models. The 24 most significantly altered metabolites were identified, including primary sex hormones, amino acids, fatty acids and metabolites involved in energy metabolism. These findings may indicate that soy isoflavones affect ovarian follicle development by inducing metabolomic variations in the follicular fluid. - Highlights: ► Modest doses of soy isoflavones (SIF) do affect ovarian follicle development. ► SIF treatment-related metabolic alterations in follicular fluid were found. ► The 24 most significantly altered metabolites were identified.« less

RHOG-DOCK1-RAC1 Signaling Axis Is Perturbed in DHEA-Induced Polycystic Ovary in Rat Model.

PubMed

Ubba, Vaibhave; Soni, Upendra Kumar; Chadchan, Sangappa; Maurya, Vineet Kumar; Kumar, Vijay; Maurya, Ruchika; Chaturvedi, Himanshu; Singh, Rajender; Dwivedi, Anila; Jha, Rajesh Kumar

2017-05-01

The function of RHOG, a RAC1 activator, was explored in the ovary during ovarian follicular development and pathological conditions. With the help of immunoblotting and immunolocalization, we determined the expression and localization of RHOG in normal (estrous cycle) and polycystic ovaries using Sprague Dawley (SD) rat model. Employing polymerase chain reaction and flow cytometry, we analyzed the transcript and expression levels of downstream molecules of RHOG, DOCK1, and RAC1 in the polycystic ovarian syndrome (PCOS) ovary along with normal antral follicular theca and granulosa cells after dehydroepiandrosterone (DHEA) supplementation. The effect of RHOG knockdown on DOCK1, VAV, and RAC1 expression was evaluated in the human ovarian cells (SKOV3), theca cells, and granulosa cells from SD rats with the help of flow cytometry. Oocyte at secondary follicles along with stromal cells showed optimal expression of RHOG. Immunoblotting of RHOG revealed its maximum expression at diestrus and proestrus, which was downregulated at estrus stage. Mild immunostaining of RHOG was also present in the theca and granulosa cells of the secondary and antral follicles. Polycystic ovary exhibited weak immunostaining for RHOG and that was corroborated by immunoblotting-based investigations. RHOG effectors DOCK1 and ELMO1 were found reduced in the ovary in PCOS condition/DHEA. RHOG silencing reduced the expression of DOCK1 and RAC1 in the theca and granulosa cells from SD rat antral follicles and that was mirrored in the human ovarian cells. Collectively, RHOG can mediate signaling through downstream effectors DOCK1 and RAC1 during ovarian follicular development (theca and granulosa cells and oocyte), but DHEA downregulated them in the PCOS ovary.

In vivo blockade of acetylcholinesterase increases intraovarian acetylcholine and enhances follicular development and fertility in the rat.

PubMed

Urra, Javier; Blohberger, Jan; Tiszavari, Michelle; Mayerhofer, Artur; Lara, Hernan E

2016-07-21

Growth and differentiation of ovarian follicles are regulated by systemic and local factors, which may include acetylcholine (ACh). Granulosa cells (GCs) of growing follicles and luteal cells produce ACh and in cultured GCs it exerts trophic actions via muscarinic receptors. However, such actions were not studied in vivo. After having established that rat ovarian GCs and luteal cells express the ACh-metabolizing enzyme ACh esterase (AChE), we examined the consequences of local application of an AChE inhibitor, huperzine A (HupA), by osmotic minipump delivery into the ovarian bursa of hemiovariectomized rats. Saline was used in the control group. Local delivery of HupA for 4 weeks increased ovarian ACh content. Estrus cyclicity was not changed indicating a locally restricted range of HupA action. The number of primordial and primary follicles was unaffected, but small secondary follicles significantly increased in the HupA group. Furthermore, a significant increase in the number of corpora lutea suggested increased ovulatory events. In support, as shown upon mating, HupA-treated females had significantly increased implantation sites and more pups. Thus the data are in support of a trophic role of ACh in follicular development and ovulation and point to an important role of ACh in female fertility.

In vivo blockade of acetylcholinesterase increases intraovarian acetylcholine and enhances follicular development and fertility in the rat

PubMed Central

Blohberger, Jan; Tiszavari, Michelle; Mayerhofer, Artur; Lara, Hernan E.

2016-01-01

Growth and differentiation of ovarian follicles are regulated by systemic and local factors, which may include acetylcholine (ACh). Granulosa cells (GCs) of growing follicles and luteal cells produce ACh and in cultured GCs it exerts trophic actions via muscarinic receptors. However, such actions were not studied in vivo. After having established that rat ovarian GCs and luteal cells express the ACh-metabolizing enzyme ACh esterase (AChE), we examined the consequences of local application of an AChE inhibitor, huperzine A (HupA), by osmotic minipump delivery into the ovarian bursa of hemiovariectomized rats. Saline was used in the control group. Local delivery of HupA for 4 weeks increased ovarian ACh content. Estrus cyclicity was not changed indicating a locally restricted range of HupA action. The number of primordial and primary follicles was unaffected, but small secondary follicles significantly increased in the HupA group. Furthermore, a significant increase in the number of corpora lutea suggested increased ovulatory events. In support, as shown upon mating, HupA-treated females had significantly increased implantation sites and more pups. Thus the data are in support of a trophic role of ACh in follicular development and ovulation and point to an important role of ACh in female fertility. PMID:27440195

The effects of electromagnetic fields on the number of ovarian primordial follicles: An experimental study.

PubMed

Bakacak, Murat; Bostancı, Mehmet Sühha; Attar, Rukset; Yıldırım, Özge Kizilkale; Yıldırım, Gazi; Bakacak, Zeyneb; Sayar, Hamide; Han, Agahan

2015-06-01

The aim of this study was to evaluate the effect of an electromagnetic field (EMF), generated close to the ovaries, on primordial follicles. A total of 16 rats were used in this study. The study group consisted of rats exposed to an EMF in the abdominal region for 15 min/d for 15 days. Both the study and control group were composed of eight rats. After the treatment period of 15 days, the ovaries of the rats were extracted, and sections of ovarian tissue were taken for histological evaluation. The independent samples t test was used to compare the two groups. In the study group, the means of the right and left ovarian follicle numbers were 34.00 ± 10.20 and 36.00 ± 10.53, respectively. The average total ovarian follicle number was 70.00 ± 19.03. In the control group, the means of the right and left ovarian follicle numbers were 78.50 ± 25.98 and 71.75 ± 29.66, respectively, and the average total ovarian follicle number was 150.25 ± 49.53. The comparisons of the means of the right and left ovarian follicle numbers and the means of the total ovarian follicle numbers between the study and control groups indicated that the study group had significantly fewer follicles (p < 0.001, p = 0.011, and p = 0.002, respectively). This study found a significant decrease in the number of ovarian follicles in rats exposed to an EMF. Further clinical studies are needed to reveal the effects of EMFs on ovarian reserve and infertility. Copyright © 2015. Published by Elsevier Taiwan.

Disruption of the ovarian follicle reservoir of prepubertal rats following prenatal exposure to a continuous 900-MHz electromagnetic field.

PubMed

Türedi, Sibel; Hancı, Hatice; Çolakoğlu, Serdar; Kaya, Haydar; Odacı, Ersan

2016-06-01

The effects on human health of electromagnetic field (EMF) have begun to be seriously questioned with the entry into daily life of devices establishing EMF, such as cell phones, wireless fidelity, and masts. Recent studies have reported that exposure to EMF, particularly during pregnancy, affects the developing embryo/fetus. The aim of this study was therefore to examine the effects of exposure to continuous 900-Megahertz (MHz) EMF applied in the prenatal period on ovarian follicle development and oocyte differentiation. Six pregnant Sprague Dawley rats were divided equally into a non-exposed control group (CNGr) and a group (EMFGr) exposed to continuous 900-MHz EMF for 1 h daily, at the same time every day, on days 13-21 of pregnancy. New groups were established from pups obtained from both groups after birth. One group consisting of female pups from CNGr rats was adopted as newborn CNGr (New-CNGr, n = 6), and another group consisting of female pups from EMFGr rats was adopted as newborn EMFGr (New-EMFGr, n = 6). No procedure was performed on New-CNGr or New-EMFGr rats. All rat pups were sacrificed on the postnatal 34th day, and their ovarian tissues were removed. Follicle count, histological injury scoring and morphological assessment with apoptotic index criteria were performed with sections obtained following routine histological tissue preparation. Follicle count results revealed a statistically significant decrease in primordial and tertiary follicle numbers in New-EMFGr compared to New-CNGr (p < 0.05), while atretic follicle numbers and apoptotic index levels increased significantly (p < 0.05). Histopathological examination revealed severe follicle degeneration, vasocongestion, a low level of increased stromal fibrotic tissue and cytoplasmic vacuolization in granulosa cell in New-EMFGr. Prenatal exposure to continuous 900-MHz EMF for 1 h each day from days 13-21 led to a decrease in ovarian follicle reservoirs in female rat pups at the beginning of the prepubertal period.

Cadmium exposure in newborn rats ovary induces developmental disorders of primordial follicles and the differential expression of SCF/c-kit gene.

PubMed

Zhang, Wenchang; Wu, Tingting; Zhang, Chenyun; Luo, Lingfeng; Xie, Meimei; Huang, Huiling

2017-10-05

Since the 1990s, the rising problem that gonad reproductive toxicity on adult female after exposing to cadmium (Cd), an environmental endocrine disruptor, has attracted high attention at home and abroad,and was systematically studied. Our research focuses on a further problem is that early cadmium exposure (during birth to before puberty) impact on development and function of ovarian cells and its possible mechanism. Our research focuses on the changes of ovarian cells growth and development after the newborn rat ovaries with cadmium exposure in vitro, and different expression of ovarian cells development-related factors, SCF/c-kit and changes of their DNA methylation status. We obtained ovaries from 4-day-old SD rats and cultured them in DMEM/F12 mixed with α-MEM media in vitro. Different doses of cadmium were designed as control, 0.5, 5, 10 and 50μM, and then the constituent ratio of ovarian follicle and follicular oocytes diameter were observed with microscope after 4-h exposure. We found that the increased constituent ratio of original follicle and decreased diameter of all levels of follicular oocytes(compared with control, with statistically significant differences, P<0.01).After the measurement of expression of SCF/c-kit by qRT-PCR and Western Blotting, the mRNA and protein expression of SCF/c-kit in ovarian were both decreased. We further found that the increased constituent ratio of growth follicle and increased diameter of oocytes under the treatment of adding SCF in cell culture media. Finally, MALDI-TOF-MS method showed DNA-low methylation status of SCF/c-kit promoter region after Cd exposure. Overall, we concluded that the exposure of cadimium (5-50μM) on newborn rats ovaries could inhibit follicle development.SCF/c-kit system might mediate follicle development damage caused by cadmium, which is associated with DNA hypomethylation of SCF/c-kit promoter region may be worthy of further study. Copyright © 2017. Published by Elsevier B.V.

Sympathetic innervation regulates macrophage activity in rats with polycystic ovary.

PubMed

Figueroa, Florencia; Mendoza, Gisela; Cardozo, Darío; Mohamed, Fabián; Oliveros, Liliana; Forneris, Myriam

2018-07-01

Polycystic ovarian syndrome (PCOS) is a low-grade inflammatory disease characterized by hyperandrogenism and ovarian hyperinnervation. The aim of this work is to investigate whether in vivo bilateral superior ovarian nerve (SON) section in adult rats with estradiol valerate-induced PCOS (PCO rats) affects macrophage spleen cells (MФ) and modifies the steroidogenic ability of their secretions. Culture media of MФ from PCO rats and PCO rats with SON section (PCO-SON rats) were used to stimulate in vitro intact ovaries. Compared with macrophages PCO, macrophages from PCO-SON rats released less tumor necrosis factor-α and nitric oxide, expressed lower Bax and Nfkb mRNA and showed reduced TUNEL staining. Also, in PCO rats, the SON section decreased kisspeptin and nerve growth factor mRNA expressions, without changes in Trka receptor mRNA levels. Macrophage secretions from PCO-SON rats decreased androstenedione and stimulated progesterone release in PCO ovaries, compared to macrophage secretions from PCO rats. No changes were observed in ovarian estradiol response. These findings emphasize the importance of the SON in spleen MΦ, since its manipulation leads to secondary modifications of immunological and neural mediators, which might influence ovarian steroidogenesis. In PCO ovaries, the reduction of androstenedione and the improvement of progesterone release induced by PCO-SON MΦ secretion, might be beneficial considering the hormonal anomalies characteristic of PCOS. We present functional evidence that modulation of the immune-endocrine function by peripheral sympathetic nervous system might have implications for understanding the pathophysiology of PCOS. © 2018 Society for Endocrinology.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daud, A.I.; Bumpus, F.M.; Husain, A.

Ovarian angiotensin I (Ang I)-converting enzyme (ACE), estimated by the specific binding of the ACE inhibitor (125I)iodo-MK-351A, is localized on multiple ovarian structures, including follicular granulosa cells, corpora lutea, terminal epithelium, and ovarian blood vessels, but total ovarian ACE does not display a cyclic pattern of variation during the rat estrous cycle. We have previously shown that ACE is localized on the granulosa cell layer of a subpopulation of rat ovarian follicles. Our present study shows that ovarian granulosa cells contain high affinity (binding site affinity (Kd), approximately 90 pM) and low capacity (binding site density (Bmax), approximately 12 fmol/2.5more » X 10(5) cells) (125I)iodo-MK-351A-binding sites and convert (125I)iodo-Ang I to (125I)iodo-Ang II (greater than 85% of this conversion was inhibited by the ACE inhibitor captopril). Throughout the rat estrous cycle, 94-100% of developing follicles and 89-96% of atretic follicles contained high levels of ACE; however, ACE was either not observed or its levels were very low in preovulatory follicles. These findings indicate the presence of high levels of biologically active ACE on the surface of granulosa cells and suggest a potential role for follicular ACE in early stages of follicular maturation and atresia. Although ACE is known to process a variety of peptides found within the ovary, and these peptides may have opposing effects on follicular maturation, we attempted to define the cumulative effect of ACE inhibition on follicular maturation.« less

Human umbilical cord mesenchymal stem cells improve the reserve function of perimenopausal ovary via a paracrine mechanism.

PubMed

Li, Jia; Mao, QiuXian; He, JingJun; She, HaoQing; Zhang, Zhi; Yin, ChunYan

2017-03-09

Human umbilical cord mesenchymal stem cells (hUCMSCs) are a type of pluripotent stem cell which are isolated from the umbilical cord of newborns. hUCMSCs have great therapeutic potential. We designed this experimental study in order to investigate whether the transplantation of hUCMSCs can improve the ovarian reserve function of perimenopausal rats and delay ovarian senescence. We selected naturally aging rats confirmed by vaginal smears as models of perimenopausal rats, divided into the control group and the treatment group, and selected young fertile female rats as normal controls. hUCMSCs were transplanted into rats of the treatment group through tail veins. Enzyme-linked immunosorbent assay (ELISA) detected serum levels of sex hormones, H&E staining showed ovarian tissue structure and allowed follicle counting, immunohistochemistry and western blot analysis revealed ovarian expression of hepatocyte growth factor (HGF), vascular endothelial cell growth factor (VEGF), and insulin-like growth factor-1 (IGF-1), polymerase chain reaction (PCR) and western blot analysis revealed hUCMSCs expression of HGF, VEGF, and IGF-1. At time points of 14, 21, and 28 days after hUCMSCs transplantation, estradiol (E 2 ) and anti-Müllerian hormone (AMH) increased while follicle-stimulating hormone (FSH) decreased; ovarian structure improved and follicle number increased; ovarian expression of HGF, VEGF, and IGF-1 protein elevated significantly. Meanwhile, PCR and western blot analysis indicated hUCMSCs have the capacity of secreting HGF, VEGF, and IGF-1 cytokines. Our results suggest that hUCMSCs can promote ovarian expression of HGF, VEGF, and IGF-1 through secreting those cytokines, resulting in improving ovarian reserve function and withstanding ovarian senescence.

Hypothalamic IGF-I Gene Therapy Prolongs Estrous Cyclicity and Protects Ovarian Structure in Middle-Aged Female Rats

PubMed Central

Rodríguez, Silvia S.; Schwerdt, José I.; Barbeito, Claudio G.; Flamini, Mirta A.; Han, Ye; Bohn, Martha C.

2013-01-01

There is substantial evidence that age-related ovarian failure in rats is preceded by abnormal responsiveness of the neuroendocrine axis to estrogen positive feedback. Because IGF-I seems to act as a permissive factor for proper GnRH neuronal response to estrogen positive feedback and considering that the hypothalamic content of IGF-I declines in middle-aged (M-A) rats, we assessed the effectiveness of long-term IGF-I gene therapy in the mediobasal hypothalamus (MBH) of M-A female rats to extend regular cyclicity and preserve ovarian structure. We used 3 groups of M-A rats: 1 group of intact animals and 2 groups injected, at 36.2 weeks of age, in the MBH with either a bicistronic recombinant adeno-associated virus (rAAV) harboring the genes for IGF-I and the red fluorescent protein DsRed2, or a control rAAV expressing only DsRed2. Daily vaginal smears were taken throughout the study, which ended at 49.5 weeks of age. We measured serum levels of reproductive hormones and assessed ovarian histology at the end of the study. Although most of the rats injected with the IGF-I rAAV had, on the average, well-preserved estrous cyclicity as well as a generally normal ovarian histology, the intact and control rAAV groups showed a high percentage of acyclic rats at the end of the study and ovaries with numerous enlarged cysts and scarce corpora lutea. Serum LH was higher and hyperprolactinemia lower in the treated animals. These results suggest that overexpression of IGF-I in the MBH prolongs normal ovarian function in M-A female rats. PMID:23584855

Obesity alters the ovarian glucidic homeostasis disrupting the reproductive outcome of female rats.

PubMed

Bazzano, María Victoria; Paz, Dante Agustín; Elia, Evelin Mariel

2017-04-01

Obesity constitutes a health problem of increasing worldwide prevalence related to many reproductive problems such as infertility, ovulation dysfunction, preterm delivery, fetal growth disorders, etc. The mechanisms linking obesity to these pathologies are not fully understood. Cafeteria diet (CAF) is the animal model used for the study of obesity that more closely reflects western diet habits. Previously we described that CAF induces obesity associated to hyperglycemia, reduced ovarian reserve, presence of follicular cysts and ovulatory impairments. The aim of the present study was to contribute in the understanding of the physiological mechanisms altered as consequence of obesity. For that purpose, female Wistar rats were fed ad libitum with a standard diet (control group) or CAF (Obese group). We found that CAF fed-rats developed obesity, glucose intolerance and insulin resistance. Ovaries from obese rats showed decreased glucose uptake and became insulin resistant, showing decreased ovarian expression of glucotransporter type 4 and insulin receptor gene expression respect to controls. These animals showed an increased follicular nitric oxyde synthase expression that may be responsible for the ovulatory disruptions and for inflammation, a common feature in obesity. Obese rats resulted subfertile and their pups were macrosomic. We conclude that obesity alters the systemic and the ovarian glucidic homeostasis impairing the reproductive outcome. Since macrosomia is a risk factor for metabolic and obstetric disorders in adult life, we suggest that obesity is impacting not only on health and reproduction but it is also impacting on health and reproduction of the offspring. Published by Elsevier Inc.

Diagnostic value of signal peptide-CUB-EGF domain-containing protein 1 as an early and late biochemical marker in the ovarian torsion rat model.

PubMed

Uzun, Özgür; Kaban, Işık; Midi, Ahmet; Uysal, Hande; Boran, Ahmet B; Bacanakgil, Besim H; Tarbaghia, Marwa

2018-04-02

Signal peptide-CUB-EGF (epidermal growth factor-like protein) domain-containing protein 1 (SCUBE1) is an experimental marker of ischemia that has been previously studied both in rat models and humans. In this study, we aim to investigate the importance of SCUBE1 levels in ovarian torsion using an ovarian torsion model in rats. A total of 18 Sprague-Dawley rats were equally divided into three groups. Group 1 (n = 6) was the Sham group and was only given a laparotomy procedure. Group 2 (n = 6) underwent bilateral ovarian torsion and ovarian ischemia lasting 8 h. Group 3 (n = 6) was subjected to bilateral ovarian torsion and ischemia lasting 24 h. Blood samples were collected from all three groups after the operations, and SCUBE1 levels were studied. Ovarian samples were collected, and microscopic evaluation was performed. The correlation of SCUBE1 levels and histopathological findings were investigated. The mean SCUBE1 level of group 3 was statistically higher than other groups (P < 0.01). Follicular degeneration and infiltration of inflammatory cells were, respectively, statistically significant in groups 2 and 3 (P = 0.002 and P = 0.045, respectively). SCUBE1 can be useful in diagnosing ovarian torsion during the first 24 h, but more randomized controlled studies are necessary in order to implement it in clinical settings. © 2018 Japan Society of Obstetrics and Gynecology.

HemoHIM improves ovarian morphology and decreases expression of nerve growth factor in rats with steroid-induced polycystic ovaries.

PubMed

Kim, Sung Ho; Lee, Hae June; Kim, Joong Sun; Moon, Changjong; Kim, Jong Choon; Bae, Chun Sik; Park, Hae Ran; Jung, Uhee; Jo, Sung Kee

2009-12-01

Estradiol valerate (EV)-induced polycystic ovaries (PCOs) in rats cause the anovulation and cystic ovarian morphology. We investigated whether treatment with HemoHIM influences the ovarian morphology and the expression of nerve growth factor (NGF) in an EV-induced PCO rat model. PCO was induced by a single intramuscular injection of EV (4 mg, dissolved in sesame oil) in adult cycling rats. HemoHIM was either administered orally (100 mg/kg of body weight/day) for 35 consecutive days or injected intraperitoneally (50 mg/kg of body weight) every other day after EV injection. Ovarian morphology was almost normalized, and NGF was normalized in the PCO + HemoHIM group. HemoHIM lowered the high numbers of antral follicles and increased the number of corpora lutea in PCOs. The results are consistent with a beneficial effect of HemoHIM in the prevention and treatment of PCO syndrome.

Effect of detorsion alone and in combination with enoxaparin therapy on ovarian reserve and serum antimüllerian hormone levels in a rat ovarian torsion model.

PubMed

Kaya, Cihan; Turgut, Hürriyet; Cengiz, Hüseyin; Turan, Ayşenur; Ekin, Murat; Yaşar, Levent

2014-09-01

To investigate the effect of enoxaparin on ovarian reserve and serum antimüllerian hormone (AMH) levels in a rat ovarian torsion model. Experimental study. Experimental surgery laboratory in a training and research hospital. Fourteen female Wistar Hannover rats. 1) Control group received no special treatment other than abdominal exposure; 2) detorsion-only group received bilateral adnexal torsion (3-hour ischemia), and then after 3-hour torsion period, detorsion (reperfusion) was performed; and 3) detorsion-enoxaparin group received 0.5 mg/kg enoxaparin subcutaneously 2 hours before the same surgery as the detorsion-only group and a second 0.5 mg/kg dose of enoxaparin 24 hours after the first surgeries. Apart from the surgeries, preoperative and postoperative 1-mL blood samples were drawn from the right jugular vein of each rat. Preoperative and postoperative serum AMH levels, histopathologic damage scores, and follicle counts in the ovarian tissue of the rats. Vascular congestion and hemorrhage scores were higher in the detorsion-enoxaparin group than in the detorsion-only and control groups. The number of small antral follicles was smaller in the detorsion-only group than in the control group. The difference in the pre- and postoperative AMH levels was higher in the detorsion-only group than in the control and detorsion-enoxaparin groups. The combination of enoxaparin therapy with conventional ovarian detorsion is more effective in protecting the ovarian reserve than detorsion alone. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Ovarian tissue vitrification and heterotopic autologous transplantation in prepubertal Wistar rats.

PubMed

Wietcovsky, Leticia; Til, David; Salvador, Rafael Alonso; Amaral, Nicole Louise Lângaro; Senn, Alfred Paul; Amaral, Vera Lucia Lângaro

2018-03-15

To evaluate the efficiency of ovarian tissue heterotopic autografting after vitrification in prepubertal rats. Fragments of excised ovaries from prepubertal rats were used after assessing post-warming cellular viability, to determine the best vitrification protocol prior to retroauricular autografting. Pre-pubertal females (N=24) were castrated and divided into three group: Group 1 - fresh ovarian tissue transplantation; Group 2 - vitrified/warmed tissue transplantation; Group 3 - bilateral oophorectomy without transplantation. The ovarian fragments were exposed to solutions from the Ingamed® commercial kit, allocated in bacteriological loops and immersed in liquid nitrogen. Sixty days after transplantation, a vaginal mucus sample was collected for cytology tests, followed by sacrificing the animal, performing a cardiac puncture for collecting a blood sample to determine luteinizing hormone and estradiol levels, and excision of the transplanted fragment for histology tests. Vaginal cytology revealed that 87.5% of females from groups 1 and 2 had estrus while all females in Group 3 remained in diestrus. The mean LH value in groups 1 (0.08 mIU/mL) and 2 (0.34 mIU/mL) were statistically different from that of Group 3 (2.27 mIU/mL). E2 values did not differ between the groups. The histological analysis of Group 1 excised grafts versus those from Group 2 showed a higher percentage of primary follicles (62.5% vs. 12.5%), developing follicles (75% vs. 25%), corpus luteum (37.5% vs. 12.5%) and stromal region (100% vs. 87.5%). This study indicated that pre-pubertal ovarian tissue vitrification can be used to preserve fertility and to restore endocrine function in castrated rats.

The characterization of obese polycystic ovary syndrome rat model suitable for exercise intervention.

PubMed

Wu, Chuyan; Lin, Feng; Qiu, Shuwei; Jiang, Zhongli

2014-01-01

To develop a new polycystic ovary syndrome (PCOS) rat model suitable for exercise intervention. Thirty six rats were randomly divided into three experimental groups: PCOS rats with high-fat diet (PF, n = 24), PCOS rats with ordinary diet (PO, n = 6), and control rats with ordinary diet (CO, n = 6). Two kinds of PCOS rat model were made by adjustment diet structure and testosterone injection for 28 days. After a successful animal model, PF model rats were randomly assigned to three groups: exercise with a continuation of high-fat diet (PF-EF, n = 6), sedentary with a continuation of high-fat diet (PF-SF, n = 6), exercise with an ordinary diet (PF-EO, n = 6). Fasting blood glucose (FBG) and insulin (FINS), estrogen (E2), progesterone (P), and testosterone (T) in serum were determined by RIA, and ovarian morphology was evaluated by Image-Pro plus 6.0. Body weight, Lee index, FINS increased significantly in PF rat model. Serum levels of E2 and T were significantly higher in PF and PO than in CO. Ovary organ index and ovarian areas were significant lower in PF than in CO. After intervention for 2 weeks, the levels of 1 h postprandial blood glucose (PBG1), 2 h postprandial blood glucose (PBG2), FINS and the serum levels of T decreased significantly in PF-EF rats and PF-EO rats. The ratio of FBG/FINS was significant higher in PF-EO rats than in PF-SF rats. Ovarian morphology showed that the numbers of preantral follicles and atretic follicles decreased significantly, and the numbers of antral follicles and corpora lutea increased significantly in the rats of PF-EF and PF-EO. By combination of high-fat diet and testosterone injection, the obese PCOS rat model is conformable with the lifestyle habits of fatty foods and insufficient exercise, and has metabolic and reproductive characteristics of human PCOS. This model can be applied to study exercise intervention.

Growth Hormone Ameliorates the Radiotherapy-Induced Ovarian Follicular Loss in Rats: Impact on Oxidative Stress, Apoptosis and IGF-1/IGF-1R Axis

PubMed Central

Mahran, Yasmen F.; El-Demerdash, Ebtehal; Nada, Ahmed S.; El-Naga, Reem N.; Ali, Azza A.; Abdel-Naim, Ashraf B.

2015-01-01

Radiotherapy is one of the standard cytotoxic therapies for cancer. However, it has a profound impact on ovarian function leading to premature ovarian failure and infertility. Since none of the currently available methods for fertility preservation guarantees future fertility, the need for an effective radioprotective agent is highly intensified. The present study investigated the mechanisms of the potential radioprotective effect of growth hormone (GH) on γ irradiation-induced ovarian failure and the impact of the insulin like growth factor 1 (IGF-1) in the underlying protection. Immature female Sprague-Dawley rats were either exposed to single whole body irradiation (3.2 Gy) and/or treated with GH (1 mg/kg s.c). Experimental γ-irradiation produced an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (PCNA), oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1R axis expression was assessed using real-time PCR and immunolocalization techniques. Furthermore, after full maturity, fertility assessment was performed. GH significantly enhanced follicular development and restored anti-Mullerian hormone serum level as compared with the irradiated group. In addition, GH significantly ameliorated the deleterious effects of irradiation on oxidative status, PCNA and apoptosis. Interestingly, GH was shown to enhance the ovarian IGF-1 at transcription and translation levels, a property that contributes significantly to its radioprotective effect. Finally, GH regained the fertility that was lost following irradiation. In conclusion, GH showed a radioprotective effect and rescued the ovarian reserve through increasing local IGF-1 level and counteracting the oxidative stress-mediated apoptosis. PMID:26465611

Growth Hormone Ameliorates the Radiotherapy-Induced Ovarian Follicular Loss in Rats: Impact on Oxidative Stress, Apoptosis and IGF-1/IGF-1R Axis.

PubMed

Mahran, Yasmen F; El-Demerdash, Ebtehal; Nada, Ahmed S; El-Naga, Reem N; Ali, Azza A; Abdel-Naim, Ashraf B

2015-01-01

Radiotherapy is one of the standard cytotoxic therapies for cancer. However, it has a profound impact on ovarian function leading to premature ovarian failure and infertility. Since none of the currently available methods for fertility preservation guarantees future fertility, the need for an effective radioprotective agent is highly intensified. The present study investigated the mechanisms of the potential radioprotective effect of growth hormone (GH) on γ irradiation-induced ovarian failure and the impact of the insulin like growth factor 1 (IGF-1) in the underlying protection. Immature female Sprague-Dawley rats were either exposed to single whole body irradiation (3.2 Gy) and/or treated with GH (1 mg/kg s.c). Experimental γ-irradiation produced an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (PCNA), oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1R axis expression was assessed using real-time PCR and immunolocalization techniques. Furthermore, after full maturity, fertility assessment was performed. GH significantly enhanced follicular development and restored anti-Mullerian hormone serum level as compared with the irradiated group. In addition, GH significantly ameliorated the deleterious effects of irradiation on oxidative status, PCNA and apoptosis. Interestingly, GH was shown to enhance the ovarian IGF-1 at transcription and translation levels, a property that contributes significantly to its radioprotective effect. Finally, GH regained the fertility that was lost following irradiation. In conclusion, GH showed a radioprotective effect and rescued the ovarian reserve through increasing local IGF-1 level and counteracting the oxidative stress-mediated apoptosis.

Furan induced ovarian damage in non-diabetic and diabetic rats and cellular protective role of lycopene.

PubMed

Uçar, Semra; Pandir, Dilek

2017-11-01

In our work, furan, lycopene, and furan + lycopene treatments were applied to non-diabetic and diabetic female rats via gavage. Ovarian tissue alterations with histopathology, immunohistochemistry, malondialdehyde levels, oxidative stress parameters such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and harmful effect on ovarian tissue DNA were evaluated in all groups for 28 days. Furan caused the changes histological, ovarian cell's DNA structure, malondialdehyde levels, antioxidant enzymes activities as in a statistically significant manner in each group. Useful effect of lycopene was determined both in non-diabetic and diabetic treatment groups against furan according to the used experimental parameters. Although some histopathological alterations were seen in diabetic and non-diabetic/diabetic plus furan-treated group's ovarians, lycopene restored these variations near to normal levels in furan + lycopene treated groups for in 28 days. Additionally, the results of our immunohistochemical analysis and alterations of the oxidative stress parameters results also supported these findings. Our result confirms that lycopene has protective effect and significantly altered diabetes and furan-induced toxicity in the rat ovarian tissue.

Dual protective role for Glutathione S-transferase class pi against VCD-induced ovotoxicity in the rat ovary

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keating, Aileen F.; Sen, Nivedita; Sipes, I. Glenn

2010-09-01

The occupational chemical 4-vinylcyclohexene diepoxide (VCD) selectively destroys ovarian small pre-antral follicles in rats and mice via apoptosis. Detoxification of VCD can occur through glutathione conjugation, catalyzed by glutathione S-transferase (GST) enzymes. Further, GST class pi (GSTp) can negatively regulate JNK activity through protein:protein interactions in extra-ovarian tissues. Dissociation of this protein complex in the face of chemical exposure releases the inhibition of pro-apoptotic JNK. Increased JNK activity during VCD-induced ovotoxicity has been shown in isolated ovarian small pre-antral follicles following in vivo dosing of rats (80 mg/kg/day; 15 days, i.p.). The present study investigated the pattern of ovarian GSTpmore » expression during VCD exposure. Additionally, the effect of VCD on an ovarian GSTp:JNK protein complex was investigated. PND4 F344 rat ovaries were incubated in control medium {+-} VCD (30 {mu}M) for 2-8 days. VCD increased ovarian GSTp mRNA (P < 0.05) relative to control on d4-d8; whereas GSTp protein was increased (P < 0.05) on d6-d8. A GSTp:JNK protein complex was detected by immunoprecipitation and Western blotting in ovarian tissues. Relative to control, the amount of GSTp-bound JNK was increased (P = 0.09), while unbound JNK was decreased (P < 0.05) on d6 of VCD exposure. The VCD-induced decrease in unbound JNK was preceded by a decrease in phosphorylated c-Jun which occurred on d4. These findings are in support of a possible dual protective role for GSTp in the rat ovary, consisting of metabolism of VCD and inhibition of JNK-initiated apoptosis.« less

Examination of the effect of ovarian radiation injury induced by hysterosalpingography on ovarian proliferating cell nuclear antigen and the radioprotective effect of amifostine: an experimental study

PubMed Central

Can, Behzat; Atilgan, Remzi; Pala, Sehmus; Kuloğlu, Tuncay; Kiray, Sule; Ilhan, Nevin

2018-01-01

Aim The aim of this study was to examine the effect of amifostine on cellular injury in the ovarian tissue induced by hysterosalpingography (HSG). Methods In total, forty 4-month old female Wistar Albino rats were assigned into 8 groups. Each group contained 5 rats. Group 1 (G1): rats were decapitated without any procedure. Group 2 (G2): rats were decapitated after 3 hours of total body irradiation. Group 3 (G3): rats were decapitated 3 hours after HSG procedure. Group 4 (G4): rats were decapitated 3 hours after HSG procedure performed 30 min after receiving amifostine 200 mg/kg intraperitoneally. Group 5 (G5): rats were decapitated after 1 month without any procedure. Group 6 (G6): rats were decapitated after 1 month of total body irradiation. Group 7 (G7): rats were decapitated 1 month after HSG procedure. Group 8 (G8): rats were decapitated 1 month after HSG procedure performed 30 min after receiving amifostine 200 mg/kg intraperitoneally. After rats were decapitated under general anesthesia in all groups, blood samples were obtained and bilateral ovaries were removed. One of the ovaries was placed in 10% formaldehyde solution for histological germinal epithelial degeneration, apoptosis and proliferating cell nuclear antigen scoring. The other ovary and blood sera were stored at −80°C. TNF-α, total antioxidant status, total oxidant status, and malondialdehyde levels were studied in tissue samples and anti-mullerian hormone levels in blood samples. Results At the end of the first month, there was significant ovarian germinal epithelium degeneration. Proliferating cell nuclear antigen immunoreactivity was significantly reduced in all other groups when compared with G1 and G5. Conclusion In conclusion, amifostine could significantly reduce the ovarian cellular injury induced by HSG. PMID:29872271

Examination of the effect of ovarian radiation injury induced by hysterosalpingography on ovarian proliferating cell nuclear antigen and the radioprotective effect of amifostine: an experimental study.

PubMed

Can, Behzat; Atilgan, Remzi; Pala, Sehmus; Kuloğlu, Tuncay; Kiray, Sule; Ilhan, Nevin

2018-01-01

The aim of this study was to examine the effect of amifostine on cellular injury in the ovarian tissue induced by hysterosalpingography (HSG). In total, forty 4-month old female Wistar Albino rats were assigned into 8 groups. Each group contained 5 rats. Group 1 (G1): rats were decapitated without any procedure. Group 2 (G2): rats were decapitated after 3 hours of total body irradiation. Group 3 (G3): rats were decapitated 3 hours after HSG procedure. Group 4 (G4): rats were decapitated 3 hours after HSG procedure performed 30 min after receiving amifostine 200 mg/kg intraperitoneally. Group 5 (G5): rats were decapitated after 1 month without any procedure. Group 6 (G6): rats were decapitated after 1 month of total body irradiation. Group 7 (G7): rats were decapitated 1 month after HSG procedure. Group 8 (G8): rats were decapitated 1 month after HSG procedure performed 30 min after receiving amifostine 200 mg/kg intraperitoneally. After rats were decapitated under general anesthesia in all groups, blood samples were obtained and bilateral ovaries were removed. One of the ovaries was placed in 10% formaldehyde solution for histological germinal epithelial degeneration, apoptosis and proliferating cell nuclear antigen scoring. The other ovary and blood sera were stored at -80°C. TNF-α, total antioxidant status, total oxidant status, and malondialdehyde levels were studied in tissue samples and anti-mullerian hormone levels in blood samples. At the end of the first month, there was significant ovarian germinal epithelium degeneration. Proliferating cell nuclear antigen immunoreactivity was significantly reduced in all other groups when compared with G1 and G5. In conclusion, amifostine could significantly reduce the ovarian cellular injury induced by HSG.

Preliminary observations on whole-ovary xenotransplantation as an experimental model for fertility preservation.

PubMed

Nichols-Burns, Stephanie M; Lotz, Laura; Schneider, Heike; Adamek, Edyta; Daniel, Christoph; Stief, Andrea; Grigo, Christina; Klump, Dorothee; Hoffmann, Inge; Beckmann, Matthias W; Dittrich, Ralf

2014-11-01

Ovarian tissue preservation and retransplantation is a promising strategy to restore fertility in cancer survivors. Ischaemia accompanying ovarian tissue grafting, however, can lead to significant follicle loss. Transplantation of the whole ovary by vascular anastomosis has been considered as an alternative to prevent widespread ischaemic damage. In this study, the feasibility and function of transplanting whole ovary with intact vasculature were evaluated, with the goal of developing a xenograft model for studies using donated human ovaries. Whole-swine ovaries with vascular pedicles were perfused and transplanted as intact ovaries by anastomosis into irradiated ovariectomized nude rats (n = 10). The observation period was between 1 and 4 weeks. Fresh swine ovaries served as controls (n = 10). Ovarian stroma and follicle populations were assessed through histological examination in both transplanted and control ovaries. Most of the transplanted whole ovaries (n = 6) maintained stromal quality and all preantral follicle classes were represented, although follicle numbers decreased compared with fresh control. Four transplanted ovaries were fibrotic after 1-4 weeks within the nude rat. Our results demonstrate transplantation of whole-pig ovary into nude rats is possible and support development of this xenograft model system for human studies. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

A Strategy Using Photodynamic Therapy and Clofibric Acid to Treat Peritoneal Dissemination of Ovarian Cancer.

PubMed

Yokoyama, Yoshihito; Shigeto, Tatsuhiko; Miura, Rie; Kobayashi, Asami; Mizunuma, Makito; Yamauchi, Aisa; Futagami, Masayuki; Mizunuma, Hideki

2016-01-01

The current study examined the effectiveness of concurrent therapy using photodynamic therapy (PDT) and clofibric acid (CA) to treat peritoneal carcinomatosis resulting from ovarian cancer. Nude rats were used to create a model of peritoneal carcinomatosis resulting from ovarian cancer and the effectiveness of PDT with 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA-PDT) was determined. The survival time of rats receiving that therapy was compared to the survival time of a control group. Rats with peritoneal carcinomatosis resulting from ovarian cancer were divided into 3 groups: a group that received debulking surgery (DS) alone, a group that received DS+methyl-ALA-PDT, and a group that received DS+methyl-ALA-PDT+CA. The survival time of the 3 groups was compared. Protoporphyrin, a metabolite of methyl-ALA, produces a photochemical action when activated by light. The level of protoporphyrin (the concentration) that reached organs in the abdomen was measured with HPLC. Rats receiving methyl- ALA-PDT had a significantly longer survival time compared to the controls. Rats with peritoneal carcinomatosis that received DS+methyl-ALA-PDT+CA had a significantly longer survival time compared to the rats that received DS alone. Some of the rats that received concurrent therapy survived for a prolonged period. Protoporphyrin was highly concentrated in peritoneal metastases, but only small amounts reached major organs in the abdomen. PDT was not found to result in necrosis in the intestines. The results indicated that concurrent therapy consisting of PDT with methyl-ALA and CA is effective at treating peritoneal carcinomatosis resulting from ovarian cancer without damaging organs.

Protective effect of mirtazapine and hesperidin on cyclophosphamide-induced oxidative damage and infertility in rat ovaries

PubMed Central

2015-01-01

Cyclophosphamide (CP) causes infertility due to ovarian toxicity. The toxicity mechanism suggests oxidative stress. We assessed whether mirtazapine (MTZ) and hesperidin (HSP) could promote ovarian protection against damage due to CP chemotherapy. Female Wistar rats aged 14 weeks were used. Animals were divided into four groups: control vehicle group (n = 8); CP group (n = 8, rats received 150 mg/kg of CP, single intraperitoneal [i.p.] injection); CP + MTZ group (n = 8, rats received same dose of CP + 30 mg/kg of MTZ, orally, daily); and HSP + CP group (n = 8, rats received same dose of CP + 100 mg/kg of HSP, orally, daily). After eight days of medication, ovaries were removed and ovarian toxicity was assessed by counting follicles and corpora lutea. Nitric oxide (NO) and malondialdehyde (MDA) levels, myeloperoxidase (MPO), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities were estimated in ovarian tissue. NO level, MDA level, and MPO activity were increased (P < 0.001), while, GPx and SOD activities were lowered significantly (P < 0.001) in CP-treated group compared with control vehicle. In addition, ovulation, number of follicles, and ovarian weight were reduced by CP treatment. On the contrary, rats pretreated with MTZ and HSP showed significant decrease in NO, MDA levels, and MPO activity, while, activities of SOD and GPx were increased (P < 0.001). Oxidative stress induced by CP in the rat ovary causes infertility in the female rats. HSP and MTZ could reverse this effect and provide protection of fertility against CP-induced toxicity. PMID:25787947

Effects of Electro-Acupuncture on Ovarian P450arom, P450c17α and mRNA Expression Induced by Letrozole in PCOS Rats

PubMed Central

Wu, Huangan; Zhao, Jimeng; Cui, Yunhua; Liu, Huirong; Wu, Lingxiang; Shi, Yin; Zhu, Bing

2013-01-01

Hyperandrogenism is a core factor in the series of reproductive and endocrine metabolic disorders involved in polycystic ovary syndrome (PCOS). Abnormalities in enzymatic activity and the expression of ovarian granular cell layer P450arom and theca cell P450c17α can lead to an atypical environment of local ovarian hormones, including excessive androgen levels. Rat models prepared with letrozole exhibit similar endocrine and histological changes to those that occur in human PCOS. We used such a model to study the role of electro-acupuncture (EA) in regulating ovarian P450arom and P450c17α enzymatic activity and mRNA expression in PCOS rats. Female Sprague Dawley (SD) rats aged 42 days were randomly divided into 3 groups (control, PCOS, and PCOS EA) consisting of 10 rats each. The PCOS and PCOS EA groups were administered a gavage of 1.0 mg/kg−1 of letrozole solution once daily for 21 consecutive days. Beginning in the ninth week, the PCOS EA group was administered low-frequency EA treatment daily for 14 consecutive days. After the treatment, we obtained the following results. The estrous cycles were restored in 8 of the 10 rats in the PCOS EA group, and their ovarian morphologies and ultrastructures normalized. The peripheral blood measurements (with ELISA) showed significantly decreased androgens (i.e., androstenedione and testosterone) with significantly increased estrogens (i.e., estrone, estradiol) and increased P450arom with decreased P450C17α. Immunohistochemistry and Western blotting methods showed enhanced expression of ovarian granular cell layer P450arom as well as decreased expression of theca cell layer P450C17α. Fluorescence quantitative PCR methods showed enhanced expression of ovarian granular cell layer P450arom mRNA as well as decreased expression of theca cell layer P450C17α mRNA. These results may help explain the effects of electro-acupuncture in changing the local ovarian hyperandrogenic environment and improving reproductive and endocrine metabolic disorders in PCOS. PMID:24260211

Effects of electro-acupuncture on ovarian P450arom, P450c17α and mRNA expression induced by letrozole in PCOS rats.

PubMed

Sun, Jie; Jin, Chunlan; Wu, Huangan; Zhao, Jimeng; Cui, Yunhua; Liu, Huirong; Wu, Lingxiang; Shi, Yin; Zhu, Bing

2013-01-01

Hyperandrogenism is a core factor in the series of reproductive and endocrine metabolic disorders involved in polycystic ovary syndrome (PCOS). Abnormalities in enzymatic activity and the expression of ovarian granular cell layer P450arom and theca cell P450c17α can lead to an atypical environment of local ovarian hormones, including excessive androgen levels. Rat models prepared with letrozole exhibit similar endocrine and histological changes to those that occur in human PCOS. We used such a model to study the role of electro-acupuncture (EA) in regulating ovarian P450arom and P450c17α enzymatic activity and mRNA expression in PCOS rats. Female Sprague Dawley (SD) rats aged 42 days were randomly divided into 3 groups (control, PCOS, and PCOS EA) consisting of 10 rats each. The PCOS and PCOS EA groups were administered a gavage of 1.0 mg/kg(-1) of letrozole solution once daily for 21 consecutive days. Beginning in the ninth week, the PCOS EA group was administered low-frequency EA treatment daily for 14 consecutive days. After the treatment, we obtained the following results. The estrous cycles were restored in 8 of the 10 rats in the PCOS EA group, and their ovarian morphologies and ultrastructures normalized. The peripheral blood measurements (with ELISA) showed significantly decreased androgens (i.e., androstenedione and testosterone) with significantly increased estrogens (i.e., estrone, estradiol) and increased P450arom with decreased P450C17α. Immunohistochemistry and Western blotting methods showed enhanced expression of ovarian granular cell layer P450arom as well as decreased expression of theca cell layer P450C17α. Fluorescence quantitative PCR methods showed enhanced expression of ovarian granular cell layer P450arom mRNA as well as decreased expression of theca cell layer P450C17α mRNA. These results may help explain the effects of electro-acupuncture in changing the local ovarian hyperandrogenic environment and improving reproductive and endocrine metabolic disorders in PCOS.

Hormone-induced rat model of polycystic ovary syndrome: A systematic review.

PubMed

Noroozzadeh, Mahsa; Behboudi-Gandevani, Samira; Zadeh-Vakili, Azita; Ramezani Tehrani, Fahimeh

2017-12-15

Despite polycystic ovary syndrome (PCOS) being one of the most common endocrine disorders affecting reproductive-aged women, the etiopathogenesis and mechanisms of this syndrome remain unclear. Considering the ethical limitations in human studies, animal models that reflect many features of PCOS are crucial resources to investigate this syndrome. We aimed to introduce the most suitable rat model of PCOS that closely mimics the endocrine, ovarian and metabolic disturbances of human PCOS phenotype, while maintaining normal reproductive system morphology in adulthood, in order to further more detailed investigations about PCOS. We searched Pubmed, Science direct, and Web of science between 1990 and 2016, for relevant English manuscripts, using keywords including the "Polycystic Ovary Syndrome AND Rat Model" to generate a subset of citations relevant to our research. Included were those articles that compared at least both ovarian histology or estrous cycle and reproductive hormonal profiles in hormone-induced rat model of PCOS and controls. Differences in the findings between hormone-induced PCOS rats appear to be a result of the degree of transplacental transfer of the steroid administered into the fetus, dose and type of hormone, route of administration and timing and duration of exposure. We conclude that prenatal hormone-induced rat model with a lower dose and shorter time of exposure during the critical period of fetal development that exhibits endocrine, ovarian and metabolic disturbances similar to PCOS in women, while maintaining normal reproductive system morphology in adulthood is more suitable than postnatal hormone-induced rat model to facilitate studies regarding PCOS. Copyright © 2017 Elsevier Inc. All rights reserved.

Development and validation of a method for precise dating of female puberty in laboratory rodents: The puberty ovarian maturation score (Pub-Score)

PubMed Central

Gaytan, Francisco; Morales, Concepción; Leon, Silvia; Heras, Violeta; Barroso, Alexia; Avendaño, Maria S.; Vazquez, Maria J.; Castellano, Juan M.; Roa, Juan; Tena-Sempere, Manuel

2017-01-01

Puberty is a key developmental event whose primary regulatory mechanisms remain poorly understood. Precise dating of puberty is crucial for experimental (preclinical) studies on its complex neuroendocrine controlling networks. In female laboratory rodents, external signs of puberty, such as vaginal opening (VO) and epithelial cell cornification (i.e., first vaginal estrus, FE), are indirectly related to the maturational state of the ovary and first ovulation, which is the unequivocal marker of puberty. Whereas in rats, VO and FE are almost simultaneous with the first ovulation, these events are not so closely associated in mice. Moreover, external signs of puberty can be uncoupled with first ovulation in both species under certain experimental conditions. We propose herein the Pubertal Ovarian Maturation Score (Pub-score), as novel, reliable method to assess peripubertal ovarian maturation in rats and mice. This method is founded on histological evaluation of pre-pubertal ovarian maturation, based on antral follicle development, and the precise timing of first ovulation, by retrospective dating of maturational and regressive changes in corpora lutea. This approach allows exact timing of puberty within a time-window of at least two weeks after VO in both species, thus facilitating the identification and precise dating of advanced or delayed puberty under various experimental conditions. PMID:28401948

EFFECT OF ATRAZINE ON OVARIAN FUNCTION IN THE RAT

EPA Science Inventory

The effect of the chlorotriazine herbicide, atrazine, on ovarian function was studied in Long-Evans hooded (LE-hooded) and SpragucDawley (SD) rats. Atrazine was administered by gavage for 21 d to females displaying regular 4-d estrous cycles. In both sfrains, 75 mg/kg/d disrupted...

Electroacupuncture decreases the progression of ovarian hyperstimulation syndrome in a rat model.

PubMed

Chen, Li; Sun, Hai-Xiang; Xia, You-Bing; Sui, Liu-Cai; Zhou, Ji; Huang, Xuan; Zhou, Jing-Wei; Shao, Yi-Dan; Shen, Tao; Sun, Qin; Liang, Yuan-Jiao; Yao, Bing

2016-05-01

This study aimed to elucidate the effect of electroacupuncture treatment on preventing early ovarian hyperstimulation syndrome (OHSS) and the potential mechanisms involved using an induced rat model. The ovarian response was examined by measuring ovary weight, vascular permeability, levels of inflammation (interleukin-6), tumour necrosis factor alpha, chemokine ligand 2 (also known as monocyte chemoactic protein 1), vascular endothelial growth factor and hormone concentrations (oestradiol, progesterone, testosterone and prolactin). Sprague-Dawley female rats underwent ovarian stimulation to induce OHSS. Hyperstimulated rats received consecutive electroacupuncture treatment from 3 days before the beginning of pregnant mare serum gonadotrophin treatment or the time point of pregnant mare serum gonadotrophin treatment respectively, and last until 3 days after HCG administration. Electroacupuncture treatment reduced ovary weight and vascular permeability in hyperstimulated rats. Electroacupuncture treatment also reduced the levels of serum steroid hormones (progesterone and testosterone), inflammatory cytokines (interleukin-6, tumour necrosis factor alpha and monocyte chemotactic protein 1 and vascular endothelial growth factor in hyperstimulated rats. The results indicate that electroacupuncture can modulate endocrine hormone secretion and affect the secretion of inflammatory cytokines and vascular endothelial growth factor, and thus prevent the progress of OHSS. Electroacupuncture may provide a simple and effective method for the prevention and treatment of OHSS. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Sex-specific prenatal stress effects on the rat reproductive axis and adrenal gland structure

PubMed Central

George, Susan O; Hogg, Charis O; Lai, Yu-Ting; Brunton, Paula J

2016-01-01

Abstract Social stress during pregnancy has profound effects on offspring physiology. This study examined whether an ethologically relevant social stress during late pregnancy in rats alters the reproductive axis and adrenal gland structure in post-pubertal male and female offspring. Prenatally stressed (PNS) pregnant rats (n=9) were exposed to an unfamiliar lactating rat for 10 min/day from day 16 to 20 of pregnancy inclusive, whereas control pregnant rats (n=9) remained in their home cages. Gonads, adrenal glands and blood samples were obtained from one female and one male from each litter at 11 to 12-weeks of age. Anogenital distance was measured. There was no treatment effect on body, adrenal or gonad weight at 11–12 weeks. PNS did not affect the number of primordial, secondary or tertiary ovarian follicles, numbers of corpora lutea or ovarian FSH receptor expression. There was an indication that PNS females had more primary follicles and greater ovarian aromatase expression compared with control females (both P=0.09). PNS males had longer anogenital distances (0.01±0.0 cm/g vs 0.008±0.00 cm/g; P=0.007) and higher plasma FSH concentrations (0.05 ng/mL vs 0.006 ng/mL; s.e.d.=0.023; P=0.043) compared with control males. There were no treatment effects on the number of Sertoli cells or seminiferous tubules, seminiferous tubule area, plasma testosterone concentration or testis expression of aromatase, FSH receptor or androgen receptor. PNS did not affect adrenal size. These data suggest that the developing male reproductive axis is more sensitive to maternal stress and that PNS may enhance aspects of male reproductive development. PMID:27026714

Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat.

PubMed

Ferder, Ianina; Parborell, Fernanda; Sundblad, Victoria; Chiauzzi, Violeta; Gómez, Karina; Charreau, Eduardo H; Tesone, Marta; Dain, Liliana

2013-04-01

Fragile X mental retardation protein (FMRP) belongs to a small family of RNA-binding proteins. Its absence or inactivity is responsible for fragile X syndrome, the most common cause of inherited mental retardation. Despite its ubiquitous expression, FMRP function and expression remain almost understudied in non-neuronal tissues, though previous studies on germline development during oogenesis may suggest a special function of this protein also in ovarian tissue. In addition, the well-documented association of FMR1 premutation state with fragile X-related premature ovarian insufficiency adds interest to the role of FMRP in ovarian physiology. The aim of the present work was to investigate the expression of Fmr1 mRNA and its protein, FMRP, at different stages of rat follicular development. By immunohistochemical studies we demonstrated FMRP expression in granulosa, theca and germ cells in all stages of follicular development. In addition, changes in Fmr1 expression, both at the protein and mRNA levels, were observed. FMRP levels increased upon follicular development while preantral and early antral follicles presented similar levels of Fmr1 transcripts with decreased expression in preovulatory follicles. These observations suggest that Fmr1 expression in the ovary is regulated at different and perhaps independent levels. In addition, our results show expression of at least four different isoforms of FMRP during all stages of follicular growth with expression patterns that differ from those observed in brain and testis. Our study shows a regulated expression of Fmr1, both at mRNA and protein levels, during rat follicular development.

Polycystic ovarian disease: animal models.

PubMed

Mahajan, D K

1988-12-01

The reproductive systems of human beings and other vertebrates are grossly similar. In the ovary particularly, the biochemical and physiologic processes are identical not only in the formation of germ cells, the development of primordial follicles and their subsequent growth to Graafian follicles, and eventual ovulation but also in anatomic structure. In a noncarcinogenic human ovary, hypersecretion of androgen causes PCOD. Such hypersecretion may result from a nonpulsatile, constant elevated level of circulating LH or a disturbance in the action of neurotransmitters in the hypothalamus. In studying the pathophysiology of PCOD in humans, one must be aware of the limitations for manipulating the hypothalamic-pituitary axis. Although the rat is a polytocous rodent, the female has a regular ovarian cyclicity of 4 or 5 days, with distinct proestrus, estrus, and diestrus phases. Inasmuch as PCOD can be experimentally produced in the rat, that species is a good model for studying the pathophysiology of human PCOD. These PCOD models and their validity have been described: (1) estradiol-valerate, (2) DHA, (3) constant-light (LL), and (4) neonatally androgenized. Among these, the LL model is noninvasive and seems superior to the others for study of the pathophysiology of PCOD. The production of the polycystic ovarian condition in the rat by the injection of estrogens or androgens in neonate animals, or estradiol or DHA in adult rats, or the administration of antigonadotropins to these animals all cause a sudden appearance of the persistent estrus state by disturbing the metabolic and physiologic processes, whereas exposure of the adult rat to LL causes polycystic ovaries gradually, similar to what is seen in human idiopathic PCOD. After about 50 days of LL, the rat becomes anovulatory and the ovaries contain thickened tunica albuginea and many atretic follicles, and the tertiary follicles are considerably distended and cystic. The granulosa and theca cells appear normal histologically, although some of the stromal cells appear hypertrophic. The anatomic features consequent to polycystic ovaries resulting from LL are similar to those in human PCOD, and both rat and human PCOD ovarian cells still retain the ability to respond to FSH/LH, LHRH, and unilateral ovariectomy. In the estradiol valerate rat model, although the anatomy and physiology of the ovary resemble those of PCOD patients, the progressive degeneration of the hypothalamus and the altered response of the pituitary to LHRH make this model inappropriate for studying the hypothalamic-pituitary-ovarian axis in the polycystic ovary condition.(ABSTRACT TRUNCATED AT 400 WORDS)

Successful ovarian autotransplant with no vascular reanastomosis in rats.

PubMed

Barros, Flávio S V; de Oliveira, Rodrigo M; Alves, Felipe M T; Sampaio, Marcos; Geber, Selmo

2008-12-15

Preservation of ovarian functions in woman with premature ovarian failure remains an issue in reproductive medicine. Hormone replacement therapy for maintaining endocrine functions, and cryopreservation of embryos or oocytes for those who wish pregnancy, are some of the choices. However, ovarian transplantation is a more physiological alternative, although problems related to ovarian ischemia have been reported. Herein, we investigated the viability of autologous transplantation of the ovarian tissue into the rat peritoneum, without vascular reanastomosis. Twenty animals in the study group had both ovaries excised, and each ovary was dissected into two halves. A half of an ovary was autotransplanted to the peritoneal surface, closely located to the left epigastric vessels. This simple procedure does not require surgical vascular reanastomosis while it maintains appropriate follicular growth and therefore should be further considered as an alternative for women undergoing oophorectomy, not only to maintain endocrine functions but also for fertility preservation.

MicroRNA-33b-5p is overexpressed and inhibits GLUT4 by targeting HMGA2 in polycystic ovarian syndrome: An in vivo and in vitro study.

PubMed

Yang, Ying; Jiang, Hua; Xiao, Ling; Yang, Xuezhou

2018-06-01

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disease, but its pathogenesis remains largely unknown. The present study explored the role of microRNA‑33b‑5p (miR‑33b‑5p) in PCOS pathogenesis, with a particular focus on its role in regulating glucose transporter 4 (GLUT4). A rat model of PCOS was developed by injecting female SD rats with insulin and HCG. miR‑33b‑5p, GLUT4, sterol regulatory element‑binding protein 1 (SREBF1), and high mobility group A2 (HMGA2) expression in rat ovarian tissues was examined by qRT‑PCR and immunohistochemistry. The effect of a high dose of either glucose or insulin on miR‑33b‑5p, GLUT4, SREBF1 and HMGA2 expression was also examined in cultured adipocytes by qRT‑PCR and western blotting. Additionally, the luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to explore the role of miR‑33b‑5p in regulating HMGA2, SREBF‑1 and/or GLUT4. Elevated levels of miR‑33b‑5p expression were detected in the ovarian tissues of insulin resistant PCOS rats, and those levels were negatively correlated with those of GLUT4, HMGA2 and SREBF1 expression (P<0.05). Immunohistochemistry studies revealed that GLUT4, SREBF1, and HMGA2 expression levels in the ovarian tissues of insulin resistant PCOS rats were significantly lower than those in other groups of rats. In cultured adipocytes, excess extracellular glucose or insulin increased miR‑33b‑5p expression but reduced GLUT4, SREBF1 and HMGA2 expression, whereas the levels of GLUT4, SREBF1 and HMGA2 were elevated by inhibition of miR‑33b‑5. HMGA2 could directly bind to the 5'‑promoter region of GLUT4 and promote its expression, and could also promote SREBF1 expression. Moreover, SREBF1 could also directly bind to the 5'‑promoter region of GLUT4 and promote its expression. Our findings revealed that miR‑33b‑5p was overexpressed in the ovarian tissues of insulin resistant PCOS rats, and thus may play an important role in the development of insulin resistance in PCOS patients. miR‑33b‑5p can inhibit GLUT4 production by targeting HMGA2, and in addition, HMGA2 and SREBF1 are important molecules involved in modulating GLUT4 expression.

Alternative treatment of ovarian cysts with Tribulus terrestris extract: a rat model.

PubMed

Dehghan, A; Esfandiari, A; Bigdeli, S Momeni

2012-02-01

Tribulus terrestris has long been used in traditional medicine to treat impotency and improve sexual functions in man. The aim of this study was to evaluate the efficiency of T. terrestris extract in the treatment of polycystic ovary (PCO) in Wistar rat. Estradiol valerate was injected to 15 mature Wistar rats to induce PCO. Rats were randomly divided into three groups (control, low-dose and high-dose groups) of five each and received 0, 5 and 10 mg of T. terrestris extract, respectively.Treatments began on days 50 and 61 after estradiol injection; at the same time, vaginal smear was prepared. The ovaries were removed on day 62, and histological sections were prepared accordingly. The number and diameter of corpora lutea, thickness of the theca interna layer and the number of all follicles were evaluated in both ovaries. In comparison with the control group, the number of corpora lutea and primary and secondary follicles significantly increased following T. terrestris treatment; however, the number of ovarian cysts significantly decreased. It can be concluded that T. terrestris have a luteinizing effect on ovarian cysts, which may relate to its gonadotropin-like activity; also, a high dose of the extract can efficiently remove ovarian cysts and resume ovarian activity. © 2011 Blackwell Verlag GmbH.

The non-preventive effects of human menopausal gonadotropins on ovarian tissues in Nandrolone decanoate-treated female rats: A histochemical and ultra-structural study.

PubMed

Mesbah, Fakhroddin; Bordbar, Hossein; Talaei Khozani, Tahereh; Dehghani, Farzaneh; Mirkhani, Hossein

2018-03-01

The follicular growth and development may be affected by abused drugs. Nandrolone decanoate (ND) as an anabolic androgenic steroid can damage the morphological and functional features of the ovary and may lead to reproductive failure. This study was designed to evaluate the effects of synchronized and non-synchronized administration of Human Menopausal Gonadotropins (hMG) with ND on ovarian tissue and level of sex hormones in the adult female rat. Forty adult female Sprague Dawley rats were divided into eight groups. The five experimental groups received 3 and/or 10 mg/kg of ND synchronized and non-synchronized with 10 IU of hMG and hMG alone. The two shams and control groups received solvents of ND and hMG. The animals' serum levels of Follicle-stimulating hormone, Luteinizing hormone, progesterone and estrogen and the weight, volume and dimensions of the ovaries were measured. The ovaries were prepared for apoptosis assessment and morphological study. The ovarian volume and sex hormones in the experimental groups were decreased, but ovarian weight and dimensions didn't change. The rate of apoptosis was increased in the experimental groups as follows; a low and high dose of ND synchronized with hMG 48.80±18.70 and 65.20±14.20 respectively vs. Sham 1, 33.20±17.80, a low and high dose of ND non-synchronized with hMD 55.80±17.20 and 75.20±14.30 respectively vs. Sham 2, 31.60±32.40 groups, p˂0.01. Follicular and stromal cells were damaged in the experimental groups except for the hMG group. Administration of ND decreased the serum level of Luteinizing hormone, Follicle-stimulating hormone, progesterone and estrogen and damaged ovarian tissue irreversibly and irreparably and hMG cannot prevent the destruction of the follicles in the adult female rats. This can be a serious warning to women who abuse ND.

The Characterization of Obese Polycystic Ovary Syndrome Rat Model Suitable for Exercise Intervention

PubMed Central

Qiu, Shuwei; Jiang, Zhongli

2014-01-01

Objective To develop a new polycystic ovary syndrome (PCOS) rat model suitable for exercise intervention. Method Thirty six rats were randomly divided into three experimental groups: PCOS rats with high-fat diet (PF, n = 24), PCOS rats with ordinary diet (PO, n = 6), and control rats with ordinary diet (CO, n = 6). Two kinds of PCOS rat model were made by adjustment diet structure and testosterone injection for 28 days. After a successful animal model, PF model rats were randomly assigned to three groups: exercise with a continuation of high-fat diet (PF-EF, n = 6), sedentary with a continuation of high-fat diet (PF-SF, n = 6), exercise with an ordinary diet (PF-EO, n = 6). Fasting blood glucose (FBG) and insulin (FINS), estrogen (E2), progesterone (P), and testosterone (T) in serum were determined by RIA, and ovarian morphology was evaluated by Image-Pro plus 6.0. Results Body weight, Lee index, FINS increased significantly in PF rat model. Serum levels of E2 and T were significantly higher in PF and PO than in CO. Ovary organ index and ovarian areas were significant lower in PF than in CO. After intervention for 2 weeks, the levels of 1 h postprandial blood glucose (PBG1), 2 h postprandial blood glucose (PBG2), FINS and the serum levels of T decreased significantly in PF-EF rats and PF-EO rats. The ratio of FBG/FINS was significant higher in PF-EO rats than in PF-SF rats. Ovarian morphology showed that the numbers of preantral follicles and atretic follicles decreased significantly, and the numbers of antral follicles and corpora lutea increased significantly in the rats of PF-EF and PF-EO. Conclusion By combination of high-fat diet and testosterone injection, the obese PCOS rat model is conformable with the lifestyle habits of fatty foods and insufficient exercise, and has metabolic and reproductive characteristics of human PCOS. This model can be applied to study exercise intervention. PMID:24905232

Zingerone ameliorates cisplatin-induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats.

PubMed

Kaygusuzoglu, Erdal; Caglayan, Cuneyt; Kandemir, Fatih Mehmet; Yıldırım, Serkan; Kucukler, Sefa; Kılınc, Mehmet Akif; Saglam, Yavuz Selim

2018-06-01

Cisplatin (CP) is a widely used chemotherapeutic drug, effective against a variety of solid tumours, though its utility is limited due to its multiple organ toxicity. Zingerone (ZO), one of the most important components of dry ginger root, has several pharmacological activities, such as antioxidant, anti-inflammatory and anti-apoptotic properties. This study aimed to investigate the ameliorative effect of ZO on CP-induced ovarian and uterine toxicity in female rats. The rats were subjected to a prophylactic oral treatment of ZO (25 and 50 mg/kg body weight) for seven days to measure the protective effect against ovarian and uterine toxicity induced by a single (i.p.) of CP (7 mg/kg body weight) on the first day whereas the rats were sacrificed on the eighth day. The results showed that ZO decreased the serum FSH hormone level, increased the serum E2 hormone level, and also maintained the ovarian and uterine histological architecture and integrity. In addition, ZO obviously increased the measured activity of antioxidant enzymes (SOD, CAT and GPx) and the GSH content, and significantly reduced MDA levels. ZO was able to reduce the levels of the inflammatory markers NF-κB, TNF-α, IL-1β, IL-6, COX-2 and iNOS in CP-induced ovarian and uterine damage. It also inhibited apoptosis and reduced oxidative DNA damage markers by the downregulation of caspase-3 and 8-OHdG expression coupled with an upregulated Bcl-2 level. The results indicate that ZO may be beneficial in ameliorating CP-induced oxidative stress, sex hormone imbalances, inflammation and apoptosis in ovarian and uterine tissues of female rats. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

DHEA-induced ovarian hyperfibrosis is mediated by TGF-β signaling pathway.

PubMed

Wang, Daojuan; Wang, Wenqing; Liang, Qiao; He, Xuan; Xia, Yanjie; Shen, Shanmei; Wang, Hongwei; Gao, Qian; Wang, Yong

2018-01-10

The polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder with pathological mechanisms remain unclear. The following study investigates the ovarian hyperfibrosis forming via transforming growth factor-β (TGF-β) signaling pathway in Dehydroepiandrosterone (DHEA)- induced polycystic ovary syndrome (PCOS) rat model. We furthermore explored whether TGF-βRI inhibitor (SB431542) decreases ovarian fibrosis by counterbalancing the expression of fibrotic biomarkers. Thirty female Sprague-Dawley rats were randomly divided into Blank group (n = 6), Oil group (n = 6), and Oil + DHEA-induced model group (n = 6 + 12). The model groups were established by subcutaneous injection of DHEA for 35 consecutive days. The 12 successful model rats were additionally divided in vehicle group (n = 6) and SB431542-treated group (n = 6). Vehicle group and SB431542-treated group, served as administration group and were intraperitoneally injected with DMSO and SB431542 for additional 14 consecutive days. Ovarian morphology, fibrin and collagen localization and expression in ovaries were detected using H&E staining, immunohistochemistry and Sirius red staining. The ovarian protein and RNA were examined using Western blot and RT-PCR. In DHEA-induced ovary in rat, fibrin and collagen had significantly higher levels, while the main fibrosis markers (TGF-β, CTGF, fibronectin, a-SMA) were obviously upregulated. SB431542 significantly reduced the expression of pro-fibrotic molecules (TGF-β, Smad3, Smad2, a-SMA) and increased anti-fibrotic factor MMP2. TGF-βRI inhibitor (SB431542) inhibits the downstream signaling molecules of TGF-β and upregulates MMP2, which in turn prevent collagen deposition. Moreover, ovarian hyperfibrosis in DHEA-induced PCOS rat model could be improved by TGF-βRI inhibitor (SB431542) restraining the transcription of accelerating fibrosis genes and modulating EMT mediator.

Reduced ovarian glyoxalase-I activity by dietary glycotoxins and androgen excess: a causative link to polycystic ovarian syndrome.

PubMed

Kandaraki, Eleni; Chatzigeorgiou, Antonis; Piperi, Christina; Palioura, Eleni; Palimeri, Sotiria; Korkolopoulou, Penelope; Koutsilieris, Michael; Papavassiliou, Athanasios G

2012-10-24

Glyoxalase detoxification system composed of glyoxalase (GLO)-I and GLO-II is ubiquitously expressed and implicated in the protection against cellular damage because of cytotoxic metabolites such as advanced glycation end products (AGEs). Recently, ovarian tissue has emerged as a new target of excessive AGE deposition and has been associated with either a high AGE diet in experimental animals or hyperandrogenic disorders such as polycystic ovarian syndrome (PCOS) in humans. This study was designed to investigate the impact of dietary AGEs and androgens in rat ovarian GLO-I activity of normal nonandrogenized (NAN, group A, n = 18) and androgenized prepubertal (AN) rats (group B, n = 29). Both groups were further randomly assigned, either to a high-AGE (HA) or low-AGE (LA) diet for 3 months. The activity of ovarian GLO-I was significantly reduced in normal NAN animals fed an HA diet compared with an LA diet (p = 0.006). Furthermore, GLO-I activity was markedly reduced in AN animals compared with NAN (p ≤ 0.001) when fed with the corresponding diet type. In addition, ovarian GLO-I activity was positively correlated with the body weight gain (r(s) = 0.533, p < 0.001), estradiol (r(s) = 0.326, p = 0.033) and progesterone levels (r(s) = 0.500, p < 0.001). A negative correlation was observed between GLO-I activity and AGE expression in the ovarian granulosa cell layer of all groups with marginal statistical significance (r(s) = -0.263, p = 0.07). The present data demonstrate that ovarian GLO-I activity may be regulated by dietary composition and androgen levels. Modification of ovarian GLO-I activity, observed for the first time in this androgenized prepubertal rat model, may present a contributing factor to the reproductive dysfunction characterizing PCOS.

Examination of the Ovarian Reserve after Generation of Unilateral Rudimentary Uterine Horns in Rats

PubMed Central

Toyganözü, Hasan; Nazik, Hakan; Narin, Raziye; Satar, Deniz; Narin, Mehmet Ali; Büyüknacar, Sinem; Api, Murat; Aytan, Hakan

2014-01-01

Objective. The purpose of this experimental rat model study is to evaluate the changes in the ovarian environment after excision of the rudimentary horn. Methods. Ten female Wistar albino rats were used in this study. One cm of right uterine horn length was excised in the first operation. Two months after the first operation, all animals were sacrificed to obtain ovaries for histological examination. Mann-Whitney U test and Student's t-test were used for statistical analysis purposes. Statistical significance was defined as P < 0.005. Results. The number of primordial follicles (P = 0.415), primary follicles (P = 0.959), preantral follicles (P = 0.645), antral follicles (P = 0.328), and Graafian follicles (P = 0.721) was decreased and the number of atretic follicles (P = 0.374) increased in the right ovarian side. Howeve,r this difference was not found to be statistically significant. Conclusion. The results of this experimental rat model study suggest that the excision of rudimentary horn could have negative effects on ipsilateral ovarian functions. PMID:24672393

Prenatal hyperandrogenism and lipid profile during different age stages: an experimental study.

PubMed

Heber, María F; Ferreira, Silvana R; Vélez, Leandro M; Motta, Alicia B

2013-02-01

The present study investigates the effect of prenatal hyperandrogenization on lipid metabolism and oxidant/antioxidant balance. Experimental study. Research institute. Pregnant Sprague Dawley rats were subcutaneously injected with 2 mg free T between days 16 and 19 of pregnancy, and controls (C) received vehicle (0.1 mL of sesame oil). Prenatally hyperandrogenized female offspring (T2) had a condition that resembles polycystic ovary (PCO). Animals were weighed and killed at 21 and 60 days of age (N = 15 rats/group). Ovarian tissue and truncal blood were obtained from the C and T2 groups. Circulating lipid profile (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL] cholesterol, and triglycerides) was quantified by colorimetric-enzymatic methods. Ovarian oxidative stress was evaluated by quantifying lipid peroxidation and glutathione content by spectofotometric assays. Ovarian fat content was evaluated by Red Oil staining and ovarian messenger RNA (mRNA) expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) by real-time polymerase chain reaction (PCR). At 60 days of age, 100% of group C rats and 20% of group T2 rats ovulated. At 21 days of age the T2 rats displayed lower body weight than C rats; however, at 60 days of age T2 and C rats showed similar body weights. The lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) was altered in the anovulatory and ovulatory phenotype of the T2 group, but the levels were higher in the anovulatory phenotype. Lipid peroxidation of rats at 21 and 60 days of age from T2 was similar to C but the antioxidant glutathione level was decreased in 21-day-old rats compared with C rats. The lipid content of ovarian tissue, determined by Red Oil staining, was higher in the T2 than in the C group. The mRNA expression of ovarian PPAR-γ, quantified by real time PCR, decreased in anovulatory rats at 60 days of age from T2 compared to C rats. Our findings reveal the importance of evaluating the complete lipid profile, especially at early stages of life after the prenatal hyperandrogenism condition. In addition, we demonstrated that the antioxidant-reduced glutathione would represent a good marker of oxidative stress as it is altered before lipid peroxidation. Prenatal hyperandrogenization also alters the gene expression of PPAR-γ in rats. Here we demonstrated for the first time that abnormalities in PPAR-γ and lipid profile were higher in rats showing an anovulatory phenotype than those displaying an ovulatory phenotype. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Consumption of bee pollen affects rat ovarian functions.

PubMed

Kolesarova, A; Bakova, Z; Capcarova, M; Galik, B; Juracek, M; Simko, M; Toman, R; Sirotkin, A V

2013-12-01

The aim of this study was to examine possible effects of bee pollen added to the feed mixture (FM) on rat ovarian functions (secretion activity and apoptosis). We evaluated the bee pollen effect on the release of insulin-like growth factor I (IGF-I) and steroid hormones (progesterone and estradiol), as well as on the expression of markers of apoptosis (Bcl-2, Bax and caspase-3) in rat ovarian fragments. Female rats (n = 15) were fed during 90 days by FM without or with rape seed bee pollen in dose either 3 kg/1000 kg FM or 5 kg/1000 kg FM. Fragments of ovaries isolated from rats of each group (totally 72 pieces) were incubated for 24 h. Hormonal secretion into the culture medium was detected by RIA. The markers of apoptosis were evaluated by Western blotting. It was observed that IGF-I release by rat ovarian fragments was significantly (p < 0.05) decreased; on the other hand, progesterone and estradiol secretion was increased after bee pollen treatment at dose 5 kg/1000 kg FM but not at 3 kg/1000 FM. Accumulation of Bcl-2 was increased by bee pollen added at 3 kg/1000 kg FM, but not at higher dose. Accumulation of Bax was increased in ovaries of rats fed by bee pollen at doses either 3 or 5 kg/1000 kg FM, whilst accumulation of caspase-3 increased after feeding with bee pollen at dose 5 kg/1000 kg FM, but not at 3 kg/1000 kg FM. Our results contribute to new insights regarding the effect of bee pollen on both secretion activity (release of growth factor IGF-I and steroid hormones progesterone and estradiol) and apoptosis (anti- and pro-apoptotic markers Bcl-2, Bax and caspase-3). Bee pollen is shown to be a potent regulator of rat ovarian functions. © 2012 Blackwell Verlag GmbH.

Mechanistic Study on Triptorelin Action in Protecting From 5-FU-Induced Ovarian Damage in Rats.

PubMed

Wang, Ying; Tian, Xiaoyu; Liang, Lingxia; Wang, Yan; Wang, Ruifang; Cheng, Xiaolin; Yan, Zhen; Chen, Yawei; Qi, Pengwei

2014-01-01

Triptorelin, a kind of GnRH agonist, is widely used in the treatment of hormone-responsive cancers in the clinic. This study aimed to discover the underlying mechanism of triptorelin in protection from 5-fluorouracil (5-FU)-induced ovarian damage in Sprague-Dawley rats. In the present study, after using 5-FU to induce ovarian damage in rats, body weight and wet ovaries were weighed, the levels of estradiol (E2), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH) in blood were detected, and the expression of Bcl-2, Bax, and NF-κB was determined. It suggested that, compared to the control, body weight gain, the ratio of ovarian wet weight to body weight, primary follicle numbers, and the levels of AMH were significantly decreased, while the concentration of E2 and FSH was heavily increased following 5-FU administration. In contrast, after coadministration of triptorelin with 5-FU, the ratio of ovarian wet weight to body weight and the levels of AMH were significantly increased, whereas the level of E2 and FSH was decreased significantly when compared with the 5-FU group. Furthermore, at indicated times, 5-FU led to the reduced Bcl-2 and NF-κB expression and increased Bax expression while triptorelin plus 5-FU increased Bcl-2 and NF-κB expression and decreased Bax expression. It was indicated that triptorelin could protect rats from 5-FU-induced ovarian damage by modulation of hormones, Bcl-2, Bax, and NF-κB. These results might highlight the mechanism of triptorelin as a protective agent in clinical chemotherapy for ovarian damage.

Early ovarian follicular development in prepubertal Wistar rats acutely exposed to androgens.

PubMed

Paixão, L; Velez, L M; Santos, B R; Tusset, C; Lecke, S B; Motta, A B; Spritzer, P M

2016-08-01

Androgens may directly modulate early ovarian follicular development in preantral stages and androgen excess before puberty may disrupt this physiological process. Therefore, the aim of this study was to investigate the dynamics of follicular morphology and circulating androgen and estradiol levels in prepubertal Wistar rats acutely exposed to androgens. Prepubertal female Wistar rats were distributed into three groups: control, equine chorionic gonadotropin (eCG) intervention and eCG plus dehydroepiandrosterone (DHEA) intervention (eCG+DHEA). Serum DHEA, testosterone and estradiol levels were determined, and ovarian morphology and morphometry were assessed. The eCG+DHEA group presented increased serum estradiol and testosterone levels as compared with the control group (P<0.01), and higher serum DHEA concentration v. the eCG-only and control groups (P<0.01). In addition, the eCG+DHEA group had a higher number of, and larger-sized, primary and secondary follicles as compared with the control group (P<0.05). The eCG group presented intermediate values for number and size of primary and secondary follicles, without significant differences as compared with the other two groups. The number of antral follicles was higher in the eCG+DHEA and eCG groups v. controls (P<0.05). The number of primordial, atretic and cystic follicles were similar in all groups. In conclusion, the present experimental model using an acute eCG+DHEA intervention was useful to investigate events involved in initial follicular development under hyperandrogenic conditions, and could provide a reliable tool to study defective follicular development with possible deleterious reproductive consequences later in life.

Optical coherence tomography imaging and fluorescence spectroscopy of a novel rat model of ovarian cancer

NASA Astrophysics Data System (ADS)

Kanter, Elizabeth; Walker, Ross; Marion, Sam; Hoyer, Patricia; Barton, Jennifer K.

2005-08-01

Ovarian cancer is relatively rare but is the fifth leading cause of death from cancer in women. Little is known about the precursors and early stages of ovarian cancer partially due to the lack of a realistic animal model. A cohesive model that incorporates ovarian cancer induction into a menopausal rodent would be well suited for comprehensive studies of ovarian cancer, and non-destructive imaging would allow carcinogenesis to be followed. Optical Coherence Tomography (OCT) and Light-Induced Fluorescence (LIF) are minimally invasive optical modalities that allow both structural and biochemical changes to be noted. Rat ovaries were exposed to 4-vinylcyclohexene diepoxide (VCD) for 20 days in order to destroy the primordial follicles. Sutures coated with 7,12-dimethylbenz(a)anthracene (DMBA) were implanted in the right ovary, in order to produce epithelial based ovarian cancers. Rats were sacrificed at 1, 3, and 5 months and ovaries were harvested and imaged with a combined OCT/LIF system. Histology was preformed on the harvested ovaries and any pathology determined. OCT was able to visualize follicle loss and DMBA-induced abnormalities. LIF spectra were also different between cycling, follicle deplete, and DMBA-exposed ovaries. Overall this pilot study demonstrated the feasibility of both the animal model and optical imaging.

Evaluation of the effects of fulvestrant and micronized progesterone on the post-operative adhesion formation and ovarian reserve in rat model with immunohistochemical and biochemical analysis.

PubMed

Oner, Gokalp; Ulug, Pasa; Demirci, Elif; Kumtepe, Yakup; Gündogdu, Cemal

2015-01-01

To evaluate the effects of fulvestrant and micronized progesterone on post-operative adhesion formation and ovarian reserve in a rat uterine horn adhesion. In this prospective randomized controlled trial, 32 female Wistar albino rats were randomly divided into four groups including control group (Group 1), the control adhesion group (Group 2), 1 mg/kg daily intramuscular fulvestrant received group (Group 3) and 1 mg/kg daily oral micronized progesterone received group (Group 4). The extent and severity of adhesions were scored and samples were taken from adhesion areas to investigate the grades of adhesions according to the immunohistochemical scoring system. Ovarian reserves were measured with anti-Müllerian hormone (AMH) and histological ovarian follicles count. The extent, severity and total adhesion scores were reduced in all treatment groups compared to control adhesion group (Group 2). Similarly, immunohistochemical adhesion scores were lower in the treatment groups. AMH and follicle count were significantly found lower in adhesion groups compared with control group. However, treatment groups were found to have higher ovarian reserve compared to control adhesion group (Group 2). Fulvestrant and micronized progesterone were found to reduce post-operative adhesion formations and have decreased detrimental effects of adhesion formation on ovarian reserve.

Trichloroethylene Metabolism in the Rat Ovary Reduces Oocyte Fertilizability

PubMed Central

Wu, Katherine Lily; Berger, Trish

2007-01-01

Exposure to trichloroethylene (TCE, an environmental toxicant) reduced oocyte fertilizability in the rat. In vivo, TCE may be metabolized by cytochrome P450 dependent oxidation or glutathione conjugation in the liver or kidneys, respectively. Cytochrome P450 dependent oxidation is the higher affinity pathway. The primary isoform of cytochrome P450 to metabolize TCE in the liver, cytochrome P450 2E1, is present in the rodent ovary. Ovarian metabolism of TCE by the oxidative pathway and the production of reactive oxygen species may occur given the presence of the metabolizing enzyme. The objectives of this study were to define the sensitive interval of oocyte growth to TCE exposure, and to determine if TCE exposure resulted in the formation of ovarian protein carbonyls, an indicator of oxidative damage. Rats were exposed to TCE in drinking water (0.45% TCE (v/v) in 3% Tween) or 3% Tween (vehicle-control) during three 4–5 day intervals of oocyte development preceding ovulation. Oocytes from TCE-exposed females were less fertilizable compared with vehicle-control oocytes. Immunohistochemical labeling of ovaries and Western blotting of ovarian proteins demonstrated TCE treatment induced a greater incidence of protein carbonyls compared with vehicle controls. Protein carbonyl formation in the ovary is consistent with TCE metabolism by the cytochrome P450 pathway. Oxidative damage following ovarian TCE metabolism or the presence of TCE metabolites may contribute to reduced oocyte fertilizability. In summary, these results indicate maturing oocytes are susceptible to very short in vivo exposures to TCE. PMID:17673192

Continuous 900-megahertz electromagnetic field applied in middle and late-adolescence causes qualitative and quantitative changes in the ovarian morphology, tissue and blood biochemistry of the rat.

PubMed

Okatan, Derya Öztürk; Kaya, Haydar; Aliyazıcıoğlu, Yüksel; Demir, Selim; Çolakoğlu, Serdar; Odacı, Ersan

2018-02-01

The purpose of this study was to use histological and biochemical methods in order to evaluate changes taking place in the ovarian of rats exposed to the effect of a 900-megahertz (MHz) electromagnetic field (EMF) in middle and late adolescence. Twenty-four 34-d-old female Sprague-Dawley rats were assigned equally to control, sham and EMF groups. EMF group rats were exposed to the effect of a 900-MHz EMF for 1 h a day, at the same time every day between postnatal days 35 and 59, while inside an EMF cage. Sham group rats were kept inside the EMF cage for the same time between postnatal days 35 and 59 without being exposed to any EMF effect. At the end of the study, rats' ovarian were removed and blood specimens were taken. Right ovarium tissues were subjected to routine histological procedures and stained with hematoxylin and eosin, periodic acid shift and Masson's trichrome. Follicles were counted in ovarian sections stained with hematoxylin and eosin. The TUNEL method was used to evaluate apoptosis. Left ovarian tissue and blood specimens were investigated biochemically. Histopathological examination of EMF group ovarian tissue revealed thinning in the zona granulosa and theca layers, shrinking in granulosa cells, reduced mitotic activity and leukocyte infiltration in the follicles and stroma. Secondary follicle numbers in the EMF group were significantly lower than in the other groups. In terms of biochemistry, EMF and sham group superoxide dismutase, catalase and anti-Mullerian hormone levels and EMF group 3-nitrotyrosine values increased significantly compared to the control group. EMF and sham group serum catalase and 8-hydroxy-deoxiguanosine values increased significantly compared to the control group, and EMF group total oxidant status and oxidative stress index values were significantly higher compared to the sham and control groups. A total of 900-MHz EMF applied in middle and late adolescence may cause changes in the morphology and biochemistry of the rat ovarium.

[Effects of electroacupuncture of "Guanyuan" (CV 4)-"Zhongji" (CV 3) on ovarian P450 arom and P450c 17alpha expression and relevant sex hormone levels in rats with polycystic ovary syndrome].

PubMed

Sun, Jie; Zhao, Ji-meng; Ji, Rong; Liu, Hui-rong; Shi, Yin; Jin, Chun-lan

2013-12-01

To observe the effect of electroacupuncture (EA) on ovarian P 450 arom and P 450 c 17 alpha (aromatases) expression and related sex hormone levels in polycystic ovary syndrome (PCOS) rats. Thirty SD rats were randomly divided into normal control group, model group and EA group (10 rats/group). PCOS model was made by intragastric administration of letrozole at 1 mg/kg per day for consecutive 21 days. "Guanyuan" (CV 4) and "Zhongji" (CV 3) acupoints were stimulated 20 min by EA (2 mA, 2 Hz), once daily for consecutive 14 days. The damp ovarian weight was weighed and the pathological changes of the ovarian tissue were observed after H. E. staining. Ultrastructural changes of the ovarian tissue were observed by transmission electron microscope. Immunohistochemical staining was adopted to detect ovarian follicle granulosa cell P 450 arom and follicle membrane cell P 450 c 17 alpha expression. The contents of estradiol (E 2), estrone (E 1), androstenedione (ASD), testosterone (T), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the ovarian tissue were measured by ELISA. Compared with the normal group, there was a significant increase in the damp weight of both left and right ovarian tissues in the model group (P < 0.01). After EA, the ovarian weight was remarkably reduced (P < 0.01). Pathological changes of the ovarian tissue such as thickening of the superficial albugineous coat of the ovary, thinning of the granular cell layer, and disappearance of the intraovular oocytes and coronaradiata under light microscope, and mitochondrion swelling, fracture or disappearance of mitochondrial cristae, and enlargement of the endoplasmic reticulum, etc. after modeling were obviously improved in the EA group. In comparison to the control group, the expression of the follicle granulosa cell P450 arom was significantly down-regulated and that of follicle membrane cell P 450 c 17 alpha was significantly upregulated in the model group (P < 0.01). After EA intervention these changes were obviously reversed (P < 0.05, P < 0.01). In the model group, there was a significant increase in the levels of ASD, T and LH in the ovarian tissues (P < 0.01) and a marked decrease in the contents of ovarian E 1 and E2 (P < 0.01) in comparison to the control group. After EA, the ovarian ASD, T and LH levels were notably decreased (P < 0.05, P < 0.01) and the E 1 and E 2 levels apparently increased (P < 0.01) compared with the model group. EA can improve letrozole-induced pathological changes of ovarian morphology and ultrastructure and obviously promote P 450 arom expression in the follicle granulosa cell layer and inhibit P 450 c 17 alpha expression in the follicle membrane cell layer, as well as regulate sex hormone levels in PCOS rats, facilitating the normal transformation of ovarian androgen to estrogen and restoring the local endocrine disorders.

Increase in endogenous estradiol in the progeny of obese rats is associated with precocious puberty and altered follicular development in adulthood.

PubMed

Ambrosetti, Valery; Guerra, Marcelo; Ramírez, Luisa A; Reyes, Aldo; Álvarez, Daniela; Olguín, Sofía; González-Mañan, Daniel; Fernandois, Daniela; Sotomayor-Zárate, Ramón; Cruz, Gonzalo

2016-07-01

Maternal obesity during pregnancy has been related with several pathological states in offspring. However, the impact of maternal obesity on reproductive system on the progeny is beginning to be elucidated. In this work, we characterize the effect of maternal obesity on puberty onset and follicular development in adult offspring in rats. We also propose that alterations in ovarian physiology observed in offspring of obese mothers are due to increased levels of estradiol during early development. Offspring of control dams and offspring of dams exposed to a high-fat diet (HF) were studied at postnatal days (PND) 1, 7, 14, 30, 60, and 120. Body weight and onset of puberty were measured. Counting of ovarian follicles was performed at PND 60 and 120. Serum estradiol, estriol, androstenedione, FSH, LH, and insulin levels were measured by ELISA. Hepatic CYP3A2 expression was determined by Western blot. HF rats had a higher weight than controls at all ages and they also had a precocious puberty. Estradiol levels were increased while CYP3A2 expression was reduced from PND 1 until PND 60 in HF rats compared to controls. Estriol was decreased at PND60 in HF rats. Ovaries from HF rats had a decrease in antral follicles at PND60 and PND120 and an increase in follicular cysts at PND60 and PND120. In this work, we demonstrated that maternal obesity in rats alters follicular development and induces follicular cysts generation in the adult offspring. We observed that maternal obesity produces an endocrine disruption through increasing endogenous estradiol in early life. A programmed failure in hepatic metabolism of estradiol is probably the cause of its increase.

Ovario-protective effects of genistein against cyclophosphamide toxicity in rats: Role of anti-müllerian hormone and oestradiol.

PubMed

Saleh, Dalia O; Mansour, Dina F

2016-10-15

Cyclophosphamide (CP), the commonly used chemotherapeutic agent in cancer treatment, is proven to cause ovarian toxicity and infertility in women. In the present study, we investigated the protective effect of genistein (GEN), a phytoestrogen found in the soy protein, against CP-induced ovarian toxicity in rats. Forty female adult rats were allocated into five groups. A normal control group received the vehicle; another group was injected with a single acute intraperitoneal dose of CP (200mg/kg). Three other groups were pretreated with GEN (0.5, 1 or 2mg/kg; s.c.) for 14 days. Sera and ovaries were obtained 48h after CP treatment. Serum levels of anti-müllerian hormone (AMH) and oestradiol (E2) were detected as well as the ovarian level of reduced glutathione (GSH), activity of superoxide dismutase (SOD), level of malondialdehyde (MDA) and interleukin 1β (IL-1β) were evaluated. Histopathological examination and immunohistochemical detection of inducible nitric oxide synthetase (iNOS) were conducted. Results of the present study revealed that CP-induced severe ovarian toxicity via decreasing serum levels of AMH and E2 and elevating oxidative stress and inflammation in ovarian tissues. Histologically, CP caused increase in primordial follicles with less graafian follicles and corpora lutea in ovarian tissues as well as severe induction of iNOS. GEN inhibited the severe decrease in serum AMH and E2 with alleviation of oxidative stress and inflammation significantly compared to CP-treated group. GEN improved ovarian histology and immunostaining of ovarian iNOS disrupted by CP. Finally, it can be concluded that GEN exerted protective effects against CP-induced ovarian toxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

[The Antitumor Effects of Fisetin on Ovarian Cancer in vitro and in vivo.

PubMed

Meng, Yi-Bo; Xiao, Chao; Chen, Xin-Lian; Bai, Peng; Yao, Yuan; Wang, He; Xiao, Xue

2016-11-01

We attempted to survey the inhibit effect of fisetin with human ovarian cancer cell line SKOV3 and the xenograft and the mechanism of the effect. The ovarian cancer cell line SKOV3 treated by fisetin were observed directly under the transmission electronmicroscope (TEM);MTT assay was used to determine cell viability.Flow cytometry was used to analyze the apoptosis in ovarian cancer cell line SKOV3.In addition,we established an ovarian cancer athymicnude rat model.We observed the neoplasia and progression after fisetin treatment.The proliferation and apoptosis of athymic nude rat model were evaluated by testing Bcl-2,Bax and poly-ADP-ribose polyerase (PARP) expression through Western blot. The chromatin were brought together and the apoptotic bodies were detected in SKOV3 cells under transmission electron microscope after the treatment by fisetin.MTT assay indicated that fisetin inhibited ovarian cancer cell proliferation in a dose-dependent manner.The flow cytometry data demonstrated that the apoptosis might induct in SKOV3 cells after treatment by fisetin.In athymic rude rat model,under the influence of fisetin,tumor volume and tumor mass were significantly decreased.Western blot demonstrated that treatment with higher concentration of fisetin resulted in a significant decrease of Bcl-2 and a significant increase of Bax.The apoptosis proteins PARP was cut apparently. The results provided the first insight into antitumor anti-proliferative and the induction of apoptosis efficacy of fisetin against ovarian cancer in vitro and in vivo .All data suggested a safe promising therapeutic potential of fisetin in ovarian cancer treatment.

Peri-pubertal high caffeine exposure increases ovarian estradiol production in immature rats.

PubMed

Kwak, Yoojin; Choi, Hyeonhae; Bae, Jaeman; Choi, Yun-Young; Roh, Jaesook

2017-04-01

Chronic caffeine consumption exerts a negligible effect on the reproductive organs of normal adult females, but it is not known whether this is also true for children and adolescents. Here, we investigated the effects of high caffeine exposure on sexual maturation and ovarian estradiol production in immature female rats. Immature female SD rats were divided into controls and caffeine groups fed 120 and 180mg/kg/day for 4 or 8 weeks. There was a significant delay in vaginal opening in the caffeine-fed groups. In addition, serum estradiol levels were elevated in the caffeine-fed animals after 2 and 4 weeks of exposure. Estradiol secretion as well as aromatase expression also increased significantly in the ovarian cells in response to caffeine. These results demonstrate that peripubertal exposure to high caffeine increases estradiol production in the ovary; this may disturb the coordinated regulation of the hypothalamo-pituitary-ovarian axis, thereby interfering with sexual maturation. Copyright © 2017 Elsevier Inc. All rights reserved.

Herbal formula menoprogen alters insulin-like growth factor-1 and insulin-like growth factor binding protein-1 levels in the serum and ovaries of an aged female rat model of menopause.

PubMed

Wei, Min; Zheng, Sheng Z; Lu, Ye; Liu, Daniel; Ma, Hong; Mahady, Gail B

2015-10-01

Menoprogen (MPG), a traditional Chinese medicine formula for menopause, improves menopausal symptoms; however, its mechanism remains unknown. Previous studies have shown that MPG is not directly estrogenic; thus, the goal of this study was to investigate the effects of MPG on insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-1 (IGFBP-1) levels in an aged female rat model of menopause. In a six-arm study, 14-month-old female Sprague-Dawley rats (n = 8 per arm) were randomly divided into the following groups: untreated aged, 17β-estradiol-treated aged (estradiol [E2]), and three arms with increasing doses of MPG (162, 324, or 648 mg/kg/d). The sixth arm contained 4-month-old female Sprague-Dawley rats as a normal comparison group. Four weeks after MPG or E2 administration, animals were killed after blood draws, and ovarian tissues were excised. Levels of E2 and progesterone (P4) were determined by radioimmunoassay. Serum and ovarian tissue levels of IGF-1, IGFBP-1, and IGF-1 receptor were determined by enzyme-linked immunosorbent assay. Compared with the normal group, aged rats had significantly reduced serum levels of E2, P4, and IGF-1, and increased serum and ovarian tissue levels of IGFBP-1. MPG restored serum IGF-1 and IGFBP-1 levels and down-regulated ovarian levels of IGFBP-1, which were closely related to increases in E2 and P4 levels in aged rats. No significant differences in either IGF-1 or IGFBP-1 were observed between the three doses of MPG. MPG exerts a direct in vivo effect on aged female rats by positively regulating serum and ovarian IGF-1 and IGFBP-1 levels.

Protective effects of ellagic acid and ozone on rat ovaries with an ischemia/reperfusion injury.

PubMed

Sayar, Ilyas; Bicer, Senol; Gursul, Cebrail; Gürbüzel, Mehmet; Peker, Kemal; Işik, Arda

2016-01-01

This study investigated the effects of the antioxidant agents, ozone (O) and ellagic acid (EA), on ischemia/reperfusion (I/R) injuries developed from an ovarian torsion-detorsion model. Arteries in the left ovaries of rats were clamped for two hours to achieve torsion, and then the clamps were removed for a two-hour detorsion period. Thirty-five female Sprague-Dawley rats were randomly divided into five groups: control: administered only with anesthesia, rats were not subjected to torsion-detorsion; I/R: subjected to torsion and subsequent detorsion, without administering any treatment agent; and I/R + EA, I/R + O and I/R + O + EA: subjected to torsion and detorsion processes and administered with EA, O or EA + O at the 75th minute of torsion. The rats were then sacrificed under general anesthesia and the ovarian tissues were excised. The tissues were homogenized and levels of glutathione reductase, catalase, superoxide dismutase and malondialdehyde (MDA) were analyzed. Tissue damage was evaluated in terms of histopathological parameters, such as hemorrhage, congestion, edema and inflammation. Antioxidant enzyme activity and MDA levels in the ovary tissue increased in the I/R group and decreased in the O, EA and O + EA groups (P < 0.05). Histopathological examination revealed that tissue damage in the O, EA and O + EA groups decreased in comparison with the I/R group (P < 0.05). These biochemical and histopathological findings suggest that EA and O are effective against ovarian I/R injury. © 2015 Japan Society of Obstetrics and Gynecology.

Dietary-Induced Chronic Hypothyroidism Negatively Affects Rat Follicular Development and Ovulation Rate and Is Associated with Oxidative Stress.

PubMed

Meng, Li; Rijntjes, Eddy; Swarts, Hans; Bunschoten, Annelies; van der Stelt, Inge; Keijer, Jaap; Teerds, Katja

2016-04-01

The long-term effects of chronic hypothyroidism on ovarian follicular development in adulthood are not well known. Using a rat model of chronic diet-induced hypothyroidism initiated in the fetal period, we investigated the effects of prolonged reduced plasma thyroid hormone concentrations on the ovarian follicular reserve and ovulation rate in prepubertal (12-day-old) and adult (64-day-old and 120-day-old) rats. Besides, antioxidant gene expression, mitochondrial density and the occurrence of oxidative stress were analyzed. Our results show that continuous hypothyroidism results in lower preantral and antral follicle numbers in adulthood, accompanied by a higher percentage of atretic follicles, when compared to euthyroid age-matched controls. Not surprisingly, ovulation rate was lower in the hypothyroid rats. At the age of 120 days, the mRNA and protein content of superoxide dismutase 1 (SOD1) were significantly increased while catalase (CAT) mRNA and protein content was significantly decreased, suggesting a disturbed antioxidant defense capacity of ovarian cells in the hypothyroid animals. This was supported by a significant reduction in the expression of peroxiredoxin 3 ( ITALIC! Prdx3), thioredoxin reductase 1 ( ITALIC! Txnrd1), and uncoupling protein 2 ( ITALIC! Ucp2) and a downward trend in glutathione peroxidase 3 ( ITALIC! Gpx3) and glutathione S-transferase mu 2 ( ITALIC! Gstm2) expression. These changes in gene expression were likely responsible for the increased immunostaining of the oxidative stress marker 4-hydroxynonenal. Together these results suggest that chronic hypothyroidism initiated in the fetal/neonatal period results in a decreased ovulation rate associated with a disturbance of the antioxidant defense system in the ovary. © 2016 by the Society for the Study of Reproduction, Inc.

The Brain as a Target for Environmental Toxicants that alter Ovarian Function.

EPA Science Inventory

In this review we discuss the ovarian cycle of the laboratory rat in order to familiarize the reader with the well-understood timing of the neuroendocrine events controlling ovarian function. This is followed by a discussion of the location and function of the estrogen and proges...

Inhibitor of apoptosis proteins and ovarian dysfunction in galactosemic rats.

PubMed

Lai, K W; Cheng, L Y L; Cheung, A L M; O, W S

2003-03-01

Galactosemia is a genetic disease with deficiency of galactose-1-uridyltransferase, resulting in the accumulation of galactose or galactose-1-phosphate in the blood and tissues. Rats were fed with normal rat chow and with a high-galactose diet for 4 weeks to give control and galactosemic groups, and their ovarian function was studied. The two groups of rats were injected with pregnant mare's serum gonadotrophin (PMSG) and were killed at different time points after human chorionic gonadotrophin (hCG) injection. The number of oocytes ovulated in the controls was significantly higher than in the galactosemic group. Morphometric studies of the ovaries also showed a higher number of corpora lutea in the controls. Western blot analysis of granulosa cells showed that the overall expressions of Fas and FasL were lower in the control group and their expressions of inhibitor of apoptosis proteins (IAPs) were higher than in the galactosemic group, especially at 8 h post hCG injection. TDT-mediated dUTP-biotin nick end-labeling (TUNEL) and immunohistochemical staining of ovarian sections with Ki-67 and IAPs showed more apoptotic granulosa cells in the galactosemic group and the expressions of IAPs in granulosa cells also confirmed the result of the Western blot. These findings support our hypothesis that ovarian dysfunction in galactosemic rats is due to increased apoptosis in granulosa cells of maturing follicles.

Experimental induction of ovarian Sertoli cell tumors in rats by N-nitrosoureas.

PubMed Central

Maekawa, A; Onodera, H; Tanigawa, H; Furuta, K; Kanno, J; Ogiu, T; Hayashi, Y

1987-01-01

Spontaneous ovarian tumors are very rare in ACI, Wistar, F344 and Donryu rats; the few neoplasms found are of the granulosa/theca cell type. Ovarian tumors were also rare in these strains of rats when given high doses of N-alkyl-N-nitrosoureas continuously in the drinking water for their life-span; however, relatively high incidences of Sertoli cell tumors or Sertoli cell tumors mixed with granulosa cell tumors were induced in Donryu rats after administration of either a 400 ppm N-ethyl-N-nitrosourea solution in the drinking water for 4 weeks or as a single dose of 200 mg N-propyl-N-nitrosourea per kg body weight by stomach tube. Typical Sertoli cell tumors consisted of solid areas showing tubular formation. The tubules were lined by tall, columnar cells, with abundant, faintly eosinophilic, often vacuolated cytoplasm, and basally oriented, round nuclei, resembling seminiferous tubules in the testes. In some cases, Sertoli cell tumor elements were found mixed with areas of granulosa cells. The induction of ovarian Sertoli cell tumors in Donryu rats by low doses of nitrosoureas may provide a useful model for these tumors in man. Images PLATE 1. PLATE 2. PLATE 3. PLATE 4. PLATE 5. PLATE 6. PLATE 7. PLATE 8. PLATE 9. PLATE 10. PLATE 11. PLATE 12. PLATE 13. PLATE 14. PLATE 15. PLATE 16. PMID:3665856

Downregulation of natriuretic peptide system and increased steroidogenesis in rat polycystic ovary.

PubMed

Pereira, Virginia M; Honorato-Sampaio, Kinulpe; Martins, Almir S; Reis, Fernando M; Reis, Adelina M

2014-10-01

Atrial natriuretic peptide (ANP) is known to regulate ovarian functions, such as follicular growth and steroid hormone production. The aim of the present study was to investigate the natriuretic peptide system in a rat model of chronic anovulation, the rat polycystic ovary. Adult female Wistar rats received a single subcutaneous injection of 2mg estradiol valerate to induce polycystic ovaries, while the control group received vehicle injection. Two months later, their ovaries were quickly removed and analyzed. Polycystic ovaries exhibited marked elevation of testosterone and estradiol levels compared to control ovaries. The levels of ANP and the expression of ANP mRNA were highly reduced in the polycystic ovaries compared to controls. By immunohistochemistry, polycystic ovaries showed weaker ANP staining in stroma, theca cells and oocytes compared to controls. Polycystic ovaries also had increased activity of neutral endopeptidase, the main proteolytic enzyme that degrades natriuretic peptides. ANP receptor C mRNA was reduced and ANP binding to this receptor was absent in polycystic ovaries. Collectively, these results indicate a downregulation of the natriuretic peptide system in rat polycystic ovary, an established experimental model of anovulation with high ovarian testosterone and estradiol levels. Together with previous evidence demonstrating that ANP inhibits ovarian steroidogenesis, these findings suggest that low ovarian ANP levels may contribute to the abnormal steroid hormone balance in polycystic ovaries. Copyright © 2014 Elsevier Inc. All rights reserved.

Hochu-ekki-to Treatment Improves Reproductive and Immune Modulation in the Stress-Induced Rat Model of Polycystic Ovarian Syndrome.

PubMed

Park, Eunkuk; Choi, Chun Whan; Kim, Soo Jeong; Kim, Yong-In; Sin, Samkee; Chu, Jong-Phil; Heo, Jun Young

2017-06-13

The traditional herbal medicine, Hochu-ekki-to, has been shown to have preventive effects on viral infection and stress. This study aimed to evaluate the clinical effects of Hochu-ekki-to on two stress-related rat models of polycystic ovarian syndrome. Female Sprague-Dawley rats were divided into control and treatment groups, the latter of which were subjected to stress induced by exposure to adrenocorticotropic hormone (ACTH) or cold temperatures. After these stress inductions, rats were orally treated with dissolved Hochu-ekki-to once per day for 7 days. Rats subjected to the two different stressors exhibited upregulation of steroid hormone receptors (in ovaries) and reproductive hormones (in blood), and consequent stimulation of abnormal follicle development accompanied by elevation of Hsp 90 expression (in ovaries). Treatment with Hochu-ekki-to for 7 days after stress induction increased immune functions, reduced the stress-induced activation of Hsp 90, and normalized the levels of the tested steroid hormone receptors and reproductive hormones. Our findings suggest that stress stimulations may promote the activation of Hsp 90 via the dysregulation of steroid hormone receptors and reproductive hormones, but that post-stress treatment with Hochu-ekki-to improves reproductive and immune functions in the ovaries of stressed rats.

Effect of the aqueous extract of Justicia insularis T. Anders (Acanthaceae) on ovarian folliculogenesis and fertility of female rats.

PubMed

Telefo, Phelix Bruno; Tagne, Simon Richard; Koona, Olga Elodie Sandrine; Yemele, Didiane M; Tchouanguep, Félicité M

2012-01-01

Justicia insularis T. Anders (Acanthaceae) is a medicinal plant whose leaves and those of three other plants are mixed for the preparation of a concoction used to improve fertility and to reduce labour pains in women of the Western Region of Cameroon. Previous studies have demonstrated the inducing potential on ovarian folliculogenesis and steroidogenesis of the aqueous extract of the leaf mixture (ADHJ) of four medicinal plants (Aloe buettneri, Dicliptera verticillata, Hibiscus macranthus and Justicia insularis) among which the later represented the highest proportion. This study was aimed at evaluating the ovarian inducing potential of J. insularis in immature female rats. Various doses of the aqueous extract of J. insularis were daily and orally given, for 20 days, to immature female rats distributed into four experimental groups of twenty animals each. At the end of the experimental period some biochemical and physiological parameters of ovarian function were assayed. The administration of the aqueous extract of Justicia insularis significantly induced an early vaginal opening in all treated groups (P < 0.001) as well as an increase (at doses of 50 or 100 mg/kg) in the number of hemorrhagic points, Corpus luteum, implantation sites, ovarian weight, uterine and ovarian proteins. Ovarian cholesterol level (P < 0.05) significantly decreased in animals treated with the lowest dose (12.5 mg/kg). The evaluation of the toxicological effects of the extract on pregnancy showed that it significantly increased pre- and post-implantation losses, resorption index and decreased the rate of nidation as well as litter's weight. These results suggest that the aqueous extract of Justicia insularis induces ovarian folliculogenesis thus justifying its high proportion in the leaf mixture of ADHJ.

The anorectic agent, lorcaserin, disturbs estrous cyclicity and produces endometrial hyperplasia without affecting ovarian population in female rats.

PubMed

Abdel-Latif, Raghda T; Zaitone, Sawsan A; Abdel-Mottaleb, Yousra; El-Maraghy, Nabila N

2017-08-15

The present study aims to investigate the effect of the new anorectic agent, lorcaserin, on estrous cyclicity, reproductive hormones and folliculogenesis in female mature rats. Rats were divided into four groups; Group i: control group. Group ii-iv: rats treated with lorcaserin (5, 10 or 30mg/kg/day, p.o.), respectively. The treatment continued for 28days. Lorcaserin (5 or 10mg/kg) caused estrous cycle disturbance in 40% of treated rats while the high dose (30mg/kg) produced disturbances in 100% of the treated rats. Lorcaserin (5-30mg/kg) altered some of female hormones where it enhanced estradiol but reduced luteinizing hormone. Minimal edema with congested vessels was observed in the medulla of ovarian sections. Further, epithelial and uterine sections showed hyperplasia. Taken together, the present results demonstrated that lorcaserin affected some reproductive hormones, disturbed estrous cyclicity and induced histopathological changes in the ovaries and uteri without affecting the ovarian populations. Therefore, lorcaserin should be used with caution in women of child bearing potential until adequate clinical safety data are available. Copyright © 2017 Elsevier Inc. All rights reserved.

Daily treatment with {alpha}-naphthoflavone enhances follicular growth and ovulation rate in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barreiro, Karina A.; Di Yorio, Maria P.; Artillo-Guida, Romina D.

2011-04-01

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and the first protein involved in a variety of physiological and toxicological processes, including those of xenobiotic metabolizing enzymes. AhR has been found in the ovary of many species and seems to mediate the ovarian toxicity of many environmental contaminants, which are AhR ligands. However, the role of AhR in the ovarian function is unknown. Therefore, the aim of this work was to study the action of {alpha}-naphthoflavone ({alpha}NF), known to be an AhR antagonist, on both follicular growth and ovulation. Immature Sprague-Dawley rats were daily injected intraperitoneally with {alpha}NFmore » (0.1-80 mg/kg) or vehicle for 12 days, and primed with gonadotrophins (eCG/hCG) to induce follicular growth and ovulation. Ovaries were obtained 20 h after hCG administration. By means of immunohistochemistry, we found that the numbers of primordial, primary and antral follicles were increased in rats treated with 80 mg/kg {alpha}NF and that there were no differences with other doses. Likewise, the ovarian weight and the ovulation rate, measured by both number of oocytes within oviducts and corpora lutea in ovarian sections, were increased when the rats received either 1 or 10 mg/kg daily. Although further studies are necessary to know the mechanism of action of {alpha}NF, it is possible that the different ovarian processes can be differentially responsive to the presence of different levels of {alpha}NF, and that the same or different endogenous AhR ligands can be involved in these ovarian processes in a cell type-dependent manner.« less

Royal Jelly Promotes Ovarian Follicles Growth and Increases Steroid Hormones in Immature Rats

PubMed Central

Ghanbari, Elham; Khazaei, Mohammad Rasool; Khazaei, Mozafar; Nejati, Vahid

2018-01-01

Background Royal jelly (RJ) is a complementary diet widely prescribed by traditional medicine specialists for treatment of in- fertility. The aim of present study was to evaluate the effects of RJ on a set of reproductive parameters in immature female rats. Materials and Methods In this experimental study, thirty two immature female rats (30-35 g) were divided into four groups (n=8/group): three experimental groups and one control. The experimental groups received 100, 200 and 400 mg/kg/body weight doses of RJ daily for 14 days, and the control group received 0.5 ml distilled water interaperito- nealy (i.p). The treated rats were sacrificed and their ovaries were dissected for histological examination. The serum levels of ovarian hormones, nitric oxide (NO) and ferric reducing antioxidant power (FRAP) were evaluated, and the ratios of the ovarian and uterine weight to body weight were calculated. One-way ANOVA was used for data analysis. Results The body weights were significantly different (P=0.002) among the rat groups, with an increase in all RJ treated animals. Uterine and ovarian weights and the serum levels of progesterone (P=0.013) and estradiol (P=0.004) were significantly increased in experimental groups compared to the control group. In addition, a significant increase in the number of mature follicles and corpora lutea (P=0.007) was seen in RJ recipients compared to the controls. A significant increase in the serum levels of FRAP (P=0.009) and a significant decrease in NO level (P=0.013) were also observed. Conclusion RJ promotes folliculogensis and increases ovarian hormones. This product can be considered as a natural growth stimulator for immature female animals. PMID:29043701

Royal Jelly Promotes Ovarian Follicles Growth and Increases Steroid Hormones in Immature Rats.

PubMed

Ghanbari, Elham; Khazaei, Mohammad Rasool; Khazaei, Mozafar; Nejati, Vahid

2018-01-01

Royal jelly (RJ) is a complementary diet widely prescribed by traditional medicine specialists for treatment of infertility. The aim of present study was to evaluate the effects of RJ on a set of reproductive parameters in immature female rats. In this experimental study, thirty two immature female rats (30-35 g) were divided into four groups (n=8/group): three experimental groups and one control. The experimental groups received 100, 200 and 400 mg/kg/body weight doses of RJ daily for 14 days, and the control group received 0.5 ml distilled water interaperitonealy (i.p). The treated rats were sacrificed and their ovaries were dissected for histological examination. The serum levels of ovarian hormones, nitric oxide (NO) and ferric reducing antioxidant power (FRAP) were evaluated, and the ratios of the ovarian and uterine weight to body weight were calculated. One-way ANOVA was used for data analysis. The body weights were significantly different (P=0.002) among the rat groups, with an increase in all RJ treated animals. Uterine and ovarian weights and the serum levels of progesterone (P=0.013) and estradiol (P=0.004) were significantly increased in experimental groups compared to the control group. In addition, a significant increase in the number of mature follicles and corpora lutea (P=0.007) was seen in RJ recipients compared to the controls. A significant increase in the serum levels of FRAP (P=0.009) and a significant decrease in NO level (P=0.013) were also observed. RJ promotes folliculogensis and increases ovarian hormones. This product can be considered as a natural growth stimulator for immature female animals. Copyright© by Royan Institute. All rights reserved.

Effects of Space Flight on Ovarian-Hypophyseal Function in Postpartum Rats

NASA Technical Reports Server (NTRS)

Burden, H. W.; Zary, J.; Lawrence, I. E.; Jonnalagadda, P.; Davis, M.; Hodson, C. A.

1997-01-01

The effect of space flight in a National Aeronautics and Space Administration (NASA) shuttle was studied in pregnant rats. Rats were launched on day 9 of gestation and recovered on day 20 of gestation. On day 20 of gestation, rats were unilaterally hysterectomized and subsequently allowed to go to term and deliver vaginally. There was no effect of space flight on pituitary and ovary mass postpartum. In addition, space flight did not alter healthy and atretic ovarian antral follicle populations, fetal wastage in utero, plasma concentrations of progesterone and luteinizing hormone (LH) or pituitary content of follicle stimulating hormone (FSH). Space flight significantly increased plasma concentrations of FSH and decreased pituitary content of LH at the postpartum sampling time. Collectively, these data show that space flight, initiated during the postimplantation period of pregnancy, and concluded before parturition, is compatible with maintenance of pregnancy and has minimal effects on postpartum hypophyseal parameters; however, none of the ovarian parameters examined was altered by space flight.

Potential role of follicle-stimulating hormone (FSH) and transforming growth factor (TGFβ1) in the regulation of ovarian angiogenesis.

PubMed

Kuo, Shih-Wei; Ke, Ferng-Chun; Chang, Geen-Dong; Lee, Ming-Ting; Hwang, Jiuan-Jiuan

2011-06-01

Angiogenesis occurs during ovarian follicle development and luteinization. Pituitary secreted FSH was reported to stimulate the expression of endothelial mitogen VEGF in granulosa cells. And, intraovarian cytokine transforming growth factor (TGF)β1 is known to facilitate FSH-induced differentiation of ovarian granulosa cells. This intrigues us to investigate the potential role of FSH and TGFβ1 regulation of granulosa cell function in relation to ovarian angiogenesis. Granulosa cells were isolated from gonadotropin-primed immature rats and treated once with FSH and/or TGFβ1 for 48 h, and the angiogenic potential of conditioned media (granulosa cell culture conditioned media; GCCM) was determined using an in vitro assay with aortic ring embedded in collagen gel and immunoblotting. FSH and TGFβ1 increased the secreted angiogenic activity in granulosa cells (FSH + TGFβ1 > FSH ≈ TGFβ1 >control) that was partly attributed to the increased secretion of pro-angiogenic factors VEGF and PDGF-B. This is further supported by the evidence that pre-treatment with inhibitor of VEGF receptor-2 (Ki8751) or PDGF receptor (AG1296) throughout or only during the first 2-day aortic ring culture period suppressed microvessel growth in GCCM-treated groups, and also inhibited the FSH + TGFβ1-GCCM-stimulated release of matrix remodeling-associated gelatinase activities. Interestingly, pre-treatment of AG1296 at late stage suppressed GCCM-induced microvessel growth and stability with demise of endothelial and mural cells. Together, we provide original findings that both FSH and TGFβ1 increased the secretion of VEGF and PDGF-B, and that in turn up-regulated the angiogenic activity in rat ovarian granulosa cells. This implicates that FSH and TGFβ1 play important roles in regulation of ovarian angiogenesis during follicle development. Copyright © 2010 Wiley-Liss, Inc.

Differential effects of leptin on ovarian metalloproteinases and their tissue inhibitors between in vivo and in vitro studies.

PubMed

Bilbao, M G; Di Yorio, M P; Faletti, A G

2011-04-01

In this study, we investigated the effect of leptin on the ovarian metalloproteinase system in the rat during the ovulatory process. Ovulation was induced in immature rats primed with gonadotropins. In both in vitro and in vivo experiments, we measured i) the protein expression of the ovarian metalloproteinases (matrix metalloproteinases, MMPs) and their tissue inhibitors (TIMPs) by western blot; ii) the gelatinase activity of the ovarian MMPs by zymography; and iii) the inhibitory action of TIMPs by reverse zymography. Using cultures of ovarian explants, leptin increased the activity but not the protein expression of MMP-2 and MMP-9 in both culture medium and ovarian tissue, and the protein expression of TIMPs, without a higher inhibitory action of the gelatinase activity. These results suggest either that the increase in TIMP proteins was not sufficient or that the inhibitory actions of TIMPs were impaired to suppress the MMP activity when the ovaries were directly exposed to leptin. To study the in vivo effect, rats received an acute treatment with high doses of leptin to inhibit ovulation. This treatment increased the expression of both the latent and the active forms of MMP-2 but did not result in a greater activity of MMP-2. In addition, the inhibitory action of TIMP-2 was also increased by this treatment. These results suggest that the administration of high doses of leptin could be regulating the follicle wall degradation, at least in part, by increasing the action of the ovarian TIMP-2 as a result of an extraovarian mechanism or signaling pathway.

Progesterone regulation of primordial follicle assembly in bovine fetal ovaries.

PubMed

Nilsson, Eric E; Skinner, Michael K

2009-12-10

Fertility in mammals is dependant on females having an adequate primordial follicle pool to supply oocytes for fertilization. The formation of primordial follicles is called ovarian follicular assembly. In rats and mice progesterone and estradiol have been shown to inhibit follicle assembly with assembly occurring after birth when the pups are removed from the high-steroid maternal environment. In contrast, primordial follicle assembly in other species, such as cattle and humans, occurs during fetal development before birth. The objective of the current study is to determine if progesterone levels regulate primordial follicle assembly in fetal bovine ovaries. Ovaries and blood were collected from bovine fetuses. Interestingly, ovarian progesterone and estradiol concentrations were found to decrease with increasing fetal age and correlated to increased primordial follicle assembly. Microarray analysis of fetal ovary RNA suggests that progesterone membrane receptor and estrogen nuclear receptor are expressed. Treatment of fetal bovine ovary cultures with a higher progesterone concentration significantly decreased primordial follicle assembly. Observations indicate that progesterone affects ovarian primordial follicle assembly in cattle, as it does in rats and mice.

Progesterone Regulation of Primordial Follicle Assembly In Bovine Fetal Ovaries

PubMed Central

Nilsson, Eric E.; Skinner, Michael K.

2009-01-01

Fertility in mammals is dependant on females having an adequate primordial follicle pool to supply oocytes for fertilization. The formation of primordial follicles is called ovarian follicular assembly. In rats and mice progesterone and estradiol have been shown to inhibit follicle assembly with assembly occurring after birth when the pups are removed from the high-steroid maternal environment. In contrast, primordial follicle assembly in other species, such as cattle and humans, occurs during fetal development before birth. The objective of the current study is to determine if progesterone levels regulate primordial follicle assembly in fetal bovine ovaries. Ovaries and blood were collected from bovine fetuses. Interestingly, ovarian progesterone and estradiol concentrations were found to decrease with increasing fetal age and correlated to increased primordial follicle assembly. Microarray analysis of fetal ovary RNA suggests that progesterone membrane receptor and estrogen nuclear receptor are expressed. Treatment of fetal bovine ovary cultures with a higher progesterone concentration significantly decreased primordial follicle assembly. Observations indicate that progesterone affects ovarian primordial follicle assembly in cattle, as it does in rats and mice. PMID:19747959

Tributyltin increases the expression of apoptosis- and adipogenesis-related genes in rat ovaries

PubMed Central

Lee, Hyojin; Lim, Sojeong; Yun, Sujin; Yoon, Ayoung; Park, Gayoung

2012-01-01

Objective Tributyltin (TBT), an endocrine disrupting chemical, has been reported to decrease ovarian function by causing apoptosis in the ovary, but the mechanism is not fully understood. Therefore, we examined whether TBT increases the expression of adipogenesis-related genes in the ovary and the increased expression of these genes is associated with apoptosis induction. Methods Three-week-old Sprague-Dawley rats were orally administered TBT (1 or 10 mg/kg body weight) or sesame oil as a control for 7 days. The ovaries were obtained and weighed on day 8, and then they were fixed for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or frozen for RNA extraction. Using the total RNA of the ovaries, adipogenesis- and apoptosis-related genes were analyzed by real-time polymerase chain reaction (PCR). Results The ovarian weight was significantly decreased in rats administered 10 mg/kg TBT compared to that in control rats. As determined by the TUNEL assay, the number of apoptotic follicles in ovary was significantly increased in rats administered 10 mg/kg TBT. The real-time PCR results showed that the expression of adipogenesis-related genes such as PPARγ, aP2, CD36, and PEPCK was increased after TBT administration. In addition, apoptosis-related genes such as TNFα and TNFR1 were expressed more in the TBT-administered rats compared with the control rats. Conclusion The present study demonstrates that TBT induces the expression of adipogenesis- and apoptosis-related genes in the ovary leading to apoptosis in the ovarian follicles. These results suggest that the increased expression of adipogenesis-related genes in the ovary by TBT exposure might induce apoptosis resulting in a loss of ovarian function. PMID:22563546

Effect of medroxyprogesterone acetate (Provera) on ovarian radiosensitivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jarrell, J.; YoungLai, E.V.; McMahon, A.

1989-04-01

Medroxyprogesterone acetate (Provera) is a drug that is commonly given to young women with cancer during chemotherapy and radiation to control heavy bleeding associated with anovulation. Because hypothalamic-pituitary-ovarian suppression has been associated with ovarian protection from the effects of chemotherapy and medroxyprogesterone acetate has been identified as a radiosensitizing agent, we explored the effects of medroxyprogesterone acetate on a rat model with known radiation injury characteristics. Sprague-Dawley rats were treated with medroxyprogesterone acetate or vehicle from day 22 to day 37 of life and were either irradiated or sham-irradiated on day 30 of life and then killed on day 44.more » Radiation with medroxyprogesterone acetate administration produced a greater loss in preantral and healthy control follicles than in control follicles. No suppression of luteinizing hormone or follicle-stimulating hormone had occurred by day 30 but ovarian glutathione content was reduced. These findings indicate that the administration of medroxyprogesterone acetate with radiotherapy may enhance ovarian injury.« less

Copper nanoparticle-induced ovarian injury, follicular atresia, apoptosis, and gene expression alterations in female rats

PubMed Central

Rao, Meng; Hu, Lixia; Lei, Hui; Wu, Yanqing; Wang, Yingying; Ke, Dandan; Xia, Wei; Zhu, Chang-hong

2017-01-01

Numerous studies have reported the accumulation of copper nanoparticles (Cu NPs) in organs and the corresponding damage, although whether Cu NPs can be translocated to the ovaries and their ovarian toxicity are still unknown. In this study, three groups of female rats were injected with 3.12, 6.25, or 12.5 mg/kg Cu NPs for 14 consecutive days. The pathological changes, hormone levels, apoptosis and apoptotic proteins, oxidative stress, and gene expression characteristics in the ovaries were then investigated. The results demonstrated that the Cu NPs exhibited obvious accumulation in the rat ovaries, leading to ovarian injury, an imbalance of sex hormones, and ovarian cell apoptosis. Cu NP exposure activated caspase 3, caspase 8, caspase 9, and tBid, decreased the protein levels of Bcl-2, increased the expression levels of the proteins Bax and cytochrome c, and promoted malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) reduction. Furthermore, gene microarray analysis showed that Cu NPs (12.5 mg/kg/d) caused 321 differentially expressed genes. Of these, 180 and 141 genes were upregulated and downregulated, respectively. Hsd17b1, Hsd3b1, Hsd3b6, and Hsd3b were involved in steroid and hormone metabolism, whereas Mt3 and Cebpb were associated with apoptosis. Overall, these findings provide strong evidence that Cu NPs trigger both intrinsic and extrinsic apoptotic pathways and regulate key ovarian genes in oxidative stress-mediated ovarian dysfunction. PMID:28860760

Can ebselen prevent cisplatin-induced ovarian damage?

PubMed

Soyman, Zeynep; Uzun, Hafize; Bayindir, Nihan; Esrefoglu, Mukaddes; Boran, Birtan

2018-06-01

The occurrence of ovarian damage is a major shortcoming in treating tumors with cisplatin (CP). The present study investigates the beneficial effects of ebselen-a seleno-organic compound with antioxidant and antiinflammatory properties-vis-à-vis CP-induced ovarian damage. Twenty-eight adult female rats were divided into four study groups. Group 1 received no treatment. The rats in Groups 2, 3, and 4 were intraperitoneally administered CP (2 mg/kg/day) twice per week, for 5 weeks. Those in Group 2 received 0.3 ml saline (0.9% NaCl) intraperitoneally 60 min before each CP treatment, while those in Group 3 received 0.2 ml dimethyl sulfoxide (DMSO) and 0.3 ml saline intraperitoneally 60 min before each CP treatment. The rats in Group 4 were pretreated with an intraperitoneal injection of 15 mg/kg/day ebselen 60 min before each CP treatment. Ovarian tissue malondialdehyde (MDA), total nitric oxide (NOx), glutathione (GSH), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and catalase levels, as well as histopathological damage scores (HDSs) and serum antimullerian hormone (AMH) levels, were assessed. Cu/Zn-SOD and GSH levels were significantly higher, and MDA and NOx levels significantly lower, in Group 4 than in Groups 2 and 3. Pretreatment with ebselen significantly improved serum AMH levels, relative to Groups 2 and 3. Additionally, HDS values were significantly lower in Group 4 than in Groups 2 and 3. Our results from using an experimental rat model of CP chemotherapy suggest that ebselen use may ameliorate ovarian damage by preventing oxidative injury.

Circulating gonadotropins and ovarian adiponectin system are modulated by acupuncture independently of sex steroid or β-adrenergic action in a female hyperandrogenic rat model of polycystic ovary syndrome.

PubMed

Maliqueo, Manuel; Benrick, Anna; Alvi, Asif; Johansson, Julia; Sun, Miao; Labrie, Fernand; Ohlsson, Claes; Stener-Victorin, Elisabet

2015-09-05

Acupuncture with combined manual and low-frequency electrical stimulation, or electroacupuncture (EA), reduces endocrine and reproductive dysfunction in women with polycystic ovary syndrome (PCOS), likely by modulating sympathetic nerve activity or sex steroid synthesis. To test this hypothesis, we induced PCOS in rats by prepubertal implantation of continuous-release letrozole pellets (200 µg/day) or vehicle. Six weeks later, rats were treated for 5-6 weeks with low-frequency EA 5 days/week, subcutaneous injection of 17β-estradiol (2.0 µg) every fourth day, or a β-adrenergic blocker (propranolol hydrochloride, 0.1 mg/kg) 5 days/week. Letrozole controls were handled without needle insertion or injected with sesame oil every fourth day. Estrous cyclicity, ovarian morphology, sex steroids, gonadotropins, insulin-like growth factor I, bone mineral density, and gene and protein expression in ovarian tissue were measured. Low-frequency EA induced estrous-cycle changes, decreased high levels of circulating luteinizing hormone (LH) and the LH/follicle-stimulating hormone (FSH) ratio, decreased high ovarian gene expression of adiponectin receptor 2, and increased expression of adiponectin receptor 2 protein and phosphorylation of ERK1/2. EA also increased cortical bone mineral density. Propranolol decreased ovarian expression of Foxo3, Srd5a1, and Hif1a. Estradiol decreased circulating LH, induced estrous cycle changes, and decreased ovarian expression of Adipor1, Foxo3, and Pik3r1. Further, total bone mineral density was higher in the letrozole-estradiol group. Thus, EA modulates the circulating gonadotropin levels independently of sex steroids or β-adrenergic action and affects the expression of ovarian adiponectin system. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The regulatory effect of Genistein on granulosa cell in ovary of rat with PCOS through Bcl-2 and Bax signaling pathways.

PubMed

Chi, Xiao-Xing; Zhang, Tao; Chu, Xiao-Li; Zhen, Jing-Long; Zhang, Dong-Jie

2018-06-22

The effect of genistein on Bcl-2 and Bax protein expression in the ovarian tissue of rats with polycystic ovarian syndrome (PCOS) was evaluated. Sixty rats were divided into six groups. Rats in the Dose group received genistein at a concentration of either 5 (L-gen), 10 (M-Gen) or 20 (H-Gen) mg per kg of body weight per day. The expression of Bcl-2 mRNA and Bax mRNA was determined by in situ hybridization. Bcl-2 and Bax protein concentration was quantified by ELISA. The results showed that the expression of Bcl-2 mRNA and Bcl-2 protein was significantly higher in the high genistein Dose group (H-Gen) when compared to the Model group (MG) (P<0.05). Genistein induced higher expression of the Bcl-2 gene at the transcriptional and translational level. Treatment with genistein resulted in an improvement of ovarian function with Bcl-2 expression being enhanced and Bax expression being suppressed. These alterations may be due to the structural and functional modifications that take place in these cells, and could be related to apoptotic changes that occur in rats with PCOS.

Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats

PubMed Central

Zonta, Yohan Ricci; Martinez, Marcelo; Camargo, Isabel Cristina C.; Domeniconi, Raquel F.; Lupi Júnior, Luiz Antonio; Pinheiro, Patricia Fernanda F.; Reiter, Russel J.; Martinez, Francisco Eduardo; Chuffa, Luiz Gustavo A.

2017-01-01

Angiogenesis is a hallmark of ovarian cancer (OC); the ingrowth of blood vessels promotes rapid cell growth and the associated metastasis. Melatonin is a well-characterized indoleamine that possesses important anti-angiogenic properties in a set of aggressive solid tumors. Herein, we evaluated the role of melatonin therapy on the angiogenic signaling pathway in OC of an ethanol-preferring rat model that mimics the same pathophysiological conditions occurring in women. OC was chemically induced with a single injection of 7,12-dimethylbenz(a)anthracene (DMBA) under the ovarian bursa. After the rats developed serous papillary OC, half of the animals received intraperitoneal injections of melatonin (200 µg/100 g body weight/day) for 60 days. Melatonin-treated animals showed a significant reduction in OC size and microvessel density. Serum levels of melatonin were higher following therapy, and the expression of its receptor MT1 was significantly increased in OC-bearing rats, regardless of ethanol intake. TGFβ1, a transforming growth factor-beta1, was reduced only after melatonin treatment. Importantly, vascular endothelial growth factor (VEGF) was severely reduced after melatonin therapy in animals given or not given ethanol. Conversely, the levels of VEGF receptor 1 (VEGFR1) was diminished after ethanol consumption, regardless of melatonin therapy, and VEGFR2 was only reduced following melatonin. Hypoxia-inducible factor (HIF)-1α was augmented with ethanol consumption, and, notably, melatonin significantly reduced their levels. Collectively, our results suggest that melatonin attenuates angiogenesis in OC in an animal model of ethanol consumption; this provides a possible complementary therapeutic opportunity for concurrent OC chemotherapy. PMID:28398226

Angiotensin II type 2 receptor stimulation improves fatty acid ovarian uptake and hyperandrogenemia in an obese rat model of polycystic ovary syndrome.

PubMed

Leblanc, Samuel; Battista, Marie-Claude; Noll, Christophe; Hallberg, Anders; Gallo-Payet, Nicole; Carpentier, André C; Vine, Donna F; Baillargeon, Jean-Patrice

2014-09-01

Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 μU/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g·min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km (P = .009), which were strongly correlated together in all PCOS/cp rats (ρ = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.

Effect of hypothyroidism on the hypothalamic-pituitary-ovarian axis and reproductive function of pregnant rats.

PubMed

Sun, Jianran; Hui, Cancan; Xia, Tongjia; Xu, Min; Deng, Datong; Pan, Faming; Wang, Youmin

2018-05-24

This study aimed to detect changes in hormone levels in the hypothalamic-pituitary-ovarian axis in Sprague-Dawley (SD) rats with hypothyroidism, and identify differences in the pregnancy and abortion rates of female adult rats. The potential role of gonadotropin releasing hormone (GnRH) as the link between the hypothalamic-pituitary-ovarian axis and reproductive function regulated by thyroid hormones was also investigated. Female SD rats (n = 136) were causally classified into two groups: the normal-drinking-water group (n = 60) and the 0.05% propylthiouracil-drinking-water group (PTU 2 mg/kg/day, n = 76) to establish an adult rat model of hypothyroidism (6 weeks). Female and male rats at a ratio of 1:2 were used to establish a hypothyroidism pregnancy model. GnRH mRNA and GnRH receptor (GnRHR) expression in rats was detected using real time quantitative PCR(qRT-PCR) and immunohistochemistry, respectively. The abortion rate differed significantly between the hypothyroidism pregnancy group and the normal pregnancy group (P < 0.05). No significant differences were found in the distribution of the GnRHR among the five nuclei (hypothalamic arcuate nucleus, hypothalamic ventromedial nucleus, hypothalamic anterior nucleus, paraventricular nucleus of the hypothalamus, and ventral premammillary nucleus) of the hypothalamus and ovary (P > 0.05). Hypothyroidism had no significant effect on GnRH mRNA expression in the hypothalamic-pituitary-ovarian axis in the four groups (normal control group, normal pregnancy group, hypothyroidism pregnancy group, and hypothyroidism group) (P > 0.05). Hypothyroidism had an adverse impact on pregnancy in rats and may affect the distribution of pituitary GnRHR, whereas it did not obviously affect the distribution of GnRHR in the nuclei of the hypothalamus and ovary. Hypothyroidism had no effect on GnRH mRNA expression.

Effects of 4-Vinylcyclohexene Diepoxide on Peripubertal and Adult Sprague–Dawley Rats: Ovarian, Clinical, and Pathologic Outcomes

PubMed Central

Muhammad, F Salih; Goode, Amanda K; Kock, Nancy D; Arifin, Esther A; Cline, J Mark; Adams, Michael R; Hoyer, Patricia B; Christian, Patricia J; Isom, Scott; Kaplan, Jay R; Appt, Susan E

2009-01-01

Young rats treated daily with intraperitoneal 4-vinylcyclohexene diepoxide (VCD) undergo selective destruction of primordial follicles, resulting in gradual ovarian failure resembling the menopausal transition in women. To determine whether VCD has similar effects on ovaries of older rats, adult and peripubertal Sprague–Dawley rats were injected intraperitoneally daily for 30 d with vehicle or VCD at 40 or 80 mg/kg. Body weight, food intake, complete blood counts, and markers of liver injury and renal function were measured during VCD treatment. Complete gross necropsy and microscopic observations were performed on day 31, and ovarian follicles were counted. At 80 mg/kg, VCD destroyed primordial and primary follicles to a similar extent in both adult and peripubertal animals, although adult rats likely started with fewer follicles and therefore approached follicle depletion. Treatment with VCD did not affect body weight, but food intake was reduced in both adult and peripubertal rats treated with 80 mg/kg VCD. Adult rats treated with 80 mg/kg VCD had neutrophilia and increased BUN and creatinine; in addition, 4 of these rats were euthanized on days 25 or 26 due to peritonitis. VCD treatment did not increase alanine aminotransferase levels, a marker of liver injury, although the 80-mg/kg dose increased liver weights. In conclusion, VCD effectively destroys small preantral follicles in adult Sprague–Dawley rats, making them a suitable model of the menopausal transition of women. However, because adult rats were more sensitive to the irritant properties of VCD, the use of a lower dose should be considered. PMID:19295054

Effects of Thyroid Dysfunction on Reproductive Hormones in Female Rats.

PubMed

Liu, Juan; Guo, Meng; Hu, Xusong; Weng, Xuechun; Tian, Ye; Xu, Kaili; Heng, Dai; Liu, Wenbo; Ding, Yu; Yang, Yanzhou; Zhang, Cheng

2018-05-10

Thyroid hormones (THs) play a critical role in the development of ovarian cells. Although the effects of THs on female reproduction are of great interest, the mechanism remains unclear. We investigated the effects of TH dysregulation on reproductive hormones in rats. Propylthiouracil (PTU) and L-thyroxine were administered to rats to induce hypo- and hyper-thyroidism, respectively, and the reproductive hormone profiles were analyzed by radioimmunoassay. Ovarian histology was evaluated with H&E staining, and gene protein level or mRNA content was analyzed by western blotting or RT-PCR. The serum levels of gonadotropin releasing hormone (GnRH) and follicle stimulating hormone (FSH) in both rat models were significantly decreased on day 21, although there were no significant changes at earlier time points. There were no significant differences in luteinizing hormone (LH) or progesterone levels between the treatment and the control groups. Both PTU and L-thyroxine treatments downregulated estradiol concentrations; however, the serum testosterone level was increased only in hypothyroid rats at day 21. In addition, the expression levels of FSH receptor, cholesterol side-chain cleavage enzyme (P450scc), and steroidogenic acute regulatory protein were decreased in both rat models. Moreover, the onset of puberty was significantly delayed in the hypothyroid group. These results provide evidence that TH dysregulation alters reproductive hormone profiles, and that the initiation of the estrous cycle is postponed in hypothyroidism.

Female Reproductive Aging Is Master-Planned at the Level of Ovary

PubMed Central

Banerjee, Sayani; Banerjee, Sutapa; Saraswat, Ghungroo; Bandyopadhyay, Soma Aditya; Kabir, Syed N.

2014-01-01

The ovary receives a finite pool of follicles during fetal life. Atresia remains the major form of follicular expenditure at all stages since development of ovary. The follicular reserve, however, declines at an exponential rate leading to accelerated rate of decay during the years preceding menopause. We examined if diminished follicle reserve that characterizes ovarian aging impacts the attrition rate. Premature ovarian aging was induced in rats by intra-embryonic injection of galactosyltransferase-antibody on embryonic day 10. On post-natal day 35 of the female litters, either a wedge of fat (sham control) or a wild type ovary collected from 25-day old control rats, was transplanted under the ovarian bursa in both sides. Follicular growth and atresia, and ovarian microenvironment were evaluated in the follicle-deficient host ovary and transplanted ovary by real time RT-PCR analysis of growth differentiation factor-9, bone morphogenetic protein 15, and kit ligand, biochemical evaluation of ovarian lipid peroxidation, superoxide dismutase (SOD) and catalase activity, and western blot analysis of ovarian pro- and anti-apoptotic factors including p53, bax, bcl2, and caspase 3. Results demonstrated that the rate of follicular atresia, which was highly preponderant in the follicle-deficient ovary of the sham-operated group, was significantly prevented in the presence of the transplanted ovary. As against the follicle-deficient ovary of the sham-operated group, the follicle-deficient host ovary as well as the transplanted ovary in the ovary-transplanted group exhibited stimulated follicle growth with increased expression of anti-apoptotic factors and down regulation of pro-apoptotic factors. Both the host and transplanted ovaries also had significantly lower rate of lipid peroxidation with increased SOD and catalase activity. We conclude that the declining follicular reserve is perhaps the immediate thrust that increases the rate of follicle depletion during the final phase of ovarian life when the follicle reserve wanes below certain threshold size. PMID:24788203

Inhibition of cyclooxygenase-2 (COX-2) by meloxicam decreases the incidence of ovarian hyperstimulation syndrome in a rat model.

PubMed

Quintana, Ramiro; Kopcow, Laura; Marconi, Guillermo; Young, Edgardo; Yovanovich, Carola; Paz, Dante A

2008-10-01

To investigate the effects of selective cyclooxygenase-2 (COX-2) inhibition on the ovarian hyperstimulation syndrome (OHSS) in an experimental model. Controlled laboratory study. University-affiliated fertility center. Female Wistar rats. Female Wistar rats (22 days old) were divided into four groups: group 1 (control group; n = 10) received 0.1 mL of intraperitoneal (IP) saline from days 22-26; group 2 (mild-stimulated group; n = 10) received 10 IU of pregnant mare serum gonadotropin (PMSG) on day 24 and 10 IU of hCG 48 hours later (day 26); group 3 (OHSS group; n = 10) was given 10 IU of PMSG for 4 consecutive days from day 22 and 30 IU hCG on the fifth day to induce OHSS; group 4 was treated the same as group 3, but received 2 muL (15 mg/mL) of meloxicam 2 hours before the PMSG injection for 4 consecutive days, and 2 hours before the hCG injection on the fifth day. All groups were killed on day 26. Number of antral and luteinized follicles, ovarian weight, semiquantitative vascular endothelial growth factor (VEGF) and COX-2 immunohistochemistry. There were no differences in the ovarian weight between groups 1 and 2. Group 3 showed significantly increased ovarian weight that was suppressed, in group 4, by meloxicam. There was no difference in the number of antral follicles among the four groups. In the mild-stimulated and OHSS groups, the granulosa cells (GC) of preovulatory follicles and the stromal cells showed intense VEGF immunoreactivity. The ovaries from the meloxicam-treated group showed less immunoreactivity than the OHSS group, indicating diminished VEGF expression associated with meloxicam treatment. Group 3 (OHSS group) showed increased COX-2 immunoreactivity that was diminished in the meloxicam-treated group. Meloxicam treatment did not affect the hormone-induced increase in serum E(2) levels seen in OHSS rats. Our results in a rat model suggest that meloxicam has a beneficial effect on OHSS by reducing the increases in ovarian weight and VEGF expression associated with OHSS. These effects may be mediated by the COX-2 inhibitory capacity of meloxicam.

Expression of SIRT1 in the ovaries of rats with polycystic ovary syndrome before and after therapeutic intervention with exenatide

PubMed Central

Tao, Xin; Zhang, Xiao; Ge, Shu-Qi; Zhang, Er-Hong; Zhang, Bin

2015-01-01

Aim: To investigate the expression of silent information regulator 1 (SIRT1) in rats with polycystic ovary syndrome (PCOS) and its alteration after exenatide treatment. Methods: PCOS rat model was established by dehydroepiandrosterone induction. The animals were randomly divided into exenatide treatment group (EX group, n = 10), metformin treatment group (MF group, n = 10), PCOS group (PCOS group, n = 9) and normal control group (NC group, n = 10). Histological changes of the ovarian tissues were examined by HE staining. SIRT1 expression in the ovarian tissue was detected by RT-PCR and immunohistochemistry. Results: Rats in the PCOS group lost their estrous cycle. Histological observation of the ovary showed saccular dilatation of the follicle, decreased number of corpora lutea, fewer layers of granulosa cells aligned loosely, and thickened layer of theca cells. The changes in reproductive hormones and the development of insulin resistance suggested the successful establishment of the animal models. Immunohistochemistry and Q-PCR detected the mRNA and protein expressions of SIRT1 in the ovary tissues of rats in the normal control group. The SIRT1 expression was significantly lower in PCOS group than in control group (P < 0.05); after drug intervention, the SIRT1 expression significantly increased in EX and MF groups (compared with the PCOS group), whereas no significant difference was noted between the EX group and MF group. Conclusions: The SIRT1 expression in the ovary tissue decreases in PCOS rats (compare with the normal rats) but can be up-regulated after Ex or MF treatment. These drugs may affect the process and development of PCOS by regulating the SIRT1 expression. Exenatide may be therapeutic for PCOS by up-regulating the SITR1 expression. PMID:26339397

Expression of SIRT1 in the ovaries of rats with polycystic ovary syndrome before and after therapeutic intervention with exenatide.

PubMed

Tao, Xin; Zhang, Xiao; Ge, Shu-Qi; Zhang, Er-Hong; Zhang, Bin

2015-01-01

To investigate the expression of silent information regulator 1 (SIRT1) in rats with polycystic ovary syndrome (PCOS) and its alteration after exenatide treatment. PCOS rat model was established by dehydroepiandrosterone induction. The animals were randomly divided into exenatide treatment group (EX group, n = 10), metformin treatment group (MF group, n = 10), PCOS group (PCOS group, n = 9) and normal control group (NC group, n = 10). Histological changes of the ovarian tissues were examined by HE staining. SIRT1 expression in the ovarian tissue was detected by RT-PCR and immunohistochemistry. Rats in the PCOS group lost their estrous cycle. Histological observation of the ovary showed saccular dilatation of the follicle, decreased number of corpora lutea, fewer layers of granulosa cells aligned loosely, and thickened layer of theca cells. The changes in reproductive hormones and the development of insulin resistance suggested the successful establishment of the animal models. Immunohistochemistry and Q-PCR detected the mRNA and protein expressions of SIRT1 in the ovary tissues of rats in the normal control group. The SIRT1 expression was significantly lower in PCOS group than in control group (P < 0.05); after drug intervention, the SIRT1 expression significantly increased in EX and MF groups (compared with the PCOS group), whereas no significant difference was noted between the EX group and MF group. The SIRT1 expression in the ovary tissue decreases in PCOS rats (compare with the normal rats) but can be up-regulated after Ex or MF treatment. These drugs may affect the process and development of PCOS by regulating the SIRT1 expression. Exenatide may be therapeutic for PCOS by up-regulating the SITR1 expression.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aguilera, G.; Millan, M.A.; Harwood, J.P.

The presence of components of the renin-angiotensin system in ovaries and testes suggests that angiotensin II (AII) is involved in gonadal function, and thus we sought to characterize receptors for AII in rat and primate gonads. In the testes, autoradiographic studies showed receptors in the interstitium in all species. In rat interstitial cells fractionated by Percoll gradient, AII receptors coincided with hCG receptors indicating that AII receptors are located on the Leydig cells. In Leydig cells and membranes from rat and rhesus monkey prepuberal testes, AII receptors were specific for AII analogues and of high affinity (Kd=nM). During development, AIImore » receptor content in rat testes decreases with age parallel to a fall in the ratio of interstitial to tubular tissue. In the ovary, the distribution of AII receptors was dependent on the stage of development, being high in the germinal epithelium and stromal tissue between five and 15 days, and becoming localized in secondary follicles in 20-and 40-day-old rats. No binding was found in primordial or primary follicles. In rhesus monkey ovary, AII receptors were higher in stromal tissue and lower in granulosa and luteal cells of the follicles. Characterization of the binding in rat and monkey ovarian membranes showed a single class of sites with a Kd in the nmol/L range and specificity similar to that of the adrenal glomerulosa and testicular AII receptors. Receptors for AII were also present in membrane fractions from PMSG/hCG primed rat ovaries. Infusion of AII (25 ng/min) or captopril (1.4 micrograms/min) during the PMSG/hCG induction period had no effect on ovarian weight or AII receptor concentration in the ovaries.« less

Low-Dose Oral Sirolimus and the Risk of Menstrual-Cycle Disturbances and Ovarian Cysts: Analysis of the Randomized Controlled SUISSE ADPKD Trial

PubMed Central

Braun, Matthias; Young, James; Reiner, Cäcilia S.; Poster, Diane; Krauer, Fabienne; Kistler, Andreas D.; Kristanto, Paulus; Wang, Xueqi; Liu, Yang; Loffing, Johannes; Andreisek, Gustav; von Eckardstein, Arnold; Senn, Oliver; Wüthrich, Rudolf P.; Serra, Andreas L.

2012-01-01

Sirolimus has been approved for clinical use in non proliferative and proliferative disorders. It inhibits the mammalian target of rapamycin (mTOR) signaling pathway which is also known to regulate ovarian morphology and function. Preliminary observational data suggest the potential for ovarian toxicity but this issue has not been studied in randomized controlled trials. We reviewed the self-reported occurrence of menstrual cycle disturbances and the appearance of ovarian cysts post hoc in an open label randomized controlled phase II trial conducted at the University Hospital Zürich between March 2006 and March 2010. Adult females with autosomal dominant polycystic kidney disease, an inherited kidney disease not known to affect ovarian morphology and function, were treated with 1.3 to 1.5 mg sirolimus per day for a median of 19 months (N = 21) or standard care (N = 18). Sirolimus increased the risk of both oligoamenorrhea (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.1 to 29) and ovarian cysts (HR 4.4, CI 1.1 to 26); one patient was cystectomized five months after starting treatment with sirolimus. We also studied mechanisms of sirolimus-associated ovarian toxicity in rats. Sirolimus amplified signaling in rat ovarian follicles through the pro-proliferative phosphatidylinositol 3-kinase pathway. Low dose oral sirolimus increases the risk of menstrual cycle disturbances and ovarian cysts and monitoring of sirolimus-associated ovarian toxicity is warranted and might guide clinical practice with mammalian target of rapamycin inhibitors. Trial Registration ClinicalTrials.gov NCT00346918 PMID:23071528

The expression of TP53 pathway-related proteins in ovarian carcinoma transplanted subcutaneously in nude mice.

PubMed

Zhang, S-R; Li, D-B; Xue, J-W

2018-03-01

Given the important functions of TP53 pathway in various biological processes, this study aimed to investigate the expression of TP53 pathway-related proteins in ovarian carcinoma transplanted subcutaneously in nude mice with and without the presence of p53 inhibitor and to explore possible roles of p53 in the development of ovarian cancer. Thirty BALB/c-nu female nude mice were randomly divided into model group, control group and p53 inhibitor group (Pftα group). There were 10 rats in each group. The nude mice were subcutaneously inoculated with human ovarian cancer cell line SKOV3, and the tumor growth was observed. Morphological changes of tumor tissue were observed by hematoxylin and eosin (HE) staining. The mRNA and protein levels of TP53 pathway related factors-p53, p21 and mouse double minute 2 homolog (MDM2) were detected by RT-PCR and Western blot. p53 inhibitor can increase the growth rate of subcutaneously transplanted tumor in nude mice. p53 inhibitor could decrease the expression of p53 and p21 at both mRNA and protein levels and increase the expression of MDM2 at both mRNA and protein levels in ovarian carcinoma transplanted subcutaneously in nude mice. TP53 pathway may play pivotal roles in the development of ovarian cancer and TP53 pathway may be a new target for the treatment of ovarian cancer.

Benefits of nanoencapsulation for the hypercin-mediated photodetection of ovarian micrometastases.

PubMed

Zeisser-Labouèbe, Magali; Delie, Florence; Gurny, Robert; Lange, Norbert

2009-02-01

The high recurrence and lethality of ovarian cancer at advanced stages is problematic, especially due to the development of numerous micrometastases scattered throughout the abdominal cavity. Fluorescence photodetection (PD) used in combination with surgical resection of malignant tissues has been suggested to improve recovery. Based on promising in vivo results for the detection of bladder cancer, hypericin (Hy), a natural photosensitizer (PS), stands as a good candidate for the photodetection of ovarian cancer. However, due to its hydrophobicity, systemic administration of Hy is problematic. Polymeric nanoparticles (NPs) help to overcome these delivery and stability problems and enable intravenous administration of Hy. In this study, Hy-loaded NPs of polylactic acid were produced with the following properties: (i) mean size of 268 nm, (ii) negative zeta potential, (iii) low residual surfactant and (iv) drug loading of 3.7 % (w/w). The potential of hypericin-loaded nanoparticles for the fluorescence photodetection of ovarian metastases in Fischer 344 rats bearing ovarian tumours was compared to free drug. The selectivity of Hy administered with both formulations was assessed first by fluorescence endoscopy, and then quantified after tissue extraction. The results showed an improved selective accumulation of Hy in ovarian micrometastases when NPs were used.

Reproductive alterations in hyperinsulinemic but normoandrogenic MSG obese female rats.

PubMed

Gaspar, Renato Simões; Benevides, Renata Ohana Alves; Fontelles, João Lucas de Lima; Vale, Caroline Castro; França, Lucas Martins; Barros, Paulo de Tarso Silva; Paes, Antonio Marcus de Andrade

2016-05-01

Obesity and metabolic syndrome are the common causes of reproductive and fertility disorders in women. In particular, polycystic ovary syndrome, which is clinically characterized by hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology, has been increasingly associated with metabolic disorders. However, given the broad interplay between metabolic and reproductive functions, this remains a field of intense research. In this study, we investigated the effect of monosodium l-glutamate (MSG)-induced obesity on reproductive biology of female rats. Newborn female rats were subcutaneously injected with MSG (4g/kg/day) or equiosmolar saline (CTR) each 2 days up to postnatal day (pnd) 10. On pnd 60, estrous cycle was evaluated using vaginal smears twice a day for 15 days, which showed MSG rats to be oligocyclic. Thereafter, animals were killed on estrous phase for blood and tissue collection. MSG rats had increased body mass, accumulation of retroperitoneal and visceral fat pads, and visceral adipocyte hypertrophy compared with CTR rats. MSG rats were also dyslipidemic and hyperinsulinemic but were normoglycemic and normoandrogenic. Ovarian morphology analysis showed that MSG rats had a two-fold decrease in oocyte count but a six-fold increase on ovarian follicular cysts, along with a higher number of total primordial and atretic follicles. Moreover, MSG rats had a four-fold increase in anti-Müllerian hormone immunohistochemical staining on antral follicles. Taken together, data presented here characterize MSG obesity as a unique model to study the metabolic pathways underlying reproductive disorders in the absence of overactivated hypothalamic-pituitary-gonadal axis. © 2016 Society for Endocrinology.

78 FR 8410 - Thiacloprid; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-06

...) were noted in dog, rat, and mouse studies. Increased prostate weight and prostatic hypertrophy were... acetylcholine receptors. In the neurotoxicity studies in rats, there was a reduction in motor and locomotor... uterine tumors in rats, thyroid follicular adenomas in rat and ovarian tumors in mice. A cancer slope...

Ovarian stimulation by exogenous gonadotrophins in fetal ethanol-exposed immature rats.

PubMed

Rudeen, P K; Hagaman, J

1988-08-15

Adult pregnant rats were given either an ad libitum liquid diet containing 5% ethanol, a pair fed liquid diet or an ad libitum diet of rat chow and water administered throughout pregnancy and during the nursing period. The female offspring received either pregnant mare's serum gonadotrophin (PMSG) or PMSG followed by human chorionic gonadotrophin (hCG) at 30 days of age. The ovaries of fetal ethanol-exposed animals responded greater to the exogenous gonadotrophins with enhanced ovarian weights, increased numbers of ova shed, greater numbers of corpora lutea and antral follicles, and higher serum progesterone levels than in animals exposed to the control diets during gestation.

Estrous cycle and ovarian changes in a rat mammary carcinogenesis model after irradiation, tamoxifen chemoprevention, and aging.

PubMed

Karim, Baktiar O; Landolfi, Jennifer A; Christian, Archie; Ricart-Arbona, Rodolfo; Qiu, Weiping; McAlonis, Melissa; Eyabi, Paul O; Khan, Khalid A; Dicello, John F; Mann, Jill F; Huso, David L

2003-10-01

Variation in the effects of selective estrogen receptor modulators (SERMs) on the estrous cycle and reproductive organs during aging could play an important role in the observed heterogeneity of tamoxifen chemoprevention efficacy against breast cancer. Of the 1,022 female Sprague Dawley rats enrolled in a long-term tamoxifen chemoprevention study, 87 were randomly chosen from four groups (irradiated, irradiated and tamoxifen treated, tamoxifen treated, and control). Vaginal smears were evaluated for determination of cycle stage, and vaginal pathologic changes. Correlation with the histologic features of reproductive tissues in 43 animals was made. More tamoxifen-treated (21.9%; 7/32) rats had irregular cycling than did control (9%; 3/23) rats. Ovarian granulosa cell hyperplasia was present in 50% (3/6) of tamoxifen-treated rats, and 20% (2/10) of control rats. Endometrial-type cells (ETCs) were present only in tamoxifen-treated (tamoxifen alone 6.25% [2/32]) and tamoxifen/ radiation-treated (28.6% [4/14]) rats. The modified Papanicolaou stain used here provided excellent morphologic detail for evaluating the estrous cycle in rodents. Tamoxifen altered vaginal cytologic and ovarian histologic features during aging. Results indicated that tamoxifen had direct and indirect effects on the reproductive tract, causing disturbance of the estrous cycle, shedding of ETCs, and promoting granulosa cell hyperplasia. Understanding of the heterogeneous response to tamoxifen chemoprevention during aging in rodents may provide important insights into the basis for tamoxifen chemoprevention failures in humans.

High-Frequency Electrical Modulation of the Superior Ovarian Nerve as a Treatment of Polycystic Ovary Syndrome in the Rat.

PubMed

Pikov, Victor; Sridhar, Arun; Lara, Hernan E

2018-01-01

The polycystic ovary syndrome (PCOS) is the most prevalent ovarian pathology in women, with excessive sympathetic activity in the superior ovarian nerve (SON) playing an important role in inducing the PCOS symptoms in the rats and humans. Our previous studies have shown that surgical transection of the SON can reverse the disease progression, prompting us to explore the effect of the kilohertz frequency alternating current (KHFAC) modulation as a method of reversible non-surgical suppression of the nerve activity in the rodent model of PCOS. 56 animals were randomly allocated to three groups: the Control group ( n = 18), the PCOS group ( n = 15), and the PCOS + KHFAC group ( n = 23). The physiological, anatomical, and biochemical parameters of ovarian function were evaluated during the progression of the experimentally-induced PCOS and during long-term KHFAC modulation applied for 2-3 weeks. The KHFAC modulation has been able to reverse the pathological changes in assessed PCOS parameters, namely the irregular or absent estrous cycling, formation of ovarian cysts, reduction in the number of corpora lutea, and ovarian norepinephrine concentration. The fertility capacity was similar in the PCOS and the PCOS + KHFAC groups, indicating the safety of KHFAC modulation approach. In summary, these results suggest that the KHFAC modulation approach of suppressing the SON activity could become a useful treatment modality for PCOS and potentially other pathological ovarian conditions.

ANP promotes proliferation and inhibits apoptosis of ovarian granulosa cells by NPRA/PGRMC1/EGFR complex and improves ovary functions of PCOS rats.

PubMed

Zheng, Qin; Li, Yulin; Zhang, Dandan; Cui, Xinyuan; Dai, Kuixing; Yang, Yu; Liu, Shuai; Tan, Jichun; Yan, Qiu

2017-10-26

Polycystic ovary syndrome (PCOS) is a complicated reproductive endocrine disease characterized by polycystic ovaries, hyperandrogenism and anovulation. It is one of the main causes of infertility. RU486 is an antagonist of progesterone receptor, and most commonly used as a contraceptive. However, whether RU486 is correlated with PCOS remains unclear. Atrial natriuretic peptide (ANP) is a small peptide with natriuretic and diuretic functions, and its availability to be used in PCOS treatment is unknown. Here, we showed that the serum ANP level was lower in PCOS patients than that in healthy women, and it was also decreased in the serum and ovarian tissues of RU486-induced PCOS rats compared with the control rats. We also found that RU486 inhibited the proliferation and promoted the apoptosis of human KGN ovarian granulosa cells by downregulating progesterone receptor membrane component 1 (PGRMC1). Meantime, ANP promoted the proliferation and inhibited the apoptosis of KGN cells through upregulating ANP receptor A (NPRA). The promotive effects of ANP on ovarian functions were mediated through the formation of an NPRA/PGRMC1/EGFR complex, which further activated MAPK/ERK signaling and transcription factor AP1. Moreover, ANP treatment reversed the PCOS symptoms, and improved the fertility of RU486-induced PCOS rats. Collectively, these findings highlight that RU486 is associated with the pathogenesis of PCOS, and ANP treatment may be a promising therapeutic option for PCOS.

ANP promotes proliferation and inhibits apoptosis of ovarian granulosa cells by NPRA/PGRMC1/EGFR complex and improves ovary functions of PCOS rats

PubMed Central

Zheng, Qin; Li, Yulin; Zhang, Dandan; Cui, Xinyuan; Dai, Kuixing; Yang, Yu; Liu, Shuai; Tan, Jichun; Yan, Qiu

2017-01-01

Polycystic ovary syndrome (PCOS) is a complicated reproductive endocrine disease characterized by polycystic ovaries, hyperandrogenism and anovulation. It is one of the main causes of infertility. RU486 is an antagonist of progesterone receptor, and most commonly used as a contraceptive. However, whether RU486 is correlated with PCOS remains unclear. Atrial natriuretic peptide (ANP) is a small peptide with natriuretic and diuretic functions, and its availability to be used in PCOS treatment is unknown. Here, we showed that the serum ANP level was lower in PCOS patients than that in healthy women, and it was also decreased in the serum and ovarian tissues of RU486-induced PCOS rats compared with the control rats. We also found that RU486 inhibited the proliferation and promoted the apoptosis of human KGN ovarian granulosa cells by downregulating progesterone receptor membrane component 1 (PGRMC1). Meantime, ANP promoted the proliferation and inhibited the apoptosis of KGN cells through upregulating ANP receptor A (NPRA). The promotive effects of ANP on ovarian functions were mediated through the formation of an NPRA/PGRMC1/EGFR complex, which further activated MAPK/ERK signaling and transcription factor AP1. Moreover, ANP treatment reversed the PCOS symptoms, and improved the fertility of RU486-induced PCOS rats. Collectively, these findings highlight that RU486 is associated with the pathogenesis of PCOS, and ANP treatment may be a promising therapeutic option for PCOS. PMID:29072679

Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR-G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6 μM) for 24 or 48 h. Cell viability was reduced (P < 0.05) after 48 h of exposure to 3 or 6more » μM PM. The NOR-G-OH DNA adduct was detected after 24 h of 6 μM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48 h by exposure to both PM concentrations. Phosphorylated H2AX (γH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, γH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response. - Highlights: • PM forms ovarian DNA adducts. • DNA damage marker γH2AX increased by PM exposure. • PM induces ovarian DNA double strand break repair.« less

A Postpartum Model in Rat: Behavioral and Gene Expression Changes Induced by Ovarian Steroid Deprivation

PubMed Central

Suda, Shiro; Segi-Nishida, Eri; Newton, Samuel S.; Duman, Ronald S.

2013-01-01

Background Postpartum depression (PPD) affects approximately 10% to 20% of women during the first 4 weeks of the postpartum period and is characterized by labile mood with prominent anxiety and irritability, insomnia,and depressive mood. During the postpartum period, elevated ovarian hormones abruptly decrease to the early follicular phase levels that are postulated to play a major role in triggering PPD. However, the underlying neurobiological mechanisms that contribute to PPD have not been determined. Methods In the present study, we examined the effect of ovarian steroids, administered at levels that occur during human pregnancy followed by rapid withdrawal to simulate postpartum conditions, on behavior and gene expression in the rat. Results The results of behavioral testing reveal that the hormone-simulated postpartum treatment results in the development of a phenotype relevant to PPD, including vulnerability for helplessness, increased anxiety, and aggression. Real-time quantitative polymerase chain reaction (PCR) demonstrated transient regulation of several genes, including Ca2+/calmodulin-dependent protein kinase II (CAMKII), serotonin transporter (SERT), myocyte enhancer factor 2A (MEF2A), brain-derived neurotrophic factor (BDNF), gamma-aminobutyric acid type A receptor α4 (GABAARA4), mothers against decapentaplegic homolog 4 (SMAD4), and aquaporin 4 (AQP4) that could underlie these behavioral effects. Conclusions These studies provide an improved understanding of the effects of withdrawal from high doses of ovarian hormones on behavior and gene expression changes in the brain that could contribute to the pathophysiology of PPD. PMID:18471802

High-fat diet exposure from pre-pubertal age induces polycystic ovary syndrome (PCOS) in rats.

PubMed

Patel, Roshni; Shah, Gaurang

2018-02-01

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, oligo-anovulation, polycystic ovaries and metabolic syndrome. Many researchers reported that PCOS often starts with menarche in adolescents. Presently available animal model focuses on ovarian but not metabolic features of PCOS. Therefore, we hypothesized that high-fat diet feeding to pre-pubertal female rats results in both reproductive and metabolic features of PCOS. Pre-pubertal female rats were divided into two groups: group I received normal pellet diet and group II received high-fat diet (HFD). In the letrozole study, adult female rats were divided into two groups: group I received 1% carboxy methyl cellulose and group II received 1 mg/kg letrozole orally. Oral glucose tolerance test, lipid profile, fasting glucose, insulin, estrus cycle, hormonal profile, ovary weight, luteinizing hormone (LH) receptor and follicle-stimulating hormone receptor expression were measured. Polycystic ovarian morphology was assessed through histopathological changes of ovary. Feeding of HFD gradually increase glucose intolerance and fasting insulin levels. Triglyceride level was higher in HFD study while total cholesterol level was higher in the letrozole study. Alteration in testosterone and estrogen levels was observed in both studies. LH receptor expression was upregulated only in HFD study. Histopathological changes like increase cystic follicle, diminished granulosa cell layer and thickened theca cell layer were observed in letrozole as well as HFD study. High-fat diet initiated at pre-puberty age in rats produces both metabolic disturbances and ovarian changes similar to that observed clinically in PCOS patients. Letrozole on the other hand induces change in ovarian structure and function. © 2018 Society for Reproduction and Fertility.

Antioxidant effect of erdosteine and lipoic acid in ovarian ischemia-reperfusion injury.

PubMed

Dokuyucu, R; Karateke, A; Gokce, H; Kurt, R K; Ozcan, O; Ozturk, S; Tas, Z A; Karateke, F; Duru, M

2014-12-01

To investigate the effects of erdosteine and alpha lipoic acid (ALA) in a rat model of ovarian ischaemia-reperfusion injury. Forty-eight female Wistar albino rats were separated, at random, into six groups of eight rats. The groups were classified as: sham, torsion, detorsion, detorsion+erdosteine 100mg/kg, detorsion+alpha lipoic acid (ALA) 100mg/kg, and detorsion+erdosteine+ALA. The investigators executing the biochemical and histological analyses were blinded to the randomization until the end of the study. The TOS (Total Oxidant Status) and OSI (Oxidative Stress Index) levels are higher in the Torsion and Detorsion groups when compared with the ones in the Sham group (p<0.05). Strong correlation was found between OSI and total histological score in the sham, torsion and detorsion groups (r=0.765, p<0.001). The mean levels of TOS and OSI in the rats that received erdosteine and/or ALA were significantly lower compared with the sham, torsion and detorsion groups (p<0.05). Mean TOS and mean OSI were lower in the detorsion+erdosteine+ALA group compared with the detorsion+erdosteine and detorsion+ALA groups (p<0.05). In comparison with the detorsion group, the numbers of primordial follicles (p=0.006) and primary follicles (p=0.036) were increased in the groups that received erdosteine and/or ALA. Erdosteine and ALA decreased ischaemia-reperfusion injury in an experimental rat ovarian torsion model; combination treatment had a greater effect than either agent alone. Treatment with erdosteine and/or ALA was found to preserve the loss of reproductive capacity normally observed after ovarian torsion. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Morphine administration during low ovarian hormone stage results in transient over expression of fear memories in females.

PubMed

Perez-Torres, Emily M; Ramos-Ortolaza, Dinah L; Morales, Roberto; Santini, Edwin; Rios-Ruiz, Efrain J; Torres-Reveron, Annelyn

2015-01-01

Acute exposure to morphine after a traumatic event reduces trauma related symptoms in humans and conditioned fear expression in male rats. We aimed to determine whether acute administration of morphine alters consolidation of fear learning and extinction. Male and female rats in proestrus and metaestrus (high and low ovarian hormones respectively) underwent fear conditioning and received saline or morphine (2.5 mg/kg s.c.). The next day they underwent extinction. Results showed increased freezing during extinction only in the morphine metaestrus group while morphine did not affect males or proestrus females. Recall of extinction was similar on all groups. On a second experiment, a subset of rats conditioned during metaestrus was administered morphine prior to extinction producing no effects. We then measured mu opioid receptor (MOR) expression in the amygdala and periaqueductal gray (PAG) at the end of extinction (day 2). In males and proestrus females, morphine caused an increase in MOR in the amygdala but no in the PAG. In metaestrus females, morphine did not change MOR expression in either structure. These data suggests that ovarian hormones may interact with MORs in the amygdala to transiently alter memory consolidation. Morphine given after trauma to females with low ovarian hormones might increase the recall of fear responses, making recovery harder.

[Morphological recovery in the polycystic ovaries of persistent-estrus rats induced by continuous illumination (author's transl)].

PubMed

Sawada, T; Kosaka, T

1981-10-01

When mature female rats having been showing at least 2 consecutive 4-day estrous cycles were raised in a room with continuous lighting (LL), their vaginal smear pattern became irregular by 7 to 9 days. and a persistent-estrus (P-E) appeared around 25 to 75 days of exposure. Ovaries from LL-exposed rats showing irregular cycles or P-E had signs of cystic follicles and anovulatory polycystic follicles, respectively. When P-E rats were placed again under the light-dark cycling condition (14L: 10D; Lights on 05: 00 h), the regular 4-day cycles were recovered soon and ovarian structures became normal after about 5 cycles. In P-E rats injected i.v. with 10 microgram LH/day at 4-day intervals under the LL condition, the regular estrous cycle reappeared and ovarian structures became normal after 5 administrations. These results suggest that the polycystic ovary of P-E rat induced by LL is reversible with cyclic stimulation by LH.

Environmentally Induced Epigenetic Transgenerational Inheritance of Ovarian Disease

PubMed Central

Nilsson, Eric; Larsen, Ginger; Manikkam, Mohan; Guerrero-Bosagna, Carlos; Savenkova, Marina I.; Skinner, Michael K.

2012-01-01

The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling primary ovarian insufficiency (POI). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states was induced by all the different classes of environmental compounds, suggesting a role of environmental epigenetics in ovarian disease etiology. PMID:22570695

Does Omegaven have beneficial effects on a rat model of ovarian ischemia/reperfusion?

PubMed

Gungor, Ayse N Cakir; Turkon, Hakan; Albayrak, Aynur; Ovali, Mehmet; Islimye, Mine; Gencer, Meryem; Hacivelioglu, Servet; Cevizci, Sibel; Cesur, Ismet; Cosar, Emine

2014-10-01

The beneficial effects of omega-3 fatty acids on an intestinal ischemia/reperfusion (I/R) model was shown previously. Therefore, we aimed to examine the potential beneficial effects of parenteral omega-3 fatty acids, a safe and inexpensive product, on a rat model of ovarian I/R. A group of 39 rats was divided into six groups. Group 1 (Sham Group; n=6) underwent two laparotomies with a 3-h interval and their ovaries were removed 3h later. Group 2 (torsion-detorsion Group; n=7) had their ovaries torsioned clockwise and fixed at 720°; 3h later a detorsion operation was done and after another 3h, their ovaries were removed. Group 3 (n=7) and Group 4 (n=7) received the same treatment as Group 2; however, half an hour prior to detorsion, these rats received Omegaven at 1mL/kg and 5mL/kg, respectively. Group 5 (n=6) and Group 6 (n=6) received the same treatment as Group 1; however, half an hour prior to the second laparotomy, these rats received Omegaven at 1mL/kg and 5mL/kg, respectively. One ovary from each rat was evaluated histologically by hematoxylin and eosin (H&E) staining and the other ovary was homogenized and evaluated for total oxidant status (TOS), total antioxidant status (TAS) and oxidative stress index (OSI). While we failed to show any significant relationship among groups in oxidative parameters, there was a significant worsening in the torsion-detorsion group in histological evaluation. High Omegaven doses, but not low doses, improved tissue injury scores of torsioned and detorsioned ovaries to the levels observed in the control group. Omegaven improves the detrimental effects of ovarian I/R when used in sufficient doses. Its effects and dose adjustment on women with ovarian torsion must be investigated by further studies. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Examination of the antioxidant effects of pre-HSG melatonin use on ovarian surface epithelium in rats: An experimental study.

PubMed

Yılmaz, Esra Saygılı; Sapmaz, Tansel; Kazgan, Halil; Yildiz, Şule Menziletoglu; Kocamaz, Derya; Akpolat, Nusret; Sapmaz, Ekrem

2018-06-28

There is no study of whether the dysplastic changes in the ovarian surface epithelium of X-ray-exposed rats during hysterosalpingography (HSG) decrease or not with the use of Lipiodol and melatonin given both intraperitoneally (i.p.) and into the suspensorium ovarii. We investigated the restorative effects of melatonin and Lipiodol administration during the HSG procedure on the dysplastic changes in the ovarian surface epithelium of X-ray-exposed rats. A total of 50 Wistar rats with regular estrous cycles were randomly divided into 5 groups. Group 1 was the control group. In other groups, X-ray was applied (group 2), 0.1 mL Lipiodol was applied to each uterine horn (group 3), 20 mg/kg intraperitoneal melatonin application was followed by 0.1 mL Lipiodol administration to each uterine horn after 15 min (group 4), and 20 mg/kg melatonin was administered to the ligamentum suspensorium ovarii, followed by 0.1 mL Lipiodol application to each uterine horn after 15 min (group 5). The rats in groups 2-5 were exposed to whole body radiation 3 times. After 3 h, the abdomens of all rats were reopened and left oophorectomy was performed. The presence of nucleoli and mitosis values were found similar among the groups. All other parameters were significantly higher in group 2 compared to other groups, except for the presence of nucleoli and mitosis values (p < 0.05). The presence of hyperchromasia and the total score were found to be the highest in group 2, followed by group 3, when compared to other groups (p < 0.05). It was detected that the detrimental effects of X-ray exposure diminished with Lipiodol use, and were further reduced by the use of melatonin in combination. We suggest that the use of melatonin and Lipiodol during HSG may prevent the carcinogenic changes exerted by radiation on the ovarian surface epithelium.

Hormone therapy alters the composition of the vaginal microflora in ovariectomized rats.

PubMed

Bezirtzoglou, E; Voidarou, Ch; Papadaki, A; Tsiotsias, A; Kotsovolou, O; Konstandi, M

2008-05-01

The aim of the present study was to evaluate the alterations that may take place in the bacterial genital tract flora in the absence of ovarian hormones. The role of hormone replacement therapy was also assessed. For this purpose, various bacteria were identified from the vaginal flora of ovariectomized and sham operated female rats, following the Bergey's manual criteria. The data of this study showed that substantial differences exist in the vaginal bacterial microflora between ovariectomized and normal cyclic rats. Ovariectomy was associated with a lower total bacterial load that may be due mainly to the absence of Lactobacillus. Anaerobic bacteria were also absent. Streptococcus and Enterococcus were also not favored in an environment lacking the ovarian hormones. In contrast, C. perfringens, Bacteroides, S. epidermidis, and S. aureus were detected in high numbers in ovariectomized rats. In terms of the impact of hormone replacement therapy on vaginal flora, only estradiol (EE2) restored Lactobacillus levels in ovariectomized rats, whereas all hormonal schemes used brought Streptococcus, Clostridium lec (-), and C. perfringens, the spore and vegetative forms, close to those detected in normal cyclic female rats. In conclusion, ovarian hormones appeared to be regulatory factors that favor the presence of a broad variety of bacteria, which are members of the normal genital tract flora. On the other hand, ovariectomy modifies the vaginal microbial profile, and hormone replacement therapy based mainly on schemes containing EE2 could alleviate this disturbance.

Electron spin resonance studies of the ovary of the rat

NASA Astrophysics Data System (ADS)

Andersen, Roy S.; Curtis, Joseph C.

1988-11-01

Electron spin resonance spectra of rat ovaries, isolated ovarian compartments, and ovarian subcellular fractions were compared with spectra of rat adrenals. Rat ovaries were found to exhibit ESR signals similar to those previously described in studies of mammalian adrenal and testis. Observations were made at 113 K in an anaerobic environment. ESR signals of the low-spin ferric cytochrome P-450, the non-heme protein ferredoxin, and the non-heme glycoprotein transferrin were consistently observed in whole ovaries. The first two signals were detected in mitochondrial fractions isolated from ovaries, while only cytochrome P-450 was detected in microsomal fractions. Signals from ferredoxin and cytochrome P-450 were also consistently observed in both whole adrenals and adrenal mitochondrial fractions. However, in the microsomal fraction only cytochrome P-450 was present. The g values for the cytochrome P-450 and ferredoxin signals found in this study of ovaries were identical to those previously reported and also found in this study in spectra of rat adrenals. The concentration of ferredoxin per milligram wet mass in rat ovaries appears to be only one-sixth of that in the rat adrenal. The concentration of cytochrome P-450 appears to be only one-ninth of that in the adrenal. Signals from ferredoxin were detected in all ovarian compartments except granulosa cells isolated from Graafian follicles. The third signal, that of transferrin, while often observed in the spectra of whole ovaries, has been attributed to residual blood in the tissues examined. The effects of oxygen on these spectra has been found to be considerable and is discussed.

Drug- and cue-induced reinstatement of cannabinoid-seeking behaviour in male and female rats: influence of ovarian hormones.

PubMed

Fattore, L; Spano, M S; Altea, S; Fadda, P; Fratta, W

2010-06-01

Animal and human studies have shown that sex and hormones are key factors in modulating addiction. Previously, we have demonstrated that self-administration of the cannabinoid CB(1) receptor agonist WIN55,212-2 (WIN; 12.5 microg.kg(-1) per infusion) is dependent on sex, intact female rats being more sensitive than males to the reinforcing properties of cannabinoids, and on the oestrous cycle, ovariectomized (OVX) females being less responsive than intact females. This follow-up study investigated whether sex and ovarian function also affect reinstatement of cannabinoid-seeking in rats after exposure to drug or cue priming. After priming with 0.15 or 0.3 mg.kg(-1) WIN, intact female rats exhibited stronger reinstatement than males and OVX females. Responses of intact female rats were higher than those of male and OVX rats even after priming with a drug-associated visual (Light) or auditory (Tone) cue, or a WIN + Light combination. However, latency to the first response did not differ between intact and OVX female rats, and males showed the longest latency to initiate lever-pressing activity. Our study provides compelling evidence for a pivotal role of sex and the oestrous cycle in modulating cannabinoid-seeking, with ovariectomy diminishing drug and cue-induced reinstatement. However, it is possible that sex differences during self-administration training are responsible for sex differences in reinstatement. Finding that not only drug primings but also acute exposure to drug-associated cues can reinstate responding in rats could have significant implications for the development of pharmacological and behavioural treatments of abstinent female and male marijuana smokers.

Transplantation of adipose-derived stem cells combined with collagen scaffolds restores ovarian function in a rat model of premature ovarian insufficiency.

PubMed

Su, Jing; Ding, Lijun; Cheng, Jie; Yang, Jun; Li, Xin'an; Yan, Guijun; Sun, Haixiang; Dai, Jianwu; Hu, Yali

2016-05-01

Does the transplantation of adipose-derived stem cells (ADSCs) on soluble collagen scaffolds (collagen/ADSCs) have better therapeutic effect than transplantation of ADSCs alone, to treat premature ovarian insufficiency (POI) in a rat model induced by Tripterygium Glycosides (TG)? The transplantation of collagen/ADSCs increased the short-term retention of ADSCs in ovaries and contributed to long-term restoration of ovarian function, as well as the fertility of rats with TG-induced ovarian damage. About 50% of young women in China, who have been treated with TG, have subsequently developed ovarian insufficiency. Rats exhibit similar symptoms to these patients when given an equivalent dose of TG. Transplantation of ADSCs improves ovarian function impaired by chemotherapy in rodent models. After the administration of TG, 54 POI model rats were randomly assigned to 4 groups: phosphate buffered saline (PBS) ( ITALIC! n = 14), collagen ( ITALIC! n = 11), ADSCs ( ITALIC! n = 16) and collagen/ADSCs ( ITALIC! n = 13). Seventeen normal rats were assigned as control group. The retention of ADSCs in ovaries was confirmed immediately or at 3, 7, 14 and 28 days after transplantation ( ITALIC! n = 9). Four weeks after transplantation, ovarian function was evaluated from estrous cycle, estradiol level, the follicle number, granulosa cell proliferation and a fertility test. To establish the POI model, rats were administered 60 mg TG/kg/day intragastrically for 50 days. The estrous cycles were assessed by vaginal smear. The concentration of plasma estradiol in diestrus stage was measured using a radioimmunoassay kit. Disordered estrous cycles and low serum estradiol levels indicated the successful establishment of the POI model. Four types of suspensions (PBS, collagen, ADSCs and collagen/ADSCs) were transplanted directly into the core of the ovaries. The short-term retention of ADSCs in ovaries was evaluated by small-animal positron emission tomography images immediately after transplantation of (18)F-Fluorodeoxyglucose ((18)F-FDG) labeled ADSCs. The long-term retention of ADSCs in ovaries was observed by immunohistochemistry after transplantation of green fluorescent protein (GFP)-labeled ADSCs. Serial sections of ovaries were prepared for histological analysis, follicle counting, and immunohistochemistry for Ki67 and Cleaved-Caspase-3. For the assessment of fertility, rats were mated with proven fertile male rats for 10 days. The (18)F-FDG signal decreased more slowly in ovaries injected with collagen/ADSCs than in ovaries with injected with ADSCs alone. Significantly more GFP-positive cells were observed in ovaries injected with collagen/GFP-ADSCs than in ovaries injected with GFP-ADSCs alone up to 14 days after the injection. However, in both groups very few GFP-positive cells were present at 4 weeks after transplantation. The collagen/ADSCs and ADSCs groups both showed better estrous cycle recovery than the PBS and collagen groups. The estradiol (E2) level in the collagen/ADSCs group was significantly increased compared with that of the PBS group ( ITALIC! P < 0.05). The number of antral follicles in the collagen/ADSCs group and the ADSCs group significantly increased compared with the PBS group ( ITALIC! P < 0.05). The granulosa cell proliferation in the collagen/ADSCs group was better than in the PBS group ( ITALIC! P < 0.01). The mating rates of the collagen/ADSCs group (88.9%) and the ADSCs group (90.9%) were higher than that of PBS group (60%, ITALIC! P < 0.05). The pregnancy rates of the collagen/ADSCs group (77.8%) and the ADSCs group (72.7%) were higher than the PBS group (50%, ITALIC! P < 0.05). We chose ADSCs for their accessibility, convenience and safety. We did not use other cells or materials for POI treatments to show that the collagen/ADSCs are the most promising materials. Soluble collagen scaffolds may be useful in stem cells transplantation therapy for POI. This work is supported by grants from the 'Strategic Priority Research Program' of the Chinese Academy of Sciences (XDA01030000); Maternal-Fetal Medicine from Jiangsu Province Health Department of China (XK2011027); Clinical Center of Obstetric, Gynecologic and Genetic Diseases, Nanjing Health Department of Jiangsu Province, China; Fundamental Research Funds for the Central Universities (20620140652). The authors declare no competing financial interests. Not applicable. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Acupuncture attenuates hyperglycaemia and improves ovarian function in female rats subjected to continuous light exposure.

PubMed

Kang, Xuezhi; Jia, Lina; Li, Yaming; Zhang, Xu

2017-10-01

Exposure to unnatural light cycles is increasingly associated with obesity and the metabolic syndrome. The purpose of this study was to examine the effects of electroacupuncture (EA) on glucose metabolism and ovarian function in female rats subjected to long-term continuous light exposure. Female Sprague-Dawley rats (n=24) were divided into three experimental groups: an LD group that was maintained under a normal light-dark cycle (healthy control); an LL group that was exposed to continuous light for 21 weeks but remained untreated; and an LL+EA group that received EA at ST36 and SP6 during weeks 17 to 21 of continuous light exposure. Oestrous cycles of female rats kept in a continuously lit environment for 21 weeks were disordered and polycystic ovarian syndrome (PCOS)-like changes occurred, accompanied by increased fasting blood glucose (6.23±0.33 vs 5.27±0.40 mmol/L in week 17, p=0.015) and reduced fasting levels of serum testosterone (0.07±0.018 vs 0.12±0.058 ng/L, p=0.043) and insulin (0.89±0.20 vs 1.43±0.46 ng/L, p=0.006). After 5 weeks of EA treatment at ST36 and SP6, ovarian cycle disruption was mitigated and blood glucose levels showed a gradual decline (5.18±0.37 vs 5.80±0.55 mmol/L, p=0.017; and 5.73±0.31 vs 6.62±0.13 mmol/L, p=0.004; in the fourth and fifth weeks of EA treatment, respectively). EA also attenuated the reductions otherwise seen in serum insulin and testosterone levels. Prolonged exposure to light can lead to a decline in ovarian and pancreatic function. EA at ST36 and SP6 may reduce abnormally elevated blood glucose levels and improve ovarian and pancreatic hormone levels. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Magnesium: does it reduce ischemia/reperfusion injury in an adnexal torsion rat model?

PubMed Central

Celik Kavak, Ebru; Gulcu Bulmus, Funda; Bulmus, Ozgur; Kavak, Salih Burcin; Kocaman, Nevin

2018-01-01

Aim The aim of the present study was to assess the protective effects of magnesium sulfate (MgSO4) on ischemia/reperfusion (I/R) induced ovarian damage in a rat ovarian torsion model. Methods Forty-two female Sprague Dawley rats were included in the study. They were divided into six groups as Group 1, sham; Group 2, bilateral ovarian torsion; Group 3, bilateral ovarian torsion–detorsion; Group 4, MgSO4–sham; Group 5, MgSO4–bilateral ovarian torsion; Group 6, bilateral ovarian torsion–MgSO4–detorsion. Both torsion and detorsion periods lasted 3 hours. In Groups 4, 5 and 6, MgSO4 (600 mg/kg) was administered by intraperitoneal route 30 minutes before sham operation, torsion and detorsion, respectively. At the end of the study period, both ovaries were removed. One of the ovaries was used for histopathological analyses and the other for biochemical analyses. Results In the torsion–detorsion group, all the histopathological scores were higher compared to the sham and torsion only group (p<0.05). Administration of MgSO4 only caused significant decrease in the inflammatory cell scores of the torsion–detorsion group (p<0.05). MgSO4, whether given before torsion or before detorsion, suppressed malondialdehyde levels when compared to the untreated groups (p<0.01 and p<0.001, respectively). Glutathione peroxidase activities were significantly higher in the MgSO4 applied torsion and detorsion groups than Groups 2 and 3 (p<0.05, for both). Administration of MgSO4 also caused an increase in glutathione levels in the torsion and detorsion groups compared to the torsion only and detorsion only groups (p<0.05, for both). Also, total oxidant status levels decreased in the MgSO4 applied torsion and detorsion groups compared to the untreated corresponding ones (p<0.01 and p<0.001, respectively). MgSO4 significantly decreased the Oxidative Stress Index levels in the torsion–detorsion group compared to Group 2 (p<0.001). Conclusion Histopathological and biochemical analysis revealed that prophylactic treatment with MgSO4 reduces the changes observed in I/R injury in a rat model. PMID:29535502

Montanoa frutescens and Montanoa grandiflora extracts reduce anxiety-like behavior during the metestrus-diestrus phase of the ovarian cycle in Wistar rats.

PubMed

Rodríguez-Landa, Juan Francisco; Vicente-Serna, Julio; Rodríguez-Blanco, Luis Alfredo; Rovirosa-Hernández, María de Jesús; García-Orduña, Francisco; Carro-Juárez, Miguel

2014-01-01

In previous studies, the anxiolytic-like effects of Montanoa tomentosa and Montanoa frutescens were reported in male rats, but the potential anxiolytic-like effects of Montanoa plants during the different phases of the ovarian cycle in rats remain to be explored. The anxiolytic-like effects of the aqueous crude extracts of M. frutescens (25 and 50 mg/kg) and M. grandiflora (25 and 50 mg/kg) in the elevated plus maze were investigated in Wistar rats during the estrous cycle and compared with 2 mg/kg diazepam as a reference anxiolytic drug. To investigate any motor effect (i.e., hyperactivity, no changes, or hypoactivity) associated with the treatments, the rats were evaluated in the open field test. The M. frutescens (25 and 50 mg/kg) and M. grandiflora (50 mg/kg) extracts exerted anxiolytic-like effects during the metestrus-diestrus phase, similar to diazepam, without disrupting spontaneous motor activity. No significant effects of the extracts were detected in either behavioral test during the proestrus-estrus phase, whereas diazepam produced motor hypoactivity in the open field test. These results indicate that the M. frutescens and M. grandiflora extracts possess anxiolytic-like effects that depend on the ovarian cycle phase, supporting the Mexican ancient medicinal use of these plants to ameliorate anxiety disorders.

Montanoa frutescens and Montanoa grandiflora Extracts Reduce Anxiety-Like Behavior during the Metestrus-Diestrus Phase of the Ovarian Cycle in Wistar Rats

PubMed Central

Rodríguez-Landa, Juan Francisco; Vicente-Serna, Julio; Rodríguez-Blanco, Luis Alfredo; Rovirosa-Hernández, María de Jesús; García-Orduña, Francisco; Carro-Juárez, Miguel

2014-01-01

In previous studies, the anxiolytic-like effects of Montanoa tomentosa and Montanoa frutescens were reported in male rats, but the potential anxiolytic-like effects of Montanoa plants during the different phases of the ovarian cycle in rats remain to be explored. The anxiolytic-like effects of the aqueous crude extracts of M. frutescens (25 and 50 mg/kg) and M. grandiflora (25 and 50 mg/kg) in the elevated plus maze were investigated in Wistar rats during the estrous cycle and compared with 2 mg/kg diazepam as a reference anxiolytic drug. To investigate any motor effect (i.e., hyperactivity, no changes, or hypoactivity) associated with the treatments, the rats were evaluated in the open field test. The M. frutescens (25 and 50 mg/kg) and M. grandiflora (50 mg/kg) extracts exerted anxiolytic-like effects during the metestrus-diestrus phase, similar to diazepam, without disrupting spontaneous motor activity. No significant effects of the extracts were detected in either behavioral test during the proestrus-estrus phase, whereas diazepam produced motor hypoactivity in the open field test. These results indicate that the M. frutescens and M. grandiflora extracts possess anxiolytic-like effects that depend on the ovarian cycle phase, supporting the Mexican ancient medicinal use of these plants to ameliorate anxiety disorders. PMID:24800255

Xenogeneic Decellularized Scaffold: A Novel Platform for Ovary Regeneration

PubMed Central

Liu, Wen-Yue; Lin, Shi-Gang; Zhuo, Ru-Yi; Xie, Yuan-Yuan; Pan, Wei

2017-01-01

Women younger than 40 years may face early menopause because of premature ovarian failure (POF). The cause of POF can be idiopathic or iatrogenic, especially the cancer-induced oophorectomy and chemo- or radiation therapy. The current treatments, including hormone replacement therapy (HRT) and cryopreservation techniques, have increased risk of ovarian cancer and may reintroduce malignant cells after autografting. Decellularization technique has been regarded as a novel regenerative medicine strategy for organ replacement, wherein the living cells of an organ are removed, leaving the extracellular matrix (ECM) for cellular seeding. This study aimed to produce a xenogeneic decellularized ovary (D-ovary) scaffold as a platform for ovary regeneration and transplantation. We have developed a novel decellularization protocol for porcine ovary by treatment with physical, chemical, and enzymatic methods. Using hematoxylin and eosin (H&E) staining, DAPI staining, scanning electron microscopy (SEM), and quantitative analysis, this approach proved effective in removing cellular components and preserving ECM. Furthermore, the results of biological safety evaluation demonstrated that the D-ovary tissues were noncytotoxic for rat ovarian cells in vitro and caused only a minimal immunogenic response in vivo. In addition, the D-ovary tissues successfully supported rat granulosa cell penetration ex vivo and showed an improvement in estradiol (E2) hormone secretion. PMID:27981878

Xenogeneic Decellularized Scaffold: A Novel Platform for Ovary Regeneration.

PubMed

Liu, Wen-Yue; Lin, Shi-Gang; Zhuo, Ru-Yi; Xie, Yuan-Yuan; Pan, Wei; Lin, Xian-Feng; Shen, Fei-Xia

2017-02-01

Women younger than 40 years may face early menopause because of premature ovarian failure (POF). The cause of POF can be idiopathic or iatrogenic, especially the cancer-induced oophorectomy and chemo- or radiation therapy. The current treatments, including hormone replacement therapy (HRT) and cryopreservation techniques, have increased risk of ovarian cancer and may reintroduce malignant cells after autografting. Decellularization technique has been regarded as a novel regenerative medicine strategy for organ replacement, wherein the living cells of an organ are removed, leaving the extracellular matrix (ECM) for cellular seeding. This study aimed to produce a xenogeneic decellularized ovary (D-ovary) scaffold as a platform for ovary regeneration and transplantation. We have developed a novel decellularization protocol for porcine ovary by treatment with physical, chemical, and enzymatic methods. Using hematoxylin and eosin (H&E) staining, DAPI staining, scanning electron microscopy (SEM), and quantitative analysis, this approach proved effective in removing cellular components and preserving ECM. Furthermore, the results of biological safety evaluation demonstrated that the D-ovary tissues were noncytotoxic for rat ovarian cells in vitro and caused only a minimal immunogenic response in vivo. In addition, the D-ovary tissues successfully supported rat granulosa cell penetration ex vivo and showed an improvement in estradiol (E2) hormone secretion.

Alteration in follistatin gene expression detected in prenatally androgenized rats.

PubMed

Salehi Jahromi, Marziyeh; Ramezani Tehrani, Fahimeh; Hill, Jennifer W; Noroozzadeh, Mahsa; Zarkesh, Maryam; Ghasemi, Asghar; Zadeh-Vakili, Azita

2017-06-01

Impaired ovarian follicle development, the hallmark of polycystic ovarian syndrome (PCOS), is believed to be due to the changes in expression of related genes such as follistatin (FST). Expression of FST gene and methylation level of its promoter in theca cells from adult female rats, prenatally exposed to androgen excess, during different phases of the estrus cycle was determined and compared with controls. Eight pregnant Wistar rats (experimental group) were treated by subcutaneous injection of 5 mg free testosterone on day 20 of pregnancy, while controls (n = 8) received 500 ml solvent. Based on observed vaginal smear, adult female offspring of mothers were divided into three groups. Levels of serum steroidogenic sexual hormones and gonadotropins, expression and promoter methylation of the FST gene were measured using ELISA, cyber-green real-time PCR and bisulfite sequence PCR (BSP), respectively. Compared to controls, the relative expression of FST gene in the treated group decreased overall by 0.85 fold; despite significant changes in different phases, but no significant differences in methylation of FST promoter. Our results reveal that manifestation of PCOS-like phenotype following prenatal exposure to excess androgen is associated with irregularity in expression of the FST gene during the estrus cycle.

Protective effects of sildenafil citrate administration on cisplatin-induced ovarian damage in rats.

PubMed

Taskin, Mine Islimye; Yay, Arzu; Adali, Ertan; Balcioglu, Esra; Inceboz, Umit

2015-04-01

The aim of this study is to evaluate the effects of sildenafil citrate on cisplatin-induced ovarian toxicity. Thirty-two female rats were divided into four groups. Group 1: saline control; group 2: cisplatin; group 3: sildenafil citrate; and group 4: cisplatin plus sildenafil citrate group. In groups 2 and 4, the rats were injected with 5 mg/kg cisplatin intraperitoneally (i.p.). In groups 3 and 4, the rats were injected with 1.4 mg/kg sildenafil citrate i.p. The ovaries were removed two weeks later in all groups. Histopathologic examination, follicle counting and classification were performed. The expression of anti-Müllerian hormone (AMH) was detected immunohistochemically in the ovarian tissues. Sildenafil alleviated cisplatin-induced histopathological changes in the ovarian tissue. Primordial, secondary and tertiary follicles were diminished in group 2 compared with group 1 (p < 0.05). Pretreatment with sildenafil citrate preserved primordial follicle count in group 4 compared with group 2, and the difference was statistically significant (p < 0.05). According to our results, immunoreactivity intensity of AMH was lower in group 2 compared with group 1 (92.4 ± 3.97 versus 88.8 ± 1.77) but not significantly, whereas immunoreactivity intensity of AMH was higher in group 4 compared with group 2 (88.8 ± 1.77 versus 94.1 ± 2.36; p < 0.05). Our results demonstrated that pretreatment with sildenafil citrate is beneficial for protecting the ovaries from cisplatin-induced damage. Sildenafil citrate can be a choice for fertility preservation.

A Unique Human Chorionic Gonadotropin Antagonist Suppresses Ovarian Hyperstimulation Syndrome in Rats

PubMed Central

Vardhana, Pratibhasri A.; Julius, Martin A.; Pollak, Susan V.; Lustbader, Evan G.; Trousdale, Rhonda K.; Lustbader, Joyce W.

2009-01-01

Ovarian hyperstimulation syndrome (OHSS) is a complication of in vitro fertilization associated with physiological changes after hCG administration to induce final oocyte maturation. It presents as widespread increases in vascular permeability and, in rare cases, results in cycle cancellation, multi-organ dysfunction, and pregnancy termination. These physiological changes are due primarily to activation of the vascular endothelial growth factor (VEGF) system in response to exogenous human chorionic gonadotropin (hCG). An hCG antagonist (hCG-Ant) could attenuate these effects by competitively binding to the LH/CG receptor, thereby blocking LH activity in vivo. We expressed a form of hCG that lacks three of its four N-linked glycosylation sites and tested its efficacy as an antagonist. The hCG-Ant binds the LH receptor with an affinity similar to native hCG and inhibits cAMP response in vitro. In a rat model for ovarian stimulation, hCG-Ant dramatically reduces ovulation and steroid hormone production. In a well-established rat OHSS model, vascular permeability and vascular endothelial growth factor (VEGF) expression are dramatically reduced after hCG-Ant treatment. Finally, hCG-Ant does not appear to alter blastocyst development when given after hCG in mice. These studies demonstrate that removing specific glycosylation sites on native hCG can produce an hCG-Ant that is capable of binding without activating the LH receptor and blocking the actions of hCG. Thus hCG-Ant will be investigated as a potential therapy for OHSS. PMID:19443574

Interictal spike frequency varies with ovarian cycle stage in a rat model of epilepsy.

PubMed Central

D’Amour, James; Magagna-Poveda, Alejandra; Moretto, Jillian; Friedman, Daniel; LaFrancois, John J.; Pearce, Patrice; Fenton, Andre A.; MacLusky, Neil J.; Scharfman, Helen E.

2015-01-01

In catamenial epilepsy, seizures exhibit a cyclic pattern that parallels the menstrual cycle. Many studies suggest that catamenial seizures are caused by fluctuations in gonadal hormones during the menstrual cycle, but this has been difficult to study in rodent models of epilepsy because the ovarian cycle in rodents, called the estrous cycle, is disrupted by severe seizures. Thus, when epilepsy is severe, estrous cycles become irregular or stop. Therefore, we modified kainic acid (KA)- and pilocarpine-induced status epilepticus (SE) models of epilepsy so that seizures were rare for the first months after SE, and conducted video-EEG during this time. The results showed that interictal spikes (IIS) occurred intermittently. All rats with regular 4-day estrous cycles had IIS that waxed and waned with the estrous cycle. The association between the estrous cycle and IIS was strong: if the estrous cycles became irregular transiently, IIS frequency also became irregular, and when the estrous cycle resumed its 4-day pattern, IIS frequency did also. Furthermore, when rats were ovariectomized, or males were recorded, IIS frequency did not show a 4-day pattern. Systemic administration of an estrogen receptor antagonist stopped the estrous cycle transiently, accompanied by transient irregularity of the IIS pattern. Eventually all animals developed severe, frequent seizures and at that time both the estrous cycle and the IIS became irregular. We conclude that the estrous cycle entrains IIS in the modified KA and pilocarpine SE models of epilepsy. The data suggest that the ovarian cycle influences more aspects of epilepsy than seizure susceptibility. PMID:25864929

Histopathological effects of short and long-term treatment of Orchis antolica crude root extract on female albino rats fertility and pregnancy.

PubMed

Khouri, Nabil A; Daradka, Haytham

2012-02-15

The present study has investigated the effects of Orchis antolica (dose of 400 mg/kg/Body Wight) on female rats reproductive system for two time periods 4 and 12 weeks. Forty adult female Sprague-Dawley rats were divided into two treatment and two control groups of 10 rats each. The two treated groups received 400 mg/kg/body weight of Orchis antolica for two periods of 4 and 12 weeks. Female rats were allowed mating with untreated males when treatment ended. Pregnancy parameters such as: total number of pregnancy, body weight, reproductive organ weight, number of implantation sites, number of resorption sites and number of viable fetuses. The significance of these results was calculated using student's "t" and Chi- square tests. Treatment with Orchis antolica for 4 weeks did not have any significant effects on most parameters investigated except for a slight increase in the relative ovarian and embryo weights. Orchis antolica for 12 weeks induces a significant increased in the percentage of pregnancies and the number of implantation sites when compared with controls. Further, an increase in ovarian weights and in viable fetuses count was also observed. Histological sections of treated female ovaries were found to have an empty blood vessels within the cortical and modularly regions. We also noted an increased in the developing follicles at primary and secondary stages in addition to an absence of degenerative areas and increased cellularity in medulla. Long-term treatment with Orchis antolica might lead to diversified positive effects on fertility and pregnancy in female rats.

Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency.

PubMed

Kim, Hyun-Bum; Kwon, Byeong-Jae; Cho, Hyun-Ji; Kim, Ji-Won; Chon, Jeong-Woo; Do, Moon-Ho; Park, Sang-Yong; Kim, Sun-Yeou; Maeng, Sung-Ho; Park, Yoo-Kyoung; Park, Ji-Ho

2015-03-01

Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post-synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders.

Effect of 2-aminoethoxydiphenyl borate on ischemia-reperfusion injury in a rat ovary model.

PubMed

Taskin, Mine Islimye; Hismiogullari, Adnan Adil; Yay, Arzu; Adali, Ertan; Gungor, Aysenur Cakir; Korkmaz, Gozde Ozge; Inceboz, Umit

2014-07-01

The aim of this study is to evaluate the effects of 2-aminoethoxydiphenyl borate (2-APB) as an antioxidant and analyze biochemical and histopathologic changes in experimental ischemia-reperfusion (I/R) injury in rat ovaries. Thirty female rats were utilized to create four groups. Group 1: I/R and 2-APB (2mg/kg); Group 2: I/R and 2-APB (4mg/kg); Group 3: I/R; Group 4: sham operation. Ovarian tissue and serum malondialdehyde, nitric oxide (NO) levels; ovarian tissue and serum total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI) were determined. In ovarian tissue samples histopathologic examination, immunoflourescence staining by TUNEL method was studied. Tissue TOS, serum TOS, and OSI levels were elevated in I/R group. After treatment with 2-APB, tissue and serum TOS levels and OSI levels were markedly decreased. There was a significant difference in terms of tissue and serum NO levels between the sham group and I/R group. Elevation in tissue NO and serum NO levels were decreased after treatment with 2-APB. TUNEL-positive cell number gradually decreased with dose of 2-APB in groups 1 and 2. Conservative treatment with 2-APB is beneficial for mitigation of I/R injury, and the ovarian protective effect of 2-APB appears to be mediated through its antiapopitotic and antioxidative effects. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Protective effect of alpha-lipoic acid in methotrexate-induced ovarian oxidative injury and decreased ovarian reserve in rats.

PubMed

Soylu Karapinar, Oya; Pinar, Neslihan; Özcan, Oğuzhan; Özgür, Tümay; Dolapçıoğlu, Kenan

2017-08-01

To determine whether the possible oxidative effect of methotrexate (Mtx) on ovary and to evaluate the effectiveness of alpha lipoic acid (ALA), which may be useful in many oxidative stress models. Thirty-two female Wistar-albino rats were randomly divided into four groups; control group, alpha lipoic acid group (ALA 100 mg/kg, 10 days), multiple dose Mtx group (Mtx 1 mg/kg 1, 3, 5, 7 days) and Mtx and ALA group (Mtx 1 mg/kg 1, 3, 5, 7 days and ALA 100 mg/kg, 10 days). Serum total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI), tumor necrosis factor-alpha (TNF-α), tissue malondialdehyde (MDA) and activities of glutathione peroxidase (GSH-Px) and catalase (CAT) and anti-Mullerian hormone (AMH) and total ovarian follicle count were evaluated. Mtx administration caused a significant decrease in TAS, a significant increase in TOS and OSI, a significant increase in MDA levels and a decrease in GSH-Px and CAT activity. Moreover the proinflammatory cytokine (TNF-α) was increased in the Mtx group. And AMH values and total follicle count were significantly decreased in Mtx group. However, ALA treatment reversed biochemical results and AMH levels and total follicle count. Alpha lipoic acid ameliorates methotrexate induced oxidative damage of ovarian in rats.

The production of nitric oxide in the coeliac ganglion modulates the effect of cholinergic neurotransmission on the rat ovary during the preovulatory period.

PubMed

Delsouc, María B; Della Vedova, María C; Ramírez, Darío; Delgado, Silvia M; Casais, Marilina

2018-05-01

The aim of the present work was to investigate whether the nitric oxide produced by the nitric oxide/nitric oxide synthase (NO/NOS) system present in the coeliac ganglion modulates the effects of cholinergic innervation on oxidative status, steroidogenesis and apoptotic mechanisms that take place in the rat ovary during the first proestrous. An ex vivo Coeliac Ganglion- Superior Ovarian Nerve- Ovary (CG-SON-O) system was used. Cholinergic stimulation of the CG was achieved by 10 -6  M Acetylcholine (Ach). Furthermore, 400 μM Aminoguanidine (AG) - an inhibitor of inducible-NOS was added in the CG compartment in absence and presence of Ach. It was found that Ach in the CG compartment promotes apoptosis in ovarian tissue, probably due to the oxidative stress generated. AG in the CG compartment decreases the release of NO and progesterone, and increases the release of estradiol from the ovary. The CG co-treatment with Ach and AG counteracts the effects of the ganglionic cholinergic agonist on ovarian oxidative stress, increases hormone production and decreases Fas mRNA expression. These results suggest that NO is an endogenous modulator of cholinergic neurotransmission in CG, with implication in ovarian steroidogenesis and the apoptotic mechanisms that take place in the ovary during the preovulatory period in rats. Copyright © 2018 Elsevier Inc. All rights reserved.

Quercetin Decreases Insulin Resistance in a Polycystic Ovary Syndrome Rat Model by Improving Inflammatory Microenvironment.

PubMed

Wang, Zhenzhi; Zhai, Dongxia; Zhang, Danying; Bai, Lingling; Yao, Ruipin; Yu, Jin; Cheng, Wen; Yu, Chaoqin

2017-05-01

Insulin resistance (IR) is a clinical feature of polycystic ovary syndrome (PCOS). Quercetin, derived from Chinese medicinal herbs such as hawthorn, has been proven practical in the management of IR in diabetes. However, whether quercetin could decrease IR in PCOS is unknown. This study aims to observe the therapeutic effect of quercetin on IR in a PCOS rat model and explore the underlying mechanism. An IR PCOS rat model was established by subcutaneous injection with dehydroepiandrosterone. The body weight, estrous cycle, and ovary morphology of the quercetin-treated rats were observed. Serum inflammatory cytokines were analyzed using enzyme-linked immunosorbent assay. In ovarian tissues, the expression of key genes involved in the inflammatory signaling pathway was detected through Western blot, real-time polymerase chain reaction, or immunohistochemistry. The nuclear translocation of nuclear factor κB (NF-κB) was also observed by immunofluorescence. The estrous cycle recovery rate of the insulin-resistant PCOS model after quercetin treatment was 58.33%. Quercetin significantly reduced the levels of blood insulin, interleukin 1β, IL-6, and tumor necrosis factor α. Quercetin also significantly decreased the granulosa cell nuclear translocation of NF-κB in the insulin-resistant PCOS rat model. The treatment inhibited the expression of inflammation-related genes, including the nicotinamide adenine dinucleotide phosphate oxidase subunit p22phox, oxidized low-density lipoprotein, and Toll-like receptor 4, in ovarian tissue. Quercetin improved IR and demonstrated a favorable therapeutic effect on the PCOS rats. The underlying mechanism of quercetin potentially involves the inhibition of the Toll-like receptor/NF-κB signaling pathway and the improvement in the inflammatory microenvironment of the ovarian tissue of the PCOS rat model.

Orthotopic Transplantation of Cryopreserved Mouse Ovaries and Gonadotrophin Releasing Hormone Analogues in the Restoration of Function following Chemotherapy-Induced Ovarian Damage

PubMed Central

Li, Qing; Szatmary, Peter; Liu, Yanyang; Ding, Zhenyu; Zhou, Jin; Sun, Yi; Luo, Feng

2015-01-01

Therapy advances are constantly improving survival rates of cancer patients, however the toxic effects of chemotherapy drugs can seriously affect patients’ quality of life. In women, fertility and premature ovarian endocrine dysfunction are of particular concern. It is urgently we find methods to preserve or reconstruct ovarian function for these women. This study compares GnRHa treatment with ovarian tissue cryopreservation and orthotopic transplantation in a chemotherapy-induced ovarian damage murine model. 56 inbred Lewis rats were divided into 4 treatment groups: Saline control (group I); cyclophosphamide only (group II); cyclophosphamide plus GnRHa (group III); cyclophosphamide and grafting of thawed cryopreserved ovaries (group IV). Body weight, estrous cycle recovery time, ovarian weight, morphology and follicle count, as well as breeding and fertility were compared among groups. Only group IV was able to restore to normal body weight by the end of the observation period and resumed normal estrous cycles in a shorter time compared to other treatment groups. There was a decrease in primordial follicles in all treatment groups, but group III had the greatest reduction. Although, there was no difference in pregnancy, only one animal littered normal pups in group II, none littered in group III and four littered in group IV. Thus, cryopreservation and orthotopic transplantation of ovarian tissue can restore the fertility of rats subjected to chemotherapy in a manner that is superior to GnRHa treatment. We also observed increased rates of hepatic, splenic and pulmonary haemorrhage in group III, suggesting there may be synergistic toxicity of GnRHa and cyclophosphamide. PMID:25811681

Hyperinsulinemia and human chorionic gonadotropin synergistically promote the growth of ovarian follicular cysts in rats.

PubMed

Poretsky, L; Clemons, J; Bogovich, K

1992-08-01

Tonically elevated serum luteinizing hormone (LH) and hyperinsulinemia are prominent features of polycystic ovary syndrome (PCO) in women, but the relative roles of LH and insulin in the pathogenesis of PCO is still unknown. The present study was undertaken to determine the effect(s) hyperinsulinemia might have on the induction of follicular cysts by LH/human chorionic gonadotropin (hCG) in the rat. Beginning on day 85 of age, adult female rats were given one of the following in vivo treatments: (1) vehicle alone; (2) a high-fat diet to control for the effects of weight-gain; (3) up to 6 U insulin per day; (4) 50 micrograms gonadotropin-releasing hormone (GnRH) antagonist (GnRHant) per day; (5) 1.5 IU hCG twice daily; (6) insulin + hCG; (7) insulin + GnRHant; (8) hCG + GnRHant; or (9) hCG + insulin + GnRHant. After 22 days of treatment, animals were killed on day 23, trunk blood was collected, and ovaries were excised for histological study. Regular cycles, assessed by vaginal smears, ceased after 10 days for most animals in treatment groups receiving hCG, but continued in all other treatment groups. All the animals in each hCG-treated group developed either unilateral or bilateral cystic ovaries, while no animals in the groups not receiving hCG developed follicular cysts. More animals from each group treated with both hCG and insulin possessed bilateral ovarian cysts than did rats treated with hCG alone: 80% and 60%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Quercetin increases the antioxidant capacity of the ovary in menopausal rats and in ovarian granulosa cell culture in vitro.

PubMed

Wang, Jiao; Qian, Xin; Gao, Qiang; Lv, Chunmei; Xu, Jie; Jin, Hongbo; Zhu, Hui

2018-06-21

Menopause is the most important sign of aging in women, and the ovary is the organ most sensitive to aging. Quercetin is a potential antioxidant and free radical scavenger that is widely found in fruits, vegetables, and leaves. However, the effect of quercetin on ovarian aging has not been elucidated, and the mechanism underlying its antioxidative effect remains unclear. The purpose of the current study was to investigate whether quercetin protects ovarian function by decreasing oxidative stress. In an in vivo experiment, female menopausal rats (12 months old) were intragastrically administered quercetin at three doses (12.5 mg/kg, 25 mg/kg, and 50 mg/kg) for 90 days, and the estrous cycles were determined by vaginal smearing. In an in vitro experiment, rat primary ovarian granulosa cells were cultured and treated with H 2 O 2 (400 μM) alone or H 2 O 2 plus quercetin at 5 μM, 20 μM, or 50 μM. The levels of the hormones estradiol (E 2 ), progesterone (P), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were detected by radioimmunoassay. The serum levels of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-PX) and glutathione S-transferase (GST) were examined. The expression levels of the oxidative stress-related genes SOD-1, catalase (CAT) and glutathione synthetase (GSS) in the ovaries and ovarian granulosa cells were detected by Western blot. The in vivo results demonstrated that quercetin had no effects on ovarian morphology, hormone secretion, or the estrous cycle in menopausal rats. Although no significant changes were detected in the serum levels of T-AOC, SOD, GSH, GSH-PX, and GST between the quercetin and control groups, the mRNA and protein expression levels of the oxidative stress-related genes SOD-1, CAT and GSS in menopausal rat ovaries were increased by low-dose quercetin. Moreover, the in vitro results demonstrated that quercetin significantly rescued the decrease in cell viability by H 2 О 2 -induced oxidative stress and enhanced the H 2 O 2 -induced decrease in expression of oxidative stress-related proteins. Together, the results of this study indicated that quercetin increased the antioxidant capacity of the ovary by upregulating the expression of some oxidative stress-related genes both in vivo and in vitro.

Effects of hypergravity on ovarian-hypophyseal function in antepartum and postpartum rats

NASA Technical Reports Server (NTRS)

Burden, Hubert W.; Zary, Joan T.; Hodson, Charles A.; Gregory, Heather L.; Baer, Lisa A.; Ronca, April E.

2003-01-01

BACKGROUND: Rats exposed to microgravity during the post-implantation phase of pregnancy had minimal alterations in ovarian and hypophyseal parameters during the antepartum and postpartum periods. In the current study, a similar parallel experimental design was employed to ascertain the effects of hypergravity on ovarian and hypophyseal function. HYPOTHESIS: We hypothesized that hypergravity exposure during the post-implantation stage of pregnancy would not alter antepartum and postpartum ovarian and hypophyseal function. METHODS: Pregnant rats were assigned to hypergravity (1.5 G, 1.75 G, or 2.0 G), rotational control, or stationary control groups (n = 10 each group) beginning on gestation day 11 and ending on day 20. Hypophyseal and ovarian analyses were conducted on 5 of the animals from each group at day 20. The remaining animals in each group were allowed to go to term and the same analyses were conducted 3 h postpartum. RESULTS: Hypergravity at all levels decreased the percent body mass gain from gestation day 11 to 20 (p < 0.05); however, the wet weight of the pituitaries and ovaries was not changed. There was no effect of hypergravity on the number of healthy or atretic antral follicles of any size at gestation day 20 or postpartum. The number of corpora lutea of pregnancy was decreased in all hypergravity groups, but the number of live fetuses at gestation day 20 or pups at term was not altered. Plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, and progesterone were not changed at gestation day 20 or postpartum. Pituitary content of LH, FSH, and prolactin was not altered by hypergravity at gestation day 20, but LH content was significantly increased (p < 0.05) at 1.5 and 1.75 G postpartum. CONCLUSIONS: We conclude that hypergravity, up to and including 2.0 G, is compatible with maintenance of pregnancy and has minimal effects on hypophyseal parameters. Ovarian follicles are not altered by hypergravity, but corpora lutea may regress at a more rapid rate.

Quantitative RT-PCR for inhibin/activin subunits: measurements of rat hypothalamic and ovarian inhibin/activin subunit mRNAs during the estrous cycle.

PubMed

Murata, T; Takizawa, T; Funaba, M; Fujimura, H; Murata, E; Takahashi, M; Torii, K

1997-02-01

Inhibins (alpha-beta(A) and alpha-beta(B)) and activins (beta(A)-beta(A), beta(A)-beta(B) and beta(B)-beta(B)) were originally isolated from ovarian follicular fluids as FSH secretion modifiers. Inhibin/activin subunits, alpha, beta(A) and beta(B), are widely distributed in several tissues, including gonads and brain, and inhibins and activins have been reported to be involved in ovarian or hypothalamic functions. In this study, we established and employed a competitive RT-PCR assay system for rat inhibin/activin subunits by capillary electrophoresis to determine rat hypothalamic and ovarian inhibin/activin subunit mRNA levels during the estrous cycle. Linearity of standards for alpha, beta(A), and beta(B) subunit assays were between 0.01-0.3 amol, 0.003-0.09 amol and 0.002-0.02 amol of each fragment DNA as a standard, respectively. Hypothalamic beta(A) subunit mRNA during the estrous morning (1000 h) tended to be increased compared with that of the proestrous evening (1700 h), although they were not significantly different. Ovarian alpha subunit mRNA levels tended to be increased during the proestrous morning (1000 h) and were significantly increased in the proestrous evening (1700 h), compared with diestrus and estrus (P < 0.05). Ovarian beta(A) subunit mRNA was also significantly higher in the proestrous evening, compared with diestrus and estrus (P < 0.05), but in the case of beta(B) subunit mRNA there was no difference among diestrus, proestrus and estrus. We thus established a sensitive competitive RT-PCR system for the measurement of inhibin/activin alpha, beta(A) and beta(B) subunits, and this assay system would be helpful for the study of inhibin/activin action in brain and other tissues where these factors are expressed at low levels.

Prolonged hypothyroidism severely reduces ovarian follicular reserve in adult rats.

PubMed

Meng, Li; Rijntjes, Eddy; Swarts, Hans J M; Keijer, Jaap; Teerds, Katja J

2017-03-16

There is substantial evidence both in humans and in animals that a prolonged reduction in plasma thyroid hormone concentration leads to reproductive problems, including disturbed folliculogenesis, impaired ovulation and fertilization rates, miscarriage and pregnancy complications. The objective of the present study is to examine the consequences of chronic hypothyroidism, induced in adulthood, for the size of the ovarian follicle pool. In order to investigate this, adult female rats were provided either a control or an iodide deficient diet in combination with perchlorate supplementation to inhibit iodide uptake by the thyroid. Sixteen weeks later animals were sacrificed. Blood was collected for hormone analyses and ovaries were evaluated histologically. At the time of sacrifice, plasma thyroid-stimulating hormone concentrations were 20- to 40-fold increased, thyroxine concentrations were negligible while tri-iothyronin concentrations were decreased by 40% in the hypothyroid group, confirming that the animals were hypothyroid. Primordial, primary and preantral follicle numbers were significantly lower in the hypothyroid ovaries compared to the euthyroid controls, while a downward trend in antral follicle and corpora lutea numbers was observed. Surprisingly the percentage of atretic follicles was not significantly different between the two groups, suggesting that the reduced preantral and antral follicle numbers were presumably not the consequence of increased degeneration of these follicle types in the hypothyroid group. Plasma anti-Müllerian hormone (AMH) levels showed a significant correlation with the growing follicle population represented by the total ovarian number of primary, preantral and antral follicles, suggesting that also under hypothyroid conditions AMH can serve as a surrogate marker to assess the growing ovarian follicle population. The induction of a chronic hypothyroid condition in adult female rats negatively affects the ovarian follicular reserve and the size of the growing follicle population, which may impact fertility.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myllymaeki, S.A.; Karjalainen, M.; Haavisto, T.E.

Phenolic compounds, such as 4-tert-octylphenol (OP), have been shown to interfere with rat ovarian steroidogenesis. However, little is known about steroidogenic effects of infantile OP exposure on immature ovary. The aim of the present study was to investigate the effects of infantile OP exposure on plasma FSH, LH, estradiol, and progesterone levels in 14-day-old female rats. The effect on ovarian steroidogenic acute regulatory protein (StAR) and FSH receptor (FSHr) expression was analyzed by Western blotting. Ex vivo analysis was carried out for follicular estradiol, progesterone, testosterone, and cAMP production. Sprague-Dawley rats were given OP (0, 10, 50, or 100 mg/kg)more » subcutaneously on postnatal days 6, 8, 10, and 12. On postnatal day 14, plasma FSH was decreased and progesterone increased significantly at a dose of 100 mg OP/kg. In addition, the highest OP dose advanced the time of vaginal opening in puberty. OP had no effect on infantile LH and estradiol levels or ovarian FSHr content. Ovarian StAR protein content and ex vivo hormone and cAMP production were decreased at all OP doses compared to controls. However, hormone levels recovered independent on FSH and even increased above the control level during a prolonged culture. On postnatal day 35, no statistically significant differences were seen between control and OP-exposed animals in plasma FSH, LH, estradiol, and progesterone levels, or in ovarian StAR protein content. The results indicate that the effect of OP on the infantile ovary is reversible, while more permanent effects in the hypothalamus and pituitary, as described earlier, are involved in the reduction of circulating FSH levels and premature vaginal opening.« less

Histopathologycal findings in the ovaries and uterus of albino female rats promoted by co-administration of synthetic steroids and nicotine.

PubMed

Camargo, Isabel Cristina Cherici; Leite, Gabriel Adan Araújo; Pinto, Tiago; Ribeiro-Paes, João Tadeu

2014-07-01

The use of anabolic androgenic steroids is often associated with the use of other substances, licit or not, such as nicotine present in the tobacco. The present study investigated for the first time the effects of co-administration of synthetic steroids and nicotine on the ovarian and uterine tissue and fertility of adult female rats. Animals were submitted to treatment groups (n=16/group): nandrolone decanoate (ND; 7.5mg/kg BW/week); testosterone mixture (T; 7.5mg/kg BW/week); nicotine (N; 2.0mg/kg BW/day), and co-administration of ND/N, T/N and ND/T/N. The control group received saline solution daily. The injections were administered subcutaneously for 30 consecutive days. Results demonstrated that all androgenized rats exhibited estral acyclicity and there was suppression of reproductive capacity due to notable ovarian and uterine histological changes. Treatments promoted decrease (p<0.05) in the ovarian weight. Uterine weight increased (p<0.05) in the T and T/N groups, in comparison to control group. ND or T co-administered or not to nicotine promoted intense follicular degeneration, with formation of cysts in the ovaries. High levels of circulating androgens in the ND/T/N group induced the presence of ovarian sex cord-stromal tumors of Sertoli cell pattern. Androgenized females presented endometrial changes characterized by papilliferous or pleated luminal epithelium, oedematous and hemorrhagic stroma and presence of gland cysts. In conclusion, the co-administration of three drugs promoted atypical morphological pattern on the ovaries and uterus of female rats. Copyright © 2014 Elsevier GmbH. All rights reserved.

Effects of different doses of nandrolone decanoate on estrous cycle and ovarian tissue of rats after treatment and recovery periods.

PubMed

Simão, Vinícius Augusto; Berloffa Belardin, Larissa; Araújo Leite, Gabriel Adan; de Almeida Chuffa, Luiz Gustavo; Camargo, Isabel Cristina Cherici

2015-10-01

This study tested the hypothesis that different doses of nandrolone decanoate (ND) will cause changes in the estrous cycle and ovarian tissue of adult rats; and investigated the duration of the recovery period that is sufficient to restore the damage in the animals treated with different doses. Wistar rats were treated with ND at doses of 1.87, 3.75, 7.5 and 15 mg/kg body weight, or received mineral oil (control group) for 15 days, subcutaneously. All animals were divided into three groups according to the treatment periods: (i) ND treatment for 15 days; (ii) ND treatment followed by a 30-day recovery; and (iii) ND treatment followed by a 60-day recovery. Estrous cycle was monitored daily, and at the end of each period, the animals were euthanized for histopathological analysis. During ND treatment and after 30-day recovery, all animals exhibited persistent diestrus. After a 60-day recovery, persistent diestrus was only maintained in the group that had received the highest dose. Ovarian weight was decreased significantly after the 30-day recovery, regardless of ND doses, compared with the control group. There was a reduction (P < 0.05) in the number of corpora lutea and antral and growing follicles, in contrast to an increase (P < 0.05) in atretic follicles in a dose- and time-dependent manner. Remarkable histopathological changes occurred in the ovaries of all ND-treated groups. In conclusion, the different doses of ND caused changes in the estrous cycle and ovarian tissue of rats, and recovery periods (30 and 60 days) were insufficient to completely restore the damage in the animals treated with the highest dose. © 2015 The Authors. International Journal of Experimental Pathology © 2015 International Journal of Experimental Pathology.

Ovarian Toxicity in Female Rats after Oral Administration of Melamine or Melamine and Cyanuric Acid

PubMed Central

Sun, Jiarui; Zhang, Xinchen; Cao, Yinan; Zhao, Qiling; Bao, Endong; Lv, Yingjun

2016-01-01

Although the toxicity of melamine to the kidneys and testes is well known, few studies have investigated the effects of melamine on female reproductive organs. Therefore, this study explores the effects of oral administration melamine or melamine and cyanuric acid for 28 days on the ovaries of female rats. Rats that were exposed to the mixture exhibited reduced ovarian and uterine weights, a shorter estrous cycle, and reduced serum estrogen and progesterone levels compared to rats that were exposed to melamine and control rats. Furthermore, morphological analysis revealed pathological changes in the ovaries of rats exposed to melamine or the mixture, such as more atretic follicles and necrosis of oocytes and granulosa cells. TUNEL staining revealed that the exposed groups had a higher proportion of TUNEL-positive granulosa cells than the control group, and the mRNA expressions of SOD1, GPX1, GPX2, P450scc, 17β-HSD I, and 17β-HSD II were reduced in the exposure groups compared with the control group. These results indicated that exposure to melamine alone or to the melamine-cyanuric acid mixture could damage the ovaries in rats. PMID:26866683

Ganglionic adrenergic action modulates ovarian steroids and nitric oxide in prepubertal rat.

PubMed

Delgado, Silvia Marcela; Casais, Marilina; Sosa, Zulema; Rastrilla, Ana María

2006-08-01

Both peripheral innervation and nitric oxide (NO) participate in ovarian steroidogenesis. The purpose of this work was to analyse the ganglionic adrenergic influence on the ovarian release of steroids and NO and the possible steroids/NO relationship. The experiments were carried out in the ex vivo coeliac ganglion-superior ovarian nerve (SON)-ovary system of prepubertal rats. The coeliac ganglion-SON-ovary system was incubated in Krebs Ringer-bicarbonate buffer in presence of adrenergic agents in the ganglionic compartment. The accumulation of progesterone, androstenedione, oestradiol and NO in the ovarian incubation liquid was measured. Norepinephrine in coeliac ganglion inhibited the liberation of progesterone and increased androstenedione, oestradiol and NO in ovary. The addition of alpha and beta adrenergic antagonists also showed different responses in the liberation of the substances mentioned before, which, from a physiological point of view, reveals the presence of adrenergic receptors in coeliac ganglion. In relation to propranolol, it does not revert the effect of noradrenaline on the liberation of progesterone, which leads us to think that it might also have a "per se" effect on the ganglion, responsible for the ovarian response observed for progesterone. Finally, we can conclude that the ganglionic adrenergic action via SON participates on the regulation of the prepubertal ovary in one of two ways: either increasing the NO, a gaseous neurotransmitter with cytostatic characteristics, to favour the immature follicles to remain dormant or increasing the liberation of androstenedione and oestradiol, the steroids necessary for the beginning of the near first estral cycle.

Biological mechanisms of premature ovarian failure caused by psychological stress based on support vector regression

PubMed Central

Wang, Xiu-Feng; Zhang, Lei; Wu, Qing-Hua; Min, Jian-Xin; Ma, Na; Luo, Lai-Cheng

2015-01-01

Psychological stress has become a common and important cause of premature ovarian failure (POF). Therefore, it is very important to explore the mechanisms of POF resulting from psychological stress. Sixty SD rats were randomly divided into control and model groups. Biomolecules associated with POF (β-EP, IL-1, NOS, NO, GnRH, CRH, FSH, LH, E2, P, ACTH, and CORT) were measured in the control and psychologically stressed rats. The regulation relationships of the biomolecules were explored in the psychologically stressed state using support vector regression (SVR). The values of β-EP, IL-1, NOS, and GnRH in the hypothalamus decreased significantly, and the value of NO changed slightly, when the values of 3 biomolecules in the hypothalamic-pituitary-adrenal axis decreased. The values of E2 and P in the hypothalamic-pituitary-ovarian axis decreased significantly, while the values of FSH and LH changed slightly, when the values of the biomolecules in the hypothalamus decreased. The values of FSH and LH in the pituitary layer of the hypothalamic-pituitary-ovarian axis changed slightly when the values of E2 and P in the target gland layer of the hypothalamic-pituitary-ovarian axis decreased. An Imbalance in the neuroendocrine-immune bimolecular network, particularly the failure of the feedback action of the target gland layer to pituitary layer in the pituitary-ovarian axis, is possibly one of the pathogenic mechanisms of POF. PMID:26885082

Effects of flaxseed lignan secoisolariciresinol diglucoside on preneoplastic biomarkers of cancer progression in a model of simultaneous breast and ovarian cancer development

PubMed Central

Delman, Devora M.; Fabian, Carol J.; Kimler, Bruce F.; Yeh, Henry; Petroff, Brian K.

2016-01-01

Breast cancer prevention efforts are focused increasingly on potentially beneficial dietary modifications due to their ease of implementation and wide acceptance. Secoisolariciresinol diglucoside (SDG) is a lignan found in high concentration in flaxseed that may have selective estrogen receptor modulator (SERM)-like effects resulting in antiestrogenic activity in a high estrogen environment. In parallel with a human phase II prevention trial, female ACI rats (n=8–10/group) received 0, 10 or 100 ppm SDG in the feed. The 100 ppm SDG treatment produced similar blood lignan levels as those observed in our human pilot study. Mammary and ovarian cancer progression were induced using local ovarian DMBA treatment and subcutaneous sustained release 17β-estradiol administered starting at 7 weeks of age. Mammary gland and ovarian tissues were collected at 3 months after initiation of treatment and examined for changes in epithelial cell proliferation (Ki-67, cell counts), histopathology and dysplasia scores as well as expression of selected genes involved in proliferation, estrogen signaling and cell adhesion. Treatment with SDG normalized several biomarkers in mammary gland tissue (dysplasia, cell number, and expression of several genes) that had been altered by carcinogen. There is no indication that SDG promotes pre-neoplastic progression in the ovarian epithelium. PMID:26010915

[Intraoperative intraperitoneal chemoperfusion treatment with cisplatin and dioxadet on a model of peritoneal carcinomatosis in ovarian cancer: safety and efficacy evaluation].

PubMed

Bespalov, V G; Kireeva, G S; Belyaeva, O A; Senchik, K Yu; Stukov, A N; Gafton, G I; Soloviev, L A; Vasilchenko, M V; Guseinov, K D; Alexeev, V V; Belyaev, A M

2015-01-01

A comparative study of safety and efficacy of normothermic and hyperthermic intraperitoneal chemoperfusion (IPEC and HIPEC) with cisplatin and dioxadet was carried out in 143 female Wistar rats. Ovarian cancer was inoculated intraperitoneally (i.p.). In 48 hours after ovarian cancer inoculation the drugs were administered i.p. or IPEC and HIPEC with the drugs were performed using maximum tolerated doses (MTD). Content of cisplatin was determined in the perfusate and blood plasma during HIPEC with the drug. The leukocyte count was measured using veterinary hematologic analyzer in peripheral blood of rats at different time points after HIPEC with dioxadet. Efficacy of the treatment was estimated in increase in median survival time (MST). During HIPEC cisplatin was accumulated in the abdominal cavity in a considerable amount with minimal systemic absorption. HIPEC with dioxadet didn't significantly affect the leukocyte count in peripheral blood while i.p. administration of dioxadet suppressed leukopoiesis. MST of rats after IPEC with cisplatin was 37.5 days which was significantly higher compared to MST after i.p. administration of cisplatin (19.5 days, p = 0.037). HIPEC with dioxadet was the most effective regimen of treatment with MST of rats reaching 49 days which was significantly higher compared to MST after HIPEC with cisplatin (25.5 days, p = 0.002).

In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myllymaeki, Sari; Haavisto, Tapio; Vainio, Minna

2005-04-01

Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10{sup -6} M) caused the strongest decline in estradiol and testosterone levels but did not havemore » detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals.« less

Effects of electroacupuncture on luteal regression and steroidogenesis in ovarian hyperstimulation syndrome model rat.

PubMed

Huang, Xuan; Chen, Li; Xia, You-Bing; Xie, Min; Sun, Qin; Yao, Bing

2018-03-15

Electroacupuncture (EA) is an effective and safe therapeutic method widely used for treating clinical diseases. Previously, we found that EA could decrease serum hormones and reduce ovarian size in ovarian hyperstimulation syndrome (OHSS) rat model. Nevertheless, the mechanisms that contribute to these improvements remain unclear. HE staining was used to count the number of corpora lutea (CL) and follicles. Immunohistochemical and ELISA were applied to examine luteal functional and structural regression. Immunoprecipitation was used for analyzing the interaction between NPY (neuropeptide Y) and COX-2; western blotting and qRT-PCR were used to evaluate the expressions of steroidogenic enzymes and PKA/CREB pathway. EA treatment significantly reduced the ovarian weight and the number of CL, also decreased ovarian and serum levels of PGE2 and COX-2 expression; increased ovarian PGF2α levels and PGF2α/PGE2 ratio; decreased PCNA expression and distribution; and increased cyclin regulatory inhibitor p27 expression to have further effect on the luteal formation, and promote luteal functional and structural regression. Moreover, expression of COX-2 in ovaries was possessed interactivity increased expression of NPY. Furthermore, EA treatment lowered the serum hormone levels, inhibited PKA/CREB pathway and decreased the expressions of steroidogenic enzymes. Hence, interaction with COX-2, NPY may affect the levels of PGF2α and PGE2 as well as impact the proliferation of granulosa cells in ovaries, thus further reducing the luteal formation, and promoting luteal structural and functional regression, as well as the ovarian steroidogenesis following EA treatment. EA treatment could be an option for preventing OHSS in ART. Copyright © 2018 Elsevier Inc. All rights reserved.

How do red and infrared low-level lasers affect folliculogenesis cycle in rat's ovary tissue in comparison with clomiphene under in vivo condition.

PubMed

Naseri, Paria; Alihemmati, Alireza; Rasta, Seyed Hossein

2017-12-01

Folliculogenesis is a cycle that produces the majority of oocyte. Any disruption to this cycle leads to ovulation diseases, like polycystic ovarian syndrome (PCOS). Treatments include drugs and surgery; lasers have also been used complementarily. Meanwhile, still there is no definite treatment for PCOS. This study investigated the photo-bio stimulation effect of near-infrared and red low-level laser on producing follicles and compared the result with result of using common drug, clomiphene. Therefore, the aim of this study was to propose the use of lasers autonomously treatment. So, there was one question: how do lasers affect folliculogenesis cycle in rat's ovary tissue? In this study, 28 rats were assigned to four groups as follows: control (CT), clomiphene drug (D), red laser (RL), and near-infrared laser (NIRL). Afterwards, 14 rats of RL and NIRL groups received laser on the first 2 days of estrous cycle, each 6 days, for 48 days. During treatment period, each rat received energy density of 5 J/cm 2 . Seven rats in D group received clomiphene. After the experiment, lasers' effects at two wavelengths of 630 and 810 nm groups have been investigated and compared with clomiphene and CT groups. Producing different follicles to complement folliculogenesis cycle increased in NIRL and RL groups, but this increase was significant only in the NIRL group. This indicates that NIRL increases ovarian activity to produce oocyte that certainly can be used in future studies for finding a cure to ovarian negligence to produce more oocyte and treat diseases caused by it like PCOS.

Letrozole increases ovarian growth and Cyp17a1 gene expression in the rat ovary

PubMed Central

Ortega, Israel; Sokalska, Anna; Villanueva, Jesus A.; Cress, Amanda B.; Wong, Donna H.; Stener-Victorin, Elisabet; Stanley, Scott D.; Duleba, Antoni J.

2012-01-01

Objective To evaluate the effects of letrozole on ovarian size and steroidogenesis in vivo, as well as on proliferation and steroidogenesis of theca-interstitial cells alone and in coculture with granulosa cells using an in vitro model. Design In vivo and in vitro studies. Setting Research laboratory. Animal(s) Immature Sprague-Dawley female rats. Intervention(s) In vivo effects of letrozole were studied in intact rats receiving either letrozole (90-day continuous-release SC pellets, 400 µg/d) or placebo pellets (control group). In in vitro experiments, theca cells were cultured alone or in coculture with granulosa cells in the absence or presence of letrozole. Main Outcome Measure(s) Deoxyribonucleic acid synthesis was determined by thymidine incorporation assay; steroidogenesis by mass spectrometry; and steroidogenic enzyme messenger RNA (mRNA) expression by polymerase chain reaction. Result(s) In vivo, letrozole induced an increase in ovarian size compared with the control group and also induced a profound increase of androgen, LH levels, and Cyp17a1 mRNA expression. Conversely, a decrease in Star, Cyp11a1, and Hsd3b1 transcripts was observed in letrozole-exposed rats. In vitro, letrozole did not alter either theca cell proliferation or Cyp17a1 mRNA expression. Similarly, letrozole did not affect Cyp17a1 transcripts in granulosa-theca cocultures. Conclusion(s) These findings suggest that letrozole exerts potent, but indirect, effect on growth of rat ovary and dramatically increases androgen levels and Cyp17a1 mRNA expression, the key enzyme regulating the androgen biosynthesis pathway. The present findings reveal novel mechanisms of action of letrozole in the rat ovary. PMID:23200686

Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency

PubMed Central

Kim, Hyun-Bum; Kwon, Byeong-Jae; Cho, Hyun-Ji; Kim, Ji-Won; Chon, Jeong-Woo; Do, Moon-Ho; Park, Sang-Yong; Kim, Sun-Yeou; Maeng, Sung-Ho; Park, Yoo-Kyoung

2015-01-01

Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post-synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders. PMID:25792871

Glutathione S-transferase class mu regulation of apoptosis signal-regulating kinase 1 protein during VCD-induced ovotoxicity in neonatal rat ovaries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhattacharya, Poulomi; Madden, Jill A.; Sen, Nivedita

2013-02-15

4-Vinylcyclohexene diepoxide (VCD) destroys ovarian primordial and small primary follicles via apoptosis. In mice, VCD exposure induces ovarian mRNA expression of glutathione S-transferase (GST) family members, including isoform mu (Gstm). Extra-ovarian GSTM negatively regulates pro-apoptotic apoptosis signal-regulating kinase 1 (ASK1) through protein complex formation, which dissociates during stress, thereby initiating ASK1-induced apoptosis. The present study investigated the ovarian response of Gstm mRNA and protein to VCD. Induction of Ask1 mRNA at VCD-induced follicle loss onset was determined. Ovarian GSTM:ASK1 protein complex formation was investigated and VCD exposure effects thereon evaluated. Phosphatidylinositol-3 kinase (PI3K) regulation of GSTM protein was also studied.more » Postnatal day (PND) 4 rat ovaries were cultured in control media ± 1) VCD (30 μM) for 2–8 days; 2) VCD (30 μM) for 2 days, followed by incubation in control media for 4 days (acute VCD exposure); or 3) LY294002 (20 μM) for 6 days. VCD exposure did not alter Gstm mRNA expression, however, GSTM protein increased (P < 0.05) after 6 days of both the acute and chronic treatments. Ask1 mRNA increased (0.33-fold; P < 0.05) relative to control after 6 days of VCD exposure. Ovarian GSTM:ASK1 protein complex formation was confirmed and, relative to control, the amount of GSTM bound to ASK1 increased 33% (P < 0.05) by chronic but with no effect of acute VCD exposure. PI3K inhibition increased (P < 0.05) GSTM protein by 40% and 71% on d4 and d6, respectively. These findings support involvement of GSTM in the ovarian response to VCD exposure, through regulation of pro-apoptotic ASK1. - Highlights: ► GSTM protein increases in response to ovarian VCD exposure. ► VCD increases Ask1 mRNA at the onset of follicle loss. ► Ovarian GSTM binds more ASK1 protein during VCD-induced ovotoxicity. ► PI3K regulates ovarian GSTM protein.« less

Effect of nebivolol treatment during pregnancy on the genital circulation, fetal growth and postnatal development in the Wistar rat.

PubMed

Altoama, Kassem; Yassine Mallem, Mohamed; Thorin, Chantal; Betti, Eric; Desfontis, Jean-Claude

2015-07-05

The aim of study was to evaluate the effects of nebivolol, a cardioselective beta-1 adrenergic receptor blocker of the third generation with vasodilatory properties, vs. bisoprolol on the genital circulation, uterine vasculature, fetal growth and postnatal development in pregnant Wistar rats. Non invasive measurements of systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), and invasive measurement of genital blood flow (GBF) were taken in pregnant rats, by tail cuff and transonic probe methods respectively, after an oral treatment by gastric gavage with nebivolol (8mg/kg/day) or bisoprolol (10mg/kg/day) from day 11 to day 18 of pregnancy. Other morphometrical and histological measurements were performed on the ovarian and uterine arteries to evaluate the effect of nebivolol on the uterine vasculature. Furthermore, postnatal mortality and pup growth were recorded. The data demonstrated that nebivolol (compared with bisoprolol) induced a significant decrease in SBP, HR and GBF while DBP remained unchanged. Moreover, nebivolol increased the diameter and the length of ovarian and uterine arteries and the number of uterine artery segmental branches. The results also showed that the body weight gain of newborns in the nebivolol group was significantly lower vs. bisoprolol and vs. control with a higher mortality rate. The nebivolol action is not only limited to its favorable hemodynamic effects represented by a decrease in blood pressure, but it also produces adverse effects on fetal growth and postnatal development that may limit its therapeutic use in females during pregnancy. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of Resveratrol on Ovarian Morphology, Plasma Anti-Mullerian Hormone, IGF-1 Levels, and Oxidative Stress Parameters in a Rat Model of Polycystic Ovary Syndrome.

PubMed

Ergenoglu, Mete; Yildirim, Nuri; Yildirim, Alkim Gulsah Sahingoz; Yeniel, Ozgur; Erbas, Oytun; Yavasoglu, Altug; Taskiran, Dilek; Karadadas, Nedim

2015-08-01

To evaluate the effects of resveratrol in a rat model of polycystic ovarian syndrome (PCOS). After PCOS model was formed by subcutaneous dihydrotestosterone pellets, rats were randomly divided into 2 groups. The first group (n = 7) was treated with 1 mL/kg/d isotonic saline and the second group (n = 7) was treated with 10 mg/kg/d resveratrol. Seven rats were taken as controls without any medication. Our results showed (1) significant reduction in the number of antral follicle counts (P < .01); (2) significantly decreased plasma anti-Mullerian hormone and insulin-like growth factor 1 levels (P < .01 and P < .05, respectively); (3) significantly lower superoxide dismutase activity (P < .05); and (4) significantly increased glutathione peroxidase content (P < .01) following resveratrol treatment. Resveratrol appears to be effective in the treatment of PCOS due to its antioxidant properties. Future clinical studies with different dosages might provide useful implementations to our practice. © The Author(s) 2015.

Induction of UO-44 gene expression by tamoxifen in the rat uterus and ovary.

PubMed

Huynh, H; Ng, C Y; Lim, K B; Ong, C K; Ong, C S; Tran, E; Tuyen Nguyen, T T; Chan, T W

2001-07-01

A complementary DNA, uterine-ovarian-specific gene 44 (UO-44), has been isolated from tamoxifen-induced rat uterine complementary DNA library using differential display techniques. UO-44 transcripts are found to be abundant in the uterus and ovary. UO-44 gene expression in the uterus is strictly regulated by estrogens, tamoxifen, and GH, whereas the pure antiestrogen ICI 182780 is inhibitory. Treatment of ovariectomized rats and hypophysectomized rats with tamoxifen and GH, respectively, resulted in up-regulation of UO-44 expression in a dose-dependent manner. In situ hybridization revealed that UO-44 gene expression was restricted to the luminal and glandular epithelial cells of the uterus and to granulosa cells of medium-size ovarian follicles. Transfection studies showed that UO-44 was a membrane-associated protein. Because estrogens, tamoxifen, and GH are stimulators of uterine luminal epithelial cell growth in vivo, UO-44 protein may serve as a mediator of the effect of these compounds in inducing epithelial proliferation and differentiation in these tissues.

Drug- and cue-induced reinstatement of cannabinoid-seeking behaviour in male and female rats: influence of ovarian hormones

PubMed Central

Fattore, L; Spano, MS; Altea, S; Fadda, P; Fratta, W

2010-01-01

Background and purpose: Animal and human studies have shown that sex and hormones are key factors in modulating addiction. Previously, we have demonstrated that self-administration of the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN; 12.5 µg·kg−1 per infusion) is dependent on sex, intact female rats being more sensitive than males to the reinforcing properties of cannabinoids, and on the oestrous cycle, ovariectomized (OVX) females being less responsive than intact females. Experimental approach: This follow-up study investigated whether sex and ovarian function also affect reinstatement of cannabinoid-seeking in rats after exposure to drug or cue priming. Key results: After priming with 0.15 or 0.3 mg·kg−1 WIN, intact female rats exhibited stronger reinstatement than males and OVX females. Responses of intact female rats were higher than those of male and OVX rats even after priming with a drug-associated visual (Light) or auditory (Tone) cue, or a WIN + Light combination. However, latency to the first response did not differ between intact and OVX female rats, and males showed the longest latency to initiate lever-pressing activity. Conclusions and implications: Our study provides compelling evidence for a pivotal role of sex and the oestrous cycle in modulating cannabinoid-seeking, with ovariectomy diminishing drug and cue-induced reinstatement. However, it is possible that sex differences during self-administration training are responsible for sex differences in reinstatement. Finding that not only drug primings but also acute exposure to drug-associated cues can reinstate responding in rats could have significant implications for the development of pharmacological and behavioural treatments of abstinent female and male marijuana smokers. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x PMID:20590575

Lateralization of the connections of the ovary to the celiac ganglia in juvenile rats

PubMed Central

Morán, Carolina; Zarate, Fabiola; Morán, José Luis; Handal, Anabella; Domínguez, Roberto

2009-01-01

During the development of the female rat, a maturing process of the factors that regulate the functioning of the ovaries takes place, resulting in different responses according to the age of the animal. Studies show that peripheral innervation is one relevant factor involved. In the present study we analyzed the anatomical relationship between the neurons in the celiac-superior mesenteric ganglia (CSMG), and the right or left ovary in 24 or 28 days old female pre-pubertal rats. The participation of the superior ovarian nerve (SON) in the communication between the CSMG and the ovaries was analyzed in animals with unilateral section of the SON, previous to injecting true blue (TB) into the ovarian bursa. The animals were killed seven days after treatment. TB stained neurons were quantified at the superior mesenteric-celiac ganglia. The number of labeled neurons in the CSMG of rats treated at 28 days of age was significantly higher than those treated on day 24. At age 24 days, injecting TB into the right ovary resulted in neuron stains on both sides of the celiac ganglia; whereas, injecting the left side the stains were exclusively ipsilateral. Such asymmetry was not observed when the rats were treated at age of 28 days. In younger rats, sectioning the left SON resulted in significantly lower number of stained neurons in the left ganglia while sectioning the right SON did not modify the number of stained neurons. When sectioning of the SON was performed to 28 days old rats, no staining was observed. Present results show that the number and connectivity of post-ganglionic neurons of the CSMG connected to the ovary of juvenile female rats change as the animal mature; that the SON plays a role in this communication process as puberty approaches; and that this maturing process is different for the right or the left ovary. PMID:19460167

Rapamycin preserves the follicle pool reserve and prolongs the ovarian lifespan of female rats via modulating mTOR activation and sirtuin expression.

PubMed

Zhang, Xing-mei; Li, Li; Xu, Jin-jie; Wang, Na; Liu, Wei-juan; Lin, Xuan-hao; Fu, Yu-cai; Luo, Li-li

2013-07-01

To maintain the normal length of female reproductive life, the majority of primordial follicles must be maintained in a quiescent state for later use. In this study, we aimed to study the effects of rapamycin on primordial follicle development and investigate the role of mTOR and sirtuin signaling. Rats were treated every other day with an intraperitoneal injection of rapamycin (5mg/kg) or vehicle. After 10weeks of treatment, ovaries were harvested for hematoxylin and eosin (HE) staining, and analysis by immunohistochemistry and Western blotting. HE staining showed that the number and percentage of primordial follicles in the rapamycin-treated group were twice the control group (P<0.001). Immunohistochemical analysis showed that mTOR and phosphorylated-p70S6K were extensively expressed in surviving follicles with strong staining observed in the cytoplasm of the oocyte. Western blotting showed decreased expression of phosphorylated mTOR and phosphorylated p70S6K in the rapamycin-treated group, and increased the expression of both SIRT1 and SIRT6 compared to the control group (P<0.05). Taken together, these results suggest that rapamycin may inhibit the transition from primordial to developing follicles and preserve the follicle pool reserve, thus extending the ovarian lifespan of female rats via the modulation of mTOR and sirtuin signalings. Copyright © 2013 Elsevier B.V. All rights reserved.

Evaluation of the protective effects of CoQ₁₀ on ovarian I/R injury: an experimental study.

PubMed

Ozler, Ali; Turgut, Abdulkadir; Görük, Neval Yaman; Alabalik, Ulas; Basarali, Mustafa Kemal; Akdemir, Fatih

2013-01-01

The aim of this study was to investigate the protective effects of coenzyme Q₁₀ (CoQ₁₀) on ovarian ischemia/reperfusion injury in an experimental rat adnexal torsion model. 48 female adult Wistar albino rats, weighing 220-250 g, were randomly equally divided into six groups (n = 8): sham, torsion, detorsion, sham+CoQ₁₀, torsion+CoQ₁₀, and detorsion+CoQ₁₀ groups. Bilateral adnexal torsion was performed for 3 h in all groups, except the sham and sham+CoQ₁₀ groups. Bilateral adnexal detorsion was performed on the detorsion and detorsion+CoQ₁₀ groups. CoQ₁₀ was injected intraperitoneally 30 min before the sham operation, torsion, and detorsion. The torsion and detorsion groups had significantly higher histologic evaluation scores, as well as higher MDA levels, TOS values, and oxidative stress index values than the sham group. A strong correlation between total histologic evaluation scores for ischemia/reperfusion injury and the oxidative stress index was found. The mean oxidant marker levels and histopathologic scores for the ovarian tissue significantly decreased after using CoQ₁₀, which is a potent antioxidant. Conservative surgery (detorsion) was found to provide inadequate protection to ovarian tissue. The results of this study suggest that CoQ₁₀ could be useful for the protection of ovarian tissue before conservative surgery. © 2013 S. Karger AG, Basel.

The Protective Effects of Alpha-Lipoic Acid and Coenzyme Q10 Combination on Ovarian Ischemia-Reperfusion Injury: An Experimental Study.

PubMed

Tuncer, Ahmet Ali; Bozkurt, Mehmet Fatih; Koken, Tulay; Dogan, Nurhan; Pektaş, Mine Kanat; Baskin Embleton, Didem

2016-01-01

Objective. This study aims to evaluate whether alpha-lipoic acid and/or coenzyme Q10 can protect the prepubertal ovarian tissue from ischemia-reperfusion injury in an experimental rat model of ovarian torsion. Materials and Methods. Forty-two female preadolescent Wistar-Albino rats were divided into 6 equal groups randomly. The sham group had laparotomy without torsion; the other groups had torsion/detorsion procedure. After undergoing torsion, group 2 received saline, group 3 received olive oil, group 4 received alpha-lipoic acid, group 5 received coenzyme Q10, and group 6 received both alpha-lipoic acid and coenzyme Q10 orally. The oxidant-antioxidant statuses of these groups were compared using biochemical measurement of oxidized/reduced glutathione, glutathione peroxidase and malondialdehyde, pathological evaluation of damage and apoptosis within the ovarian tissue, and immunohistochemical assessment of nitric oxide synthase. Results. The left ovaries of the alpha-lipoic acid + coenzyme Q10 group had significantly lower apoptosis scores and significantly higher nitric oxide synthase content than the left ovaries of the control groups. The alpha-lipoic acid + coenzyme Q10 group had significantly higher glutathione peroxidase levels and serum malondialdehyde concentrations than the sham group. Conclusions. The combination of alpha-lipoic acid and coenzyme Q10 has beneficial effects on oxidative stress induced by ischemia-reperfusion injury related to ovarian torsion.

Use of multiple imaging modalities to detect ovarian cancer

NASA Astrophysics Data System (ADS)

Kanter, Elizabeth; Walker, Ross; Marion, Sam; Hoyer, Patricia; Barton, Jennifer K.

2005-04-01

Ovarian cancer is not a common cancer-approximately 25,000 new cases in 2004-but it is the fifth leading cause of death from cancer in women (over 16,000 in 2004). Little is known about the precursors and early stages of ovarian cancer partially due to the lack of human samples at the early stages. A cohesive model that incorporates ovarian cancer induction into a menopausal rodent would be well suited for comprehensive studies of ovarian cancer. Non-destructive imaging would allow carcinogenesis to be followed. Optical Coherence Tomography (OCT), Optical Coherence Microscopy (OCM) and Light-Induced Fluorescence (LIF) are minimally invasive optical modalities that allow both structural and biochemical changes to be noted. Rat ovaries were exposed to 4-vinylcyclohexene diepoxide (VCD) for 20 days in order to destroy the primordial follicles. Plain sutures and sutures coated with 7,12-dimethylbenz(a)anthracene (DMBA) were implanted in the right ovary, in order to produce epithelial based ovarian cancers (a plain suture was inserted in the control). Rats were sacrificed at 4 weeks and ovaries were harvested and imaged with a combined OCT/LIF system and with the OCM. Histology was preformed on the harvested ovaries and any pathology determined. Two of the ovaries were visually abnormal; the OCT/LIF imaging confirmed these abnormalities. The normal ovary OCM and OCT images show the organized structure of the ovary, the follicles, bursa and corpus lutea are visible. The OCM images show the disorganized structure of one of the abnormal ovaries. Overall this pilot study demonstrated the feasibility of both the animal model and optical imaging.

Adolescent Premature Ovarian Insufficiency Following Human Papillomavirus Vaccination

PubMed Central

Ward, Harvey Rodrick Grenville

2014-01-01

Three young women who developed premature ovarian insufficiency following quadrivalent human papillomavirus (HPV) vaccination presented to a general practitioner in rural New South Wales, Australia. The unrelated girls were aged 16, 16, and 18 years at diagnosis. Each had received HPV vaccinations prior to the onset of ovarian decline. Vaccinations had been administered in different regions of the state of New South Wales and the 3 girls lived in different towns in that state. Each had been prescribed the oral contraceptive pill to treat menstrual cycle abnormalities prior to investigation and diagnosis. Vaccine research does not present an ovary histology report of tested rats but does present a testicular histology report. Enduring ovarian capacity and duration of function following vaccination is unresearched in preclinical studies, clinical and postlicensure studies. Postmarketing surveillance does not accurately represent diagnoses in adverse event notifications and can neither represent unnotified cases nor compare incident statistics with vaccine course administration rates. The potential significance of a case series of adolescents with idiopathic premature ovarian insufficiency following HPV vaccination presenting to a general practice warrants further research. Preservation of reproductive health is a primary concern in the recipient target group. Since this group includes all prepubertal and pubertal young women, demonstration of ongoing, uncompromised safety for the ovary is urgently required. This matter needs to be resolved for the purposes of population health and public vaccine confidence. PMID:26425627

77 FR 72223 - Clodinafop-Propargyl; Pesticide Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-05

... carcinogenic to humans based on increased incidences of prostate tumors in male rats, ovarian adenomas in... cancer risk using a linear (non-threshold) approach. Since that time, additional data have been submitted, including a re-evaluation of the proliferative lesions in the rat ovary and prostate as well as [[Page 72225...

Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells.

PubMed

Ganesan, Shanthi; Keating, Aileen F

2015-02-01

Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR-G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6μM) for 24 or 48h. Cell viability was reduced (P<0.05) after 48h of exposure to 3 or 6μM PM. The NOR-G-OH DNA adduct was detected after 24h of 6μM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48h by exposure to both PM concentrations. Phosphorylated H2AX (γH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, γH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response. Copyright © 2014 Elsevier Inc. All rights reserved.

Expression of anti-Müllerian hormone in two rat models of polycystic ovary syndrome.

PubMed

Du, Dan-Feng; Li, Xue-Lian; Zheng, Sai-Hua

2016-12-01

Anti-Müllerian hormone (AMH) levels are two to three times higher in patients with polycystic ovary syndrome (PCOS), but the mechanism of increased AMH levels in PCOS remains unclear. The purpose of our experiment was to investigate a change in AMH levels in two kinds of commonly used rat models and to determine an ideal model for future research of AMH in the pathogenesis of PCOS. Thirty female Sprague Dawley rats were treated using two modeling methods: implantation of a levonorgestrel silastic implant or injection with sodium prasterone sulfate plus human chorionic gonadotropin (hCG). Rats in the control group were implanted with a blank silastic stick. Serum steroid concentrations, ovarian morphology and ovarian expression of AMH and AMH-receptor II (RII) proteins were determined and their correlations were studied. The results from the levonorgestrel and hCG group were closer to those displayed by human PCOS patients than the sodium prasterone sulfate and hCG group. Ovarian local expression of AMH and AMH-RII was increased in these both models compared with the control group; however, an elevation of serum AMH concentration was not observed (12.53 ± 0.99 ng/ml and 13.22 ± 1.09 ng/ml vs 16.30 ± 0.98 ng/ml). The levonorgestrel and hCG model is more suitable for the study of PCOS in puberty. © 2016 Japan Society of Obstetrics and Gynecology.

High-fat high-sugar diet induces polycystic ovary syndrome in a rodent model.

PubMed

Roberts, Jacob S; Perets, Ron A; Sarfert, Kathryn S; Bowman, John J; Ozark, Patrick A; Whitworth, Gregg B; Blythe, Sarah N; Toporikova, Natalia

2017-01-27

Obesity has been linked with a host of metabolic and reproductive disorders including polycystic ovary syndrome (PCOS). While a clear association exists between obesity and PCOS, the exact nature of this relationship remains unexplained. The primary symptoms of PCOS include hyperandrogenism, anovulation, and polycystic ovaries. Most animal models utilize androgen treatments to induce PCOS. However, these models often fail to address the underlying causes of the disease and do not effectively reproduce key metabolic features such as hyperinsulinemia. Here, we present a novel rodent model of diet-induced obesity that recapitulates both the metabolic and reproductive phenotypes of human PCOS. Rats on a high-fat high-sugar (HFHS) diet not only demonstrated signs of metabolic impairment, but they also developed polycystic ovaries and experienced irregular estrous cycling. Though hyperandrogenism was not characteristic of HFHS animals as a group, elevated testosterone levels were predictive of high numbers of ovarian cysts. Alterations in steroidogenesis and folliculogenesis gene expression were also found via RNA sequencing of ovarian tissue. Importantly, the PCOS-like symptoms induced in these rats may share a similar etiology to PCOS in humans. Therefore, this model offers a unique opportunity to study PCOS at its genesis rather than following the development of disease symptoms.

Potential protective effect of Tualang honey on BPA-induced ovarian toxicity in prepubertal rat.

PubMed

Zaid, Siti Sarah Mohamad; Othman, Shatrah; Kassim, Normadiah M

2014-12-17

To investigate the potential protective effects of Tualang honey against the toxicity effects induced by Bisphenol A (BPA) on pubertal development of ovaries. This study was conducted on pre-pubertal female Sprague Dawley rats. Animals were divided into four groups (n = 8 in each group). Group I was administered with vehicle 0.2 ml of corn oil (Sigma-Aldrich, USA) using oral gavage daily for six weeks; these animals served as negative control (CO group), Group II was administered with BPA suspended in corn oil at 10 mg/kg body weight and served as positive control (PC group), Group III was administered with 200 mg/kg body weight of Tualang honey 30 min before the administration of BPA at 10 mg/kg (TH group) while Group IV was administered with 200 mg/kg body weight of Tualang honey 30 min before the administration of corn oil (THC group). Body weight of all animals were monitored weekly. The BPA-exposed animals exhibited disruption of their estrus cycle, while those animals treated with BPA together with Tualang honey, exhibited an improvement in percentage of normal estrous cycle. Their ovaries had lower numbers of atretic follicles compared to the PC group but higher than the CO group. Tualang honey has a potential role in reducing BPA-induced ovarian toxicity by reducing the morphological abnormalities of the ovarian follicles and improving the normal estrous cycle.

Diurnal rhythmicity of the clock genes Per1 and Per2 in the rat ovary.

PubMed

Fahrenkrug, Jan; Georg, Birgitte; Hannibal, Jens; Hindersson, Peter; Gräs, Søren

2006-08-01

Circadian rhythms are generated by endogenous clocks in the central brain oscillator, the suprachiasmatic nucleus, and peripheral tissues. The molecular basis for the circadian clock consists of a number of genes and proteins that form transcriptional/translational feedback loops. In the mammalian gonads, clock genes have been reported in the testes, but the expression pattern is developmental rather than circadian. Here we investigated the daily expression of the two core clock genes, Per1 and Per2, in the rat ovary using real-time RT-PCR, in situ hybridization histochemistry, and immunohistochemistry. Both Per1 and Per2 mRNA displayed a statistically significant rhythmic oscillation in the ovary with a period of 24 h in: 1) a group of rats during proestrus and estrus under 12-h light,12-h dark cycles; 2) a second group of rats representing a mixture of all 4 d of the estrous cycle under 12-h light,12-h dark conditions; and 3) a third group of rats representing a mixture of all 4 d of estrous cycle during continuous darkness. Per1 mRNA was low at Zeitgeber time 0-2 and peaked at Zeitgeber time 12-14, whereas Per2 mRNA was delayed by approximately 4 h relative to Per1. By in situ hybridization histochemistry, Per mRNAs were localized to steroidogenic cells in preantral, antral, and preovulatory follicles; corpora lutea; and interstitial glandular tissue. With newly developed antisera, we substantiated the expression of Per1 and Per2 in these cells by single/double immunohistochemistry. Furthermore, we visualized the temporal intracellular movements of PER1 and PER2 proteins. These findings suggest the existence of an ovarian circadian clock, which may play a role both locally and in the hypothalamo-pituitary-ovarian axis.

Polycystic ovary syndrome: possible involvement of androgen-induced, chemerin-mediated ovarian recruitment of monocytes/macrophages.

PubMed

Lima, Patricia D A; Nivet, Anne-Laure; Wang, Qi; Chen, Yi-An; Leader, Arthur; Cheung, Annie; Tzeng, Chii-Ruey; Tsang, Benjamin K

2018-04-24

Polycystic ovary syndrome (PCOS) is a continuum of endocrine and reproductive disorders characterized by hyperandrogenism, antral follicle growth arrest and chronic inflammation. Macrophages play key role in inflammation and the balance between M1 (inflammatory) and M2 (anti-inflammatory) macrophages determines physiological/pathological outcomes. Here, we investigated if hyperandrogenism increases ovarian chemerin altering the balance of M1 and M2 macrophages and the granulosa cell death. Ovarian chemerin was up-regulated by 5α-dihydrotestosterone (DHT) in lean and overweight rats; while increased serum chemerin levels were only evident in overweight rats, suggesting that the serum chemerin may be reflective of a systemic response and associated with obesity, whereas increased ovarian chemerin expression is a localized response independent of the metabolic status. DHT altered follicle dynamics while increased the M1: M2 macrophages ratio in antral and pre-ovulatory follicles. While ovarian M1 macrophages expressing chemokine-like receptor 1 (CMKLR1) were increased, CMKLR1 + monocytes, which migrated towards chemerin-rich environment, were markedly decreased after 15 days of DHT. Androgen-induced granulosa cell apoptosis was dependent on the presence of macrophages. In humans, chemerin levels in follicular fluid, but not in serum, was higher in lean PCOS patients compared to BMI-matched controls and was associated with increased M1: M2 ratio. Our results support the concept that in PCOS, hyperandrogenemia increases chemerin expression while promotes CMKLR1 + monocytes recruitment and deregulates the immunological niche of ovaries. This study established a new immunological perspective in PCOS at the ovarian level. Hyperandrogenism is associated with up-regulation of chemerin and macrophage unbalance in the ovaries.

Transitional gene expression profiling in ovarian follicle during ovulation in normal-cycle rats.

PubMed

Tsubota, Kenjiro; Kanki, Masayuki; Noto, Takahisa; Shiraki, Katsuhisa; Takeuchi, Ayano; Nakatsuji, Shunji; Seki, Jiro; Oishi, Yuji; Matsumoto, Masahiro; Nakayama, Hiroyuki

2011-06-01

Evaluation of ovarian toxicity requires an understanding of the physiological changes related to the estrous cycle in the ovary. The authors investigated the transitional gene expression profile of ovulatory follicles in rats that show normal estrous cyclicity. Ovaries were collected at 10:00 and 22:00 on the proestrus day and at 10:00 on the estrus day. Ovarian follicles or early corpora lutea were isolated using laser microdissection, and extracted total RNA was analyzed using microarray technology. Clustering analysis revealed four different expression patterns: transient up- or down-regulation only at 22:00 on the proestrus day (pattern 1), up- or down-regulation only at 10:00 on the estrus day (pattern 2), continuous increase at 22:00 on the proestrus day and at 10:00 on the estrus day (pattern 3), and up- or down-regulation at 22:00 on the proestrus day and level maintenance at 10:00 on the estrus day (pattern 4). In addition, these probe sets were functionally categorized in each pattern using the Ingenuity Pathways Analysis database. These data will aid in understanding the physiology of ovulation and may be useful in assessing ovarian toxicity and its mechanism, such as in investigations of chemical-induced ovulatory impairment.

Expression of regulator of G-protein signaling protein-2 gene in the rat ovary at the time of ovulation.

PubMed

Ujioka, T; Russell, D L; Okamura, H; Richards, J S; Espey, L L

2000-11-01

The ovulatory process in mammals begins when an endogenous surge in LH circulates to the ovary and couples with receptors in the plasma membranes of granulosa cells in mature ovarian follicles. This study provides evidence that the ovulatory stimulus includes induction of the gene for regulator of G-protein signaling protein-2 (RGS2). Immature Wistar rats were primed with 10 IU eCG s.c., and 48 h later the 12-h ovulatory process was initiated by 10 IU hCG (a homolog of LH) s.c. Ovarian RNA was extracted at 0, 2, 4, 8, 12, and 24 h after injecting the animals with hCG. The RNA extracts were used for reverse transcription-polymerase chain reaction differential display to detect gene expression in the stimulated ovarian tissue. Two of the amplified cDNAs that were upregulated within 2 h after the ovaries had been stimulated by hCG were homologous to segments of the mouse gene for RGS2. In situ hybridization indicated that the RGS2 mRNA was expressed in the granulosa layer of mature follicles. In conclusion, the gene for RGS2, which is known to regulate membrane signaling pathways, is transcribed in ovarian follicles in response to an ovulatory dose of gonadotropin.

Expression of hypoxia-inducible factor-1α during ovarian follicular growth and development in Sprague-Dawley rats.

PubMed

Zhang, Z H; Chen, L Y; Wang, F; Wu, Y Q; Su, J Q; Huang, X H; Wang, Z C; Cheng, Y

2015-06-01

Hypoxia-inducible factor-1α (HIF-1α) has been identified as a transcription factor that is involved in diverse physiological and pathological processes in the ovary. In this study, we examined whether HIF-1α is expressed in a cell- and stage-specific manner during follicular growth and development in the mammalian ovaries. Using immunohistochemistry and Western blot analysis, HIF-1α expression was observed in granulosa cells specifically and was significantly increased during the follicular growth and development of postnatal rats. Furthermore, pregnant mare serum gonadotropin also induced HIF-1α expression in granulosa cells and ovaries during the follicular development of immature rats primed with gonadotropin. Moreover, we also examined proliferation cell nuclear antigen, a cell proliferation marker, during follicular growth and development and found that its expression pattern was similar to that of HIF-1α protein. Granulosa cell culture experiments revealed that proliferation cell nuclear antigen expression may be regulated by HIF-1α. These results indicated that HIF-1α plays an important role in the follicular growth and development of these 2 rat models. The HIF-1α-mediated signaling pathway may be an important mechanism regulating follicular growth and development in mammalian ovaries in vivo.

INFLUENCE OF THE DRINKING WATER DISINFECTION BY-PRODUCT DIBROMOACETIC ACID ON RAT ESTROUS CYCLICITY AND OVARIAN FOLLICULAR STEROID RELEASE IN VITRO

EPA Science Inventory

The drinking water disinfection by-product, dibromoacetic acid (DBA) has been reported to affect gonadal functions in the male rat. However, there is little information regarding its influence on female reproductive activity. Consequently, the present study investigated the eff...

[Study on the oxidative stress in the ovaries of a rat model of polycystic ovary].

PubMed

Gong, Jin; Wu, Dong-bo; Zhang, Lan-lan; Li, Jia; Zhao, Xing; Zhang, Dan

2015-03-01

To establish a pathological animal model of polycystic ovary (PCO) by letrozole in rats. Investigate whether PCO were mediated by the effect of oxidative stress by measuring oxidative stress levels in this cohort of rats with PCO, and proceed a new way of treatment for polycystic ovary syndrom (PCOS). 90 SD female rats aged 6 weeks were randomly divided into two groups, including a control group of 45 rats that received vehicle only [19% aqueous solution of carboxmethlycellulose (CMC), 1 mL/d] once daily orally (p.o.), and an experimental group of 45 rats, which were administered letrozole at concentrations of 1 mg/kg p.o. dissolved in 1% CMC (1 mL/d) once daily. The treatment period was 28 d. During this period, vaginal smears were collected daily for estrus cycle determination and body masses were measured every 7 d. On the day subsequent to the last letrozole dose administration, rats were killed; Uteri and ovaries were then excised and weighed for the calculation of organ indexes. Serum hormone levels, SHBG and histologic changes in the ovaries were examined. Then testosterone free index (FAD) was calculated. Oxidant status was evaluated by determination of ovarian total oxidant status (TOS), malondialdehyde (MDA) concentration and intracellular reactive oxygen species (ROS) level, while antioxidant status was evaluated by determination of total antioxidant status (TAS) and superoxide dismutase (SOD) concentration. Vaginal smear test showed the estrus cycle began to disappear from day 12 to day 15. A statistically significant difference in growth curves, ovarian weights, uterine weights and organ indexes between the groups were also observed. In rats with PCO serum testosterone (T), follicle-stimulating hormone (FSH) concentrations and free androgen index (FADI) were significantly increased compared with the control group (rats without PCO). However, rats with PCO had decreased levels of estrogen (E2), luteinizing hormone (LH), and progesterone (P) compared with the control group. In a rat model of PCO achieved via letrozole, it was found that the levels of TOS, MDA, oxidative stress index (OSI) and intracellular ROS were significantly increased, while the TAS level, SOD content were significantly decreased in the ovary homogenates (P<0.05). The results indicated that the PCOS pathological process significantly increased the oxidative stress production. PCO rat model successfully induced via letrozole, and it is a suitable model for study of ovarian lesions. Oxidative stress also contributes to the PCO rat model, the protective effect of antioxidant might provide a new insight into the potential therapeutic solution to PCOS.

Molecular mechanisms of a novel selenium-based complementary medicine which confers protection against hyperandrogenism-induced polycystic ovary.

PubMed

Rezvanfar, M A; Rezvanfar, M A; Ahmadi, A; Shojaei-Saadi, H A; Baeeri, M; Abdollahi, M

2012-08-01

The objective was to evaluate ovarian functionality and oxidative response in hyperandrogenism-induced polycystic ovary (PCO) and the protective effects of immunomodulator drug (IMOD), an electromagnetically-treated, selenium-based, herbal medicine. Daily oral administration of letrozole (1 mg/kg) for 21 consecutive days induced ovarian cysts in female rats. An effective dose of IMOD (30 mg/kg per day) was given intraperitoneally for 21 days. Biomarkers of ovarian function, serum concentrations of estradiol, progesterone, testosterone, and ovarian prostaglandin-E (PGE), were analyzed. To determine the role of oxidative stress (OS) in hyperandrogenism-induced PCO, concentrations of cellular lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxynitrite (ONOO), and tumor necrosis factor (TNF)-α as a marker of inflammation and apoptosis were measured in serum and ovaries. Letrozole-induced PCO resulted in significant increases in concentrations of lipid peroxidation and peroxynitrite in serum and ovary, but significantly decreased superoxide dismutase, catalase, and glutathione peroxidase. Serum concentrations of testosterone and TNF-α, and ovarian prostaglandin-E were increased (P < 0.001) in animals with cysts versus control, whereas estradiol and progesterone were decreased (P < 0.01 and P < 0.001, respectively). When compared with controls, letrozole induced irregular cycles and PCO characterized by a high incidence of subcapsular ovarian cysts with a diminished granulosa cell layer, luteinized granulosa cells in the cyst wall, significantly more atretic preantral and antral follicles, and absence of CL. There were almost no intact primary, secondary, and tertiary follicles in PCO rats. All end points assessed were significantly improved by IMOD and reached close to normal levels. In conclusion, the present study provided evidence that toxic free radicals and TNF-α were involved in the pathogenesis of PCO; furthermore, IMOD prevented ovarian histopathologic, endocrine, and biochemical alterations induced by hyperandrogenism. Copyright © 2012 Elsevier Inc. All rights reserved.

Elevated expression of steroidogenesis pathway genes; CYP17, GATA6 and StAR in prenatally androgenized rats.

PubMed

Jahromi, Marziyeh Salehi; Tehrani, Fahimeh Ramezani; Noroozzadeh, Mahsa; Zarkesh, Maryam; Ghasemi, Asghar; Zadeh-Vakili, Azita

2016-11-15

It is believed that excess androgen exposure of the fetus, via altered gene expression, causes hyperandrogenism a key feature of polycystic ovary syndrome (PCOS). The aim of this study was to evaluate expression of Cytochrome P450-17 (CYP17), GATA-binding protein (GAGT6) and Steroidogenic acute regulatory protein (StAR), genes of adult female rats prenatally exposed to androgen excess, closely reflect endocrine and ovarian disturbances of PCOS in women, by comparing them during different phases of estrus cycle with those of non-treated rats. Both the adult prenatally testosterone exposed and control rats (n=23, each) were divided into four groups based on their observed vaginal smear (proestrus, estrus, metestrus and diestrus) and the relative expression of CYP17, GATA6 and StAR genes was measured in ovarian theca cells using Cyber-green Real-Time PCR. Serum sex steroid hormones and gonadotropins levels were measured using the ELISA method; a comparison of these two groups showed that there was an overall increase in the studied genes (CYP17; 2.39 fold change, 95% CI: 1.23-3.55; P<0.05, GATA6; 2.08 fold change, 95% CI: 1.62-2.55; P<0.0001, and StAR; 1.4 fold change, 95% CI: 1.02-1.78; P<0.05), despite variations in different phases with maximum elevation for all genes in diestrus. The changes observed may impair the normal development of ovaries that mediate the programming of adult PCOS. Copyright © 2016 Elsevier B.V. All rights reserved.

Ovarian expression of cellular Ki-ras p21 varies with physiological status.

PubMed Central

Palejwala, S; Goldsmith, L T

1992-01-01

To elucidate the potential role of the ras protooncogene proteins in a specific tissue, the present study determined the levels of individual c-ras-encoded p21 proteins in the rat ovary during various stages of physiological function. p21 protein was extracted from ovaries taken from immature normal female rats, mature nonpregnant animals in the metestrus stage of the estrus cycle, rats at various stages of pregnancy, and actively lactating animals. Levels of individual p21s were evaluated by immunoblot analysis with specific antibodies to the p21 proteins encoded by the Kirsten, Harvey, and neuroblastoma c-ras protooncogenes, c-Ki-ras, c-Ha-ras, and N-ras. Results showed that c-Ki-ras p21 is at its lowest level in the immature ovary and increases with development of the corpora lutea to its highest levels at day 16 of pregnancy, after which levels decline and then rise again during lactation. This pattern, which mimics that of circulating progesterone levels, suggests that ovarian c-Ki-ras p21 levels are regulated and that c-Ki-ras p21 plays a role in the differentiated function of the rat ovary, likely the luteal compartment. In contrast, levels of c-N-ras p21 did not appear to vary with changes in the physiological function of the ovary but appeared to be constitutive. A preferential role for the c-Ki-ras p21 may be due to the documented unique differences in the structure of the carboxyl terminus of this particular c-ras p21. Images PMID:1570348

Effect of immune stress on body weight regulation is altered by ovariectomy in female rats.

PubMed

Iwasa, Takeshi; Matsuzaki, Toshiya; Kinouchi, Riyo; Gereltsetseg, Ganbat; Murakami, Masahiro; Nakazawa, Hiroshi; Fujisawa, Shinobu; Yamamoto, Satoshi; Kuwahara, Akira; Yasui, Toshiyuki; Irahara, Minoru

2011-09-01

It has been suggested that obesity and loss of ovarian function alter the inflammatory response to immune stress. Ovariectomized (OVX) rats, which are used as a model of human menopause, exhibit both hyperphagia-induced obesity and gonadal steroid deficiency. To evaluate the effects of ovariectomy on inflammatory responses, we compared the anorectic response to LPS in OVX rats and gonad intact female rats. As leptin and hypothalamic interleukin-1β (IL1β) play pivotal roles in the anorectic response to immune stress, these factors were also measured. It was found that the OVX rats exhibited an increased anorectic response to LPS compared with the sham-operated rats. The OVX rats showed higher serum leptin concentrations and a greater increase in hypothalamic IL1β mRNA expression after LPS injection. In addition, in order to determine whether gonadal steroid deficiency contributes to the changes in the inflammatory responses of OVX rats, we compared responses between OVX rats treated with gonadal steroids and untreated OVX rats. There were no differences in appetite, the serum leptin level, and hypothalamic IL1β mRNA expression between the two groups after LPS injection. These findings suggest that the loss of ovarian function increases the induction of leptin and hypothalamic IL1β synthesis and consequently increases the anorectic response under immune stress conditions. It is possible that these alterations are caused by OVX-induced obesity rather than the direct effects of gonadal steroid deficiency. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Ovarian membrane-type matrix metalloproteinases: induction of MMP14 and MMP16 during the periovulatory period in the rat, macaque, and human.

PubMed

Puttabyatappa, Muraly; Jacot, Terry A; Al-Alem, Linah F; Rosewell, Katherine L; Duffy, Diane M; Brännström, Mats; Curry, Thomas E

2014-08-01

An intrafollicular increase in proteolytic activity drives ovulatory events. Surprisingly, the periovulatory expression profile of the membrane-type matrix metalloproteinases (MT-MMPs), unique proteases anchored to the cell surface, has not been extensively examined. Expression profiles of the MT-MMPs were investigated in ovarian tissue from well-characterized rat and macaque periovulatory models and naturally cycling women across the periovulatory period. Among the six known MT-MMPs, mRNA expression of Mmp14, Mmp16, and Mmp25 was increased after human chorionic gonadotropin (hCG) administration in rats. In human granulosa cells, mRNA expression of MMP14 and MMP16 increased following hCG treatment. In contrast, mRNA levels of MMP16 and MMP25 in human theca cells were unchanged before ovulation but declined by the postovulatory stage. In macaque granulosa cells, hCG increased mRNA for MMP16 but not MMP14. Immunoblotting showed that protein levels of MMP14 and MMP16 in rats increased, similar to their mRNA expression. In macaque granulosa cells, only the active form of the MMP14 protein increased after hCG, unlike its mRNA or the proprotein. By immunohistochemistry, both MMP14 and MMP16 localized to the different ovarian cell types in rats and humans. Treatment with hCG resulted in intense immunoreactivity of MMP14 and MMP16 proteins in the granulosa and theca cells. The present study shows that MMP14 and MMP16 are increased by hCG administration in the ovulating follicle, demonstrating that these MMPs are conserved among rats, macaques, and humans. These findings suggest that MT-MMPs could have an important role in promoting ovulation and remodeling of the ovulated follicle into the corpus luteum. © 2014 by the Society for the Study of Reproduction, Inc.

Ovarian Membrane-Type Matrix Metalloproteinases: Induction of MMP14 and MMP16 During the Periovulatory Period in the Rat, Macaque, and Human1

PubMed Central

Puttabyatappa, Muraly; Jacot, Terry A.; Al-Alem, Linah F.; Rosewell, Katherine L.; Duffy, Diane M.; Brännström, Mats; Curry, Thomas E.

2014-01-01

ABSTRACT An intrafollicular increase in proteolytic activity drives ovulatory events. Surprisingly, the periovulatory expression profile of the membrane-type matrix metalloproteinases (MT-MMPs), unique proteases anchored to the cell surface, has not been extensively examined. Expression profiles of the MT-MMPs were investigated in ovarian tissue from well-characterized rat and macaque periovulatory models and naturally cycling women across the periovulatory period. Among the six known MT-MMPs, mRNA expression of Mmp14, Mmp16, and Mmp25 was increased after human chorionic gonadotropin (hCG) administration in rats. In human granulosa cells, mRNA expression of MMP14 and MMP16 increased following hCG treatment. In contrast, mRNA levels of MMP16 and MMP25 in human theca cells were unchanged before ovulation but declined by the postovulatory stage. In macaque granulosa cells, hCG increased mRNA for MMP16 but not MMP14. Immunoblotting showed that protein levels of MMP14 and MMP16 in rats increased, similar to their mRNA expression. In macaque granulosa cells, only the active form of the MMP14 protein increased after hCG, unlike its mRNA or the proprotein. By immunohistochemistry, both MMP14 and MMP16 localized to the different ovarian cell types in rats and humans. Treatment with hCG resulted in intense immunoreactivity of MMP14 and MMP16 proteins in the granulosa and theca cells. The present study shows that MMP14 and MMP16 are increased by hCG administration in the ovulating follicle, demonstrating that these MMPs are conserved among rats, macaques, and humans. These findings suggest that MT-MMPs could have an important role in promoting ovulation and remodeling of the ovulated follicle into the corpus luteum. PMID:24920038

Assessment of the biopotency of follitropin alfa and lutropin alfa combined in one injection: a comparative trial in Sprague-Dawley rats

PubMed Central

Alper, Michael; Meyer, Randal; Dekkers, Chris; Ezcurra, Diego; Schertz, Joan; Kelly, Eduardo

2008-01-01

Background The current study was designed to determine if follitropin alfa (recombinant human follicle-stimulating hormone; r-hFSH) and lutropin alfa (recombinant human luteinizing hormone; r-hLH) biopotencies were unchanged by reconstituting in sterile water for injection and mixing prior to injection. Methods The biopotencies of r-hFSH and r-hLH were determined following injection of female Sprague-Dawley rats with a mixture of follitropin alfa revised formulation female (RFF) and lutropin alfa (1:1, r-hFSH:r-hLH). Biopotencies of follitropin alfa RFF and lutropin alfa were measured using ovarian weight and ascorbic acid depletion assays, respectively, and compared with a reference standard. Stock mixtures of follitropin alfa RFF and lutropin alfa (1:1) were prepared within 1 h prior to each respective assay's injection and stored at 6 +/- 2°C. Separate low dose (follitropin alfa RFF 1.5 IU/rat, lutropin alfa 2 IU/rat) and high dose (follitropin alfa RFF 3 IU/rat, lutropin alfa 8 IU/rat) treatments were prepared from stock mixtures or individual solutions by diluting with 0.22% bovine serum albumin saline solution and injected within 1 h of preparation. The main outcome measures were ovarian weight and ovarian ascorbic acid depletion. Results FSH bioactivities were similar (p > 0.10) between the individual follitropin alfa RFF test solution (84.2 IU) and follitropin alfa RFF/lutropin alfa (87.6 IU) mixtures prepared within 1 h of injection and stored at 6 +/- 2°C. LH bioactivities were similar (p > 0.10) between lutropin alfa (94.7 IU) test solution and lutropin alfa/follitropin alfa RFF (85.3 IU) mixtures prepared within 1 h of injection and stored at 6 +/- 2°C for not more than 1 h prior to injection. Conclusion Mixing follitropin alfa RFF and lutropin alfa did not alter the bioactivity of either FSH or LH. PMID:18647398

INTERACTION OF ESTRADIOL AND 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN AN OVULATION MODEL: EVIDENCE FOR SYSTEMIC POTENTIATION AND LOCAL OVARIAN EFFECTS. (R826132)

EPA Science Inventory

Immature rats were treated with estradiol cypionate, (ECP, 0, 0.1, 1, or 2 mg/kg s.c.) followed 24 h later by TCDD (0 or 10 g/kg orally). Follicular development was induced with eC...

Pharmacology and toxicology of the novel investigational agent Cantrixil (TRX-E-002-1).

PubMed

Saif, Muhammad Wasif; Heaton, Andrew; Lilischkis, Kimberley; Garner, James; Brown, David M

2017-02-01

Recurrent, chemo-resistant ovarian cancer is thought to be due to a subgroup of slow-growing, drug-resistant cancer cells with stem-like properties and a high capacity for tumour repair. Cantrixil targets this sub-population of cells and is being developed as an intraperitoneal therapy to be used as first-line therapy in combination with carboplatin for epithelial ovarian cancer. The studies presented here justify further development. A GLP dog CV study using a 4 × 4 Latin Square Crossover study was conducted using telemetric ECG recordings from dogs post IP administration to assess for cardiac abnormalities. Mutagenic potential was assessed using the bacterial reverse mutation assay. Clastogenicity was assessed by determining micronuclei formation in the bone marrow of SPF Arc(S) Swiss mice dosed at clinical concentrations. TRX-E-002-1 toxicology was evaluated in GLP-compliant MTD and 28-day repeat-dose studies in rats and dogs. In vitro TRX-E-002-1 has potent cytotoxic activity against human cancer cells including CD44+/MyD88+ ovarian cancer stem cells. TRX-E-002-1 increased phosphorylated c-Jun levels in these cancer cells resulting in caspase-mediated apoptosis. In vivo, Cantrixil was active in a model of disseminated ovarian cancer as a monotherapy and in combination with Cisplatin. Cantrixil was active as maintenance therapy in a model of drug-resistant, recurrent ovarian cancer and in an orthotopic model of pancreatic cancer. In animals, this clinical formulation and route of administration of Cantrixil demonstrated acceptable activity, safety pharmacology, genotoxicity and toxicology profile and constituted a successful Investigational New Drug application to the US Food and Drug Administration.

A combination of stereological methods, biochemistry and electron microscopy for the investigation of drug treatment effects in experimental animals.

PubMed

De Moraes, Alan C N; Andrade, Cherley B V; Salata, Camila; Nascimento, Ana L R; Ramos, Isalira P; Goldenberg, Regina C S; Carvalho, Jorge J; Machado, Ana C S

2016-03-01

Some chemotherapeutic agents used for breast cancer (BC) treatment can induce severe side effects in the ovarian tissue. The combination of cyclophosphamide and docetaxel (TC) is widely used for BC treatment; however, its late effects in the ovary are not completely understood. The main purpose of this study was to evaluate the structural and ultrastructural alterations in the ovarian stroma induced by TC treatment. Wistar rats were divided into two groups: a control group and a TC group. They were euthanized 5 months after the end of treatment, and their plasma and ovaries were collected. Important alterations were noted. The serum estradiol level was significantly reduced in the TC group compared with the control group. Additionally, the number of apoptotic nuclei was higher in the TC group. The role of the inflammatory response in the development of ovarian damage was investigated, and we found an increased number of mast cells and increased expression of TNF-α in the TC group. The involvement of fibrosis was also investigated. The results showed that the TC group had increased expression levels of TGF-β1, collagen type I (col-I) and collagen type III (col-III) compared with the control group. Ultrastructural analysis revealed the presence of collagen fibrils in the treated group and illustrated that the ovarian tissue architecture was more disorganized in this group than in the control group. The results from this study are important in the study of chemotherapy-induced ovarian failure and provide further insight into the mechanisms involved in the development of this disease. © 2015 The Authors Journal of Microscopy © 2015 Royal Microscopical Society.

Pre- and Postnatal Nutritional Histories Influence Reproductive Maturation and Ovarian Function in the Rat

PubMed Central

Sloboda, Deborah M.; Howie, Graham J.; Pleasants, Anthony; Gluckman, Peter D.; Vickers, Mark H.

2009-01-01

Background While prepubertal nutritional influences appear to play a role in sexual maturation, there is a need to clarify the potential contributions of maternal and childhood influences in setting the tempo of reproductive maturation. In the present study we employed an established model of nutritional programming to evaluate the relative influences of prenatal and postnatal nutrition on growth and ovarian function in female offspring. Methods Pregnant Wistar rats were fed either a calorie-restricted diet, a high fat diet, or a control diet during pregnancy and/or lactation. Offspring then were fed either a control or a high fat diet from the time of weaning to adulthood. Pubertal age was monitored and blood samples collected in adulthood for endocrine analyses. Results We report that in the female rat, pubertal timing and subsequent ovarian function is influenced by the animal's nutritional status in utero, with both maternal caloric restriction and maternal high fat nutrition resulting in early pubertal onset. Depending on the offspring's nutritional history during the prenatal and lactational periods, subsequent nutrition and body weight gain did not further influence offspring reproductive tempo, which was dominated by the effect of prenatal nutrition. Whereas maternal calorie restriction leads to early pubertal onset, it also leads to a reduction in adult progesterone levels later in life. In contrast, we found that maternal high fat feeding which also induces early maturation in offspring was associated with elevated progesterone concentrations. Conclusions These observations are suggestive of two distinct developmental pathways leading to the acceleration of pubertal timing but with different consequences for ovarian function. We suggest different adaptive explanations for these pathways and for their relationship to altered metabolic homeostasis. PMID:19707592

Persistent estrus rat models of polycystic ovary disease: an update.

PubMed

Singh, Krishna B

2005-10-01

To critically review published articles on polycystic ovary (PCO) disease in rat models, with a focus on delineating its pathophysiology. Review of the English-language literature published from 1966 to March 2005 was performed through PubMed search. Keywords or phrases used were persistent estrus, chronic anovulation, polycystic ovary, polycystic ovary disease, and polycystic ovary syndrome. Articles were also located via bibliographies of published literature. University Health Sciences Center. Articles on persistent estrus and PCO in rats were selected and reviewed regarding the methods for induction of PCO disease. Changes in the reproductive cycle, ovarian morphology, hormonal parameters, and factors associated with the development of PCO disease in rat models were analyzed. Principal methods for inducing PCO in the rat include exposure to constant light, anterior hypothalamic and amygdaloidal lesions, and the use of androgens, estrogens, antiprogestin, and mifepristone. The validated rat PCO models provide useful information on morphologic and hormonal disturbances in the pathogenesis of chronic anovulation in this condition. These studies have aimed to replicate the morphologic and hormonal characteristics observed in the human PCO syndrome. The implications of these studies to human condition are discussed.

Potential protective effect of arginine against 4-nitrophenol-induced ovarian damage in rats.

PubMed

Xu, Wei-Feng; Li, Yan-Sen; Dai, Peng-Yuan; Li, Chun-Mei

2016-01-01

4-nitrophenol (PNP) is generally regarded as a diesel exhaust particle (DEP). Arginine plays an important role as a new feed additive, possessing highly efficient antioxidant activities. Here we investigated the effects of dietary supplementation with arginine against ovarian damage induced by PNP in rats. A total of thirty-two female rats postnatal day 28 (PND 28) were randomly divided into four groups. Two groups were fed with basal diet or 13 g/kg arginine in diet for 4 weeks, respectively; the other two groups were given PNP (100 mg/kg b.w.) daily by subcutaneous injection for 2 weeks following pretreatment with either basal diet or arginine diet for 2 weeks. The values of body weight gain (BWG), average daily gain (ADG) and percentage weight gain (PWG) upon PNP treatment were significantly reduced than those in other groups. The relative liver weight in the PNP group was significantly decreased compared with the control group. Treatment with PNP significant reduced the number of corpora lutea, although serum 17β-estradiol (E2) and progesterone (P4) concentrations were unchanged. The morphology of the ovaries in PNP-treated rats displayed necrosis, follicular deformation and granulosa cells irregular arrangement. Moreover, exposure to PNP enhanced production of malondialdehyde (MDA) and hydrogen peroxide (H2O2), and decreased the activities of total superoxide dismutase (T-SOD) and catalase (CAT), and the co-administration of arginine can attenuate the oxidative stress caused by PNP. These results suggest that arginine may have a protective effect against ovarian damage induced by PNP owing to its antioxidant capacity effect.

Ovarian histology and follicular score in female rats treated with nandrolone decanoate and submitted to physical effort.

PubMed

Cherici Camargo, Isabel Cristina; Barreiros de Souza, Roberta; de Fátima Paccola Mesquita, Suzana; Chuffa, L G A; Frei, F

2009-09-01

The study was conducted to analyze the histology of the ovaries of adults rats treated with steroids, and submitted or not to physical effort. The control group consisted of females submitted to physical effort and sedentary females, both of which received a physiological solution of 0.9% saline. Treated females, sedentary or not, received 6 mg/kg of body weight of nandrolone decanoate. The steroid and physiological solution were administered intraperitoneally, with a single injection per week for 4 consecutive weeks. The applied physical effort was swimming (20 minutes daily, 5 days/week, for the 4 weeks of treatment). Serial sections (5 mum) of ovaries were prepared for histological evaluation and follicular score. The weight of ovaries and hypophysis, the number of antral and atretic follicles, and the area of corpus luteum were all affected by the steroids. In the ovaries of the control groups, well-developed corpus luteum was observed. In the treated groups, the cortical stroma was occupied by ovarian interstitial tissue. The females treated with steroids presented estral acyclicity. The use of nandrolone decanoate, whether associated with physical effort or not, affected the morphological pattern of the ovaries.

Polyethylene glycol-conjugated chondroitin sulfate A derivative nanoparticles for tumor-targeted delivery of anticancer drugs.

PubMed

Lee, Jae-Young; Park, Ju-Hwan; Lee, Jeong-Jun; Lee, Song Yi; Chung, Suk-Jae; Cho, Hyun-Jong; Kim, Dae-Duk

2016-10-20

Polyethylene glycol (PEG)-decorated chondroitin sulfate A-deoxycholic acid (CSD) nanoparticles (NPs) were fabricated for the selective delivery of doxorubicin (DOX) to ovarian cancer. CSD-PEG was synthesized via amide bond formation between the NH2 group of methoxypolyethylene glycol amine and the COOH group of CSD. CSD-PEG/DOX NPs with a 247nm mean diameter, negative zeta potential, and >90% drug encapsulation efficiency were prepared. Sustained and pH-dependent DOX release profiles from CSD-PEG NPs were observed in dissolution tests. Endocytosis of NPs by SKOV-3 cells (CD44 receptor-positive human ovarian cancer cells), based on the CSA-CD44 receptor interaction, was determined by flow cytometry and confocal laser scanning microscopy (CLSM) studies. PEGylation of NPs also resulted in reduced drug clearance (CL) in vivo and improved relative bioavailability, compared to non-PEGylated NPs, as determined by the pharmacokinetic study performed after intravenous administration in rats. Developed CSD-PEG NPs can be a promising delivery vehicle for the therapy of CD44 receptor-expressing ovarian cancers. Copyright © 2016 Elsevier Ltd. All rights reserved.

Is ursodeoxycholic acid crucial for ischemia/reperfusion-induced ovarian injury in rat ovary?

PubMed

Akdemir, Ali; Sahin, Cagdas; Erbas, Oytun; Yeniel, Ahmet O; Sendag, Fatih

2015-08-01

Ursodeoxycholic acid is frequently used in cholestatic liver diseases. Also, it protects hepatocytes against oxidative stress induced by hydrophobic bile acids. We investigated the anti-oxidative effect of ursodeoxycholic acid on ischemia/reperfusion injury after ovarian de-torsion in rats. We designed five study groups. Group 1 (n = 6): Sham-operated group; group 2 (n = 6): torsion group; group 3 (n = 6): torsion and ursodeoxycholic acid, group 4 (n = 7): torsion/de-torsion group; and group 5 (n = 7): torsion/de-torsion and ursodeoxycholic acid. After that, ovarian samples were obtained and examined histologically and tissue levels of malondialdehyde were measured. Follicular degeneration, edema and inflammatory cells were significantly decreased in groups 3 and 5 in comparison with groups 2 and 4. Also, groups 4 and 5 were compared in terms of vascular congestion and hemorrhage and these were found to be significantly decreased in group 5. In addition, levels of malondialdehyde were significantly decreased in groups 3 and 5 in comparison with groups 2 and 4. We concluded that ursodeoxycholic acid might be useful to protect the ovary against ischemia and reperfusion injury.

Effect of the aqueous extract of Senecio biafrae (Oliv. & Hiern) J. Moore on some fertility parameters in immature female rat.

PubMed

Lienou, L L; Telefo, P B; Njimou, J R; Nangue, C; Bayala, B R; Goka, S C; Biapa, P; Yemele, M D; Donfack, N J; Mbemya, J T; Tagne, S R; Rodrigues, A P R

2015-02-23

Senecio biafrae is a plant from the huge family of Asteraceae used in the African pharmacopoeia for the treatment of many ailments among which is infertility. The aqueous extract, which was primarily subjected to polyphenol analysis, has been administered to immature female rats for 20 days at 8, 32, 64 and 128 mg/kg of body weight. The day following the treatment, the animals were sacrificed; their serum, ovary and uterus were retained respectively for reproductive hormones, ovarian and uterine proteins, and ovarian cholesterol assays. Light body weight gain variation of treated animals was observed during the experimental period. A significant increase (p ˂ 0.05) in serum estradiol and proteins as well as in uterine weight (p ˂ 0.01) of all Senecio biafrae treated animals was noted. No significant variation was noticed in the ovarian weight and follicle numbers. The various biochemical and physiological parameters of fertility were significantly improved with the aqueous extract of Senecio biafrae, thus attesting some of its traditional usage. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

ROLE OF STEROID HORMONES AND DECIDUAL INDUCTION IN THE REGULATION OF ADENOSINE DIPHOSPHORIBOSYL TRANSFERASE ACTIVITY IN RAT ENDOMETRIUM

EPA Science Inventory

To assess the effect of ovarian steroid hormones on enzyme activity, adenosine diphosphoribosyl transferase (ADPRT) was measured in endometrial nuclei isolated on estrus and on d 4 from rats ovariectomized on estrus (d 0) and treated d 0-3 with (a) vehicle, (b) 1 ug estrone/d (E)...

Influence of sex, estrous cycle and estrogen on intracranial dural mast cells

PubMed Central

Boes, Tanner; Levy, Dan

2014-01-01

Background The frequency of migraine headaches is higher in women than in men and in susceptible women attacks are related to changes in ovarian hormone levels. Intracranial mast cells (MCs) are likely to play a role in migraine headache genesis, and changes in the dural MC population might influence headache susceptibility. The present study thus tested the hypothesis that sex and ovarian hormones influence the density and phenotypic makeup of dural MCs. Methods Histochemistry combined with quantitative analyses was employed to investigate sex differences, estrous cycle and ovarian hormone influences on dural MCs density, phenotype and degranulation level in males and females rats. Results Our data show that in female rats, dural MC density fluctuates during the estrous cycle and is overall higher than in males. In ovariectomized rats, estradiol, but not progesterone, promoted an increase in dural MCs density. This effect was abolished by a splenectomy, suggesting estrogen-related recruitment of MCs from the spleen. Finally, our data suggest that the phenotypic make up of dural MCs, which represents the level of cellular maturity, is also governed by changes in estrogen levels. Conclusions Given the potential role of dural MCs in triggering headache, our data suggest that estrogen-related modulation of dural MC density and phenotypic makeup could play a role in mediating the higher frequency and severity of headaches, such as migraine, in women. PMID:22833613

Protective effects of tempol in an experimental ovarian ischemia-reperfusion injury model in female Wistar albino rats.

PubMed

Pınar, Neslihan; Soylu Karapınar, Oya; Özcan, Oğuzhan; Atik Doğan, Esin; Bayraktar, Suphi

2017-07-01

The aim of this study was to investigate the antioxidant effects of tempol on ovarian ischemia-reperfusion (I/R) injury in rats. Forty female Wistar albino rats were randomly divided into 5 groups: Group I, sham; Group II, ischemia (I); Group III, I/R; Group IV, I/R + tempol 30 mg/kg i.p; Group V, I/R + tempol 50 mg/kg i.p. Oxidative stress index (OSI) was significantly higher in the ischemia group and the I/R group than in the sham group. Catalase levels were significantly lower in the I/R group than in the I/R + tempol 30 mg/kg i.p. and the I/R + tempol 50 mg/kg i.p. groups. Glutathione peroxidase levels were lower in the I/R group than in the I/R + tempol 30 mg/kg i.p. and the I/R + tempol 50 mg/kg i.p. groups. MDA levels were significantly lower in the I/R + tempol 30 mg/kg i.p. group and the I/R + tempol 50 mg/kg i.p. group than in the I/R group. The levels of the histopathological parameters were significantly decreased in the I/R + tempol 50 mg/kg i.p. group compared with the I/R group. Tempol can be used for reducing ovarian I/R injury.

Sex differences in paradoxical sleep: influences of estrus cycle and ovariectomy.

PubMed

Fang, J; Fishbein, W

1996-09-23

Previously, we reported that paradoxical sleep (PS) is sexually dimorphic in mice and rats. Since some early studies indicate that PS is suppressed during proestrus night, it is important to know whether the estrus cycle and accompanying circulating ovarian hormones could explain the sexual dimorphism of PS. To examine this, sleep patterns of male rats were compared with those of normal cycling female rats and ovariectomized females in a 12:12 h light/dark cycle. Slow wave sleep and total sleep time are indistinguishable between the males, cycling females and ovariectomized females. However, normal males display significantly more PS than cycling females during both daytime and nighttime (average of all estrus stages). On the other hand, while ovariectomy has no visible effect on daytime sleep--the sexual dimorphism of PS is unchanged by ovariectomy--during nighttime, ovariectomy produces a selective increase of PS, eliminating the sex difference during the night. In sum, normal cycling females show no change in daytime sleep patterns across the estrus cycle, but have significantly less PS during proestrus nights than during metestrus and diestrus nights. The results indicate that the sex difference in nighttime PS is due to the suppression of PS by ovarian hormones during proestrus and, to a less extent, estrus nights. The sex difference in daytime PS, on the other hand, appears to be independent of circulating ovarian hormones.

Early Life Exposure to Undernutrition Induces ER Stress, Apoptosis, and Reduced Vascularization in Ovaries of Adult Rat Offspring1

PubMed Central

Chan, Kaitlyn A.; Bernal, Angelica B.; Vickers, Mark H.; Gohir, Wajiha; Petrik, Jim J.; Sloboda, Deborah M.

2015-01-01

ABSTRACT Maternal nutritional restriction has been shown to induce impairments in a number of organ systems including the ovary. We have previously shown that maternal undernutrition induces fetal growth restriction and low birth weight, and results in an offspring ovarian phenotype characteristic of premature ovarian aging with reduced ovarian reserve. In the present study, we set out to investigate the underlying mechanisms that lead offspring of undernourished mothers to premature ovarian aging. Pregnant dams were randomized to 1) a standard diet throughout pregnancy and lactation (control), 2) a calorie-restricted (50% of control) diet during pregnancy, 3) a calorie-restricted (50% of control) diet during pregnancy and lactation, or 4) a calorie-restricted (50% of control) diet during lactation alone. The present study shows that early life undernutrition-induced reduction of adult ovarian follicles may be mediated by increased ovarian endoplasmic reticulum stress in a manner that increased follicular apoptosis but not autophagy. These changes were associated with a loss of ovarian vessel density and are consistent with an accelerated ovarian aging phenotype. Whether these changes are mediated specifically by a reduction in the local antioxidant environment is unclear, although our data suggest the possibility that ovarian melatonin may play a part in early life nutritional undernutrition and impaired offspring folliculogenesis. PMID:25810471

A fetal whole ovarian culture model for the evaluation of CrVI-induced developmental toxicity during germ cell nest breakdown

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stanley, Jone A.; Arosh, Joe A.; Burghardt, Robert C.

Prenatal exposure to endocrine disrupting chemicals (EDCs), including bisphenol A, dioxin, pesticides, and cigarette smoke, has been linked to several ovarian diseases such as premature ovarian failure (POF) and early menopause in women. Hexavalent chromium (CrVI), one of the more toxic heavy metals, is widely used in more than 50 industries. As one of the world's leading producers of Cr compounds, the U.S. is facing growing challenges in protecting human health against adverse effects of CrVI. Our recent findings demonstrated that in vivo CrVI exposure during gestational period caused POF in F1 offspring. Our current research focus is three-fold: (i)more » to identify the effect of CrVI on critical windows of great vulnerability of fetal ovarian development; (ii) to understand the molecular mechanism of CrVI-induced POF; (iii) to identify potential intervention strategies to mitigate or inhibit CrVI effects. In order to accomplish these goals we used a fetal whole ovarian culture system. Fetuses were removed from the normal pregnant rats on gestational day 13.5. Fetal ovaries were cultured in vitro for 12 days, and treated with or without 0.1 ppm potassium dichromate (CrVI) from culture day 2–8, which recapitulated embryonic day 14.5–20.5, in vivo. Results showed that CrVI increased germ cell/oocyte apoptosis by increasing caspase 3, BAX, p53 and PUMA; decreasing BCL2, BMP15, GDF9 and cKIT; and altering cell cycle regulatory genes and proteins. This model system may serve as a potential tool for high throughput testing of various drugs and/or EDCs in particular to assess developmental toxicity of the ovary. - Highlights: • CrVI (0.1 ppm, a regulatory dose) increased germ cell apoptosis of fetal ovaries. • CrVI (0.1 ppm) increased pro-apoptotic proteins. • CrVI (0.1 ppm) decreased cyclins and CDK1 and cell survival proteins. • CrVI (0.1 ppm) increased oxidative stress during fetal ovarian development. • We propose fetal ovarian culture model for high-throughput testing of heavy-metals.« less

Acetaminophen Enhances Cisplatin- and Paclitaxel-mediated Cytotoxicity to SKOV3 Human Ovarian Carcinoma

PubMed Central

Wu, Y. Jeffrey; Neuwelt, Alexander J.; Muldoon, Leslie L.; Neuwelt, Edward A.

2013-01-01

Background Ovarian cancer is commonly treated with cisplatin/paclitaxel but many tumors become resistant. Acetaminophen reduced glutathione and enhanced chemotherapy efficacy in treating hepatic cancer. The objective of this study was to examine if acetaminophen enhances the cytotoxicity of cisplatin/paclitaxel in ovarian cancer. Materials and Methods SKOV3 human ovarian carcinoma cells in vitro and a subcutaneous tumor nude rat model were used and treated with cisplatin/paclitaxel with or without acetaminophen. Results In vitro, acetaminophen enhanced apoptosis induced by cisplatin and paclitaxel with similar effects on glutathione, reactive oxygen species and mitochondrial membrane potential but different effects on nuclear factor erythroid 2-related factor 2 (NRF2) translocation. In vivo, acetaminophen was uniformly distributed in tissue and significantly reduced hepatic glutathione. Acetaminophen enhanced cisplatin chemotherapeutic effect by reducing tumor recurrence Conclusion Our results suggest that acetaminophen as a chemoenhancing adjuvant could improve the efficacy of cisplatin and paclitaxel in treating patients with ovarian carcinoma and other tumor types. PMID:23749887

Altered expression of miRNAs in the uterus from a letrozole-induced rat PCOS model.

PubMed

Li, Chunjin; Chen, Lu; Zhao, Yun; Chen, Shuxiong; Fu, Lulu; Jiang, Yanwen; Gao, Shan; Liu, Zhuo; Wang, Fengge; Zhu, Xiaoling; Rao, Jiahui; Zhang, Jing; Zhou, Xu

2017-01-20

Polycystic ovary syndrome (PCOS) causes female subfertility with ovarian disorders and may be associated with increased rate of early-pregnancy failure. Rat PCOS models were established using letrozole to understand the uterine pathogenesis of PCOS. The differential expression of microRNAs (miRNAs) was observed in rat uterus with PCOS. After estrous cycles were disrupted, significantly abnormal ovarian morphology and hormone level were observed in rats with PCOS. A total of 148 miRNAs differentially expressed were identified in the uterus from the letrozole-induced rat model compared with the control. These miRNAs included 111 upregulated miRNAs and 37 downregulated miRNAs. The differential expression of miR-484, miR-375-3p, miR-324-5p, and miR-223-3p was further confirmed by quantitative reverse transcription polymerase chain reaction. Bioinformatic analysis showed that these four miRNAs were predicted to regulate a large number of genes with different functions. Pathway analysis supported that target genes of miRNAs were involved in insulin secretion and signaling pathways, such as wnt, AMPK, PI3K-Akt, and Ras. These data indicated that miRNAs differentially expressed in rat uterus with PCOS may be associated with PCOS pathogenesis in the uterus. Our findings can help clarify the mechanism of uterine defects in PCOS. Copyright © 2016. Published by Elsevier B.V.

Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner

PubMed Central

Saland, Samantha K.; Schoepfer, Kristin J.; Kabbaj, Mohamed

2016-01-01

We recently reported a greater sensitivity of female rats to rapid antidepressant-like effects of ketamine compared to male rats, and that ovarian-derived estradiol (E2) and progesterone (P4) are essential for this response. However, to what extent testosterone may also contribute, and whether duration of response to ketamine is modulated in a sex- and hormone-dependent manner remains unclear. To explore this, we systematically investigated the influence of testosterone, estradiol and progesterone on initiation and maintenance of hedonic response to low-dose ketamine (2.5 mg/kg) in intact and gonadectomized male and female rats. Ketamine induced a sustained increase in sucrose preference of female, but not male, rats in an E2P4-dependent manner. Whereas testosterone failed to alter male treatment response, concurrent administration of P4 alone in intact males enhanced hedonic response low-dose ketamine. Treatment responsiveness in female rats only was associated with greater hippocampal BDNF levels, but not activation of key downstream signaling effectors. We provide novel evidence supporting activational roles for ovarian-, but not testicular-, derived hormones in mediating hedonic sensitivity to low-dose ketamine in female and male rats, respectively. Organizational differences may, in part, account for the persistence of sex differences following gonadectomy and selective involvement of BDNF in treatment response. PMID:26888470

Effect of pregnant mare's serum gonadotrophin on the activities of delta 4-5 alpha-reductase, aromatase, and other enzymes in the ovaries of immature rats.

PubMed

Suzuki, K; Kawakura, K; Tamaoki, B I

1978-05-01

After incubation of progesterone, 17 alpha-hydroxyprogesterone, androstenedione, and testostrone with an ovarian preparation (supernatant fluid at 10,000 x g) of immature rats (21-23 days of age) in the presence of NADPH, 3 alpha- and 3 beta-hydroxy-5 alpha-reduced steroids were obtained as the major metabolites. Among the enzyme activities relevant to the metabolism, delta 4-5 alpha-reductase and 3 beta-hydroxysteroid dehydrogenase were intracellularly localized to the microsomal fraction (10,000--105,000 x g), and 3 alpha-hydroxysteroid dehydrogenase was detected exclusively in the cytosol fraction (supernatant fluid at 105,000 x g). Within 2 days after a single injection of pregnant mare's serum gonadotrophin (10 IU/rat) to 21-day-old female rats, the following occurred: 1) an enhancement of 17 alpha-hydroxylase and C-17-C-20 lyase activities; 2) a suppression of delta 4-5 alpha-reductase activity; and 3) an increase in aromatizing activity. From the above-mentioned results, it was concluded that the increased secretion of estrogen from ovaries of immature rats stimulated by pregnant mare's serum gonadotrophin administration was caused by a modification of the ovarian enzyme activities relevant to estrogen production.

Ovarian structure and hormonal status of the UChA and UChB adult rats in response to ethanol.

PubMed

Chuffa, Luiz Gustavo A; Padovani, Carlos R; Martinez, Francisco E

2009-01-20

In females, chronic alcoholism has a current and dangerous incidence to fertility. This work had the goal of elucidating the alterations on the ovary of UChA and UChB adult rats (ethanol 10% (v/v) voluntary drinkers). After the treatment period, 42 female rats divided into three experimental groups (UChA, UChB and Wistar) suffered decapitation and their ovaries were removed and processed to further analysis on light and electron microscopy. The ovary was entirely sliced and stained by hematoxylin-eosin, toluidine blue, periodic acid Schiff (PAS) and Masson's tricromic. Thereby, the enzymatic reaction to acid and alkaline phosphatase, estral cyclicity, reproductive hormonal status and frequency in oestrous-related ovarian structures were assigned. The UChB rats showed an increase in body mass gain index and the ovaries relative weight was significantly lower comparing to the other groups. UCh rats presented the longest estral cycle durations and also persistent oestrous phasis, with uninterrupted cycles. Advanced follicular atresia was common in UCh animals, and degenerating intracellular fragments could be observed through acid phosphatase and electron microscopy techniques. There were some estral cyclicity irregularities caused by chronic ethanol intake in the UCh groups which were consequently reflected as morphologic injury in the ovary structure.

The effect of dexpanthenol on experimentally induced ovarian ischaemia/reperfusion injury: a biochemical and histopathological evaluation.

PubMed

Soylu Karapinar, Oya; Pinar, Neslihan; Özcan, Oğuzhan; Atik Doğan, Esin; Bayraktar, Suphi; Şahin, Hanifi; Dolapçioğlu, Kenan

2017-03-01

The aim of this study was to evaluate the effect of two different doses of dexpanthenol (Dxp) onexperimentally induced ovarian ischaemia/reperfusion (I/R) injury ina rat model. Forty female rats were randomly divided into fivegroups: Group 1: sham operation; Group 2: 3-h ischaemia; Groups 3: 3-h ischaemia, 3-h reperfusion (I/R); Group 4: I/R + 300 mg/kg Dxp intraperitoneally (i.p) Group 5: I /R + 500 mg/kg Dxpi.p. Total anti-oxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), tissue malondialdehyde (MDA) and activities of glutathione peroxidase and catalase were calculated. Ovarian tissue damage was assessed using a histopathological scoring system. The TOS and OSI values were significantly lower in Group 5, as compared to Groups 2 and 3 (p < 0.05). The MDA levels in Group 1 and Group 5 were significantly lower than those in Group 3 (p < 0.05). CAT and GSH-Px activity was higher in Group 5 than in Group 2 and Group 3 (p = 0.00). Tissue damage scores were elevated in all the groups compared with sham group, but the treatment with the different doses of Dxp before reperfusion ameliorated the tissue damage scores. The results showed that Dxp reduced ovarian I/R injury.

Role of sex steroids in modulating tumor necrosis factor alpha induced changes in vascular function and blood pressure

PubMed Central

LaMarca, Babbette D.; Chandler, Derrick L.; Grubbs, Lee; Bain, Jennifer; McLemore, Gerald R.; Granger, Joey P.; Ryan, Michael J.

2007-01-01

Background We previously showed that infusion of TNF-α induces hypertension and vascular dysfunction in late pregnant but not virgin rats. In the present study we tested the hypothesis that levels of ovarian hormones to mimic pregnancy are required for TNF-α induced changes in vascular function and blood pressure in rats. Methods 21 day release pellets containing 17β-estradiol, progesterone, or both were implanted in ovariectomized (OVX) rats. Sham OVX rats were used as controls. 12 days after implantation, TNF-α or vehicle was infused via osmotic minipumps (days 12-17). On day 18, mean arterial pressure was measured and animals were sacrificed to assess vascular function. Results Average estrogen and progesterone levels across all groups were 106±6 pg/ml and 88±5 ng/ml. TNF-α was 41±7 pg/ml compared to OVX rats infused with vehicle (4±1 pg/ml). The results show that TNF-α did not cause elevated mean arterial pressure in OVX rats with increased estrogen, progesterone, both. Vascular responses to the endothelium dependent and independent agonists, acetylcholine and sodium nitroprusside, were also not changed. Phenylephrine induced contraction was moderately but significantly increased at the highest concentrations (10-4 M) only in TNF-α infused rats. Conclusion These data suggest that increased ovarian hormones to levels observed during pregnancy are not sufficient to promote TNF-α induced increases in blood pressure or vascular dysfunction. PMID:17954370

The effects of 6-Gingerol on reproductive improvement, liver functioning and Cyclooxygenase-2 gene expression in estradiol valerate - Induced polycystic ovary syndrome in Wistar rats.

PubMed

Pournaderi, Parisa Sadat; Yaghmaei, Parichehreh; Khodaei, Hamidreza; Noormohammadi, Zahra; Hejazi, Seyed Hossein

2017-03-04

6-Gingerol is the major pungent ingredient of ginger with anti-inflammatory and antioxidant properties. In this study, we evaluate the effects of 6-gingerol on the biochemical parameters and ovarian histological improvements in estradiol valerate (EV) induced PCOS rats. Thirty six female Wistar rats were divided into 4 groups: control, received normal diet, PCOS control, received 4 mg/kg EV injection for 28 days and two experimental groups, received an EV injection for 28 days and followed by 6-gingerol (200 μg/ kg and 400 μg/ kg ) for 14 days. The administration of EV led to increase body and ovarian weights, abnormality in serum sex steroid profile, decrease in antioxidant activity and increase in COX-2 gene expression. 6-gingerol treatments, particularly the 400 μg/ kg dose, markedly attenuated these alterations. 6-gingerol showed beneficial effects in the EV induced PCOS rats via decreased expression of COX-2, restored biochemical parameters to normal and decreased of cysts in the ovaries. Copyright © 2017 Elsevier Inc. All rights reserved.

Xiao-Yao-San, a Chinese Medicine Formula, Ameliorates Chronic Unpredictable Mild Stress Induced Polycystic Ovary in Rat

PubMed Central

Sun, Hao-Yu; Li, Quan; Liu, Yu-Ying; Wei, Xiao-Hong; Pan, Chun-Shui; Fan, Jing-Yu; Han, Jing-Yan

2017-01-01

Chronic stress induces endocrine disturbance, which contributes to the development of polycystic ovary syndrome (PCOS), a condition that remains a challenge for clinicians to cope with. The present study investigated the effect of Xiao-Yao-San (XYS), a traditional Chinese medicine formula used for treatment of gynecological disease, on the chronic stress-induced polycystic ovary and its underlying mechanism. Female Sprague-Dwaley rats underwent a 3 weeks chronic unpredictable mild stress (CUMS) procedure to establish the PCOS model, followed by 4 weeks treatment with XYS (0.505 g/kg or 1.01 g/kg) by gavage. Granulosa cells were exposed to noradrenaline (1 mM) in vitro for 24 h, followed by incubation with or without XYS-treated rat serum for 24 h. Post-treatment with XYS ameliorated CUMS-induced irregular estrous cycles and follicles development abnormalities, decrease of estradiol and progesterone level as well as increase of luteinizing hormone in serum, reduced cystic follicles formation and the apoptosis and autophagy of granulosa cells, attenuated the increase in dopamine beta hydroxylase and c-fos level in locus coeruleus, the noradrenaline level in serum and ovarian tissue, and the expression of beta 2 adrenergic receptor in ovarian tissue. Besides, XYS alleviated the reduction of phosphorylation of ribosomal protein S6 kinase polypeptide I and protein kinase B, as well as the increase of microtubule-associated protein light chain 3-I to microtubule-associated protein light chain 3-II conversion both in vivo and in vitro. This study demonstrated XYS as a potential strategy for CUMS induced polycystic ovary, and suggested that the beneficial role of XYS was correlated with the regulation of the sympathetic nerve activity. PMID:29018356

Localization and expression of messenger RNAs for the peroxisome proliferator-activated receptors in ovarian tissue from naturally cycling and pseudopregnant rats.

PubMed

Komar, Carolyn M; Curry, Thomas E

2002-05-01

Structural and functional development of the corpus luteum (CL) involves tissue remodeling, angiogenesis, lipid metabolism, and steroid production. The peroxisome proliferator-activated receptors (PPARs) have been shown to play a role in these as well as in a multitude of other cellular processes. To examine the expression of mRNA corresponding to the PPAR family members (alpha, delta, and gamma) in luteal tissue, ovaries were collected from gonadotropin-treated, immature rats on Days 1, 4, 8, and 14 of pseudopregnancy and from adult, cycling animals on each day of the estrous cycle. Ovaries were processed for in situ hybridization or RNA isolation for analysis by RNase protection assay. The expression of PPARgamma mRNA was abundant in granulosa cells of developing follicles during both pseudopregnancy and the estrous cycle and was low to undetectable in CL from pseudopregnant rats. However, luteal tissue in cycling animals, especially CL remaining from previous cycles, had high levels of PPARgamma mRNA. The PPARalpha mRNA was localized mainly in the theca and stroma, and PPARdelta mRNA was expressed throughout the ovary. Levels of mRNA for PPARgamma decreased between Days 1 and 4 of pseudopregnancy, and PPARalpha mRNA levels were lower on the day of estrus compared to pro- and metestrus (P < 0.05). The PPARdelta mRNA levels remained steady throughout the estrous cycle and pseudopregnancy. These data illustrate a difference in the luteal expression of mRNA for PPARgamma between the adult, cycling rat and the immature, gonadotropin-treated rat. This differential pattern of expression may be related to the difference in timing of the preovulatory prolactin surge, because the gonadotropin-primed animals would not experience a prolactin surge coincident with the LH surge, as occurs in adult, cycling animals. Additionally, the expression pattern of PPARdelta mRNA indicates that it may be involved in cellular functions involved with maintaining basal ovarian function, whereas PPARalpha may play a role in lipid metabolism in the theca and stroma.

Estrogen modulates sexually dimorphic contextual fear extinction in rats through estrogen receptor beta.

PubMed

Chang, Yao-Ju; Yang, Chih-Hao; Liang, Ying-Ching; Yeh, Che-Ming; Huang, Chiung-Chun; Hsu, Kuei-Sen

2009-11-01

Females and males are different in brain and behavior. These sex differences occur early during development due to a combination of genetic and hormonal factors and continue throughout the lifespan. Previous studies revealed that male rats exhibited significantly higher levels of contextual fear memory than female rats. However, it remains unknown whether a sex difference exists in the contextual fear extinction. To address this issue, male, normally cycling female, and ovariectomized (OVX) female Sprague-Dawley rats were subjected to contextual fear conditioning and extinction trials. Here we report that although male rats exhibited higher levels of freezing than cycling female rats after contextual fear conditioning, female rats subjected to conditioning in the proestrus and estrus stage exhibited an enhancement of fear extinction than male rats. An estrogen receptor (ER) beta agonist diarylpropionitrile but not an ERalpha agonist propyl-pyrazole-triol administration also enhanced extinction of contextual fear in OVX female rats, suggesting that estrogen-mediated facilitation of extinction involves the activation of ERbeta. Intrahippocampal injection of estradiol or diarylpropionitrile before extinction training in OVX female rats remarkably reduced the levels of freezing response during extinction trials. In addition, the locomotion or anxiety state of female rats does not vary across the ovarian cycle. These results reveal a crucial role for estrogen in mediating sexually dimorphic contextual fear extinction, and that estrogen-mediated enhancement of fear extinction involves the activation of ERbeta.

Ovarian Expression and Regulation of the Stromelysins During the Periovulatory Period in the Human and the Rat1

PubMed Central

McCord, Lauren A.; Li, Feixue; Rosewell, Katherine L.; Brännström, Mats; Curry, Thomas E.

2011-01-01

ABSTRACT The matrix metalloproteinases (MMPs) are postulated to facilitate follicular rupture. In the present study, expression of the stromelysins (MMP3, MMP10, MMP11) was analyzed in the periovulatory human and rat ovary. Human granulosa and theca cells were collected from the dominant follicle at various times after human chorionic gonadotropin (hCG). Intact rat ovaries, granulosa cells, and residual tissue (tissue remaining after granulosa cell collection) were isolated from equine CG (eCG)-hCG-primed animals. Mmp10 mRNA was highly induced in human granulosa and theca cells and intact rat ovaries, granulosa cells, and residual tissue. Localization of MMP10 to granulosa and theca cells in both human and rat ovarian follicles was confirmed by immunohistochemistry. Mmp3 mRNA was unchanged in human cells and rat granulosa cells, but increased in intact rat ovaries and residual tissue. Mmp11 mRNA decreased following hCG treatment in human granulosa and theca cells as well as rat granulosa cells. Regulation of Mmp10 in cultured rat granulosa cells revealed that the EGF inhibitor AG1478 and the progesterone receptor antagonist RU486 suppressed the induction of Mmp10 mRNA, whereas the prostaglandin inhibitor NS398 had no effect. Studies on the Mmp10 promoter demonstrated that forskolin plus PMA stimulated promoter activity, which was dependent upon a proximal AP1 site. In conclusion, there are divergent patterns of stromelysin expression associated with ovulation, with a marked induction of Mmp10 mRNA and a decrease in Mmp11 mRNA, yet a species-dependent pattern on Mmp3 mRNA expression. The induction of Mmp10 expression suggests an important role for this MMP in the follicular changes associated with ovulation and subsequent luteinization. PMID:22116802

Ovarian expression and regulation of the stromelysins during the periovulatory period in the human and the rat.

PubMed

McCord, Lauren A; Li, Feixue; Rosewell, Katherine L; Brännström, Mats; Curry, Thomas E

2012-03-01

The matrix metalloproteinases (MMPs) are postulated to facilitate follicular rupture. In the present study, expression of the stromelysins (MMP3, MMP10, MMP11) was analyzed in the periovulatory human and rat ovary. Human granulosa and theca cells were collected from the dominant follicle at various times after human chorionic gonadotropin (hCG). Intact rat ovaries, granulosa cells, and residual tissue (tissue remaining after granulosa cell collection) were isolated from equine CG (eCG)-hCG-primed animals. Mmp10 mRNA was highly induced in human granulosa and theca cells and intact rat ovaries, granulosa cells, and residual tissue. Localization of MMP10 to granulosa and theca cells in both human and rat ovarian follicles was confirmed by immunohistochemistry. Mmp3 mRNA was unchanged in human cells and rat granulosa cells, but increased in intact rat ovaries and residual tissue. Mmp11 mRNA decreased following hCG treatment in human granulosa and theca cells as well as rat granulosa cells. Regulation of Mmp10 in cultured rat granulosa cells revealed that the EGF inhibitor AG1478 and the progesterone receptor antagonist RU486 suppressed the induction of Mmp10 mRNA, whereas the prostaglandin inhibitor NS398 had no effect. Studies on the Mmp10 promoter demonstrated that forskolin plus PMA stimulated promoter activity, which was dependent upon a proximal AP1 site. In conclusion, there are divergent patterns of stromelysin expression associated with ovulation, with a marked induction of Mmp10 mRNA and a decrease in Mmp11 mRNA, yet a species-dependent pattern on Mmp3 mRNA expression. The induction of Mmp10 expression suggests an important role for this MMP in the follicular changes associated with ovulation and subsequent luteinization.

The ovarian DNA damage repair response is induced prior to phosphoramide mustard-induced follicle depletion, and ataxia telangiectasia mutated inhibition prevents PM-induced follicle depletion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

Phosphoramide mustard (PM) is an ovotoxic metabolite of cyclophosphamide and destroys primordial and primary follicles potentially by DNA damage induction. The temporal pattern by which PM induces DNA damage and initiation of the ovarian response to DNA damage has not yet been well characterized. This study investigated DNA damage initiation, the DNA repair response, as well as induction of follicular demise using a neonatal rat ovarian culture system. Additionally, to delineate specific mechanisms involved in the ovarian response to PM exposure, utility was made of PKC delta (PKCδ) deficient mice as well as an ATM inhibitor (KU 55933; AI). Fishermore » 344 PND4 rat ovaries were cultured for 12, 24, 48 or 96 h in medium containing DMSO ± 60 μM PM or KU 55933 (48 h; 10 nM). PM-induced activation of DNA damage repair genes was observed as early as 12 h post-exposure. ATM, PARP1, E2F7, P73 and CASP3 abundance were increased but RAD51 and BCL2 protein decreased after 96 h of PM exposure. PKCδ deficiency reduced numbers of all follicular stages, but did not have an additive impact on PM-induced ovotoxicity. ATM inhibition protected all follicle stages from PM-induced depletion. In conclusion, the ovarian DNA damage repair response is active post-PM exposure, supporting that DNA damage contributes to PM-induced ovotoxicity. - Highlights: • PM exposure induces DNA damage repair gene expression. • Inhibition of ATM prevented PM-induced follicle depletion. • PKCδ deficiency did not impact PM-induced ovotoxicity.« less

High-fat diets exaggerate endocrine and metabolic phenotypes in a rat model of DHEA-induced PCOS.

PubMed

Zhang, Haolin; Yi, Ming; Zhang, Yan; Jin, Hongyan; Zhang, Wenxin; Yang, Jingjing; Yan, Liying; Li, Rong; Zhao, Yue; Qiao, Jie

2016-04-01

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder with unclear etiology and unsatisfactory management. Effects of diets on the phenotype of PCOS were not fully understood. In the present study, we applied 45 and 60% high-fat diets (HFDs) on a rat model of PCOS induced by postnatal DHEA injection. We found that both DHEA and DHEA+HFDs rats exhibited reproductive abnormalities, including hyperandrogenism, irregular cycles and polycystic ovaries. The addition of HFDs, especially 60% HFDs, exaggerated morphological changes of ovaries and a number of metabolic changes, including increased body weight and body fat content, impaired glucose tolerance and increased serum insulin levels. Results from qPCR showed that DHEA-induced increased expression of hypothalamic androgen receptor and LH receptor were reversed by the addition of 60% HFDs. In contrast, the ovarian expression of LH receptor and insulin receptor mRNA was upregulated only with the addition of 60% HFDs. These findings indicated that DHEA and DHEA+HFDs might influence PCOS phenotypes through distinct mechanisms: DHEA affects the normal function of hypothalamus-pituitary-ovarian axis through LH, whereas the addition of HFDs exaggerated endocrine and metabolic dysfunction through ovarian responses to insulin-related mechanisms. We concluded that the addition of HFDs yielded distinct phenotypes of DHEA-induced PCOS and could be used for studies on both reproductive and metabolic features of the syndrome. © 2016 Society for Reproduction and Fertility.

Ovarian folliculogenesis: detrimental effect of prenatal exposure to cyclophosphamide: a preliminary study.

PubMed

Ray, B; Potu, B K

2010-01-01

To investigate whether cyclophosphamide interferes with ovarian folliculogenesis. In this experiment, pregnant rats (n=12) were randomly assigned into two groups, control group (n=6) and cyclophosphamide treatment group (n=6). In the cyclophosphamide treatment group cyclophosphamide was injected intraperitoneally from day 10 of gestation till 20th day, at 2 mg/kg of body weight. The pregnant rats were sacrificed on gestation day 20 and the fetus was collected. The collected fetuses were processed for sectioning and stained with haematoxyline and eosin for microscopic observation of the ovaries. A meshwork-like appearance of mesenchyme with decreased number of somatic cells and absence of the majority of the germ cells in the ovarian follicles were found in treated fetus. Non-availability of primordial germ cells stopped the interaction between primordial germ cells and somatic supporting cells leading to nonproliferation and degeneration of somatic cells and fluid-filled vacant spaces in the meshwork -like arrangement of mesenchymal cells. We conclude that cyclophosphamide exposure prevents folliculogenesis by causing anovulation and results in infertility. The same detrimental effect might be seen in human fertility with environmental pollutants which are also metabolites of the drug (Fig. 2, Ref. 25).

Physical-chemical and biological characterization of different preparations of equine chorionic gonadotropin

PubMed Central

Natal, Fabio Luis Nogueira; Ribela, Maria Teresa Carvalho Pinto; de Almeida, Beatriz Elane; de Oliveira, João Ezequiel; Bartolini, Paolo

2016-01-01

Ovarian stimulation with commercial preparations of equine chorionic gonadotropin (eCG) produces extremely variable responses in domestic animals, ranging from excessive stimulation to practically no stimulation, when applied on the basis of their declared unitage. This study was conducted to analyze four commercial preparations from different manufacturers via reversed-phase HPLC (RP-HPLC) in comparison with a reference preparation and an official International Standard from the World Health Organization. The peaks obtained by this qualitative and quantitative physical–chemical analysis were compared using an in vivo bioassay based on the ovarian weight gain of prepubertal female rats. The RP-HPLC data showed one or two peaks close to a main peak (tR = 27.9 min), which were related to the in vivo bioactivity. Commercial preparations that have this altered peak showed very little or no in vivo activity, as demonstrated by rat ovarian weight and in peripubertal gilts induced to ovulate. Overall, these findings indicate that RP-HPLC can be a rapid and reliable tool to reveal changes in the physicochemical profile of commercial eCG that is apparently related to decreased biological activity of this hormone. PMID:27297410

Elevated Peritoneal Fluid TNF-α Incites Ovarian Early Growth Response Factor 1 Expression and Downstream Protease Mediators

PubMed Central

Birt, Julie A.; Nabli, Henda; Stilley, Julie A.; Windham, Emma A.; Frazier, Shellaine R.

2013-01-01

Endometriosis-associated infertility manifests itself via multiple, poorly understood mechanisms. Our goal was to characterize signaling pathways, between peritoneal endometriotic lesions and the ovary, leading to failed ovulation. Genome-wide microarray analysis comparing ovarian tissue from an in vivo endometriosis model in the rat (Endo) with controls (Sham) identified 22 differentially expressed genes, including transiently expressed early growth response factor 1 (Egr1). The Egr1 regulates gene requisites for ovulation. The Egr1 promoter is responsive to tumor necrosis factor-alpha (TNF-α) signaling. We hypothesized that altered expression of ovarian EGR1 is induced by elevated peritoneal fluid TNF-α which is upregulated by the presence of peritoneal endometriosis. Endo rats, compared to controls, had more peritoneal fluid TNF-α and quantitative, spatial differences in Egr1 mRNA and EGR1 protein localization in follicular compartments. Interactions between elevated peritoneal fluid TNF-α and overexpression of follicular Egr1/EGR1 expression may affect downstream protease pathways impeding ovulation in endometriosis. Preliminary studies identified similar patterns of EGR1 protein localization in human ovaries from women with endometriosis and compared to those without endometriosis. PMID:23427178

Short and long effects of Citrullus colocynthis L. on reproductive system and fertility in female Spague-Dawley rats.

PubMed

Qazan, Walid Sh; Almasad, Motasem M; Daradka, Haytham

2007-08-15

Aim of this study is to investigate the toxic effects of Citrullus colocynthis L. (400 mg/kg/body wight) on the reproductive system after administration to female Sprague-Dawley rats weighting 250-300 g for two time periods 4 and 12 weeks. Twenty adult female rats were divided into two groups and Citrullus colocynthis L. were intraperitoneally injected to experimental animals in dose of 400 mg/kg/body wight. First group containing 10 rats received treatment for 4 weeks and a second group of 10 rats received the same dose of treatment for a period of 12 weeks and compared with twenty non-exposed female rats received vehicle treatment. Female rats were allowed mating with males after 10 days prior to the last administration dose. Animals were autopsied under light anesthesia after mating and several parameters were determined including: number of pregnant rats, body and reproductive organ weight, number of implantation sites, viable fetuses and resorption sites. Assessment of pregnancies in females was measured and the significance of these results was calculated using students t and Chi-square tests. The effect of Citrullus colocynthis L. exposure on fertility was assessed in terms of pregnant rats number, implantation sites, viable fetuses and resorption sites. Exposure to Citrullus colocynthis L. for 4 weeks did not have much effect on fertility. Significant decrease in the relative ovarian weights and embryo weights in rats exposed to Citrullus colocynthis L. were observed. Exposure to Citrullus colocynthis L. for a 12 weeks resulted in a reduction in the percentage of pregnancies and in the number of implantation sites when compared with controls in both treatment periods. Rats receiving 12 weeks treatment showed a decrease in ovarian weights and a decrease in viable fetus's number. These results indicate that long-term exposure of female rats to Citrullus colocynthis L. causes adverse effects on the reproductive system and fertility.

Estradiol promotes the rewarding effects of nicotine in female rats.

PubMed

Flores, Rodolfo J; Pipkin, Joseph A; Uribe, Kevin P; Perez, Adriana; O'Dell, Laura E

2016-07-01

It is presently unclear whether ovarian hormones, such as estradiol (E2), promote the rewarding effects of nicotine in females. Thus, we compared extended access to nicotine intravenous self-administration (IVSA) in intact male, intact female, and OVX female rats (Study 1) as well as OVX females that received vehicle or E2 supplementation (Study 2). The E2 supplementation procedure involved a 4-day injection regimen involving 2 days of vehicle and 2 days of E2 administration. Two doses of E2 (25 or 250μg) were assessed in separate groups of OVX females in order to examine the dose-dependent effects of this hormone on the rewarding effects of nicotine. The rats were given 23-hour access to nicotine IVSA using an escalating dose regimen (0.015, 0.03, and 0.06mg/kg/0.1mL). Each dose was self-administered for 4 days with 3 intervening days of nicotine abstinence. The results revealed that intact females displayed higher levels of nicotine intake as compared to males. Also, intact females displayed higher levels of nicotine intake versus OVX females. Lastly, our results revealed that OVX rats that received E2 supplementation displayed a dose-dependent increase in nicotine intake as compared to OVX rats that received vehicle. Together, our results suggest that the rewarding effects of nicotine are enhanced in female rats via the presence of the ovarian hormone, E2. Copyright © 2016 Elsevier B.V. All rights reserved.

Essential fatty acid deficiency delays the onset of puberty in the female rat.

PubMed

Smith, S S; Neuringer, M; Ojeda, S R

1989-09-01

This study assessed the effect of a dietary deficiency in the essential fatty acids (EFA) linoleic and linolenic acids on the onset of female puberty. EFA deficiency was produced in female rats by means of a semipurified diet and was biochemically documented by analyzing serum and erythrocyte fatty acid levels of more than 30 fatty acids, including all members of the n-6 and n-3 series. Levels of linoleic acid (18:2 n-6) and all n-6 derivatives, particularly arachidonic acid, were strikingly reduced. A less pronounced but clear-cut decrease in n-3 fatty acids, including docosahexaenoic acid (22:6 n-3) was also found. The times of puberty and first ovulation, as assessed by the ages at vaginal opening and first diestrus, were significantly delayed in EFA-deficient rats. The mechanisms underlying this delay appear to reside at both hypothalamic and ovarian sites. Simulation of preovulatory plasma estradiol (E2) levels via implantation of E2-containing Silastic capsules evoked a LH surge 30 h later in control juvenile rats, but not in EFA-deficient animals, indicating a delay in the development of the hypothalamic component of E2-positive feedback in the latter group. This delay appears to be due at least in part to reduced prostaglandin E2 (PGE2) synthesis, as the ability of the neurotransmitter norepinephrine to induce PGE2 release from median eminence nerve terminals was markedly reduced in EFA-deficient rats compared with that in controls. The decrease in hypothalamic PGE2 release was related to the EFA deficiency and not to reduced PG synthase activity, as determined by HPLC analysis of PG synthase products derived from exogenous [14C]arachidonic acid. Basal and hCG-stimulated PGE2 synthesis was also compromised in ovaries from EFA-deficient rats. Depressed gonadal function resulting from the EFA deficiency was further evidenced by a reduced gonadotropin receptor content, a blunted E2 response to hCG in vitro, and an increase in mean serum FSH levels. These results suggest that the delay in puberty resulting from EFA deficiency is due to a reduced availability of arachidonic acid for synthesis of bioactive metabolites. This results in delayed development of both the hypothalamic and ovarian components of the reproductive axis.

Conditionally immortal ovarian cell lines for investigating the influence of ovarian stroma on the estrogen sensitivity and tumorigenicity of ovarian surface epithelial cells.

PubMed

Jiang, Feng; Saunders, Beatriz O; Haller, Edward; Livingston, Sandra; Nicosia, Santo V; Bai, Wenlong

2003-01-01

The tendency of the ovarian surface epithelium (OSE) to undergo metaplastic and morphogenetic changes during the life cycle, at variance with the adjacent peritoneal mesothelial cells, suggests that its biology may be regulated by underlying ovarian stromal cues. However, little is known about the role that the ovarian stroma plays in the pathobiology of the OSE, largely because of the lack of a suitable in vitro model. Here, we describe the establishment and characterization of conditionally immortalized ovarian stromal and surface epithelial cell lines from H-2K(b)-tsA58 transgenic mice that carry the thermolabile mutant of SV-40 large T antigen under the control of an interferon-gamma (IFN-gamma)-inducible promoter. These cells express functional T antigens, grow continuously under permissive conditions at 33 degrees C in the presence of IFN-gamma, and stop dividing when the activity and expression of the tumor antigen is suppressed by restrictive conditions without IFN-gamma at 39 degrees C. Morphological, immunohistochemical, and ultrastructural analyses show that conditionally immortal OSE cells form cobblestone-like monolayers, express cytokeratin and vimentin, contain several microvilli, and develop tight junctions, whereas stromal cells are spindle-like, express vimentin but not cytokeratin, and contain rare microvilli, thus exhibiting epithelial and stromal phenotypes, respectively. At variance with the reported behavior of rat epithelial cells, conditionally immortal mouse epithelial cells are not spontaneously transformed after continuous culture in vitro. More importantly, conditioned media from stromal cells cultured under permissive conditions increase the specific activity of the endogenous estrogen receptor in BG-1 human ovarian epithelial cancer cells and promote these cells' anchorage-independent growth, suggesting the paracrine influence of a stromal factor. In addition, stromal cells cultured under restrictive conditions retain this growth-stimulatory activity, which, therefore, appears to be independent of T antigen expression. These established cell lines should provide a useful in vitro model system for studying the role of cellular interactions in OSE cell growth and tumorigenesis.

Artemisinin induces hormonal imbalance and oxidative damage in the erythrocytes and uterus but not in the ovary of rats.

PubMed

Farombi, E O; Abolaji, A O; Adedara, I A; Maduako, I; Omodanisi, I

2015-01-01

Artemisinin is an antimalarial drug previously reported to induce neurotoxicity and embryotoxicity in animal models. This study investigated the erythrocytes and reproductive toxicity potentials of artemisinin in female rats. Animals were randomly divided into four study groups of eight rats each. The control group (group I) received corn oil, the vehicle, while groups II-IV were orally exposed to 7, 35 and 70 mg kg(-1) day(-1) of artemisinin, respectively, by gastric intubation for 7 consecutive days. Subsequently, we evaluated the impact of artemisinin on the endocrine environment and selected markers of oxidative damage and antioxidant status of the erythrocytes, ovary and uterus. Artemisinin significantly increased hydrogen peroxide (H2O2) and malondialdehyde (MDA) levels and decreased catalase, glutathione peroxidase and superoxide dismutase activities in erythrocytes and uterus of rats compared with control group (p < 0.05). However, artemisinin did not alter ovarian MDA, H2O2, glutathione levels and catalase activity, while ovarian and uterine histological assessment revealed absence of visible lesions. Moreover, artemisinin significantly decreased follicle-stimulating hormone and increased progesterone levels compared with control (p < 0.05). Thus, these data suggest that in the absence of malarial parasite infection, artemisinin induced hormonal imbalance and oxidative damage in the erythrocytes and uterus but spared the ovary of rats. © The Author(s) 2014.

Brown adipose tissue activation by rutin ameliorates polycystic ovary syndrome in rat.

PubMed

Hu, Tao; Yuan, Xiaoxue; Ye, Rongcai; Zhou, Huiqiao; Lin, Jun; Zhang, Chuanhai; Zhang, Hanlin; Wei, Gang; Dong, Meng; Huang, Yuanyuan; Lim, Wonchung; Liu, Qingsong; Lee, Hyuek Jong; Jin, Wanzhu

2017-09-01

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy that is characterized by anovulation, hyperandrogenism and polycystic ovary. However, there is a lack of effective treatment for PCOS at present because the pathologic cause of PCOS has not been elucidated. Although it has been known that brown adipose tissue transplantation ameliorates PCOS by activating endogenous BAT, BAT transplantation is not applicable in clinic. Therefore, BAT activation with natural compound could be an effective treatment strategy for PCOS patients. Here, we found that 3 weeks of rutin (a novel compound for BAT activation) treatment increased BAT activation, thereby it improved thermogenesis and systemic insulin sensitivity in dehydroepiandrosterone (DHEA)-induced PCOS rat. In addition, the expression levels of ovarian steroidogenic enzymes such as P450C17, aromatase, 3β-HSD, 17β-HSD and STAR were up-regulated in rutin-treated PCOS rat. Furthermore, acyclicity and the serum level of luteinizing hormone were normalized, and a large number of mature ovulated follicle with a reduction of cystic formation were observed in PCOS rat after rutin treatment. Finally, rutin treatment surprisingly improved fertility and birth defect in PCOS rat. Collectively, our results indicate that rutin treatment significantly improves systemic insulin resistance and ovarian malfunction in PCOS, and our findings in this study provide a novel therapeutic option for the treatment of PCOS by activating BAT with rutin. Copyright © 2017 Elsevier Inc. All rights reserved.

Regulation of connexin26 and connexin43 expression in rat endometrium by ovarian steroid hormones.

PubMed

Grümmer, R; Chwalisz, K; Mulholland, J; Traub, O; Winterhager, E

1994-12-01

A distinct spatial and temporal pattern of connexin26 and connexin43 (cx26 and cx43) expression was observed in the rat endometrium in response to embryo implantation; however, connexin expression was suppressed during the preimplantation period. Pseudopregnant rats did not show connexin mRNA, while artificial decidualization induced by a scratch led to a strong expression of cx26 and cx43 in the endometrium of these animals. In order to examine the regulatory effects of ovarian steroid hormones on connexin expression, ovariectomized rats were treated with progesterone (P) and/or estradiol-17 beta (E2). Untreated, ovariectomized animals expressed mRNA for cx43, but not for cx26. Endometrial expression of mRNA for both connexins was strongly enhanced by E2 treatment; immunolabeling revealed protein for cx26 in the uterine luminal epithelial cells and for cx43 in the uterine stromal cells. P treatment, either alone or in combination with E2, suppressed expression of connexin mRNA. P suppression in the presence of E2 was reversible when P was withdrawn. When administered on Days 0-2 of pregnancy, the antiprogestin onapristone inhibited the effect of P and gave rise to strong expression of both connexin transcripts. These results demonstrate that expression of cx26 and cx43 in the rat uterine endometrium is differentially regulated by E2 and P during early pregnancy.

Ingestive behavior and body temperature during the ovarian cycle in normotensive and hypertensive rats.

PubMed

Rashotte, Michael E; Ackert, Allison M; Overton, J Michael

2002-01-01

The relationship between ingestive behavior (eating + drinking) and core body temperature (T(b)) in naturally cycling female rats was compared in a normotensive strain (Sprague-Dawley; SD) and a hypertensive strain reputed to have chronically elevated T(b) (spontaneously hypertensive rats; SHR). T(b) (by telemetry) and ingestive behavior (automated recording) were quantified every 30 s. Ingestive behavior and T(b) were related on all days of the ovarian cycle in both strains, but the strength of that relationship was reduced on the day of estrus (E) compared with nonestrous days. Several strain differences in T(b) were found as well. In SHR, dark-phase T(b) was elevated on E, whereas SD remained at the lower nonestrous values. Fluctuations in dark-phase T(b) were correlated with ingestive behavior in both strains but had greater amplitude in SHR except on E. Short-term fasting or sucrose availability did not eliminate elevated dark-phase T(b) on E in SHR. We propose that estrus-related changes unique to SHR may indicate heightened thermal reactivity to hormonal changes, ingestive behavior, and general locomotor activity.

Environmental obesogen tributyltin chloride leads to abnormal hypothalamic-pituitary-gonadal axis function by disruption in kisspeptin/leptin signaling in female rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sena, Gabriela C.; Freitas-Lima, Leandro C.; Merlo

Tributyltin chloride (TBT) is a xenobiotic used as a biocide in antifouling paints that has been demonstrated to induce endocrine-disrupting effects, such as obesity and reproductive abnormalities. An integrative metabolic control in the hypothalamus-pituitary-gonadal (HPG) axis was exerted by leptin. However, studies that have investigated the obesogenic TBT effects on the HPG axis are especially rare. We investigated whether metabolic disorders as a result of TBT are correlated with abnormal hypothalamus-pituitary-gonadal (HPG) axis function, as well as kisspeptin (Kiss) action. Female Wistar rats were administered vehicle and TBT (100 ng/kg/day) for 15 days via gavage. We analyzed their effects onmore » the tin serum and ovary accumulation (as biomarker of TBT exposure), estrous cyclicity, surge LH levels, GnRH expression, Kiss action, fertility, testosterone levels, ovarian apoptosis, uterine inflammation, fibrosis, estrogen negative feedback, body weight gain, insulin, leptin, adiponectin levels, as well as the glucose tolerance (GTT) and insulin sensitivity tests (IST). TBT led to increased serum and ovary tin levels, irregular estrous cyclicity, and decreased surge LH levels, GnRH expression and Kiss responsiveness. A strong negative correlation between the serum and ovary tin levels with lower Kiss responsiveness and GnRH mRNA expression was observed in TBT rats. An increase in the testosterone levels, ovarian and uterine fibrosis, ovarian apoptosis, and uterine inflammation and a decrease in fertility and estrogen negative feedback were demonstrated in the TBT rats. We also identified an increase in the body weight gain and abnormal GTT and IST tests, which were associated with hyperinsulinemia, hyperleptinemia and hypoadiponectinemia, in the TBT rats. TBT disrupted proper functioning of the HPG axis as a result of abnormal Kiss action. The metabolic dysfunctions co-occur with the HPG axis abnormalities. Hyperleptinemia as a result of obesity induced by TBT may be associated with abnormal HPG function. A strong negative correlation between the hyperleptinemia and lower Kiss responsiveness was observed in the TBT rats. These findings provide evidence that TBT leads to toxic effects direct on the HPG axis and/or indirectly by abnormal metabolic regulation of the HPG axis. - Highlights: • TBT disrupted proper functioning of the HPG axis in female rats. • TBT leads to obesity and abnormal kisspeptin/leptin signaling in female rats. • TBT impairs GnRH neurons function, estrogen negative feedback role and fertility in female rats. • TBT leads to hyperleptinemia that may be associated at least in part with abnormal HPG function.« less

Changes in the expression of genes involved in the ovarian function of rats caused by daily exposure to 3-methylcholanthrene and their prevention by α-naphthoflavone.

PubMed

Rhon-Calderón, Eric Alejandro; Toro, Carlos Alejandro; Lomniczi, Alejandro; Galarza, Rocío Alejandra; Faletti, Alicia Graciela

2018-02-01

Daily exposure to low doses of 3-methylcholanthrene (3MC) during the pubertal period in rats disrupts both follicular growth and ovulation. Thus, to provide new insights into the toxicity mechanism of 3MC in the ovary, here we investigated the effect of daily exposure to 3MC on selected ovarian genes, the role of the aryl hydrocarbon receptor (AhR) and the level of epigenetic remodeling of histone post-transcriptional modifications. Immature rats were daily injected with 3MC (0.1 or 1 mg/kg) and mRNA expression of genes involved in different ovarian processes were evaluated. Of the 29 genes studied, 18 were up-regulated, five were down-regulated and six were not altered. To assess whether AhR was involved in these changes, we used the chromatin immunoprecipitation assay. 3MC increased AhR binding to promoter regions of genes involved in Notch signaling (Hes1, Jag1), activation of primordial follicles (Cdk2), cell adhesion (Icam1), stress and tumor progression (Dnajb6), apoptosis (Bax, Caspase-9) and expression of growth and transcription factors (Igf2, Sp1). Studying the trimethylation and acetylation of histone 3 (H3K4me3 and H3K9Ac, respectively) of these genes, we found that 3MC increased H3K4me3 in Cyp1a1, Jag1, Dnajb6, Igf2, Notch2, Adamts1, Bax and Caspase-9, and H3K9Ac in Cyp1a1, Jag1, Cdk2, Dnajb6, Igf2, Icam1, and Sp1. Co-treatment with α-naphthoflavone (αNF), a specific antagonist of AhR, prevented almost every 3MC-induced changes. Despite the low dose used in these experiments, daily exposure to 3MC induced changes in both gene expression and epigenomic remodeling, which may lead to premature ovarian failure.

Protective effect of oestradiol in the coeliac ganglion against ovarian apoptotic mechanism on dioestrus.

PubMed

Cynthia, Bronzi; Cristina, Daneri Becerra; Adriana, Vega Orozco; Belén, Delsouc María; María, Rastrilla Ana; Marilina, Casais; Zulema, Sosa

2013-05-01

The aims of this work were to investigate if oestradiol 10(-8)M in the incubation media of either the ovary alone (OV) or the ganglion compartment of an ex vivo coeliac ganglion-superior ovarian nerve-ovary system (a) modifies the release of ovarian progesterone (P4) and oestradiol (E2) on dioestrus II, and (b) modifies the ovarian gene expression of 3β-HSD and 20α-HSD enzymes and markers of apoptosis. The concentration of ovarian P4 release was measured in both experimental schemes, and ovarian P4 and E2 in the ex vivo system by RIA at different times. The expression of 3β-hydroxysteroid dehydrogenase, 20α-hydroxysteroid dehydrogenase and antiapoptotic bcl-2 and proapoptotic bax by RT-PCR were determined. E2 added in the coeliac ganglion caused an increase in the ovarian release of the P4, E2 and 3β-HSD, while in the ovary incubation alone it decreased P4 and 3β-HSD but increased and 20α-HSD and bax/bcl-2 ratio. It is concluded that through a direct effect on the ovary, E2 promotes luteal regression in DII rats, but the addition of E2 in the coeliac ganglion does not have the same effect. The peripheral nervous system, through the superior ovarian nerve, has a protective effect against the apoptotic mechanism on DII. Copyright © 2013 Elsevier Ltd. All rights reserved.

Rat inferior caval vein (ICV) ligature and particular new insights with the stable gastric pentadecapeptide BPC 157.

PubMed

Vukojević, Jakša; Siroglavić, Marko; Kašnik, Katarina; Kralj, Tamara; Stanćić, Duje; Kokot, Antonio; Kolarić, Darko; Drmić, Domagoj; Sever, Anita Zenko; Barišić, Ivan; Šuran, Jelena; Bojić, Davor; Patrlj, Masa Hrelec; Sjekavica, Ivica; Pavlov, Katarina Horvat; Vidović, Tinka; Vlainić, Josipa; Stupnišek, Mirjana; Seiwerth, Sven; Sikirić, Predrag

2018-03-03

Rat inferior caval vein (ICV) ligation (up to the right ovarian vein (ROV)) commonly represents a recapitulation of Virchow: with ligation leading to vessel injury, stasis, thrombosis and hemodynamic changes. We revealed that BPC 157's therapy collectively attenuated or counteracted all these events and the full syndrome. We applied BPC 157 (10 μg, 10 ng/kg) as an early regimen or as a delayed therapy. Assessment includes gross assessment by microcamera; microscopy, venography, bleeding, blood pressure, ECG, thermography, MDA and NO-level in plasma and ICV, and gene expression. Direct vein injury, thrombosis, thrombocytopenia, prolonged bleeding were all counteracted. Also, rapid presentation of collaterals and redistribution of otherwise trapped blood volume (bypassing through the left ovarian vein (LOV) and other veins), with venous hypertension, arterial hypotension and tachycardia counteraction were shown. BPC 157-rats presented raised plasma NO-values, but normal MDA-values; in ICV tissue reverted low NO-values and counteracted increased MDA-levels. Altered expression of EGR, NOS, SRF, VEGFR and KRAS in ICV, ROV and LOV revealed increased or decreased levels, while some genes continuously remained unchanged. As a new insight, BPC 157 application largely attenuated or even completely eliminated all consequences of ICV ligation in rats. Copyright © 2018 Elsevier Inc. All rights reserved.

Neuroimmune response to endogenous and exogenous pyrogens is differently modulated by sex steroids.

PubMed

Mouihate, A; Pittman, Q J

2003-06-01

The objective of this study was to explore whether and how ovarian hormones interact with the febrile response to pyrogens. Estrogen and progesterone treatment of ovariectomized rats was associated with a reduction in lipopolysaccharide (LPS)-induced fever, compared with ovariectomized controls. LPS-fever reduction was accompanied by reduced levels of the inducible cyclooxygenase-2 (COX-2) protein expression in the hypothalamus as well as reduced plasma levels of IL-1beta. The amount of LPS-induced IL-6 in the plasma was not affected by ovarian hormone replacement. In contrast, hypothalamic COX-2 expression in response to intraperitoneal injection of IL-1beta was potentiated by the ovarian hormone replacement. IL-1beta induced a moderate increase in plasma levels of IL-6 that was suppressed by ovarian hormone replacement. These data suggest that ovarian hormone replacement attenuated the proinflammatory response to LPS by suppressing the LPS-induced IL-1beta production and COX-2 expression in the hypothalamus. The markedly different action of ovarian hormones on IL-1beta and LPS effects suggests that this sex hormone modulation of the immune response is a function of the nature of infection and provides further evidence that LPS actions are different from those of IL-1beta.

Biological effects of combined resveratrol and vitamin D3 on ovarian tissue.

PubMed

Uberti, Francesca; Morsanuto, Vera; Aprile, Silvio; Ghirlanda, Sabrina; Stoppa, Ian; Cochis, Andrea; Grosa, Giorgio; Rimondini, Lia; Molinari, Claudio

2017-09-15

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural antioxidant polyphenol able to exert a wide range of biological effect on several tissues. Despite its important beneficial properties, it has a low water solubility, which limits its therapeutic applications in humans. Resveratrol also acts as a phytoestrogen that modulates estrogen receptor (ER)-mediated transcription. In addition, it has been shown that ovarian tissues benefit greatly from vitamin D3, which exerts its beneficial effects through VDR receptors. The aim was to evaluate the cooperative effects of resveratrol combined with vitamin D3 on ovarian cells and tissues and some other organs as well. Moreover, the modulation of specific intracellular pathways involving ER and VDR receptors has been studied. The experiments were performed both in vitro and in vivo, to analyze cell viability, radical oxygen species production, signal transductions through Western Blot, and resveratrol quantification by HPLC. Cell viability, radical oxygen species production, and intracellular pathways have been studied on CHO-K1 cells. Also, the relative mechanism activated following oral intake in female Wistar rats as animal model was investigated, evaluating bioavailability, biodistribution and signal transduction in heart, kidney, liver and ovarian tissues. Both in in vitro and in vivo experiments, resveratrol exerts more evident effects when administered in combination with vitD in ovarian cells, showing a common biphasic cooperative effect: The role of vitamin D3 in maintaining and supporting the biological activity of resveratrol has been clearly observed. Moreover, resveratrol plus vitamin D3 blood concentrations showed a biphasic absorption rate. Such results could be used as a fundamental data for the development of new therapies for gynecological conditions, such as hot-flashes.

Brown adipose tissue transplantation ameliorates polycystic ovary syndrome

PubMed Central

Yuan, Xiaoxue; Hu, Tao; Zhao, Han; Huang, Yuanyuan; Ye, Rongcai; Lin, Jun; Zhang, Chuanhai; Zhang, Hanlin; Wei, Gang; Zhou, Huiqiao; Dong, Meng; Zhao, Jun; Wang, Haibin; Liu, Qingsong; Lee, Hyuek Jong; Jin, Wanzhu; Chen, Zi-Jiang

2016-01-01

Polycystic ovary syndrome (PCOS), which is characterized by anovulation, hyperandrogenism, and polycystic ovaries, is a complex endocrinopathy. Because the cause of PCOS at the molecular level is largely unknown, there is no cure or specific treatment for PCOS. Here, we show that transplantation of brown adipose tissue (BAT) reversed anovulation, hyperandrogenism, and polycystic ovaries in a dehydroepiandrosterone (DHEA)-induced PCOS rat. BAT transplantation into a PCOS rat significantly stabilized menstrual irregularity and improved systemic insulin sensitivity up to a normal level, which was not shown in a sham-operated or muscle-transplanted PCOS rat. Moreover, BAT transplantation, not sham operation or muscle transplantation, surprisingly improved fertility in PCOS rats. Interestingly, BAT transplantation activated endogenous BAT and thereby increased the circulating level of adiponectin, which plays a prominent role in whole-body energy metabolism and ovarian physiology. Consistent with BAT transplantation, administration of adiponectin protein dramatically rescued DHEA-induced PCOS phenotypes. These results highlight that endogenous BAT activity is closely related to the development of PCOS phenotypes and that BAT activation might be a promising therapeutic option for the treatment of PCOS. PMID:26903641

The role of MiR-324-3p in polycystic ovary syndrome (PCOS) via targeting WNT2B.

PubMed

Jiang, Y-C; Ma, J-X

2018-06-01

To investigate the expression of microRNA-324-3p (miR-324-3p) in polycystic ovary syndrome (PCOS) and its effects on the proliferation and apoptosis of ovarian granulosa cells. A total of 60 Sprague-Dawley (SD) rats were randomly divided into normal group (n=30) and experimental group (n=30). Rats in the experimental group were intramuscularly injected with dehydroepiandrosterone (DHEA) (6 mg/100 g of body weight) and 0.2 mL oil for injection, while those in normal group were intramuscularly injected with 0.2 mL oil for injection. The ovarian tissues of PCOS model rats were removed to extract the total ribose nucleic acid (RNA). The expression of miR-324-3p was detected via reverse transcription-polymerase chain reaction (RT-PCR). Primary ovarian granulosa cells were isolated and cultured, and NC-miRNA and miR-324-3p mimic were transfected into cells. After 48 h, cell proliferation and apoptosis were detected via cell counting kit 8 (CCK-8) and flow cytometry assay, respectively. The targeted molecule of miR-324-3p was explored using bioinformatics, and dual-luciferase assay was performed to verify the effect of miR-324-3p on WNT2B expression. Granulosa cells were co-transfected with WNT2B-small-interfering RNA (siRNA) and miR-324-3p mimic, and then cell proliferation and apoptosis were detected via CCK-8 and flow cytometry assay, respectively. The expression of miR-324-3p in ovarian tissues of PCOS group was significantly lower than that of normal group (p < 0.01). After transfection with miR-324-3p mimic into granulosa cells, cell proliferation was significantly inhibited and cell apoptosis was promoted (p < 0.01). MiR-324-3p exerted its effect on granulosa cells by directly targeting WNT2B. Silencing WNT2B expression could reverse the effects of miR-324-3p on proliferation and apoptosis of granulosa cells (p < 0.05). The expression of miR-324-3p in the ovary of PCOS rats is decreased significantly. Overexpression of miR-324-3p can reduce the proliferation and induce the apoptosis of granulosa cells via targeting of WNT2B.

Effects of the estrous cycle and ovarian hormones on behavioral indices of anxiety in female rats.

PubMed

Mora, S; Dussaubat, N; Díaz-Véliz, G

1996-10-01

The influence of the estrous cycle and the effects of exogenous administration of estradiol and progesterone on level of anxiety were studied in intact and ovariectomized rats. Intact Sprague-Dawley female rats were classified according to the stages of estrous cycle. Another group of rats was ovariectomized bilaterally and, 14 days after surgery, they received estradiol benzoate (10 micrograms/kg, s.c.) and/or progesterone (25 mg/kg, s.c.) or corn oil (1 ml/kg). The behavioral tests began 3 h after estradiol or 6 h after progesterone and consisted of: (1) exploration of an elevated plus-maze; and (2) retention of a passive avoidance response. Open-arm exploration of the plus-maze varied according to light intensity and the stages of the estrous cycle. There was a slight increase in open-arm exploration by rats in metestrus, under high light intensity. Low light intensity increased the exploration of the open arms by rats in proestrus and estrus, compared to the other phases of the cycle. Retention of the passive avoidance response was inhibited during proestrus and estrus. Progesterone increased open-arm exploration of the plus-maze under high light conditions, whereas estradiol antagonized this effect. Retention of passive avoidance was inhibited after estradiol or progesterone injection. These results suggest that the behavioral indices of anxiety can vary across the estrous cycle, that low light intensities have anxiolytic-like effects, and that the sensitivity to this effect is higher during proestrus and estrus. This could be explained through modulatory effects of ovarian hormones upon behavioral indices of anxiety.

Excess androgen during puberty disrupts circadian organization in female rats.

PubMed

Sellix, Michael T; Murphy, Zachary C; Menaker, Michael

2013-04-01

Circadian clocks have been described in each tissue of the hypothalamo-pituitary-ovarian axis. Although a role for the clock in the timing of ovulation is indicated, the impact of diseases that disrupt fertility on clock function or the clocks' role in the etiology of these pathologies has yet to be fully appreciated. Polycystic ovary syndrome (PCOS) is a particularly devastating endocrinopathy, affecting approximately 10% of women at childbearing age. Common features of PCOS are a polycystic ovary, amenorrhea, and excess serum androgen. Approximately 40% of these women have metabolic syndrome, including hyperinsulinemia, dyslipidemia, and hyperleptinemia. It has been suggested that excess androgen is a critical factor in the etiology of PCOS. We have examined the effects of androgen excess during puberty on the phase of circadian clocks in tissues of the metabolic and hypothalamo-pituitary-ovarian axes. Female period1-luciferase (per1-luc) rats were exposed to androgen (5α-dihydrotestosterone [DHT]) or placebo for 4-6 weeks (short term) or 9-15 weeks (long term). As expected, DHT-treated animals gained more weight than controls and had disrupted estrous cycles. At the end of treatment, tissues, including the liver, lung, kidney, white adipose, cornea, pituitary, oviduct, and ovarian follicles, were cultured, and per1-luc expression in each was recorded. Analysis of per1-luc expression revealed that DHT exposure increased phase distribution of multiple oscillators, including ovarian follicles, liver, and adipose, and altered phase synchrony between animals. These data suggest that excess androgen during puberty, a common feature of PCOS, negatively affects internal circadian organization in both the reproductive and metabolic axes.

Excess Androgen During Puberty Disrupts Circadian Organization in Female Rats

PubMed Central

Murphy, Zachary C.; Menaker, Michael

2013-01-01

Circadian clocks have been described in each tissue of the hypothalamo-pituitary-ovarian axis. Although a role for the clock in the timing of ovulation is indicated, the impact of diseases that disrupt fertility on clock function or the clocks' role in the etiology of these pathologies has yet to be fully appreciated. Polycystic ovary syndrome (PCOS) is a particularly devastating endocrinopathy, affecting approximately 10% of women at childbearing age. Common features of PCOS are a polycystic ovary, amenorrhea, and excess serum androgen. Approximately 40% of these women have metabolic syndrome, including hyperinsulinemia, dyslipidemia, and hyperleptinemia. It has been suggested that excess androgen is a critical factor in the etiology of PCOS. We have examined the effects of androgen excess during puberty on the phase of circadian clocks in tissues of the metabolic and hypothalamo-pituitary-ovarian axes. Female period1-luciferase (per1-luc) rats were exposed to androgen (5α-dihydrotestosterone [DHT]) or placebo for 4-6 weeks (short term) or 9-15 weeks (long term). As expected, DHT-treated animals gained more weight than controls and had disrupted estrous cycles. At the end of treatment, tissues, including the liver, lung, kidney, white adipose, cornea, pituitary, oviduct, and ovarian follicles, were cultured, and per1-luc expression in each was recorded. Analysis of per1-luc expression revealed that DHT exposure increased phase distribution of multiple oscillators, including ovarian follicles, liver, and adipose, and altered phase synchrony between animals. These data suggest that excess androgen during puberty, a common feature of PCOS, negatively affects internal circadian organization in both the reproductive and metabolic axes. PMID:23417420

Regulation of the ovarian oxidative status by leptin during the ovulatory process in rats.

PubMed

Bilbao, María Guillermina; Di Yorio, María Paula; Galarza, Rocío Alejandra; Varone, Cecilia Laura; Faletti, Alicia Graciela

2015-04-01

Leptin exerts both stimulatory and inhibitory effects on the ovulatory process. In this study, we investigated whether these opposite effects involve changes in the oxidative status in response to different levels of leptin. To this end, we performed both in vivo and in vitro assays using ovaries of immature rats primed with gonadotropins to induce ovulation. Superoxide dismutase (SOD) and catalase (CAT) activity, lipid peroxidation, glutathione (GSH) content, and reactive oxygen species (ROS) were studied as oxidative damage-related parameters. The expression of BCL2, BAX, and caspase 3 were measured by western blot as apoptosis-related biomarkers. The acute treatment with leptin, which inhibits ovulation, decreased SOD activity and increased active caspase 3 expression. No differences were found in CAT activity, lipid peroxidation, or total GSH. In contrast, the daily administration of leptin, which induces ovulation, decreased GSH content, ROS levels, and Bax and active caspase 3 expression, but caused no changes in other parameters. In addition, the daily administration of leptin induced follicular growth, measured by the number of antral follicles in ovarian sections. Using ovarian explant cultures, we found increased BCL2 expression and decreased SOD activity at low and high concentrations of leptin respectively. Thus, leptin can modulate the oxidative status of the ovarian tissue, during the ovulatory process, by acting on different targets according to its circulating levels. At low concentration, leptin seems to play a protective role against the oxidative stress, whereas at high concentrations, this protein seems to be involved in cell death. © 2015 Society for Reproduction and Fertility.

Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: Towards targeted stem cell therapy.

PubMed

Sharrow, Allison C; Perkins, Brandy; Collector, Michael I; Yu, Wayne; Simons, Brian W; Jones, Richard J

2016-08-01

The cancer stem cell (CSC) paradigm hypothesizes that successful clinical eradication of CSCs may lead to durable remission for patients with ovarian cancer. Despite mounting evidence in support of ovarian CSCs, their phenotype and clinical relevance remain unclear. We and others have found high aldehyde dehydrogenase 1 (ALDH(high)) expression in a variety of normal and malignant stem cells, and sought to better characterize ALDH(high) cells in ovarian cancer. We compared ALDH(high) to ALDH(low) cells in two ovarian cancer models representing distinct subtypes: FNAR-C1 cells, derived from a spontaneous rat endometrioid carcinoma, and the human SKOV3 cell line (described as both serous and clear cell subtypes). We assessed these populations for stem cell features then analyzed expression by microarray and qPCR. ALDH(high) cells displayed CSC properties, including: smaller size, quiescence, regenerating the phenotypic diversity of the cell lines in vitro, lack of contact inhibition, nonadherent growth, multi-drug resistance, and in vivo tumorigenicity. Microarray and qPCR analysis of the expression of markers reported by others to enrich for ovarian CSCs revealed that ALDH(high) cells of both models showed downregulation of CD24, but inconsistent expression of CD44, KIT and CD133. However, the following druggable targets were consistently expressed in the ALDH(high) cells from both models: mTOR signaling, her-2/neu, CD47 and FGF18/FGFR3. Based on functional characterization, ALDH(high) ovarian cancer cells represent an ovarian CSC population. Differential gene expression identified druggable targets that have the potential for therapeutic efficacy against ovarian CSCs from multiple subtypes. Copyright © 2016 Elsevier Inc. All rights reserved.

The Cooccurrence of Obesity, Osteoporosis, and Sarcopenia in the Ovariectomized Rat: A Study for Modeling Osteosarcopenic Obesity in Rodents.

PubMed

Ezzat-Zadeh, Zahra; Kim, Jeong-Su; Chase, P Bryant; Arjmandi, Bahram H

2017-01-01

Obesity, osteoporosis, and sarcopenia may individually occur due to age-related gradual alterations in body composition. This study investigates the cooccurrence of these age-related diseases in female animals with low levels of ovarian hormone in the absence of complex multifactorial process of chronological aging. Thirty-six 5- and 10-month-old female rats were chosen to model pre- and postmenopausal women, respectively. Rats were divided into three treatment groups in each age category-sham, ovariectomized (ovx), and ovx + E 2 (17 β -estradiol, 10  μ g/kg)-and were pair-fed. Volunteer wheel running activity, body composition, bone microstructure, serum C-telopeptides of type I collagen, bone specific alkaline phosphatase, E 2 , and gastrocnemius and soleus muscles were analyzed. The cooccurrence of osteoporosis, sarcopenia, and obesity was observed in the older ovx rats associated with a significant ( p < 0.05) increased fat mass (30%), bone loss (9.6%), decreased normalized muscle mass-to-body-weight ratio (10.5%), and a significant decrease in physical activity (57%). The ratio of tibial bone mineral density to combined muscle mass was significantly decreased in both ovx age categories. Ovariectomized rat could be used as an experimental model to examine the effect of loss of ovarian hormones, while controlling for energy intake and expenditure, to conduct obesity and body composition translational research in females without the confounding effect of genetic background.

Ovarian expressed microsomal epoxide hydrolase: Role in detoxification of 4-vinylcyclohexene diepoxide and regulation by phosphatidylinositol-3 kinase signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhattacharya, Poulomi, E-mail: poulomib@iastate.edu; Sen, Nivedita, E-mail: nsen@email.arizona.edu; Hoyer, Patricia B., E-mail: Hoyer@u.arizona.edu

2012-01-01

4-vinylcyclohexene diepoxide (VCD) is a metabolite of 4-vinylcyclohexene (VCH) which has the potential to be formed in the ovary through CYP2E1 activity. VCD specifically destroys primordial and small primary follicles in the rodent ovary. Mouse ovaries exposed to VCD demonstrate increased mRNA and protein expression of microsomal epoxide hydrolase (mEH), and an inactive tetrol metabolite (4-(1,2-dihydroxy)ethyl-1,2-dihydroxycyclohexane) can be formed in mouse ovarian follicles, potentially through detoxification action of mEH. In contrast, mEH can bioactivate another ovotoxic chemical, 7,12-dimethylbenz[a]anthracene (DMBA) to a more toxic compound, DMBA-3,4-diol-1,2-epoxide. Thus, the present study evaluated a functional role for mEH during detoxification of VCD. Additionally,more » because inhibition of the phosphatidyinositol-3 kinase (PI3K) signaling pathway in a previous study protected primordial follicles from VCD-induced destruction, but accelerated DMBA-induced ovotoxicity, a role for PI3K in ovarian mEH regulation was evaluated. Using a post-natal day (PND) 4 Fischer 344 rat whole ovary culture system inhibition of mEH using cyclohexene oxide during VCD exposure resulted in a greater (P < 0.05) loss of primordial and small primary follicles relative to VCD-treated ovaries. Also, relative to controls, meh mRNA was increased (P < 0.05) on day 4 of VCD (30 μM) exposure, followed by increased (P < 0.05) mEH protein after 6 days. Furthermore, inhibition of PI3K signaling increased mEH mRNA and protein expression. Thus, these results support a functional role for mEH in the rat ovary, and demonstrate the involvement of PI3K signaling in regulation of ovarian xenobiotic metabolism by mEH. -- Highlights: ► Ovarian mEH functions to metabolize VCD to a less toxic compound. ► mEH expression is increased in a temporal pattern in response to VCD exposure. ► PI3K signaling is involved in regulation of ovarian mEH expression.« less

Nickel nanoparticles exposure and reproductive toxicity in healthy adult rats.

PubMed

Kong, Lu; Tang, Meng; Zhang, Ting; Wang, Dayong; Hu, Ke; Lu, Weiqi; Wei, Chao; Liang, Geyu; Pu, Yuepu

2014-11-17

Nickel is associated with reproductive toxicity. However, the reproductive toxicity of nickel nanoparticles (Ni NPs) is unclear. Our goal was to determine the association between nickel nanoparticle exposure and reproductive toxicity. According to the one-generation reproductive toxicity standard, rats were exposed to nickel nanoparticles by gavage and we selected indicators including sex hormone levels, sperm motility, histopathology, and reproductive outcome etc. Experimental results showed nickel nanoparticles increased follicle stimulating hormone (FSH) and luteinizing hormone (LH), and lowered etradiol (E2) serum levels at a dose of 15 and 45 mg/kg in female rats. Ovarian lymphocytosis, vascular dilatation and congestion, inflammatory cell infiltration, and increase in apoptotic cells were found in ovary tissues in exposure groups. For male rats, the weights decreased gradually, the ratio of epididymis weight over body weight increased, the motility of rat sperm changed, and the levels of FSH and testosterone (T) diminished. Pathological results showed the shedding of epithelial cells of raw seminiferous tubule, disordered arrangement of cells in the tube, and the appearance of cell apoptosis and death in the exposure group. At the same time, Ni NPs resulted in a change of the reproductive index and the offspring development of rats. Further research is needed to elucidate exposure to human populations and mechanism of actions.

Nickel Nanoparticles Exposure and Reproductive Toxicity in Healthy Adult Rats

PubMed Central

Kong, Lu; Tang, Meng; Zhang, Ting; Wang, Dayong; Hu, Ke; Lu, Weiqi; Wei, Chao; Liang, Geyu; Pu, Yuepu

2014-01-01

Nickel is associated with reproductive toxicity. However, the reproductive toxicity of nickel nanoparticles (Ni NPs) is unclear. Our goal was to determine the association between nickel nanoparticle exposure and reproductive toxicity. According to the one-generation reproductive toxicity standard, rats were exposed to nickel nanoparticles by gavage and we selected indicators including sex hormone levels, sperm motility, histopathology, and reproductive outcome etc. Experimental results showed nickel nanoparticles increased follicle stimulating hormone (FSH) and luteinizing hormone (LH), and lowered etradiol (E2) serum levels at a dose of 15 and 45 mg/kg in female rats. Ovarian lymphocytosis, vascular dilatation and congestion, inflammatory cell infiltration, and increase in apoptotic cells were found in ovary tissues in exposure groups. For male rats, the weights decreased gradually, the ratio of epididymis weight over body weight increased, the motility of rat sperm changed, and the levels of FSH and testosterone (T) diminished. Pathological results showed the shedding of epithelial cells of raw seminiferous tubule, disordered arrangement of cells in the tube, and the appearance of cell apoptosis and death in the exposure group. At the same time, Ni NPs resulted in a change of the reproductive index and the offspring development of rats. Further research is needed to elucidate exposure to human populations and mechanism of actions. PMID:25407529

Systemic compensatory response to neonatal estradiol exposure does not prevent depletion of the oocyte pool in the rat.

PubMed

Chalmey, Clémentine; Giton, Frank; Giton, Franck; Chalmel, Frédéric; Fiet, Jean; Jégou, Bernard; Mazaud-Guittot, Séverine

2013-01-01

The formation of ovarian follicles is a finely tuned process that takes place within a narrow time-window in rodents. Multiple factors and pathways have been proposed to contribute to the mechanisms triggering this process but the role of endocrine factors, especially estrogens, remains elusive. It is currently hypothesized that removal from the maternal hormonal environment permits follicle formation at birth. However, experimentally-induced maintenance of high 17β-estradiol (E2) levels leads to subtle, distinct, immediate effects on follicle formation and oocyte survival depending on the species and dose. In this study, we examined the immediate effects of neonatal E2 exposure from post-natal day (PND) 0 to PND2 on the whole organism and on ovarian follicle formation in rats. Measurements of plasma E2, estrone and their sulfate conjugates after E2 exposure showed that neonatal female rats rapidly acquire the capability to metabolize and clear excessive E2 levels. Concomitant modifications to the mRNA content of genes encoding selected E2 metabolism enzymes in the liver and the ovary in response to E2 exposure indicate that E2 may modify the neonatal maturation of these organs. In the liver, E2 treatment was associated with lower acquisition of the capability to metabolize E2. In the ovary, E2 depleted the oocyte pool in a dose dependent manner by PND3. In 10 µg/day E2-treated ovaries, apoptotic oocytes were observed in newly formed follicles in addition to areas of ovarian cord remodeling. At PND6, follicles without any visible oocyte were present and multi-oocyte follicles were not observed. Our study reveals a major species-difference. Indeed, neonatal exposure to E2 depletes the oocyte pool in the rat ovary, whereas in the mouse it is well known to increase oocyte survival.

Estradiol does not influence strategy choice but place strategy choice is associated with increased cell proliferation in the hippocampus of female rats.

PubMed

Rummel, Julia; Epp, Jonathan R; Galea, Liisa A M

2010-09-01

Adult neurogenesis occurs in the hippocampus of most mammals. While the function of adult hippocampal neurogenesis is not known, there is a relationship between neurogenesis and hippocampus-dependent learning and memory. Ovarian hormones can influence learning and memory and strategy choice. In competitive memory tasks, higher levels of estradiol shift female rats towards the use of the place strategy. Previous studies using a cue-competition paradigm find that 36% of male rats will use a hippocampus-dependent place strategy and place strategy users had lower levels of cell proliferation in the hippocampus. Here, we used the same paradigm to test whether endogenous or exogenous ovarian hormones influence strategy choice in the cue-competition paradigm and whether cell proliferation was related to strategy choice. We tested ovariectomized estradiol-treated (10 microg of estradiol benzoate) or sham-operated female rats on alternating blocks of hippocampus-dependent and hippocampus-independent versions of the Morris water task. Rats were then given a probe session with the platform visible and in a novel location. Preferred strategy was classified as place strategy (hippocampus-dependent) if they swam to the old platform location or cue strategy (hippocampus-independent) if they swam to the visible platform. All groups showed a preference for the cue strategy. However, proestrous rats were more likely to be place strategy users than rats not in proestrus. Female place strategy users had increased cell proliferation in the dentate gyrus compared to cue strategy users. Our study suggests that 78% of female rats chose the cue strategy instead of the place strategy. In summary the present results suggest that estradiol does not shift strategy use in this paradigm and that cell proliferation is related to strategy use with greater cell proliferation seen in place strategy users in female rats. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Long-term effects of in utero and lactational exposure to butyl paraben in female rats.

PubMed

Guerra, Marina Trevizan; Sanabria, Marciana; Cagliarani, Stephannie Vieira; Leite, Gabriel Adan Araújo; Borges, Cibele Dos Santos; De Grava Kempinas, Wilma

2017-03-01

Parabens are used as preservatives in cosmetic, pharmaceutical, and food industries, and are frequently detected as contaminants in human fluids and tissues. The endocrine disrupting effects of parabens in female rodents include uterotrophic response, steroidogenesis impairment, and ovarian disturbances. The objective of this study was to determine the effects of maternal butyl paraben (BP) exposure on female sexual development. Pregnant Wistar rats were treated subcutaneously with either corn oil or BP at doses of 10, 100, or 200 mg/kg, from gestational day (GD) 12 until GD 20 for female foetal gonad evaluation, and from GD 12 until the end of lactation to evaluate sexual parameters on the female offspring. Immature female rats were also used in the uterotrophic assay to evaluate the possible estrogenic action of parabens. Our results revealed that, in this experimental protocol, BP did not show estrogenic activity at the doses used and did not impair sexual development and fertility capacity in the female rats, but impaired sexual behavior. We conclude that brain sexual development may be more sensitive to BP effects and we speculate that doses higher than 100 mg/kg (the male lowest observed adverse effect level (LOAEL) for rodent reproductive parameters) would be necessary to promote damages in the female reproduction, regarding the same protocol of exposure. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 776-788, 2017. © 2016 Wiley Periodicals, Inc.

Presence of gonadotropin-releasing hormone and its messenger ribonucleic acid in human ovarian epithelial carcinoma.

PubMed

Ohno, T; Imai, A; Furui, T; Takahashi, K; Tamaya, T

1993-09-01

The purpose of this study was to investigate the expression of gonadotropin-releasing hormone messenger ribonucleic acid and the presence of gonadotropin-releasing hormone in human ovarian carcinoma known to have gonadotropin-releasing hormone binding sites and to be affected by gonadotropin-releasing hormone analog. Human ovarian carcinomas surgically removed and human ovarian carcinoma cell lines were examined. Gonadotropin-releasing hormone was determined by a radioimmunoassay and a bioassay. Gonadotropin-releasing hormone messenger ribonucleic acid was determined by reverse transcription polymerase chain reaction using oligonucleotide primers synthesized according to the published human gonadotropin-releasing hormone sequence. Gonadotropin-releasing hormone was shown to be present in extracts of ovarian mucinous cystadenocarcinoma sample (0.8 +/- 0.12 pg/mg of protein) and ovarian adenocarcinoma cell line SK-OV3 (0.92 +/- 0.17 pg/mg of protein) but not in the normal ovary and placenta. Two of two extract samples from individual cases evoked dose-dependent phosphoinositide breakdown in rat granulosa cells similar to that caused by authentic gonadotropin-releasing hormone. Gonadotropin-releasing hormone messenger ribonucleic acid was detected in two of two mucinous cystadenocarcinoma specimens, one of one serous cystadenocarcinoma, and SK-OV3 cells but not in the dysgerminoma, mucinous cystadenoma, and normal ovary and placenta. The demonstration of gonadotropin-releasing hormone and its messenger ribonucleic acid raises the possibility that gonadotropin-releasing hormone may play an autocrine regulatory role in the growth of ovarian carcinoma.

Cell structure and function and response to chemotherapy in tumors heterotransplanted into the subrenal capsule of mice and rats.

PubMed

Stenbäck, F; Kangas, L; Wasenius, V M

1985-12-01

Specimens from 16 freshly biopsied human tumors, two mammary adenocarcinomas, ten ovarian adenocarcinomas, two squamous cell carcinomas, one malignant histiocytoma and one chondrosarcoma of the bone, two human ovarian adenocarcinomas established by transplantation into nude mice and two adenocarcinomas induced in rat mammary gland were transplanted under the renal capsule of 510 normal immunocompetent mice and 180 rats and the effects of chemotherapy were evaluated. The results showed successful transplantation of all types of tumors in both animal species. Morphological analysis revealed preserved glandular structures with surface microvilli, mucin and CEA production and partially preserved basement membranes. Treatment with cyclophosphamide, vinblastine, adriamycin and cisplatin caused cell shrinkage, degradation and partial or total disappearance of the tumor cells. Vascularization was distinct in all specimens. A cellular infiltrate was found frequently but not consistently. A common end stage was a fibrotic scar with no cellular activity, occasionally giving a misleading impression of a growing tumor on gross observation. The results were obtained rapidly and suggest that the subrenal capsule assay would be useful for evaluating the sensitivity of human tumors to therapeutic manipulation, but needs supplementary histological examination.

Environmental obesogen tributyltin chloride leads to abnormal hypothalamic-pituitary-gonadal axis function by disruption in kisspeptin/leptin signaling in female rats.

PubMed

Sena, Gabriela C; Freitas-Lima, Leandro C; Merlo, Eduardo; Podratz, Priscila L; de Araújo, Julia F P; Brandão, Poliane A A; Carneiro, Maria T W D; Zicker, Marina C; Ferreira, Adaliene V M; Takiya, Christina M; de Lemos Barbosa, Carolina M; Morales, Marcelo M; Santos-Silva, Ana Paula; Miranda-Alves, Leandro; Silva, Ian V; Graceli, Jones B

2017-03-15

Tributyltin chloride (TBT) is a xenobiotic used as a biocide in antifouling paints that has been demonstrated to induce endocrine-disrupting effects, such as obesity and reproductive abnormalities. An integrative metabolic control in the hypothalamus-pituitary-gonadal (HPG) axis was exerted by leptin. However, studies that have investigated the obesogenic TBT effects on the HPG axis are especially rare. We investigated whether metabolic disorders as a result of TBT are correlated with abnormal hypothalamus-pituitary-gonadal (HPG) axis function, as well as kisspeptin (Kiss) action. Female Wistar rats were administered vehicle and TBT (100ng/kg/day) for 15days via gavage. We analyzed their effects on the tin serum and ovary accumulation (as biomarker of TBT exposure), estrous cyclicity, surge LH levels, GnRH expression, Kiss action, fertility, testosterone levels, ovarian apoptosis, uterine inflammation, fibrosis, estrogen negative feedback, body weight gain, insulin, leptin, adiponectin levels, as well as the glucose tolerance (GTT) and insulin sensitivity tests (IST). TBT led to increased serum and ovary tin levels, irregular estrous cyclicity, and decreased surge LH levels, GnRH expression and Kiss responsiveness. A strong negative correlation between the serum and ovary tin levels with lower Kiss responsiveness and GnRH mRNA expression was observed in TBT rats. An increase in the testosterone levels, ovarian and uterine fibrosis, ovarian apoptosis, and uterine inflammation and a decrease in fertility and estrogen negative feedback were demonstrated in the TBT rats. We also identified an increase in the body weight gain and abnormal GTT and IST tests, which were associated with hyperinsulinemia, hyperleptinemia and hypoadiponectinemia, in the TBT rats. TBT disrupted proper functioning of the HPG axis as a result of abnormal Kiss action. The metabolic dysfunctions co-occur with the HPG axis abnormalities. Hyperleptinemia as a result of obesity induced by TBT may be associated with abnormal HPG function. A strong negative correlation between the hyperleptinemia and lower Kiss responsiveness was observed in the TBT rats. These findings provide evidence that TBT leads to toxic effects direct on the HPG axis and/or indirectly by abnormal metabolic regulation of the HPG axis. Copyright © 2017 Elsevier Inc. All rights reserved.

Orphanin FQ-ORL-1 regulation of reproduction and reproductive behavior in the female.

PubMed

Sinchak, Kevin; Dalhousay, Lauren; Sanathara, Nayna

2015-01-01

Orphanin FQ (OFQ/N) and its receptor, opioid receptor-like receptor-1 (ORL-1), are expressed throughout steroid-responsive limbic and hypothalamic circuits that regulate female ovarian hormone feedback and reproductive behavior circuits. The arcuate nucleus of the hypothalamus (ARH) is a brain region that expresses OFQ/N and ORL-1 important for both sexual behavior and modulating estradiol feedback loops. Within the ARH, the activation of the OFQ/N-ORL-1 system facilitates sexual receptivity (lordosis) through the inhibition of β-endorphin neuronal activity. Estradiol initially activates ARH β-endorphin neurons to inhibit lordosis. Simultaneously, estradiol upregulates coexpression of OFQ/N and progesterone receptors and ORL-1 in ARH β-endorphin neurons. Ovarian hormones regulate pre- and postsynaptic coupling of ORL-1 to its G protein-coupled signaling pathways. When the steroid-primed rat is nonreceptive, estradiol acts pre- and postsynaptically to decrease the ability of the OFQ/N-ORL-1 system to inhibit ARH β-endorphin neurotransmission. Conversely, when sexually receptive, ORL-1 signaling is restored to inhibit β-endorphin neurotransmission. Although steroid signaling that facilitates lordosis converges to deactivate ARH β-endorphin neurons, estradiol-only facilitation of lordosis requires the activation of ORL-1, but estradiol+progesterone does not, indicating that multiple circuits mediate ovarian hormone signaling to deactivate ARH β-endorphin neurons. Research on the role of OFQ/N-ORL-1 in ovarian hormone feedback loops is just beginning. In the rat, OFQ/N may act to terminate gonadotropin-releasing hormone and luteinizing hormone release under positive and negative feedbacks. In the ewe, it appears to directly inhibit gonadotropin-releasing hormone release to mediate progesterone-negative feedback. As a whole, the localization and actions of OFQ/N-ORL-1 system indicate that it may mediate the actions of estradiol and progesterone to synchronize reproductive behavior and ovarian hormone feedback loops. © 2015 Elsevier Inc. All rights reserved.

The impact of electromagnetic radiation (2.45 GHz, Wi-Fi) on the female reproductive system: The role of vitamin C.

PubMed

Saygin, Mustafa; Ozmen, Ozlem; Erol, Onur; Ellidag, Hamit Yasar; Ilhan, Ilter; Aslankoc, Rahime

2018-01-01

The present study investigated the effects of applied continuous 2.45 GHz electromagnetic radiation (EMR), which might cause physiopathological or morphological changes in the ovarian, fallopian tubal, and uterine tissues of rats. We proposed that the addition of vitamin C (Vit C) may reduce these severe effects. Eighteen female Sprague Dawley rats were randomly divided into three groups with six animals in each: Sham, EMR (EMR, 1 h/day for 30 days), and EMR + Vit C (EMR, 1 h/day for 30 days 250 mg/kg/daily). Total oxidant status (TOS) and oxidative stress index (OSI) levels increased ( p = 0.011 and p = 0.002, respectively) in the EMR-only group in ovarian tissues. In all tissues, TOS and OSI levels significantly decreased in the Vit C-treated group in ovarian, fallopian tubal, and uterine tissues ( p < 0.05). Anti-müllerian hormone levels significantly increased in the EMR group ( p < 0.05) and decreased in the Vit C-treated groups. Estrogen (E2) levels were unchanged in the EMR group, as the differences were not statistically significant. Immunohistochemical examination of the ovaries revealed significant increases in Caspase-3 expressions in the epithelial cells of the EMR group ( p < 0.05). In the EMR group, hyperemia was observed in uterine tissues. Also, Caspase-3 and Caspase-8 were significantly increased in the EMR group ( p < 0.001). Caspase-3 was significantly diminished with Vit C application in the ovarian and uterine tissues ( p < 0.05). Caspase-8 was significantly diminished only in uterine tissues ( p < 0.05). These results indicate that prolonged EMR exposure induced physiopathological changes in the ovarian, fallopian tubal, and uterine tissues due to oxidative damage. Under the conditions of this study, Vit C may have protective effects on female reproductive system against oxidative damage.

Wheel running decreases palatable diet preference in Sprague-Dawley rats.

PubMed

Moody, Laura; Liang, Joy; Choi, Pique P; Moran, Timothy H; Liang, Nu-Chu

2015-10-15

Physical activity has beneficial effects on not only improving some disease conditions but also by preventing the development of multiple disorders. Experiments in this study examined the effects of wheel running on intakes of chow and palatable diet e.g. high fat (HF) or high sucrose (HS) diet in male and female Sprague-Dawley rats. Experiment 1 demonstrated that acute wheel running results in robust HF or HS diet avoidance in male rats. Although female rats with running wheel access initially showed complete avoidance of the two palatable diets, the avoidance of the HS diet was transient. Experiment 2 demonstrated that male rats developed decreased HF diet preferences regardless of the order of diet and wheel running access presentation. Running associated changes in HF diet preference in females, on the other hand, depended on the testing schedule. In female rats, simultaneous presentation of the HF diet and running access resulted in transient complete HF diet avoidance whereas running experience prior to HF diet access did not affect the high preference for the HF diet. Ovariectomy in females resulted in HF diet preference patterns that were similar to those in male rats during simultaneous exposure of HF and wheel running access but similar to intact females when running occurred before HF exposure. Overall, the results demonstrated wheel running associated changes in palatable diet preferences that were in part sex dependent. Furthermore, ovarian hormones play a role in some of the sex differences. These data reveal complexity in the mechanisms underlying exercise associated changes in palatable diet preference. Published by Elsevier Inc.

Wheel running decreases palatable diet preference in Sprague-Dawley rats

PubMed Central

Moody, Laura; Liang, Joy; Choi, Pique P.; Moran, Timothy H.; Liang, Nu-Chu

2015-01-01

Physical activity has beneficial effects on not only improving some disease conditions but also by preventing the development of multiple disorders. Experiments in this study examined the effects of wheel running on intakes of chow and palatable diet e.g. high fat (HF) or high sucrose (HS) diet in male and female Sprague Dawley rats. Experiment 1 demonstrated that acute wheel running results in robust HF or HS diet avoidance in male rats. Although female rats with running wheel access initially showed complete avoidance of the two palatable diets, the avoidance of the HS diet was transient. Experiment 2 demonstrated that male rats developed decreased HF diet preferences regardless of the order of diet and wheel running access presentation. Running associated changes in HF diet preference in females, on the other hand, depended on the testing schedule. In female rats, simultaneous presentation of the HF diet and running access resulted in transient complete HF diet avoidance whereas running experience prior to HF diet access did not affect the high preference for the HF diet. Ovariectomy in females resulted in HF diet preference patterns that were similar to those in male rats during simultaneous exposure of HF and wheel running access but similar to intact females when running occurred before HF exposure. Overall, the results demonstrated wheel running associated changes in palatable diet preferences that were in part sex dependent. Furthermore, ovarian hormones play a role in some of the sex differences. These data reveal complexity in the mechanisms underlying exercise associated changes in palatable diet preference. PMID:25791204

The value of DCE-MRI in assessing histopathological and molecular biological features in induced rat epithelial ovarian carcinomas.

PubMed

Yuan, Su Juan; Qiao, Tian Kui; Qiang, Jin Wei; Cai, Song Qi; Li, Ruo Kun

2017-09-26

To investigate dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for assessing histopathological and molecular biological features in induced rat epithelial ovarian carcinomas (EOCs). 7,12-dimethylbenz[A]anthracene (DMBA) was applied to induce EOCs in situ in 46 SD rats. Conventional MRI and DCE-MRI were performed to evaluate the morphology and perfusion features of the tumors, including the time-signal intensity curve (TIC), volume transfer constant (K trans ), rate constant (K ep ), extravascular extracellular space volume ratio (V e ) and initial area under the curve (IAUC). DCE-MRI parameters were correlated with histological grade, microvascular density (MVD), vascular endothelial growth factor (VEGF) and fraction of Ki67-positive cells and the serum level of cancer antigen 125 (CA125). Thirty-five of the 46 rats developed EOCs. DCE-MRI showed type III TIC more frequently than type II (29/35 vs. 6/35, p < 0.001) in EOCs. The two types of TIC of tumors had significant differences in the histological grade, MVD, expression of VEGF and Ki67, and the serum level of CA125 (all p < 0.01). K trans , K ep and IAUC values showed significant differences in different histological grades in overall and pairwise comparisons except for IAUC in grade 2 vs. grade 3 (all p < 0.01). There was no significant difference in V e values among the three grade groups (p > 0.05). K trans , K ep and IAUC values were positively correlated with MVD, VEGF and Ki67 expression (all p < 0.01). V e was not significantly correlated with MVD, VEGF expression, Ki67 expression and the CA125 level (all p > 0.05). TIC types and perfusion parameters of DCE-MRI can reflect tumor grade, angiogenesis and cell proliferation to some extent, thereby helping treatment planning and predicting prognosis.

Protective Effect of Platelet Rich Plasma on Experimental Ischemia/Reperfusion Injury in Rat Ovary.

PubMed

Bakacak, Murat; Bostanci, Mehmet Suhha; İnanc, Fatma; Yaylali, Asli; Serin, Salih; Attar, Rukset; Yildirim, Gazi; Yildirim, Ozge Kizilkale

2016-01-01

Ovarian torsion is a common cause of local ischemic damage, reduced follicular activity and infertility. Platelet-rich plasma (PRP) contains growth factors with demonstrated cytoprotective properties; so we evaluated PRP efficacy in a rat ischemia/reperfusion (I/R) model. Sixty adult female Sprague-Dawley albino rats were randomly assigned to 6 groups of 8 animals each: Sham, Ischemia, I/R, Sham + PRP, I + PRP and I/R + PRP; and the remaining 12 used to prepare PRP. Ischemia groups were subjected to bilateral adnexal torsion for 3 h, while I/R and I/R + PRP groups received subsequent detorsion for 3 h. Intraperitoneal PRP was administered 30 min prior to ischemia (Ischemia + PRP) or reperfusion (I/R + PRP). Total oxidant status (TOS), oxidative stress index (OSI) and total ovarian histopathological scores were higher in Ischemia and I/R groups than in the Sham group (p < 0.05). PRP decreased mean TOS, OSI and histopathological scores in I + PRP and I/R + PRP groups compared to the corresponding Ischemia and I/R groups (p < 0.001). There was a strong correlation between total histopathological score and OSI (r = 0.877, p < 0.001). Peritoneal vascular endothelial growth factor was significantly higher in PRP-treated groups than corresponding untreated groups (p < 0.05). PRP is effective for the prevention of ischemia and reperfusion damage in rat ovary. © 2015 S. Karger AG, Basel.

Ovariectomy increases the age-induced hyperphosphorylation of Tau at hippocampal CA1.

PubMed

Picazo, O; Espinosa-Raya, J; Briones-Aranda, A; Cerbón, M

2016-11-01

One of the main hallmarks of Alzheimer's disease includes the neurofibrillary tangles formation produced by hyperphosphorylation of the Tau protein, whose expression is putatively regulated by the ovarian hormones estradiol and progesterone. Hippocampus is a brain region that participates in many functions related to learning and memory; in addition, it is abundant in both estradiol and progesterone receptors. In this study, we explore the expression of Tau hyperphosphorylation at hippocampus and the performance of rats in an autoshaping learning task at 5, 10 and 15 months after the ovaries removal. In these animals, ovariectomy was performed at 3 months of age. These data were compared with those derived from intact rats at 8, 13 and 18 months old. A clear decrease in the number of conditioned responses of both intact and ovariectomized rats in the autoshaping learning task was observed. The interaction of both factors confirms that, in this test, learning varies depending on aging and the presence or absence of ovaries. A progressive increase in hippocampal Tau phosphorylation at Ser-396 was observed in either intact or ovariectomized rats. Interestingly, an interaction between the analyzed factors shows that such hyperphosphorylation was potentiated by the absence of ovaries. These results emphasize the importance of aging and the lack of ovarian hormones for an associative learning test and for the expression of one of the most important hallmarks of Alzheimer's disease.

DISTRIBUTION OF ATRAZINE IN PC12 CELLS AND MODULATION OF CATECHOLAMINE SYNTHESIS

EPA Science Inventory

Previously, we reported that atrazine disrupts ovarian function by altering hypothalamic catecholamine (CA) concentrations and the consequent regulation of pituitary LH release and prolactin secretion in the young female rat. We also showed that atrazine directly interacts with t...

Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations.

PubMed

Tracey, Rebecca; Manikkam, Mohan; Guerrero-Bosagna, Carlos; Skinner, Michael K

2013-04-01

Environmental compounds have been shown to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a hydrocarbon mixture involving jet fuel (JP-8) promotes epigenetic transgenerational inheritance of disease. Gestating F0 generation female rats were transiently exposed during the fetal gonadal development period. The direct exposure F1 generation had an increased incidence of kidney abnormalities in both females and males, prostate and pubertal abnormalities in males, and primordial follicle loss and polycystic ovarian disease in females. The first transgenerational generation is the F3 generation, and the jet fuel lineage had an increased incidence of primordial follicle loss and polycystic ovarian disease in females, and obesity in both females and males. Analysis of the jet fuel lineage F3 generation sperm epigenome identified 33 differential DNA methylation regions, termed epimutations. Observations demonstrate hydrocarbons can promote epigenetic transgenerational inheritance of disease and sperm epimutations, potential biomarkers for ancestral exposures. Copyright © 2012 Elsevier Inc. All rights reserved.

Hydrocarbons (Jet Fuel JP-8) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations

PubMed Central

Tracey, Rebecca; Manikkam, Mohan; Guerrero-Bosagna, Carlos; Skinner, Michael K.

2012-01-01

Environmental compounds have been shown to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a hydrocarbon mixture involving jet fuel (JP-8) promotes epigenetic transgenerational inheritance of disease. Gestating F0 generation female rats were transiently exposed during the fetal gonadal development period. The direct exposure F1 generation had an increased incidence of kidney abnormalities in both females and males, prostate and pubertal abnormalities in males, and primordial follicle loss and polycystic ovarian disease in females. The first transgenerational generation is the F3 generation, and the jet fuel lineage had an increased incidence of primordial follicle loss and polycystic ovarian disease in females, and obesity in both females and males. Analysis of the jet fuel lineage F3 generation sperm epigenome identified 33 differential DNA methylation regions, termed epimutations. Observations demonstrate hydrocarbons can promote epigenetic transgenerational inheritance of disease and sperm epimutations, potential biomarkers for ancestral exposures. PMID:23453003

A novel method of extraction of bamboo seed oil (Bambusa bambos Druce) and its promising effect on metabolic symptoms of experimentally induced polycystic ovarian disease

PubMed Central

Soumya, V.; Muzib, Y. Indira; Venkatesh, P.

2016-01-01

Objective: To evaluate the potential effect of bamboo seed oil in decreasing the major metabolic symptoms associated with letrozole-induced polycystic ovarian disease using female rat model. Materials and Methods: A new method of microwave-assisted extraction was developed. Female rats were grouped into four with six animals each. All rats were daily administered with letrozole (1 mg/kg b.wt.) for 21 days except control, and during this period, changes in estrous cycle were observed. After letrozole treatment, Group 2 was considered negative control, Groups 3 and 4 were treated orally with bamboo oil, 0.5 ml/kg b.wt. and 1 ml/kg b.wt., respectively, for 3 weeks (five consecutive estrus cycles). Various parameters such as estrus cycle, blood sugar level, lipid profile, and weights of reproductive system were determined. The characteristics of cystic ovaries were evaluated by histopathological studies. Results: The isolated bamboo oil restored estrus cyclicity showed hypoglycemic and hypolipidemic effects. 1 ml/kg b.wt. of bamboo oil showed a marked glucose reduction from 254.04 ± 2.08 to 92.6 ± 1.63, and levels of total cholesterol, very low-density lipoprotein, triglyceride were reduced from 186.45 ± 2.28, 30.07 ± 2.36, 100.36 ± 2.35 to 152.14 ± 2.63, 25.94 ± 1.66, 93.32 ± 1.09, respectively. Histopathological results showed the presence of ovulation and recovery from cystic ovaries. Conclusion: A novel and promising drug was isolated in the treatment and maintenance of various metabolic symptoms associated with polycystic ovary disease. PMID:27127318

Neovascularization of the corpus luteum of rats during the estrus cycle.

PubMed

Tsukada, K; Matsushima, T; Yamanaka, N

1996-06-01

In order to elucidate the chronological morphological changes of the corpus luteum (CL) of rats, as a physiological angiogenesis model, the CL of rat ovaries was studied light microscopically using periodic acid methenamine silver staining (PAM) and immunostaining for type IV collagen, laminin, thrombomodulin (TM), factor VIII related antigen (factor VIII) and alpha-smooth muscle actin (alpha-SMA). The CL was also studied electron microscopically. Female Wistar-Imamichi rats were used, which have a regular 4-day estrous cycle. The histological changes of the CL were observed in 6-hour intervals from 4 h before the ovulation to 28 h post-ovulation during the estrous cycle. Once the basement membrane (BM) of the follicle disintegrated following ovulation, developing capillaries entered into the CL and formed a vascular lumen with a surrounding BM, which showed positive for PAM staining, type IV collagen and laminin. The developing capillaries in the CL showed a weakly positive reaction for TM and factor VIII, but were negative for alpha-SMA. However, the appearance of immature pericytes around the well-developed capillary was obvious with electron microscopy. The study reported here provides detailed descriptions of angiogenesis during luteinization. It is concluded that the angiogenesis of the CL begins at the time of destruction of the BM of the ovarian follicle, and that the capillary BM appears when the capillary forms its lumen. Moreover, it was demonstrated that the capillary does not develop into an arteriole during luteinization.

The GnRH analogue triptorelin confers ovarian radio-protection to adult female rats.

PubMed

Camats, N; García, F; Parrilla, J J; Calaf, J; Martín-Mateo, M; Caldés, M Garcia

2009-10-02

There is a controversy regarding the effects of the analogues of the gonadotrophin-releasing hormone (GnRH) in radiotherapy. This has led us to study the possible radio-protection of the ovarian function of a GnRH agonist analogue (GnRHa), triptorelin, in adult, female rats (Rattus norvegicus sp.). The effects of the X-irradiation on the oocytes of ovarian primordial follicles, with and without GnRHa treatment, were compared, directly in the female rats (F(0)) with reproductive parameters, and in the somatic cells of the resulting foetuses (F(1)) with cytogenetical parameters. In order to do this, the ovaries and uteri from 82 females were extracted for the reproductive analysis and 236 foetuses were obtained for cytogenetical analysis. The cytogenetical study was based on the data from 22,151 metaphases analysed. The cytogenetical parameters analysed to assess the existence of chromosomal instability were the number of aberrant metaphases (2234) and the number (2854) and type of structural chromosomal aberrations, including gaps and breaks. Concerning the reproductive analysis of the ovaries and the uteri, the parameters analysed were the number of corpora lutea, implantations, implantation losses and foetuses. Triptorelin confers radio-protection of the ovaries in front of chromosomal instability, which is different, with respect to the single and fractioned dose. The cytogenetical analysis shows a general decrease in most of the parameters of the triptorelin-treated groups, with respect to their controls, and some of these differences were considered to be statistically significant. The reproductive analysis indicates that there is also radio-protection by the agonist, although minor to the cytogenetical one. Only some of the analysed parameters show a statistically significant decrease in the triptorelin-treated groups.

PI3K/Akt-Independent NOS/HO Activation Accounts for the Facilitatory Effect of Nicotine on Acetylcholine Renal Vasodilations: Modulation by Ovarian Hormones

PubMed Central

Gohar, Eman Y.; El-gowilly, Sahar M.; El-Gowelli, Hanan M.; El-Demellawy, Maha A.; El-Mas, Mahmoud M.

2014-01-01

We investigated the effect of chronic nicotine on cholinergically-mediated renal vasodilations in female rats and its modulation by the nitric oxide synthase (NOS)/heme oxygenase (HO) pathways. Dose-vasodilatory response curves of acetylcholine (0.01–2.43 nmol) were established in isolated phenylephrine-preconstricted perfused kidneys obtained from rats treated with or without nicotine (0.5–4.0 mg/kg/day, 2 weeks). Acetylcholine vasodilations were potentiated by low nicotine doses (0.5 and 1 mg/kg/day) in contrast to no effect for higher doses (2 and 4 mg/kg/day). The facilitatory effect of nicotine was acetylcholine specific because it was not observed with other vasodilators such as 5′-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) or papaverine. Increases in NOS and HO-1 activities appear to mediate the nicotine-evoked enhancement of acetylcholine vasodilation because the latter was compromised after pharmacologic inhibition of NOS (L-NAME) or HO-1 (zinc protoporphyrin, ZnPP). The renal protein expression of phosphorylated Akt was not affected by nicotine. We also show that the presence of the two ovarian hormones is necessary for the nicotine augmentation of acetylcholine vasodilations to manifest because nicotine facilitation was lost in kidneys of ovariectomized (OVX) and restored after combined, but not individual, supplementation with medroxyprogesterone acetate (MPA) and estrogen (E2). Together, the data suggests that chronic nicotine potentiates acetylcholine renal vasodilation in female rats via, at least partly, Akt-independent HO-1 upregulation. The facilitatory effect of nicotine is dose dependent and requires the presence of the two ovarian hormones. PMID:24733557

Low Concentrations of o,p’-DDT Inhibit Gene Expression and Prostaglandin Synthesis by Estrogen Receptor-Independent Mechanism in Rat Ovarian Cells

PubMed Central

Liu, Jing; Zhao, Meirong; Zhuang, Shulin; Yang, Yan; Yang, Ye; Liu, Weiping

2012-01-01

o,p’-DDT is an infamous xenoestrogen as well as a ubiquitous and persistent pollutant. Biomonitoring studies show that women have been internally exposed to o,p’-DDT at range of 0.3–500 ng/g (8.46×10−10 M−1.41×10−6 M) in blood and other tissues. However, very limited studies have investigated the biological effects and mechanism(s) of o,p’-DDT at levels equal to or lower than current exposure levels in human. In this study, using primary cultures of rat ovarian granulosa cells, we determined that very low doses of o,p’-DDT (10−12−10−8 M) suppressed the expression of ovarian genes and production of prostaglandin E2 (PGE2). In vivo experiments consistently demonstrated that o,p’-DDT at 0.5–1 mg/kg inhibited the gene expression and PGE2 levels in rat ovary. The surprising results from the receptor inhibitors studies showed that these inhibitory effects were exerted independently of either classical estrogen receptors (ERs) or G protein-coupled receptor 30 (GPR30). Instead, o,p’-DDT altered gene expression or hormone action via inhibiting the activation of protein kinase A (PKA), rather than protein kinase C (PKC). We further revealed that o,p’-DDT directly interfered with the PKA catalytic subunit. Our novel findings support the hypothesis that exposure to low concentrations of o,p’-DDT alters gene expression and hormone synthesis through signaling mediators beyond receptor binding, and imply that the current exposure levels of o,p’-DDT observed in the population likely poses a health risk to female reproduction. PMID:23209616

N-hexane inhalation during pregnancy alters DNA promoter methylation in the ovarian granulosa cells of rat offspring.

PubMed

Li, Hong; Liu, Jin; Sun, Yan; Wang, Wenxiang; Weng, Shaozheng; Xiao, Shihua; Huang, Huiling; Zhang, Wenchang

2014-08-01

The N-hexane-induced impact on the reproductive system of the offspring of animals exposed to n-hexane has caused great concern. Pregnant Wistar rats inhaled 500, 2 500 or 12 500 ppm n-hexane during gestational days 1-20. Clinical characteristics and developmental indices were observed. Ovarian granulosa cells were extracted from F1 rats, the number of follicles was determined in ovarian slices and promoter methylation was assessed using MeDIP-Chip. Several methods were used to analyze the scanned genes, including the Gene Ontology Consortium tools, the DAVID Functional Annotation Clustering Tool, hierarchical clustering and KEGG pathway analysis. The results indicated that the live pups/litter ratio was significantly lowest in the 12 500 ppm group. A significant decrease in secondary follicles and an increase in atresic follicles were observed in the 12 500 ppm group. The number of shared demethylated genes was higher than that of the methylated genes, and the differentially methylated genes were enriched in cell death and apoptosis, cell growth and hormone regulation. The methylation profiles of the offspring from the 500 ppm and control groups were different from those of the 2500 and 12 500 ppm groups. Furthermore, the methylation status of genes in the PI3K-Akt and NF-kappa B signaling pathways was changed after n-hexane exposure. The Cyp11a1, Cyp17a1, Hsd3b1, Cyp1a1 and Srd5a1 promoters were hypermethylated in the n-hexane-exposed groups. These results indicate that the developmental toxicity of n-hexane in F1 ovaries is accompanied by the altered methylation of promoters of genes associated with apoptotic processes and steroid hormone biosynthesis. Copyright © 2013 John Wiley & Sons, Ltd.

Decreased Expression of Arginine-Phenylalanine-Amide-Related Peptide-3 Gene in Dorsomedial Hypothalamic Nucleus of Constant Light Exposure Model of Polycystic Ovarian Syndrome

PubMed Central

Shaaban, Zahra; Jafarzadeh Shirazi, Mohammad Reza; Nooranizadeh, Mohammad Hossein; Tamadon, Amin; Rahmanifar, Farhad; Ahmadloo, Somayeh; Ramezani, Amin; Zamiri, Mohammad Javad; Razeghian Jahromi, Iman; Sabet Sarvestani, Fatemeh; Hosseinabadi, Omid Koohi

2018-01-01

Background An abnormality in pulse amplitude and frequency of gonadotropin releasing hormone (GnRH) secretion is the most characteristics of polycystic ovarian syndrome (PCOS). On the other hand, arginine-phenylalanine-amide (RFamide)-related peptide-3 (RFRP3) inhibits the secretion of GnRH in mammalian hypothalamus. The current study performed in order to investigate the expression of RFRP3 mRNA in the dorsomedial hypothalamic nucleus (DMH) after the induction of PCOS in a rat model of constant light exposure, and the possible role of parity on occurrence of PCOS. Materials and Methods In the experimental study, female nulliparous (n=12) and primiparous (n=12) rats were randomly subdivided into control and PCOS subgroups (n=6). PCOS were induced by 90 days exposure to constant light. After 90 days, blood, brain, and ovaries were sampled. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were evaluated. In addition, six adult female ovariectomized rats as a control of real-time polymerase chain reaction (PCR) tests were prepared and in the DMH of all rats, the relative mRNA expression of RFRP3 was assessed. Results Histological evaluation of ovaries represented the polycystic features. In addition, serum concentrations of testosterone in the PCOS subgroups were more than the controls (P<0.05). Furthermore, the relative expression of RFRP3 mRNA in PCOS subgroups was lower than the controls (P<0.05). Conclusion Constant light model of the PCOS-induced rats decreased the gene expression of RFRP3 in the DMH that suggests the decrease of RFRP3 may reduce its inhibitory effect on GnRH during the PCOS pathogenesis. This effect was stronger in the nulliparous rats than the primiparous. PMID:29334206

The antitumor efficacy of cisplatin in combination with triptorelin and exemestane therapy for an ovarian cancer ascites model in Wistar rats.

PubMed

Tkalia, I G; Vorobyova, L I; Grabovoy, A N; Svintsitsky, V S; Tarasova, T O

2015-03-01

To study antitumor activity of triptorelin - agonist of gonadotropin-releasing hormone and exemestane - inhibitor of aromatase in combination with cisplatin on the model of receptor-positive for estrogens and progesterone malignant transplantable ascites ovarian tumor (OT); to assess tumor response to treatment and VEGF expression in tumor cells under different combinations of cytostatic and hormonal drugs. 36 female Wistar rats, which underwent intraperitoneal transplantation of ascites OT (5×10(6) cells per animal), have been involved in the study. Rats were distributed into 4 groups (9 rats in each group): group 1 - animals, which received combination of cisplatin and triptorelin; group 2 - rats treated with combination of cisplatin and exemestane; group 3 - animals, which were administered with combination of cisplatin, triptorelin and exemestane; group 4 - rats, which received combination of triptorelin and exemestane. Histological study with assessment of treatment pathomorphosis in OT and immunohistochemical study have been carried out to analyze VEGF expression in OT cells. Survival of animals has been evaluated. Combination of cytostatic agent with triptorelin or exemestane has demonstrated significantly higher rates of treatment pathomorphosis (10.1 ± 0.1% and 16.2 ± 0.3%, respectively) and antiangiogenic activity in OT (21.4 ± 1.4% and 15.0 ± 1.3%, respectively), as well as the highest survival of animals (100.0 and 85.7%, respectively) as compared with the same in rats treated in regimen of monotherapy with cisplatin, triptorelin, exemestane or by combination of hormonal drugs. Among animals treated by combination of cytostatic drug with triptorelin, two were cured (22.2%), and among rats, which received cisplatin and exemestane, one animal (11.1%) was cured. Triptorelin and exemestane increase antitumor activity of cisplatin in respect to the transplantable malignant ascites OT and significantly increase survival of animals, especially when triptorelin and cisplatin are used in combination.

A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development

DTIC Science & Technology

2016-05-01

1 AWARD NUMBER: W81XWH-15-1-0082 TITLE: A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development PRINCIPAL INVESTIGATOR: Qinglei Li...5a. CONTRACT NUMBER A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development 5b. GRANT NUMBER W81XWH-15-1-0082 5c. PROGRAM ELEMENT NUMBER 6...role of sustained activation of oocyte TGFBR1 in ovarian tumor development using an in vitro approach. 2. Keywords Ovarian tumor, Sex cord

Females transplanted with ovaries subjected to hypoxic preconditioning show impair of ovarian function.

PubMed

Damous, Luciana Lamarão; Nakamuta, Juliana Sanajotti; Soares, José Maria; Maciel, Gustavo Arantes Rosa; Simões, Ricardo Dos Santos; Montero, Edna Frasson de Souza; Krieger, José Eduardo; Baracat, Edmund Chada

2014-03-20

Cryopreservation of the ovarian tissue has shown promising results. However, there remain controversial issues such as the short half-life of grafts. In this aspect, there are some evidences that preconditioning the ovarian tissue before transplantation is beneficial. To determine the effect of hypoxic preconditioning in vitro on ovarian tissue prior to transplantation. Eighteen female adult Wistar rats, were sorted into three experimental groups. Ovaries were maintained in DMEM low glucose serum free at 37°C with 5% CO2, at atmospheric oxigen concentration (normoxia) or 1% O2 (hypoxia) for 16 hours. Oxigen concentration was determined by injection of nitrogen in the incubator. Animals submitted to ovarian transplantation immediately after oophorectomy were the Control Group (C). After this, the ovaries were implanted in the retroperitoneum with nonabsorbable suture and animals evaluated for thirty days after transplantation. Beginning on postoperative (PO) day 11, a daily collection of vaginal smear was carried out. Analyses comprised morphological, morphometric (counting ovarian follicles and corpora lutea) and immunohistochemistry for cleaved caspase-3 (apoptosis). In normoxia and control groups all animals recovered their estrous cycles, while in the hypoxia group, two animals did not ovulate but, among those which did, resumption took longer than in the other groups (p < 0.05). The number of ovarian follicles and corpora lutea decreased significantly in the hypoxia group when compared to the other two groups (p < 0.001) and apoptosis was increased in the few ovarian follicles which remained viable (p < 0.001). The hypoxic preconditioning in vitro was not beneficial to the graft and worsened their viability, compromising its functionality or delaying the return of this.

Females transplanted with ovaries subjected to hypoxic preconditioning show impair of ovarian function

PubMed Central

2014-01-01

Background Cryopreservation of the ovarian tissue has shown promising results. However, there remain controversial issues such as the short half-life of grafts. In this aspect, there are some evidences that preconditioning the ovarian tissue before transplantation is beneficial. Objective To determine the effect of hypoxic preconditioning in vitro on ovarian tissue prior to transplantation. Methods Eighteen female adult Wistar rats, were sorted into three experimental groups. Ovaries were maintained in DMEM low glucose serum free at 37°C with 5% CO2, at atmospheric oxigen concentration (normoxia) or 1% O2 (hypoxia) for 16 hours. Oxigen concentration was determined by injection of nitrogen in the incubator. Animals submitted to ovarian transplantation immediately after oophorectomy were the Control Group (C). After this, the ovaries were implanted in the retroperitoneum with nonabsorbable suture and animals evaluated for thirty days after transplantation. Beginning on postoperative (PO) day 11, a daily collection of vaginal smear was carried out. Analyses comprised morphological, morphometric (counting ovarian follicles and corpora lutea) and immunohistochemistry for cleaved caspase-3 (apoptosis). Results In normoxia and control groups all animals recovered their estrous cycles, while in the hypoxia group, two animals did not ovulate but, among those which did, resumption took longer than in the other groups (p < 0.05). The number of ovarian follicles and corpora lutea decreased significantly in the hypoxia group when compared to the other two groups (p < 0.001) and apoptosis was increased in the few ovarian follicles which remained viable (p < 0.001). Conclusion The hypoxic preconditioning in vitro was not beneficial to the graft and worsened their viability, compromising its functionality or delaying the return of this. PMID:24655551

The promising effect of linagliptin and/or indole-3-carbinol on experimentally-induced polycystic ovarian syndrome.

PubMed

Kabel, Ahmed M; Al-Shehri, Aisha H; Al-Talhi, Rehab A; Abd Elmaaboud, Maaly A

2017-08-01

Polycystic ovarian syndrome (PCOS) is one of the most common medical conditions that lead to female infertility worldwide. The aim of this study was to assess the effect of linagliptin and/or indole-3-carbinol (I3C) on PCOS in female rats. Fifty female Wistar rats were randomly allocated into five equal groups: Control group; Letrozole-induced PCOS group; Letrozole + Linagliptin group; Letrozole + I3C group and Letrozole + Linagliptin + I3C group. Body weight, body mass index, Lee index and ovarian indices were determined. Plasma levels of luteinizing hormone (LH), free testosterone, estradiol, progesterone, prolactin, fasting blood glucose (FBG) and fasting plasma insulin were measured. Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated. Tissue antioxidant status, transforming growth factor beta 1 (TGF-β1), tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10) and Nrf2/HO-1 content were assessed. Histopathological and immunohistochemical examination of the ovaries were done. Linagliptin and/or I3C induced significant decrease in tissue TGF-β1, TNF-α, IL-10, plasma free testosterone, luteinizing hormone, progesterone, estradiol, FBG and insulin levels associated with significant improvement of insulin resistance whereas tissue Nrf2/HO-1 content and antioxidant enzymes were significantly increased compared to PCOS group. In addition, final body weight, final body mass and Lee indices were significantly decreased compared to PCOS group. Also, there was significant improvement of the ovarian morphology compared to PCOS group. This improvement was significant with linagliptin/I3C combination compared to the use of each of these drugs alone. In conclusion, linagliptin/I3C combination might represent a beneficial therapeutic modality for amelioration of PCOS. Copyright © 2017 Elsevier B.V. All rights reserved.

Collaborative work on evaluation of ovarian toxicity. 13) Two- or four-week repeated dose studies and fertility study of PPAR alpha/gamma dual agonist in female rats.

PubMed

Sato, Norihiro; Uchida, Keisuke; Nakajima, Mikio; Watanabe, Atsushi; Kohira, Terutomo

2009-01-01

The main focus of this study was to determine the optimal dosing period in a repeated dose toxicity study based on toxic effects as assessed by ovarian morphological changes. To assess morphological and functional changes induced in the ovary by a peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, the compound was administered to female rats at dose levels of 0, 4, 20, and 100 mg/kg/day in a repeated dose toxicity study for 2 or 4 weeks, and from 2 weeks prior to mating to Day 7 of pregnancy in a female fertility study. In the repeated dose toxicity study, an increase in atresia of large follicles, a decrease in corpora lutea, and an increase in stromal cells were observed in the treated groups. In addition, the granulosa cell exfoliations into antrum of large follicles and corpora lutea with retained oocyte are morphological characteristics induced by this compound, and they might be related with abnormal condition of ovulation. In the female fertility study, the pregnancy rate tended to decrease in the 100 mg/kg/day group. At necropsy, decreases in the number of corpora lutea, implantations and live embryos were noted in the 20 and 100 mg/kg/day group. No changes were observed in animals given 4 mg/kg/day. These findings indicated that histopathological changes in the ovary are important endpoints for evaluation of drugs inducing ovarian damage. In conclusion, a 2-week administration period is sufficient to detect ovarian toxicity of this test compound in the repeated dose toxicity study.

GABA function may be related to the impairment of learning and memory caused by systemic prenatal hypoxia-ischemia.

PubMed

Cunha-Rodrigues, Marta Cristina; Balduci, Cassiana Thayara do Nascimento; Tenório, Frank; Barradas, Penha Cristina

2018-03-01

Intrauterine adverse conditions may be responsible for long-lasting damages which impact health even during adult phase. Hypoxic-ischemic (HI) events are a relevant cause of newborn mortality and the principal factor leading to permanent brain lesions. Using a model in which the ovarian and uterine flux of a pregnant rat is obstructed for 45 min we have described oligodendrocyte death, astrogliosis and neuronal loss. In this work we investigated hippocampal neuronal population and performed a functional evaluation of memory and learning of young rats that had been affected by prenatal HI. Anesthetized Wistar rats on the 18th gestation day had the uterine horns exposed and the ovarian and uterine arteries clamped for 45 min (HI group). Sham-operated rats (SH group) had the horns exposed but no arteries were clamped. We measured the levels of different proteins related to excitatory/inhibitory transmission in the hippocampi of young pups (P45). Histological evaluation was also performed in order to characterize hippocampal neuronal population. Rats from both groups were tested through Novel Object Recognition Test (NORT) using two inter-trial intervals: 5 min and 8 h. Here we show a loss in the total number of hippocampal neurons although the immunostaining of parvalbumin and levels of GAD enzyme were increased in HI group. Functional assessment indicated a marked difference concerning HI learning and memory abilities. Our results reflect permanent damages concerning GABA function which may disturb neurotransmitter homeostasis leading to the observed deficits in learning and memory. Copyright © 2018 Elsevier Inc. All rights reserved.

The latest animal models of ovarian cancer for novel drug discovery.

PubMed

Magnotti, Elizabeth; Marasco, Wayne A

2018-03-01

Epithelial ovarian cancer is a heterogeneous disease classified into five subtypes, each with a different molecular profile. Most cases of ovarian cancer are diagnosed after metastasis of the primary tumor and are resistant to traditional platinum-based chemotherapeutics. Mouse models of ovarian cancer have been utilized to discern ovarian cancer tumorigenesis and the tumor's response to therapeutics. Areas covered: The authors provide a review of mouse models currently employed to understand ovarian cancer. This article focuses on advances in the development of orthotopic and patient-derived tumor xenograft (PDX) mouse models of ovarian cancer and discusses current humanized mouse models of ovarian cancer. Expert opinion: The authors suggest that humanized mouse models of ovarian cancer will provide new insight into the role of the human immune system in combating and augmenting ovarian cancer and aid in the development of novel therapeutics. Development of humanized mouse models will take advantage of the NSG and NSG-SGM3 strains of mice as well as new strains that are actively being derived.

Estrogen and voluntary exercise interact to attenuate stress-induced corticosterone release but not anxiety-like behaviors in female rats.

PubMed

Jones, Alexis B; Gupton, Rebecca; Curtis, Kathleen S

2016-09-15

The beneficial effects of physical exercise to reduce anxiety and depression and to alleviate stress are increasingly supported in research studies. The role of ovarian hormones in interactions between exercise and anxiety/stress has important implications for women's health, given that women are at increased risk of developing anxiety-related disorders, particularly during and after the menopausal transition. In these experiments, we tested the hypothesis that estrogen enhances the positive impact of exercise on stress responses by investigating the combined effects of exercise and estrogen on anxiety-like behaviors and stress hormone levels in female rats after an acute stressor. Ovariectomized female rats with or without estrogen were given access to running wheels for one or three days of voluntary running immediately after or two days prior to being subjected to restraint stress. We found that voluntary running was not effective at reducing anxiety-like behaviors, whether or not rats were subjected to restraint stress. In contrast, stress-induced elevations of stress hormone levels were attenuated by exercise experience in estrogen-treated rats, but were increased in rats without estrogen. These results suggest that voluntary exercise may be more effective at reducing stress hormone levels if estrogen is present. Additionally, exercise experience, or the distance run, may be important in reducing stress. Copyright © 2016 Elsevier B.V. All rights reserved.

Olfactory conditioned same-sex partner preference in female rats: Role of ovarian hormones.

PubMed

Tecamachaltzi-Silvaran, M B; Barradas-Moctezuma, M; Herrera-Covarrubias, D; Carrillo, P; Corona-Morales, A A; Perez, C A; García, L I; Manzo, J; Coria-Avila, Genaro A

2017-11-01

The dopamine D2-type receptor agonist quinpirole (QNP) facilitates the development of conditioned same-sex partner preference in males during cohabitation, but not in ovariectomized (OVX) females, primed with estradiol benzoate (EB) and progesterone (P). Herein we tested the effects of QNP on OVX, EB-only primed females. Females received a systemic injection (every four days) of either saline (Saline-conditioned) or QNP (QNP-conditioned) and then cohabited for 24h with lemon-scented stimulus females (CS+), during three trials. In test 1 (female-female) preference was QNP-free, and females chose between the CS+ female and a novel female. In test 2 (male-female) they chose between the CS+ female and a sexually experienced male. In test 1 Saline-conditioned females displayed more hops & darts towards the novel female, but QNP-conditioned females displayed more sexual solicitations towards the CS+ female. In test 2 Saline-conditioned females displayed a clear preference for the male, whereas QNP-conditioned females displayed what we considered a bisexual preference. We discuss the effect of dopamine and ovarian hormones on the development of olfactory conditioned same-sex preference in females. Copyright © 2017 Elsevier Inc. All rights reserved.

Medial prefrontal cortex lesions in the female rat affect sexual and maternal behavior and their sequential organization.

PubMed

Afonso, Veronica M; Sison, Margarette; Lovic, Vedran; Fleming, Alison S

2007-06-01

Temporal sequences of sexual and maternal behaviors in female rats and their correlation with each other and with performance on a sensory-motor gating response inhibition task assessed by prepulse inhibition (PPI) were investigated following medial prefrontal cortex (mPFC) lesions. Following excitotoxic mPFC (n = 10) or sham (n = 9) lesions, sexual behaviors across the ovarian cycle were scored. After mating and parturition, maternal interactions were scored until pups reached postnatal Day 10. After resumption of the ovarian cycle, the female rats were tested for PPI. Compared with sham lesions, mPFC lesions impaired proceptive behaviors and some maternal behaviors (e.g., pup retrieval, pup licking) but did not affect others (e.g., nest building, pup mouthing). Lesions disrupted temporal sequences of solicitations (number of male orientations followed, within 4 s, by a level change) and pup retrievals (number of pup retrievals followed, within 5 s, by another retrieval). These sequential behavior patterns were significantly correlated with each other and with PPI. However, when PPI effects were partialled out, group differences were less strong, but persisted. This study demonstrated that mPFC manipulations affect actions rich in sequential structure in response to biologically relevant stimuli. Copyright (c) 2007 APA, all rights reserved.

GC-MS analysis of Cocus nucifera flower extract and its effects on heterogeneous symptoms of polycystic ovarian disease in female Wistar rats.

PubMed

Soumya, V; Muzib, Y Indira; Venkatesh, P; Hariprasath, K

2014-09-01

To evaluate the effect of Cocus nucifera L. flowers in reducing the major multiple symptoms of letrozole-induced polycystic ovarian disease (PCOD) in female rats. Female, virgin Wistar rats were treated with letrozole (1 mg/kg body wt) to induce PCOD, and after 21 days of induction rats were administered orally with 100 and 200 mg·kg(-1) of Cocus nucifera flower aqueous extract, respectively. Estrus cycle and blood sugar were monitored once a week throughout the study. After scarification, various biochemical parameters, such as antioxidant status (superoxide dismutase (SOD) and glutathione reductase (GSH)) of the uterus homogenate, lipid profile (total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides (TG)) of the serum were determined. Weights of the uterus and ovaries were separately monitored. The characteristics of changes in the ovary were evaluated by histopathological studies. GC-MS analysis of the aqueous extract showed the presence of volatile and pharmacologically active phytoconstituents. C. nucifera flower extract-treated groups showed estrus cyclicity and increased uterus weight which indicates the estrogenic effect. The improved blood sugar level, ideal lipid profile, good antioxidant status, and histopathology results revealed the recovery from poly cystic ovaries. The results indicate that C. nucifera flower is a potential medicine for the treatment of PCOD and this study supports the traditional uses of C. nucifera flower. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Exposure of Female Rats to an Environmentally Relevant Mixture of Brominated Flame Retardants Targets the Ovary, Affecting Folliculogenesis and Steroidogenesis1

PubMed Central

Lefèvre, Pavine L.C.; Berger, Robert G.; Ernest, Sheila R.; Gaertner, Dean W.; Rawn, Dorothea F.K.; Wade, Michael G.; Robaire, Bernard; Hales, Barbara F.

2015-01-01

Brominated flame retardants (BFRs) are incorporated into various consumer products to prevent flame propagation. These compounds leach into the domestic environment, resulting in chronic exposure and contamination. Pregnancy failure is associated with high levels of BFRs in human follicular fluid, raising serious questions regarding their impact on female reproductive health. The goal of this study is to elucidate the effects of an environmentally relevant BFR mixture on female rat ovarian functions (i.e., folliculogenesis and steroidogenesis). A BFR dietary mixture formulated to mimic the relative BFR congener levels in North American house dust was administered to adult female Sprague-Dawley rats from 2 to 3 wk before mating until Gestational Day 20; these diets were designed to deliver nominal doses of 0, 0.06, 20, or 60 mg/kg/day of the BFR mixture. Exposure to BFRs triggered an approximately 50% increase in the numbers of preantral and antral follicles and an enlargement of the antral follicles in the ovaries of the dams. A significant reduction in the expression of catalase, an antioxidant enzyme, and downregulation of the expression of insulin-like factor 3 (Insl3) and 17alpha-hydroxylase (Cyp17a1) were observed in the ovary. In addition, BFR exposure affected steroidogenesis; we observed a significant decrease in circulating 17-hydroxypregnenolone and an increase in testosterone concentrations in BFR-exposed dams. Thus, BFRs target ovarian function in the rat, adversely affecting both folliculogenesis and steroidogenesis. PMID:26607716

The importance of neuronal growth factors in the ovary.

PubMed

Streiter, S; Fisch, B; Sabbah, B; Ao, A; Abir, R

2016-01-01

The neurotrophin family consists of nerve growth factor (NGF), neurotrophin 3 (NT3) and neurotrophin 4/5 (NT4/5), in addition to brain-derived neurotrophic factor (BDNF) and the neuronal growth factors, glial cell line-derived neurotrophic factor (GDNF) and vasointestinal peptide (VIP). Although there are a few literature reviews, mainly of animal studies, on the importance of neurotrophins in the ovary, we aimed to provide a complete review of neurotrophins as well as neuronal growth factors and their important roles in normal and pathological processes in the ovary. Follicular assembly is probably stimulated by complementary effects of NGF, NT4/5 and BDNF and their receptors. The neurotrophins, GDNF and VIP and their receptors have all been identified in preantral and antral follicles of mammalian species, including humans. Transgenic mice with mutations in the genes encoding for Ngf, Nt4/5 and Bdnf and their tropomyosin-related kinase β receptor showed a reduction in preantral follicles and an abnormal ovarian morphology, whereas NGF, NT3, GDNF and VIP increased the in vitro activation of primordial follicles in rats and goats. Additionally, NGF, NT3 and GDNF promoted follicular cell proliferation; NGF, BDNF and VIP were shown to be involved in ovulation; VIP inhibited follicular apoptosis; NT4/5, BDNF and GDNF promoted oocyte maturation and NGF, NT3 and VIP stimulated steroidogenesis. NGF may also exert a stimulatory effect in ovarian cancer and polycystic ovarian syndrome (PCOS). Low levels of NGF and BDNF in follicular fluid may be associated with diminished ovarian reserve and high levels with endometriosis. More knowledge of the roles of neuronal growth factors in the ovary has important implications for the development of new therapeutic drugs (such as anti-NGF agents) for ovarian cancer and PCOS as well as various infertility problems, warranting further research. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

ELEVATED OVARIAN AND THYMIC CELL APOPTOSIS IN WILD COTTON RATS INHABITING PETROCHEMICAL-CONTAMINATED TERRESTRIAL ECOSYSTEMS. (R826242)

EPA Science Inventory

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Prior weight loss exacerbates the biological drive to gain weight after the loss of ovarian function.

PubMed

Sherk, Vanessa D; Jackman, Matthew R; Giles, Erin D; Higgins, Janine A; Foright, Rebecca M; Presby, David M; Johnson, Ginger C; Houck, Julie A; Houser, Jordan L; Oljira, Robera; MacLean, Paul S

2017-05-01

Both the history of obesity and weight loss may change how menopause affects metabolic health. The purpose was to determine whether obesity and/or weight loss status alters energy balance (EB) and subsequent weight gain after the loss of ovarian function. Female lean and obese Wistar rats were randomized to 15% weight loss (WL) or ad libitum fed controls (CON). After the weight loss period, WL rats were kept in EB at the reduced weight for 8 weeks prior to ovariectomy (OVX). After OVX, all rats were allowed to eat ad libitum until weight plateaued. Energy intake (EI), spontaneous physical activity, and total energy expenditure (TEE) were measured with indirect calorimetry before OVX, immediately after OVX, and after weight plateau. Changes in energy intake (EI), TEE, and weight gain immediately after OVX were similar between lean and obese rats. However, obese rats gained more total weight and fat mass than lean rats over the full regain period. Post-OVX, EI increased more ( P  ≤ 0.03) in WL rats (58.9 ± 3.5 kcal/d) than CON rats (8.5 ± 5.2 kcal/d), and EI partially normalized (change from preOVX: 20.5 ± 4.2 vs. 1.5 ± 4.9 kcal/day) by the end of the study. As a result, WL rats gained weight (week 1:44 ± 20 vs. 7 ± 25 g) more rapidly (mean = 44 ± 20 vs. 7 ± 25 g/week; P  < 0.001) than CON Prior obesity did not affect changes in EB or weight regain following OVX, whereas a history of weight loss prior to OVX augmented disruptions in EB after OVX, resulting in more rapid weight regain. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Prevalence and Risk Factors of Ovarian Metastases in Breast Cancer Patients < 41 Years of Age in the Netherlands: A Nationwide Retrospective Cohort Study.

PubMed

Peters, Inge T A; van Zwet, Erik W; Smit, Vincent T H B M; Liefers, Gerrit Jan; Kuppen, Peter J K; Hilders, Carina G J M; Trimbos, J Baptist

2017-01-01

Breast cancer is one of the primary indications for cryopreservation and subsequent autotransplantation of ovarian tissue. The safety of this fertility preservation method remains questionable, as the presence of disseminated breast tumor cells cannot yet be excluded in the ovarian autografts. We explored the prevalence of ovarian metastases among young breast cancer patients and determined risk factors for the development of ovarian metastases. Using the nationwide database of the Dutch Pathology Registry (PALGA), we identified a cohort of 2648 women with primary invasive breast cancer at age < 41 years in the period 2000-2010 in the Netherlands who subsequently underwent an oophorectomy. From this source population, all cases who had histologically confirmed ovarian metastases were included. For each case of whom clinical data were available, one control without ovarian metastases who matched the time interval between breast cancer diagnosis and oophorectomy was selected. Data were collected on patient characteristics, diagnosis, treatment and follow-up. Ovarian metastases were found in 63 out of 2648 patients who met the inclusion criteria. The risk of developing ovarian metastases increased with time passed since breast cancer diagnosis. Multivariate logistic regression analyses showed significant association between tumor stage and the development of ovarian metastases (p = 0.024). The prevalence of ovarian metastases was 2.4% among young breast cancer patients. Early ovary removal may reduce the risk of developing ovarian metastases. In breast cancer patients with tumors > 5 cm and/or inflammatory carcinoma, we recommend a cautious approach to ovarian tissue autotransplantation.

Therapeutic potentials of Quercetin in management of polycystic ovarian syndrome using Letrozole induced rat model: a histological and a biochemical study.

PubMed

Jahan, Sarwat; Abid, Abira; Khalid, Sidra; Afsar, Tayyaba; Qurat-Ul-Ain; Shaheen, Ghazala; Almajwal, Ali; Razak, Suhail

2018-04-03

PCOS is a leading endocrinopathy of young women instigating androgens elevation, insulin resistance, obesity, cardiometabolic and menstrual complications. The study investigated the effects of quercetin in a letrozole induced rat model of polycystic ovarian syndrome, which displayed both clinical and metabolic features as in PCOS women. Female Sprague Dawley (SD) rats were divided into four groups; control group received aqueous solution of carboxymethyl (CMC 0.5%); PCOS group administered with letrozole (1 mg/kg) dissolved in solution (CMC 0.5%); Metformin group given with metformin (20 mg/kg) + letrozole (1 mg/kg); and Quercetin group provided with quercetin (30 mg/kg) + letrozole (1 mg/kg). All doses were given orally via gavage, for 21 consecutive days and colpocytological analysis was carried till end. After 21rst day, blood was taken out, centrifuged and plasma was kept for biochemical analysis (ELISA, anti-oxidant enzymes, lipid profile) and the reproductive organs were dissected out for histopathological evaluation. Quercetin as a chief member of flavonoid, showed beneficial effects by decreasing body weight, ovarian diameter, cysts and restoring healthy follicles, follicle's extra-glandular layers, and corpora lutea in contrast to the positive control. Additionally, lipid profile and anti-oxidant status were also maintained to baseline which was very high in diseased rats (p < 0.001).Quercetin depicted a mark regulation in steroidogenesis by decreasing the levels of testosterone (0.78 ng/ml ± 0.14 in quercetin vs. PCOS positive control 1.69 ng/ml ± 0.17, p < 0.001) and estradiol (8.85 pg/ml ± 0.19 in quercetin vs. PCOS positive 1.61 pg/ml ± 0.29) and increasing progesterone levels (34.47 ng/ml ± 1.65 in quercetin vs. 11.08 ng/ml ± 1.17 in PCOS positive). The effects of quercetin were moderately parallel to the standard drug available in market i.e. metformin. The present study has confirmed that quercetin has the potentials to alleviate the hormonal and metabolic disturbances occurring in PCOS.

Regulation of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase expression and activity in the hypophysectomized rat ovary: Interactions between the stimulatory effect of human chorionic gonadotropin and the luteolytic effect of prolactin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martel, C.; Labrie, C.; Dupont, E.

1990-12-01

The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) catalyzes an obligatory step in the conversion of pregnenolone and other 5-ene-3 beta-hydroxysteroids into progesterone as well as precursors of all androgens and estrogens in the ovary. Since 3 beta-HSD is likely to be an important target for regulation by pituitary hormones, we have studied the effect of chronic treatment with LH (hCG), FSH, and PRL on ovarian 3 beta-HSD expression and activity in hypophysectomized adult female rats. Human CG (hCG) (10 IU, twice a day (bid)), ovine FSH (0.5 microgram, bid), and ovine PRL (1 mg, bid) were administered,more » singly or in combination, for a period of 10 days starting 15 days after hypophysectomy. In hypophysectomized rats, PRL exerted a potent inhibitory effect on all the parameters studied. In fact, PRL caused a 81% decrease in ovarian 3 beta-HSD mRNA content accompanied by a similar decrease in 3 beta-HSD activity and protein levels. In addition, ovarian weight decreased by 40% whereas serum progesterone fell dramatically from 1.92 nmol/liter to undetectable levels after treatment with PRL. Whereas hCG alone had only slight stimulatory effects on 3 beta-HSD mRNA, protein content and activity levels, treatment with the gonadotropin partially or completely reversed the potent inhibitory effects of oPRL on all the parameters measured. FSH, on the other hand, had no significant effect on 3 beta-HSD expression and activity. In situ hybridization experiments using the 35S-labeled rat ovary 3 beta-HSD cDNA probe show that the inhibitory effect of PRL is exerted primarily on luteal cell 3 beta-HSD expression and activity. On the other hand, it can be seen that hCG stimulates 3 beta-HSD mRNA accumulation in interstitial cells.« less

Expression of PTHrP and PTH/PTHrP receptor 1 in the superior cervical ganglia of rats.

PubMed

Filipović, Natalija; Vrdoljak, Marija; Vuica, Ana; Jerić, Milka; Jeličić Kadić, Antonia; Utrobičić, Toni; Mašek, Tomislav; Grković, Ivica

2014-12-01

PTHrP and its receptor PTHR1 are found in the CNS and peripheral nervous system. The presence of PTHrP mRNA has been detected in the superior cervical ganglion (SCG), but there are no data on the cellular distribution of PTHrP and PTHR1 in the SCG. Although it is known that ovarian activity and reproductive status influence sympathetic activity, and the PTHrP/PTHR1 system is influenced by estrogens in different tissues, it is not known whether these factors have a similar effect on expression of PTHrP and PTHR1 in the nervous system. Hence, we investigated the presence and distribution of PTHrP and PTHR1 in neurons and glia of the SCG of rats, as well as the influence of ovariectomy on their expression, by using immunohistochemistry. PTHrP and PTHR1 immunoreactivity was observed in cytoplasm as well as in nuclei of almost all neurons in the SCG. In male rats, intensity of PTHrP fluorescence was significantly higher in cytoplasm of NPY-, in comparison to NPY+ neurons (p < 0.05). In female rats, 2 months post-ovariectomy, significantly lower intensity of PTHrP fluorescence in cytoplasm of the SCG neurons was observed in comparison to sham operated animals (p < 0.05). In addition to neurons, PTHrP and PTHR1 immunoreactivity was observed in most of the glia and was not influenced by ovariectomy. Results show the expression of PTHrP and its receptor, PTHR1, in the majority of neurons and glial cells in the SCG of rats. Expression of PTHrP, but not PTHR1 in the cytoplasm of SCG neurons is influenced by ovarian activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats

PubMed Central

Molenda-Figueira, Heather A.; Williams, Casey A.; Griffin, Andreana L.; Rutledge, Eric M.; Blaustein, Jeffrey D.; Tetel, Marc J.

2008-01-01

The ovarian hormones, estradiol (E) and progesterone (P) facilitate the expression of sexual behavior in female rats. E and P mediate many of these behavioral effects by binding to their respective intracellular receptors in specific brain regions. Nuclear receptor coactivators, including Steroid Receptor Coactivator-1 (SRC-1) and CREB Binding Protein (CBP), dramatically enhance ligand-dependent steroid receptor transcriptional activity in vitro. Previously, our lab has shown that SRC-1 and CBP modulate estrogen receptor (ER)-mediated induction of progestin receptor (PR) gene expression in the ventromedial nucleus of the hypothalamus (VMN) and hormone-dependent sexual receptivity in female rats. Female sexual behaviors can be activated by high doses of E alone in ovariectomized rats, and thus are believed to be ER-dependent. However, the full repertoire of female sexual behavior, in particular, proceptive behaviors such as hopping, darting and ear wiggling, are considered to be PR-dependent. In the present experiments, the function of SRC-1 and CBP in distinct ER- (Exp. 1) and PR- (Exp. 2) dependent aspects of female sexual behavior was investigated. In Exp. 1, infusion of antisense oligodeoxynucleotides to SRC-1 and CBP mRNA into the VMN decreased lordosis intensity in rats treated with E alone, suggesting that these coactivators modulate ER-mediated female sexual behavior. In Exp. 2, antisense to SRC-1 and CBP mRNA around the time of P administration reduced PR-dependent ear wiggling and hopping and darting. Taken together, these data suggest that SRC-1 and CBP modulate ER and PR action in brain and influence distinct aspects of hormone-dependent sexual behaviors. These findings support our previous studies and provide further evidence that SRC-1 and CBP function together to regulate ovarian hormone action in behaviorally-relevant brain regions. PMID:16769066

Neonatal stress affects the aging trajectory of female rats on the endocrine, temperature, and ventilatory responses to hypoxia.

PubMed

Fournier, Sébastien; Gulemetova, Roumiana; Baldy, Cécile; Joseph, Vincent; Kinkead, Richard

2015-04-01

Human and animal studies on sleep-disordered breathing and respiratory regulation show that the effects of sex hormones are heterogeneous. Because neonatal stress results in sex-specific disruption of the respiratory control in adult rats, we postulate that it might affect respiratory control modulation induced by ovarian steroids in female rats. The hypoxic ventilatory response (HVR) of adult female rats exposed to neonatal maternal separation (NMS) is ∼30% smaller than controls (24), but consequences of NMS on respiratory control in aging female rats are unknown. To address this issue, whole body plethysmography was used to evaluate the impact of NMS on the HVR (12% O2, 20 min) of middle-aged (MA; ∼57 wk old) female rats. Pups subjected to NMS were placed in an incubator 3 h/day for 10 consecutive days (P3 to P12). Controls were undisturbed. To determine whether the effects were related to sexual hormone decline or aging per se, experiments were repeated on bilaterally ovariectomized (OVX) young (∼12 wk old) adult female rats. OVX and MA both reduced the HVR significantly in control rats but had little effect on the HVR of NMS females. OVX (but not aging) reduced the anapyrexic response in both control and NMS animals. These results show that hormonal decline decreases the HVR of control animals, while leaving that of NMS female animals unaffected. This suggests that neonatal stress alters the interaction between sex hormone regulation and the development of body temperature, hormonal, and ventilatory responses to hypoxia. Copyright © 2015 the American Physiological Society.

Delay of constant light-induced persistent vaginal estrus by 24-hour time cues in rats.

PubMed

Weber, A L; Adler, N T

1979-04-20

The normal ovarian cycle of female rats is typically replaced by persistent estrus when these animals are housed under constant light. Evidence presented here shows that the maintenance of periodicity in the environment can at least delay (if not prevent) the photic induction of persistent vaginal estrus. Female rats in constant light were exposed to vaginal smearing at random times or at the same time every day. In another experiment, female rats were exposed to either constant bright light, constant dim light, or a 24-hour photic cycle of bright and dim light. The onset of persistent vaginal estrus was delayed in rats exposed to 24-hour time cues even though the light intensities were the same as or greater than those for the aperiodic control groups. The results suggest that the absence of 24-hour time cues in constant light contributes to the induction of persistent estrus.

Dietary aspirin decreases the stage of ovarian cancer in the hen.

PubMed

Urick, M E; Giles, J R; Johnson, P A

2009-01-01

We aimed to determine the effects of dietary aspirin treatment on ovarian cancer incidence and progression in the hen as a model for the human disease. Hens were fed a standard layer diet (control) or the same diet containing 0.1% aspirin for 1 year. Liver prostaglandin E(2) (PGE(2)) was measured using an enzyme immunoassay. Incidence and stage of ovarian cancer were determined through necropsy and immunohistochemical analysis of ovarian sections for each hen. Aspirin treatment decreased liver PGE(2) in treated hens as compared to control hens. Treatment with aspirin did not decrease ovarian cancer incidence. Significantly more control hens developed late stage ovarian cancer than early stage, while the same was not true for aspirin-treated hens. Hens that developed ovarian cancer, even early ovarian cancer, produced significantly fewer eggs in the year prior to diagnosis than hens without ovarian cancer. Aspirin treatment may inhibit the progression of ovarian cancer in the hen and egg production may be used to identify hens with early stages of the disease.

Selenium protects reproductive system and foetus development in a rat model of gestational lead exposure.

PubMed

Shen, W; Chen, J; Yin, J; Wang, S-L

2016-01-01

Lead is a common environmental contaminant. Lead accumulation in the body is especially dangerous for pregnant women and newborns. Selenium is a trace element which may rectify the damaging effects of lead. Here we tested potential protective effects of selenium against gestational lead exposure. Pregnant SD rats were exposed to 200 mg/L of lead acetate (given with water), with or without sodium selenite supplementation (2-8 mg/kg/day via intragastric administration). Pregnant rats not exposed to lead or selenium served as control animals. The outcomes in pregnant rats were serum lead and selenium levels, reproductive hormone (follicle-stimulating hormone, luteinizing hormone, prolactin, oestradiol, progesterone) levels, and uterine and ovarian morphological changes. The outcomes in the offspring were sex differentiation, survival rates (day 21 after birth), weight (days 0-35 after birth), weight of reproductive organs, and puberty onset (foreskin separation or vaginal opening). Selenium supplementation dose-dependently decreased serum lead levels, rectified reproductive hormone levels, and attenuated reproductive morphological changes caused by lead exposure. Lead exposure did not affect sex differentiation, but significantly (p < 0.05 vs. control animals) decreased the offspring weight on days 0-28 and the weight of their reproductive organs. Furthermore, lead exposure delayed the onset of puberty. These pathological changes were dose-dependently rectified or attenuated by selenium supplementation. Gestational lead exposure causes damages to the reproductive system of pregnant rats, and negatively modulates growth and reproductive system development of the offspring. These adverse effects are rectified or attenuated by selenium supplementation.

Neuroendocrine mechanisms of development of experimental hyperandrogen-induced anovulation.

PubMed

Reznikov, A G; Sinitsyn, P V; Tarasenko, L V; Polyakova, L I

2003-10-01

An experimental model of hyperandrogen-induced anovulatory infertility (s.c. implantation of Silastic capsules containing testosterone into adult female rats) was used to study morphological, hormonal, and biochemical measures characterizing the state of the hypothalamo-hypophyseal-ovarian system. Impairments in functional androgen metabolism in the hypothalamus were seen, with decreases in the Luliberin sensitivity of the hypophysis, changes in the structure of estral cycles, and morphological changes in the ovaries; these findings are evidence for neuroendocrine disturbances in the control of ovulation. Flutamide, an experimental antiandrogen, led to partial normalization of the hormonal, biochemical, and morphological characteristics, as well as to recovery of fertility in females with anovulatory infertility.

Risk factors and the economic impact of ovarian cysts on reproductive performance of dairy cows in Korea.

PubMed

Kim, Ki-Doek; Ki, Kwang-Sook; Kang, Hyun-Gu; Kim, Ill-Hwa

2005-08-01

The objectives of this study were to determine the risk factors for development of postpartum ovarian cysts by evaluating several reproductive factors in individual cows, and to determine the economic impact of ovarian cysts on subsequent reproductive performance in dairy herds in Korea. The data, including cow parity, abnormal puerperium, endometritis, body condition score (BCS), and breeding status were collected from 634 cows in 9 dairy herds. We used logistic regression to evaluate the effects of these factors on ovarian cysts. A stepwise procedure, used to obtain the appropriate model with alpha=0.05, revealed that cow parity was the most important risk factor for ovarian cyst development within 8 weeks postpartum, while development of endometritis and BCS loss>or=1 from the dry period to 8 weeks postpartum were the most important risk factors for ovarian cyst development beyond 8 weeks postpartum. The occurrence of ovarian cysts beyond 8 weeks postpartum prolonged (P<0.01) the mean intervals from calving to first service (27 days) and conception (77 days), and increased (P<0.05) the culling rate (7.8%), while ovarian cyst development within 8 weeks postpartum did not affect (P>0.05) the mean intervals from calving to first service and conception or the culling rate. The economic loss resulting from the occurrence of ovarian cysts was estimated at approximately 823,996 won ($687) due to effects on the cost of nutrition, average growth of calves, labor and medical costs, and culling. These results suggest that cow parity is correlated with the development of ovarian cysts within 8 weeks postpartum, and endometritis and BCS loss>or=1 from the dry period to 8 weeks postpartum are correlated with the development of ovarian cysts after 8 weeks postpartum, which decreases reproductive performance and results in economic loss in dairy herds in Korea.

Postnatal Ovary Development in the Rat: Morphologic Study and Correlation of Morphology to Neuroendocrine Parameters

PubMed Central

Picut, Catherine A.; Dixon, Darlene; Simons, Michelle L.; Stump, Donald G.; Parker, George A.; Remick, Amera K.

2014-01-01

Histopathologic examination of the immature ovary is a required end point on juvenile toxicity studies and female pubertal and thyroid function assays. To aid in this evaluation and interpretation of the immature ovary, the characteristic histologic features of rat ovary through the developmental periods are described. These histologic features are correlated with published changes in neuroendocrine profiles as the hypothalamic–pituitary–gonadal axis matures. During the neonatal stage (postnatal day [PND] 0–7), ovarian follicle development is independent of pituitary gonadotropins (luteinizing hormone [LH] or follicle-stimulating hormone [FSH]), and follicles remain preantral. Antral development of “atypical” follicles occurs in the early infantile period (PND 8–14) when the ovary becomes responsive to pituitary gonadotropins. In the late infantile period (PND 15–20), the zona pellucida appears, the hilus forms, and antral follicles mature by losing their “atypical” appearance. The juvenile stage (PND 21–32) is the stage when atresia of medullary follicles occurs corresponding to a nadir in FSH levels. In the peripubertal period (PND 33–37), atresia subsides as FSH levels rebound, and LH begins its bimodal surge pattern leading to ovulation. This report will provide pathologists with baseline morphologic and endocrinologic information to aid in identification and interpretation of xenobiotic effects in the ovary of the prepubertal rat. PMID:25107574

Localization of vascular endothelial growth factor in the zona pellucida of developing ovarian follicles in the rat: a possible role in destiny of follicles.

PubMed

Celik-Ozenci, Ciler; Akkoyunlu, Gokhan; Kayisli, Umit Ali; Arici, Aydin; Demir, Ramazan

2003-11-01

There is increasing evidence that in many species angiogenic factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), may have important roles in folliculogenesis. The aim of this study is to determine the localization of VEGF and its receptors, Flt-1 and KDR, and bFGF expression in the rat ovary and to evaluate their distributions throughout the different follicular stages. Out of 20 virginal female rats, 10 were studied during the natural ovarian cycle without any ovulation induction. The other 10 were superovulated and their ovaries were studied by western analysis and immunohistochemistry. Granulosa cells (GC) and oocytes of primordial follicles were negative for VEGF. In early primary follicles, VEGF was present in the oocyte but its immunoreactivity was weak, while newly developing zona pellucida (ZP) of primary follicles was negative for VEGF. Subsequently, with the commencement of antral spaces between GC of the secondary follicle, ZP of some secondary follicles became strongly positive for VEGF, forming a continuous ring around the oocyte. In preovulatory mature follicles granulosa and theca interna (TI) cells showed a weak immunoreactivity for VEGF. Western blot analyses have also demonstrated that VEGF, a 26-kDa protein, was present in follicles. Moreover, in ovulated cumulus-oocyte complex we observed a halo-like immunoreactivity of VEGF around the fully mature oocyte. The immunoreactivity for Flt-1 and KDR receptors in growing follicles was mostly limited to GC and TI cells. Anti-bFGF did not exhibit any immunoreactivity in ZP of follicles at any stage. Its expression was weak in GC of the follicles at different stages, whereas, it could be localized to some extent in the blood capillaries of TI of antral follicles and in blood vessels localized in the stroma. Interestingly, VEGF immunoreactivity in the ZP of some secondary follicles is very striking. Accordingly, the possibility that VEGF may be an important regulatory molecule for the dominant follicle selection or atresia should be considered.

Exposure of Female Rats to an Environmentally Relevant Mixture of Brominated Flame Retardants Targets the Ovary, Affecting Folliculogenesis and Steroidogenesis.

PubMed

Lefèvre, Pavine L C; Berger, Robert G; Ernest, Sheila R; Gaertner, Dean W; Rawn, Dorothea F K; Wade, Michael G; Robaire, Bernard; Hales, Barbara F

2016-01-01

Brominated flame retardants (BFRs) are incorporated into various consumer products to prevent flame propagation. These compounds leach into the domestic environment, resulting in chronic exposure and contamination. Pregnancy failure is associated with high levels of BFRs in human follicular fluid, raising serious questions regarding their impact on female reproductive health. The goal of this study is to elucidate the effects of an environmentally relevant BFR mixture on female rat ovarian functions (i.e., folliculogenesis and steroidogenesis). A BFR dietary mixture formulated to mimic the relative BFR congener levels in North American house dust was administered to adult female Sprague-Dawley rats from 2 to 3 wk before mating until Gestational Day 20; these diets were designed to deliver nominal doses of 0, 0.06, 20, or 60 mg/kg/day of the BFR mixture. Exposure to BFRs triggered an approximately 50% increase in the numbers of preantral and antral follicles and an enlargement of the antral follicles in the ovaries of the dams. A significant reduction in the expression of catalase, an antioxidant enzyme, and downregulation of the expression of insulin-like factor 3 (Insl3) and 17alpha-hydroxylase (Cyp17a1) were observed in the ovary. In addition, BFR exposure affected steroidogenesis; we observed a significant decrease in circulating 17-hydroxypregnenolone and an increase in testosterone concentrations in BFR-exposed dams. Thus, BFRs target ovarian function in the rat, adversely affecting both folliculogenesis and steroidogenesis. © 2016 by the Society for the Study of Reproduction, Inc.

Ultrafine Angelica gigas powder normalizes ovarian hormone levels and has antiosteoporosis properties in ovariectomized rats: particle size effect.

PubMed

Choi, Kyeong-Ok; Lee, Inae; Paik, Sae-Yeol-Rim; Kim, Dong Eun; Lim, Jung Dae; Kang, Wie-Soo; Ko, Sanghoon

2012-10-01

The root of Angelica gigas (Korean angelica) is traditionally used to treat women's ailments that are caused by an impairment of menstrual blood flow and cycle irregularities. This study evaluated the effect particle size of Korean angelica powder on its efficacy for treating estrogen-related symptoms of menopause. Initially, Korean angelica roots were pulverized into ultrafine powder, and orally administered to the rats at a concentration of 500 mg/kg body weight for 8 weeks. The effects of Korean angelica powder particle size on extraction yield, contents of bioactive compounds (decursin and decursinol angelate), levels of serum ovarian hormones (estradiol and progesterone), reproductive hormones (luteinizing hormone and follicle-stimulating hormone), and experimental osteoporosis parameters (mineral density, strength, and histological features) were determined. A significant increase (fivefold) in the contents of decursin and decursinol angelate in the extract of the ultrafine Korean angelica powder was observed compared to coarse Korean angelica powder. Rats were divided into sham-operated or ovariectomized (OVX) groups that were fed coarse (CRS) or ultrafine (UF) ground Korean angelica root. The serum levels of estradiol in the OVX_UF group were 19.2% and 54.1% higher than that of OVX_CRS group. Serum bone-alkaline phosphatase/total-alkaline phosphatase index in the OVX_UF group was half that of the OVX_CRS group. In addition, less trabecular bone loss and thick cortical areas were observed in rats administered ultrafine powder. Therefore, ultrafine grinding may enhance the bioactivity of herbal medicines and be especially useful when their extracted forms lose bioactivity during processing, storage, and oral intake.

[Peripubertal ovarian cyst torsion as an early complication of undiagnosed polycystic ovarian syndrome].

PubMed

Ságodi, László; Schmidt, Ildikó; Vámosi, Ildikó; Barkai, László

2013-01-20

The aim of the authors is to present two cases which raise the possibility of an association between polycystic ovarian syndrome/hyperandrogenism and ovarian cyst torsion in peripubertal girls. Androgen excess may cause more frequently ovarian cyst formation in premenarcheal or young adolescents with undiagnosed polycystic ovarian syndrome than in adults. The authors recommend that polycystic ovarian syndrome as well as late onset congenital adrenal hyperplasia should be considered in peripubertal adolescents with ovarian cyst torsion. In case polycystic ovarian syndrome is confirmed, adequate management according to age and pubertal development of the patients should be commenced.

Effects of Spirulina on Cyclophosphamide-Induced Ovarian Toxicity in Rats: Biochemical and Histomorphometric Evaluation of the Ovary

PubMed Central

Yener, Nese Arzu; Sinanoglu, Orhun; Ilter, Erdin; Celik, Aygen; Sezgin, Gulbuz; Midi, Ahmet; Aksungar, Fehime

2013-01-01

Cyclophosphamide (Cyc) is known to cause ovotoxicity and infertility in women. Our aim is to investigate the possible ovotoxic effects of Cyc and possible antioxidant and protective effects of blue-green algae, Spirulina (Sp), in rat ovaries. Eighteen rats were given: group I (n = 6, control); group II (n = 6, CP), a single dose Cyc; group III (n = 6, Sp+Cyc), 7 days Sp+single dose Cyc. Tissue malondialdehyde (MDA) levels, superoxide dismutase (SOD), and catalase (CAT) activities are assessed biochemically. Normal and atretic primordial and primary follicle counts for all sections obtained for each ovary are calculated. Mean number of follicle counts for each group are compared. In Sp+Cyc group, tissue MDA levels were significantly lower than those in the CP and higher than those in the C group (CP > Sp+Cyc > C). Tissue SOD activity was significantly higher in Sp+Cyc group than that in the CP group and lower than that in the C group (C > Sp+Cyc > C). No statistically significant difference was found between the ovarian CAT activities in any group. Histomorphometrically, there was also no significant difference between the mean numbers of normal and atretic small follicle counts. Our results suggest that single dose Cyc has adverse effects on oxidant status of the ovaries and Sp has protective effects in Cyc-induced ovotoxicity. PMID:23762559

Examination of diagnostic features in multiphoton microscopy and optical coherence tomography images of ovarian tumorigenesis in a mouse model

NASA Astrophysics Data System (ADS)

Watson, Jennifer M.

Ovarian cancer is a deadly disease owing to the non-specific symptoms and suspected rapid progression, leading to frequent late stage detection and poor prognosis. Medical imaging methods such as CT, MRI and ultrasound as well as serum testing for cancer markers have had extremely poor performance for early disease detection. Due to the poor performance of available screening methods, and the impracticality and ineffectiveness of taking tissue biopsies from the ovary, women at high risk for developing ovarian cancer are often advised to undergo prophylactic salpingo-oophorectomy. This surgery results in many side effects and is most often unnecessary since only a fraction of high risk women go on to develop ovarian cancer. Better understanding of the early development of ovarian cancer and characterization of morphological changes associated with early disease could lead to the development of an effective screening test for women at high risk. Optical imaging methods including optical coherence tomography (OCT) and multiphoton microscopy (MPM) are excellent tools for studying disease progression owing to the high resolution and depth sectioning capabilities. Further, these techniques are excellent for optical biopsy because they can image in situ non-destructively. In the studies described in this dissertation OCT and MPM are used to identify cellular and tissue morphological changes associated with early tumor development in a mouse model of ovarian cancer. This work is organized into three specific aims. The first aim is to use the images from the MPM phenomenon of second harmonic generation to quantitatively examine the morphological differences in collagen structure in normal mouse ovarian tissue and mouse ovarian tumors. The second aim is to examine the differences in endogenous two-photon excited fluorescence in normal mouse ovarian tissue and mouse ovarian tumors. The third and final aim is to identify changes in ovarian microstructure resulting from early disease development by imaging animals in vivo at three time points during a long-term survival study.

Effects of Perinatal Polychlorinated Biphenyls on Adult Female Rat Reproduction: Development, Reproductive Physiology, and Second Generational Effects

PubMed Central

Steinberg, Rebecca M.; Walker, Deena M.; Juenger, Thomas E.; Woller, Michael J.; Gore, Andrea C.

2009-01-01

Perinatal exposures to endocrine-disrupting chemicals such as polychlorinated biphenyls (PCBs) can cause latent effects on reproductive function. Here, we tested whether PCBs administered during late pregnancy would compromise reproductive physiology in both the fetally-exposed female offspring (F1 generation), as well as in their female offspring (F2 generation). Pregnant Sprague-Dawley rats were treated with the PCB mixture Aroclor (A) 1221 (0, 0.1, 1 or 10 mg/kg) on embryonic days 16 and 18. Somatic and reproductive development of F1 and their F2 female offspring were monitored, including ages of eye opening, pubertal landmarks, and serum reproductive hormones. The results showed that low doses of A1221 given during this critical period of neuroendocrine development caused differential effects of A1221 on F1 and F2 female rats. In both generations, litter sex ratio was skewed towards females. In the F1 generation, additional effects were found including a significant alteration of serum luteinizing hormone (LH) in the 1 mg/kg A1221 group. The F2 generation showed more profound alterations, particularly with respect to fluctuations in hormones and reproductive tract tissues across the estrous cycle. On proestrus, the day of the preovulatory GnRH/gonadotropin surge, F2 females whose mothers had been perinatally exposed to A1221 exhibited substantially suppressed LH and progesterone concentrations, and correspondingly smaller uterine and ovarian weights on estrus, compared to F2 decendants of control rats. These latter changes suggest a dysregulation of reproductive physiology. Thus, low levels of exposure to PCBs during late fetal development cause significant consequences on the maturation and physiology of two generations of female offspring. These findings have implications for reproductive health and fertility of wildlife and humans. PMID:18305224

[Expression and clinical significance of Xiap and Caspase-3 protien in primary epithelia ovarian cancer].

PubMed

Chen, Wei; Peng, Ping

2010-07-01

To study the expression and clinical significance of Xiap, Caspase-3 protein in primary epithelia ovarian cancer. The Xiap and Caspase-3 were detected by immunohistochemical in 40 cases of epithelial ovarian cancer 20 cases of borderline ovarian tumor, 15 cases of benign ovarian tumor, and 15 normal ovarian tissues. There were significantly different between the expression of Xiap in epithelial ovarian cancer, borderline ovarian tumor, benign ovarian tumor and normal ovarian tissues. The expression of Caspase-3 in epithelial ovarian cancer and borderline ovarian tumor was significantly lower than that in benign ovarian tumor and normal ovarian tissue (P<0.01). The expression of Xiap in epithelial ovarian cancer was related to clinc stage, pathological grade and living. The expression of caspase-3 in epithelial ovarian cancer was related to clinc stage and living (P<0.01). The expressions of Xiap and Caspase-3 may be important roles for the formation and development of epithelia ovarian cancer. The expressions of Xiap and Caspase-3 are the poor prognostic factors in epithelial ovarian carcinomas.

Effect of the estrous cycle on water maze acquisition depends on the temperature of the water.

PubMed

Rubinow, Marisa J; Arseneau, Linda M; Beverly, J Lee; Juraska, Janice M

2004-08-01

The literature on the effects of ovarian hormones on rodent learning and memory is mixed. In this study, the authors examined the role of task stressfulness. Female hooded rats were tested during proestrus or estrus on the hidden-platform water maze in warm (33 degrees C) or cold (19 degrees C) water. There were no effects of cycle or temperature, but estrous phase interacted with temperature such that proestrous rats performed better overall under the warm condition and estrous rats performed better under the cold condition. Plasma corticosterone, measured after 4 trials, varied significantly with estrous phase. Water temperature, perhaps through stress, influences the effect of estrous phase on water maze performance.

Impact of food restriction on ovarian development, RFamide-related peptide-3 and the hypothalamic-pituitary-ovarian axis in pre-pubertal ewes.

PubMed

Li, H; Song, H; Huang, M; Nie, H; Wang, Z; Wang, F

2014-10-01

RFamide-related peptide-3 (RFRP-3), the mammalian ortholog of gonadotropin-inhibiting hormone, has been implicated as a mediator between reproduction and energy balance. This study aimed to investigate the physiological effects of RFRP-3 on the process of ovarian development in food-restricted pre-pubertal ewes. The results showed that food restriction significantly inhibited the ovarian development and follicular growth. The data of qPCR in the hypothalamic-pituitary-ovarian (HPO) axis showed that food restriction not only upregulated RFRP-3 mRNA expression but also downregulated the mRNA expression of gonadotropin-releasing-hormone receptor, follicle-stimulating hormone receptor and luteinizing hormone receptor (LHR). Immunohistochemistry of RFRP-3 in the ovaries suggested that RFRP-3 may regulate the follicular development. These results suggested that the changes of RFRP-3 in response to food restriction might influence the HPO axis and inhibit ovarian development. © 2014 Blackwell Verlag GmbH.

ESTROGENS AND AGE-RELATED MEMORY DECLINE IN RODENTS: WHAT HAVE WE LEARNED AND WHERE DO WE GO FROM HERE?

PubMed Central

Frick, Karyn M.

2009-01-01

The question of whether ovarian hormone therapy can prevent or reduce age-related memory decline in menopausal women has been the subject of much recent debate. Although numerous studies have demonstrated a beneficial effect of estrogen and/or progestin therapy for certain types of memory in menopausal women, recent clinical trials suggest that such therapy actually increases the risk of cognitive decline and dementia. Because rodent models have been frequently used to examine the effects of age and/or ovarian hormone deficiency on mnemonic function, rodent models of age-related hormone and memory decline may be useful in helping to resolve this issue. This review will focus on evidence suggesting that estradiol modulates memory, particularly hippocampal-dependent memory, in young and aging female rats and mice. Various factors affecting the mnemonic response to estradiol in aging females will be highlighted to illustrate the complications inherent to studies of estrogen therapy in aging females. Avenues for future development of estradiol-based therapies will also be discussed, and it is argued that an approach to drug development based on identifying the molecular mechanisms underlying estrogenic modulation of memory may lead to promising future treatments for reducing age-related mnemonic decline. PMID:18835561

Oocyte-somatic cell interactions in the human ovary-novel role of bone morphogenetic proteins and growth differentiation factors.

PubMed

Chang, Hsun-Ming; Qiao, Jie; Leung, Peter C K

2016-12-01

Initially identified for their capability to induce heterotopic bone formation, bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor β superfamily. Using cellular and molecular genetic approaches, recent studies have implicated intra-ovarian BMPs as potent regulators of ovarian follicular function. The bi-directional communication of oocytes and the surrounding somatic cells is mandatory for normal follicle development and oocyte maturation. This review summarizes the current knowledge on the physiological role and molecular determinants of these ovarian regulatory factors within the human germline-somatic regulatory loop. The regulation of ovarian function remains poorly characterized in humans because, while the fundamental process of follicular development and oocyte maturation is highly similar across species, most information on the regulation of ovarian function is obtained from studies using rodent models. Thus, this review focuses on the studies that used human biological materials to gain knowledge about human ovarian biology and disorders and to develop strategies for preventing, diagnosing and treating these abnormalities. Relevant English-language publications describing the roles of BMPs or growth differentiation factors (GDFs) in human ovarian biology and phenotypes were comprehensively searched using PubMed and the Google Scholar database. The publications included those published since the initial identification of BMPs in the mammalian ovary in 1999 through July 2016. Studies using human biological materials have revealed the expression of BMPs, GDFs and their putative receptors as well as their molecular signaling in the fundamental cells (oocyte, cumulus/granulosa cells (GCs) and theca/stroma cells) of the ovarian follicles throughout follicle development. With the availability of recombinant human BMPs/GDFs and the development of immortalized human cell lines, functional studies have demonstrated the physiological role of intra-ovarian BMPs/GDFs in all aspects of ovarian functions, from follicle development to steroidogenesis, cell-cell communication, oocyte maturation, ovulation and luteal function. Furthermore, there is crosstalk between these potent ovarian regulators and the endocrine signaling system. Dysregulation or naturally occurring mutations within the BMP system may lead to several female reproductive diseases. The latest development of recombinant BMPs, synthetic BMP inhibitors, gene therapy and tools for BMP-ligand sequestration has made the BMP pathway a potential therapeutic target in certain human fertility disorders; however, further clinical trials are needed. Recent studies have indicated that GDF8 is an intra-ovarian factor that may play a novel role in regulating ovarian functions in the human ovary. Intra-ovarian BMPs/GDFs are critical regulators of folliculogenesis and human ovarian functions. Any dysregulation or variations in these ligands or their receptors may affect the related intracellular signaling and influence ovarian functions, which accounts for several reproductive pathologies and infertility. Understanding the normal and pathological roles of intra-ovarian BMPs/GDFs, especially as related to GC functions and follicular fluid levels, will inform innovative approaches to fertility regulation and improve the diagnosis and treatment of ovarian disorders. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Sexually dimorphic effects of unpredictable early life adversity on visceral pain behavior in a rodent model.

PubMed

Chaloner, Aaron; Greenwood-Van Meerveld, Beverley

2013-03-01

Visceral pain is the hallmark feature of irritable bowel syndrome (IBS), a gastrointestinal disorder, which is more commonly diagnosed in women. Female IBS patients frequently report a history of early life adversity (ELA); however, sex differences in ELA-induced visceral pain and the role of ovarian hormones have yet to be investigated. Therefore, we tested the hypothesis that ELA induces visceral hypersensitivity through a sexually dimorphic mechanism mediated via estradiol. As a model of ELA, neonatal rats were exposed to different pairings of an odor and shock to control for trauma predictability. In adulthood, visceral sensitivity was assessed via a visceromotor response to colorectal distension. Following ovariectomy and estradiol replacement in a separate group of rats, the visceral sensitivity was quantified. We found that females that received unpredictable odor-shock developed visceral hypersensitivity in adulthood. In contrast, visceral sensitivity was not significantly different following ELA in adult males. Ovariectomy reversed visceral hypersensitivity following unpredictable ELA, whereas estradiol replacement reestablished visceral hypersensitivity in the unpredictable group. This study is the first to show sex-related differences in visceral sensitivity following unpredictable ELA. Our data highlight the activational effect of estradiol as a pivotal mechanism in maintaining visceral hypersensitivity. This article directly implicates a critical role for ovarian hormones in maintaining visceral hypersensitivity following ELA, specifically identifying the activational effect of estradiol as a key modulator of visceral sensitivity. These data suggest that ELA induces persistent functional abdominal pain in female IBS patients through an estrogen-dependent mechanism. Copyright © 2013 American Pain Society. All rights reserved.

Evaluation of preventive effect of shilajit on radiation-induced apoptosis on ovaries.

PubMed

Kececi, Mete; Akpolat, Meryem; Gulle, Kanat; Gencer, Ercan; Sahbaz, Ahmet

2016-06-01

Canc er is the second leading cause of death in children in developed countries and most of childhood malignancies can be treated with chemo-radiotherapy. Although radiation therapy is a successful treatment modality in cancer patients, it has various adverse effects. Especially the gonads are very sensitive and prone to radiation-related damage. Radiation impairs the ovaries by triggering apoptosis of follicular cells and chromosomal damage and oxidative stress. Shilajit, a traditional medicinal agent in India, Russia, and other parts of the world, contains various antioxidant agents and has ovogenic effects. To evaluate the ability of shilajit to prevent radiation-induced ovarian damage. Forty Wistar albino female rats were divided into four groups as: Control group, shilajit group, radiation only group, and radiation + shilajit group. Four days after radiation exposure, the rats were sacrificed and the ovaries were removed and evaluated immuno-histopathologically. There was a statistically significant difference in follicle counts (primordial, primary, preantral, antral, and atretic follicles) between the groups (p < 0.001). Almost all follicles at all stages were atretic in the radiation only group whereas normal-looking primordial follicles were detected in the radiation + shilajit group. In radiation + shilajit group, p53, Bax and caspase 3 expression was less intense than that in the radiation only group follicles. This is the first reported study evaluating the effects of shilajit on radiation-related ovarian damage prevention. Shilajit decreased the expression of p53, Bax, and caspase 3, thereby blocking the apoptotic pathways. Shilajit was found to be especially protective of primordial follicles.

BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy.

PubMed

Lee, F Y; Borzilleri, R; Fairchild, C R; Kim, S H; Long, B H; Reventos-Suarez, C; Vite, G D; Rose, W C; Kramer, R A

2001-05-01

BMS-247550, a novel epothilone derivative, is being developed by Bristol-Myers Squibb Company (BMS) as an anticancer agent for the treatment of patients with malignant tumors. BMS-247550 is a semisynthetic analogue of the natural product epothilone B and has a mode of action analogous to that of paclitaxel (i.e., microtubule stabilization). In vitro, it is twice as potent as paclitaxel in inducing tubulin polymerization. Like paclitaxel, BMS-247550 is a highly potent cytotoxic agent capable of killing cancer cells at low nanomolar concentrations. Importantly, BMS-247550 retains its antineoplastic activity against human cancers that are naturally insensitive to paclitaxel or that have developed resistance to paclitaxel, both in vitro and in vivo. Tumors for which BMS-247550 demonstrated significant antitumor activity encompass both paclitaxel-sensitive and -refractory categories, i.e., (a) paclitaxel-resistant: HCT116/VM46 colorectal (multidrug resistant), Pat-21 breast and Pat-7 ovarian carcinoma (clinical isolates; mechanisms of resistance not fully known), and A2780Tax ovarian carcinoma (tubulin mutation); (b) paclitaxel-insensitive: Pat-26 human pancreatic carcinoma (clinical isolate) and M5076 murine fibrosarcoma; and (c) paclitaxel sensitive: A2780 ovarian, LS174T, and HCT116 human colon carcinoma. In addition, BMS-247550 is p.o. efficacious against preclinical human tumor xenografts grown in immunocompromised mice or rats. Schedule optimization studies indicate that BMS-247550 is efficacious when administered frequently (every 2 days x 5) or intermittently (every 4 days x 3 or every 8 days x 2). These efficacy data demonstrate that BMS-247550 has the potential to surpass Taxol in both clinical efficacy and ease of use (i.e., less frequent treatment schedule and/or oral administration).

Development of molecular markers for zebrafish (Danio rerio) ovarian follicle growth assessment following in-vitro culture in cryopreservation studies.

PubMed

Anil, Siji; Rawson, David; Zhang, Tiantian

2018-05-29

Development of in vitro culture protocol for early stage ovarian follicles of zebrafish is important since cryopreserved early stage ovarian follicles would need to be matured in vitro following cryopreservation before they can be fertilised. Development of molecular markers for zebrafish (Danio rerio) ovarian follicle growth assessment following in vitro culture of early stage zebrafish ovarian follicles in ovarian tissue fragments is reported here for the first time although some work has been reported for in vitro culture of isolated early stage zebrafish ovarian follicles. The main aim of the present study was to develop molecular markers in an optimised in vitro culture protocol for stage I and stage II zebrafish ovarian follicles in ovarian tissue fragments. The effect of concentration of the hormones human chorionic gonadotropin and follicle stimulating hormones, and additives such as Foetal Bovine Serum and Bovine Serum Albumin were studied. The results showed that early stage zebrafish ovarian fragments containing stage I and stage II follicles which are cultured in vitro for 24 h in 20% FBS and 100mIU/ml FSH in 90% L-15 medium at 28 °C can grow to the size of stage II and stage III ovarian follicles respectively. More importantly the follicle growth from stage I to stage II and from stage II to stage III were confirmed using molecular markers such as cyp19a1a (also known as P450aromA) and vtg1 genes respectively. However, no follicle growth was observed following cryopreservation and in vitro culture. Copyright © 2018 Elsevier Inc. All rights reserved.

Ovarian factors inhibit and fetal factors stimulate the secretion of rat placental lactogen.

PubMed

Robertson, M C; Owens, R E; McCoshen, J A; Friesen, H G

1984-01-01

Removal of fetuses at day 14 of gestation (Ftx14) in the pregnant rat leads to a marked suppression of serum levels of rat placental lactogen (rPL-II). One might attribute this to compromised placental growth in the absence of a fetus. However, if ovariectomy and fetectomy (Ftx14 Ovx14) are carried out at the same time, a great increase in serum rPL-II levels is seen. This occurs despite a significant decrease in placental weight. When Ftx14 was performed on day 14 and Ovx was delayed 1, 2, or 3 days, the expected large increase in serum rPL-II was progressively attenuated compared to that seen when Ftx and Ovx were carried out simultaneously. Daily administration of 17 beta-estradiol (4 micrograms/rat X day) to Ftx14 Ovx14 pregnant rats resulted in a significant suppression of rPL-II and elevation of rPRL levels, a reversal of what is seen for these hormones in untreated Ftx14 Ovx14 animals. To test whether 17 beta-estradiol was acting through rat PRL (rPRL), serum levels of rPRL were elevated in Ftx13 Ovx13 animals with pimozide (0.6 mg/kg), a dopamine receptor blocker. There was no effect of this treatment on rPL-II levels. In late pregnancy (day 17) serum rPL-II levels remained high after removal of half the fetuses (1/2 Ftx), compared to the rapid fall in pregnant rats in which all fetuses were removed (Ftx17). Serum levels were also elevated in 1/2 Ftx animals compared to those in which half of the fetuses and placentas were removed by hemi-hysterectomy, suggesting that the increase in rPL-II levels in 1/2 Ftx animals was due to a stimulatory effect of the remaining fetuses on all of the placentas. These results indicate that the presence of the fetus is necessary for the normally observed increase in rPL-II levels in late pregnancy. In conclusion, fetal stimulators and ovarian inhibitors influence rPL-II secretion.

P-MAPA immunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling.

PubMed

de Almeida Chuffa, Luiz Gustavo; de Moura Ferreira, Grazielle; Lupi, Luiz Antonio; da Silva Nunes, Iseu; Fávaro, Wagner José

2018-01-17

Toll-like receptors (TLRs) are transmembrane proteins expressed on the surface of ovarian cancer (OC) and immune cells. Identifying the specific roles of the TLR-mediated signaling pathways in OC cells is important to guide new treatments. Because immunotherapies have emerged as the adjuvant treatment for patients with OC, we investigated the effect of a promising immunotherapeutic strategy based on protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) combined with cisplatin (CIS) on the TLR2 and TLR4 signaling pathways via myeloid differentiation factor 88 (MyD88) and TLR-associated activator of interferon (TRIF) in an in vivo model of OC. Tumors were chemically induced by a single injection of 100 μg of 7,12-dimethylbenz(a)anthracene (DMBA) directly under the left ovarian bursa in Fischer 344 rats. After the rats developed serous papillary OC, they were given P-MAPA, CIS or the combination P-MAPA+CIS as therapies. To understand the effects of the treatments, we assessed the tumor size, histopathology, and the TLR2- and TLR4-mediated inflammatory responses. Although CIS therapy was more effective than P-MAPA in reducing the tumor size, P-MAPA immunotherapy significantly increased the expressions of TLR2 and TLR4. More importantly, the combination of P-MAPA with CIS showed a greater survival rate compared to CIS alone, and exhibited a significant reduction in tumor volume compared to P-MAPA alone. The combination therapy also promoted the increase in the levels of the following OC-related proteins: TLR4, MyD88, TRIF, inhibitor of phosphorylated NF-kB alpha (p-IkBα), and nuclear factor kappa B (NF-kB p65) in both cytoplasmic and nuclear sites. While P-MAPA had no apparent effect on tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6, it seems to increase interferon-γ (IFN-γ), which may induce the Thelper (Th1)-mediated immune response. Collectively, our results suggest that P-MAPA immunotherapy combined with cisplatin could be considered an important therapeutic strategy against OC cells based on signaling pathways activated by TLR4.

Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis

PubMed Central

Emmanuel, Catherine; Gava, Natalie; Kennedy, Catherine; Balleine, Rosemary L.; Sharma, Raghwa; Wain, Gerard; Brand, Alison; Hogg, Russell; Etemadmoghadam, Dariush; George, Joshy; Birrer, Michael J.; Clarke, Christine L.; Chenevix-Trench, Georgia; Bowtell, David D. L.; Harnett, Paul R.; deFazio, Anna

2011-01-01

Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute to the development of ovarian cancer. PMID:21423607

Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion.

PubMed

Herraiz, Sonia; Buigues, Anna; Díaz-García, César; Romeu, Mónica; Martínez, Susana; Gómez-Seguí, Inés; Simón, Carlos; Hsueh, Aaron J; Pellicer, Antonio

2018-05-01

To assess if infusion of human bone marrow-derived stem cells (BMDSCs) could promote follicle development in patients with impaired ovarian functions. Experimental design. University research laboratories. Immunodeficient NOD/SCID female mice. Human BMDSCs were injected into mice with chemotherapy-induced ovarian damage and into immunodeficient mice xenografted with human cortex from poor-responder patients (PRs). Follicle development, ovulation, and offspring. Apoptosis, proliferation, and vascularization were evaluated in mouse and human ovarian stroma. Fertility rescue and spontaneous pregnancies were achieved in mice ovaries mimicking PRs and ovarian insufficiency, induced by chemotherapy, after BMDSC infusion. Furthermore, BMDSC treatment resulted in production of higher numbers of preovulatory follicles, metaphase II oocytes, 2-cell embryos, and healthy pups. Stem cells promoted ovarian vascularization and cell proliferation, along with reduced apoptosis. In xenografted human ovarian tissues from PRs, infusion of BMDSCs and their CD133+ fraction led to their engraftment close to follicles, resulting in promotion of follicular growth, increases in E 2 secretion, and enhanced local vascularization. Our results raised the possibility that promoting ovarian angiogenesis by BMDSC infusion could be an alternative approach to improve follicular development in women with impaired ovarian function. NCT02240342. Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

[Effect of jingui shenqi pill and its disassembled recipes on ovarian functions in shen yang deficiency female rats].

PubMed

Long, Yong-Ling; Li, Zheng-Mu

2013-07-01

To observe the effect of Jingui Shenqi Pill (JSP) and its disassembled recipes (supplementing Shen yang, supplementing Shen yin, and supplementing Shen yang and Shen yin) on ovarian functions of female rats of Shen yang deficiency syndrome (SYDS). Totally 55 SD female rats were randomly divided into 5 groups, i.e., the normal control group, the model group, the Shen yang supplementing group, the Shen yin supplementing group, the Shen yang and Shen yin supplementing group, 11 in each group. Except the normal control group, rats in the rest group were injected with hydrocortisone at the daily dose of 25 mg/kg at the muscle of femoribus internus for 12 successive days. From the 13th day after successful modeling, rats were administered by gastrogavage with different recipes at the dose of 1 mL/100 g (2.75 g/kg Shen yang supplementing recipe; 6.25 g/kg Shen yin supplementing recipe; 6.75 g/kg JSP), once daily for 20 successive days. Equal volume of normal saline was given to those in the normal control group and the model group, once daily for 20 successive days. Blood was withdrawn from the orbit on the 2nd day after intervention. The serum estradiol (E2) and progesterone (P) were detected using ELISA. The weight of uterus and ovarian index (VI) were calculated. The pathological changes were observed by HE staining. The general condition of rats in the Shen yang and Shen yin supplementing group were improved. The body weight (g) was added by 35.0 +/- 12.5 in the normal control group, 16.7 +/- 7.4 in the model group, 20.2 +/- 6.9 in the Shen yang supplementing group, 18.3 +/- 3.6 in the Shen yin supplementing group, and 29.4 +/- 12.2 in the Shen yang and Shen yin supplementing group. The uterus VI (mg/100 g) was 183.4 +/- 11.6 in the normal control group,144.0 +/- 6.5 in the model group,158.7 +/- 6.3 in the Shen yang supplementing group,152.1 +/- 6.9 in the Shen yin supplementing group, and 172.8 +/- 8.1 in the Shen yang and Shen yin supplementing group. The ovarian VI (mg/100 g) were 32.9 +/- 2.4 in the normal control group, 22.6 +/- 1.1 in the model group, 25.0 +/- 1.4 in the Shen yang supplementing group, 23.0 +/- 0.4 in the Shen yin supplementing group, and 31.4 +/- 3.3 in the Shen yang and Shen yin supplementing group. Compared with the model group, the body weight and ovarian VI increased in the Shen yang supplementing group and the Shen yang and Shen yin supplementing group (P < 0.05, P < 0.01). The uterus VI increased in each medicated group (P < 0.05, P < 0.01). Compared with the Shen yang supplementing group and the Shen yin supplementing group, all indices increased in the Shen yang and Shen yin supplementing group (P < 0.05, P < 0.01). The E2 and P levels increased in the Shen yang supplementing group and the Shen yang and Shen yin supplementing group (P < 0.05, P < 0.01). The content of E2 (pg/mL) was 22.1 +/- 9.4 in the normal control group, 9.8 +/- 3.0 in the model group, 11.3 +/- 2.2 in the Shen yang supplementing group, 10.5 +/- 0.8 in the Shen yin supplementing group, and 16.0 +/- 5.5 in the Shen yang and Shen yin supplementing group. The content of P (ng/mL) was 14.6 +/- 7.5 in the normal control group, 4.3 +/- 1.8 in the model group, 8.3 +/- 2.8 in the Shen yang supplementing group, 5.9 +/- 2.9 in the Shen yin supplementing group, and 9.5 +/- 3.4 in the Shen yang and Shen yin supplementing group. Compared with the Shen yang supplementing group and the Shen yin supplementing group, the E2 level increased in the Shen yang and Shen yin supplementing group (P < 0.05, P < 0.01). Compared with the Shen yin supplementing group, the P level increased in the Shen yang and Shen yin supplementing group (P < 0.05). Compared with the model group, the ovarian follicle at each stage increased and pathological follicular ovarian follicles decreased in the Shen yang and Shen yin supplementing group (P < 0.01). Less primary follicles, secondary follicles, and mature follicles could be seen in the Shen yang supplementing group and the Shen yin supplementing group. The total numbers of all-level follicles were obviously higher in the Shen yang and Shen yin supplementing group than in the Shen yang supplementing group and the Shen yin supplementing group (P < 0.05). The number of pathological follicles was obviously less in the Shen yang and Shen yin supplementing group than in the Shen yin supplementing group (P < 0.05). As for SYDS, JSP and its dissembled recipes could improve damaged ovarian functions to some degree. But better effect could not be obtained by Shen yang supplementing method or Shen yin supplementing method alone. Shen yang and Shen yin supplementing method could elevate the efficacy.

Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation.

PubMed

Wallace, W Hamish B; Smith, Alice Grove; Kelsey, Thomas W; Edgar, Angela E; Anderson, Richard A

2014-09-01

Ovarian tissue cryopreservation with later reimplantation has been shown to preserve fertility in adult women, but this approach remains unproven and experimental in children and adolescents. We aimed to assess the use of the Edinburgh selection criteria for ovarian tissue cryopreservation in girls and young women with cancer to determine whether we are offering this invasive procedure to the patients who are most at risk of premature ovarian insufficiency. Cryopreservation of ovarian tissue has been selectively offered to girls and young women with cancer who met the Edinburgh selection criteria since 1996. Between Jan 1, 1996, and June 30, 2012, 410 female patients younger than 18 years at diagnosis were treated for cancer (including leukaemia and brain tumours) at the Edinburgh Children's Cancer Centre, which serves the whole South East of Scotland region. We determined the ovarian status of these patients from review of clinical records and classified them as having premature ovarian insufficiency or not, or as unable to be determined. Patients younger than 12 years at time of data cutoff (Jan 31, 2013) were excluded from the analysis. 34 (8%) of the 410 patients met the Edinburgh selection criteria and were offered ovarian tissue cryopreservation before starting cancer treatment. 13 patients declined the procedure and 21 consented, and the procedure was completed successfully in 20 patients. Of the 20 patients who had ovarian tissue successfully cryopreserved, 14 were available for assessment of ovarian function. Of the 13 patients who had declined the procedure, six were available for assessment of ovarian function. Median age at the time of follow-up for the 20 assessable patients was 16·9 years (IQR 15·5-21·8). Of the 14 assessable patients who had successfully undergone ovarian cryopreservation, six had developed premature ovarian insufficiency at a median age of 13·4 years (IQR 12·5-14·6), one of whom also had a natural pregnancy. Of the six assessable patients who had declined the procedure, one had developed premature ovarian insufficiency. Assessment of ovarian function was possible for 141 of the 376 patients who were not offered cryopreservation; one of these patients had developed premature ovarian insufficiency. The cumulative probability of developing premature ovarian insufficiency after treatment was completed was significantly higher for patients who met the criteria for ovarian tissue cryopreservation than for those who did not (15-year probability 35% [95% CI 10-53] vs 1% [0-2]; p<0·0001; hazard ratio 56·8 [95% CI 6·2-521·6] at 10 years). The results of this analysis show that the Edinburgh selection criteria accurately identify the few girls and young women who will develop premature ovarian insufficiency, and validate their use for selection of patients for ovarian tissue cryopreservation. Further follow-up of this cohort of patients is likely to allow refinement of the criteria for this experimental procedure in girls and young women with cancer. UK Medical Research Council. Copyright © 2014 Wallace et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd. All rights reserved.

Tachykinin receptor and neutral endopeptidase gene expression in the rat uterus: characterization and regulation in response to ovarian steroid treatment.

PubMed

Pinto, F M; Armesto, C P; Magraner, J; Trujillo, M; Martín, J D; Candenas, M L

1999-06-01

Tachykinin neuropeptides, such as substance P, are localized to a population of sensory fibers that innervate the mammalian female reproductive tract. In the present study, we have characterized tachykinin NK1 receptor (NK1R), NK2 receptor (NK2R), and NK3 receptor (NK3R) gene expression by semiquantitative RT-PCR in uteri from ovariectomized rats and studied their regulation in response to 17beta-estradiol (E2), progesterone (P4), or a combination of both. In addition, we analyzed the expression and regulation of the neutral endopeptidase 24.11 (NEP), the most important enzyme involved in tachykinin degradation in the rat uterus. In uteri from control (olive oil-treated) rats, RT-PCR assays revealed single bands corresponding to the expected product sizes encoding complementary DNA for NK1R (232 bp), NK2R (491 bp), NK3R (325 bp), and NEP (221 bp). The identity of the amplified fragments was confirmed by DNA sequence analysis. Compared with control rats, NK1R messenger RNA (mRNA) was increased by 2-fold in uteri from rats treated with E2, was decreased by 3.3-fold in rats treated with P4, and was decreased by 1.8-fold in rats treated with both E2 and P4. Uterine NK2R mRNA levels were not altered by any steroid treatment. E2 treatment decreased by 15-fold NK3R mRNA. P4 was without effect if administered alone and did not influence the E2-induced decrease in NK3R mRNA. NEP mRNA levels were about 4-fold lower in E2-treated than in P4-treated rats. Functional studies were carried out in uteri from E2- or P4-treated ovariectomized rats to characterize the contractile response evoked by the selective tachykinin receptor agonists [Sar9Met(O2)11]substance P (NK1R selective), [Nle10]NKA-(4-10) (NK2R selective), and [MePhe7]NKB (NK3R selective) in the presence of the NEP inhibitor phosphoramidon (1 microM). A marked correlation was observed between the magnitude of the contractile response to each agonist and the level of expression determined by RT-PCR for each tachykinin receptor. The present findings show that tachykinin NK1R, NK2R, NK3R, and NEP are expressed in the rat uterus and that ovarian steroids differentially regulate their expression.

Ovulation and extra-ovarian origin of ovarian cancer

PubMed Central

Yang-Hartwich, Yang; Gurrea-Soteras, Marta; Sumi, Natalia; Joo, Won Duk; Holmberg, Jennie C.; Craveiro, Vinicius; Alvero, Ayesha B.; Mor, Gil

2014-01-01

The mortality rate of ovarian cancer remains high due to late diagnosis and recurrence. A fundamental step toward improving detection and treatment of this lethal disease is to understand its origin. A growing number of studies have revealed that ovarian cancer can develop from multiple extra-ovarian origins, including fallopian tube, gastrointestinal tract, cervix and endometriosis. However, the mechanism leading to their ovarian localization is not understood. We utilized in vitro, ex vivo, and in vivo models to recapitulate the process of extra-ovarian malignant cells migrating to the ovaries and forming tumors. We provided experimental evidence to support that ovulation, by disrupting the ovarian surface epithelium and releasing chemokines/cytokines, promotes the migration and adhesion of malignant cells to the ovary. We identified the granulosa cell-secreted SDF-1 as a main chemoattractant that recruits malignant cells towards the ovary. Our findings revealed a potential molecular mechanism of how the extra-ovarian cells can be attracted by the ovary, migrate to and form tumors in the ovary. Our data also supports the association between increased ovulation and the risk of ovarian cancer. Understanding this association will lead us to the development of more specific markers for early detection and better prevention strategies. PMID:25135607

The impact of nandrolone decanoate administration on ovarian and uterine tissues in rat: Luteinizing hormone profile, histopathological and morphometric assessment.

PubMed

Saddick, Salina Y

2018-03-01

The study had been conducted to evaluate the effects of nandrolone decanoate (abused repeated doses) on female rat's ovary and uterus during administration and withdrawal. The study included 18 rats that were divided into control group (n = 6) and treated group (n = 12). The treated group was injected intramuscular (IM) with nandrolone decanoate (7 mg/kg body weight) for three consecutive days, for two weeks. The study stated that nandrolone decanoate increases the weights of body, ovary, and uterus. Moreover, it has a tendency of bringing upon modifications in the biochemical, histopathological, and morphological makeup of the female reproductive aspects. In conclusion, nandrolone decanoate has been identified as deleterious element for the female rats, and it is suggested that keen observations must be made on the human abusers to control and manage the possible pathologies.

Benefits and risks of ovarian function and reproduction for cancer development and prevention.

PubMed

Schindler, Adolf E

2011-12-01

Ovarian function and menstrual cycle disturbances, pregnancy, and reproductive medicine procedures can either increase gynecological cancer risk or prevent cancer development. For ovarian cancer development, there are two hypotheses, which are connected with ovulation and gonadotropin secretion. Most of the ovarian cancers seem to be derived from displaced ovarian surfice epithelial cells. One year of ovulatory cycles increases the ovarian cancer risk by 6%. Ovulation between 22 and 29 years of age causes the highest risk increase per year. In contrast, progesterone or progestins appear to create protection. Lifestyle can affect or modify ovarian cancer risk. Breast cancer risk is very much related to age of menarche and menopause, pregnancy, and breast feeding. All of which are related to ovarian function and progestogenic impact that translates either into breast cancer risk increase or decrease. This is modified by body mass index, physical activity, and lifestyle in general. The risk of endometrial cancer is most closely related to endogenous progesterone during the menstrual cycle and pregnancy or by exogenous progestogens as in oral contraceptives. These effects are progestogen dose and time dependent. Endometrial cancer risk can also be increased by estrogen-producing tumors or long-term estrogen treatment.

Simultaneous multiplane imaging of human ovarian cancer by volume holographic imaging

PubMed Central

Orsinger, Gabriel V.; Watson, Jennifer M.; Gordon, Michael; Nymeyer, Ariel C.; de Leon, Erich E.; Brownlee, Johnathan W.; Hatch, Kenneth D.; Chambers, Setsuko K.; Barton, Jennifer K.; Kostuk, Raymond K.; Romanowski, Marek

2014-01-01

Abstract. Ovarian cancer is the most deadly gynecologic cancer, a fact which is attributable to poor early detection and survival once the disease has reached advanced stages. Intraoperative laparoscopic volume holographic imaging has the potential to provide simultaneous visualization of surface and subsurface structures in ovarian tissues for improved assessment of developing ovarian cancer. In this ex vivo ovarian tissue study, we assembled a benchtop volume holographic imaging system (VHIS) to characterize the microarchitecture of 78 normal and 40 abnormal tissue specimens derived from ovarian, fallopian tube, uterine, and peritoneal tissues, collected from 26 patients aged 22 to 73 undergoing bilateral salpingo-oophorectomy, hysterectomy with bilateral salpingo-oophorectomy, or abdominal cytoreductive surgery. All tissues were successfully imaged with the VHIS in both reflectance- and fluorescence-modes revealing morphological features which can be used to distinguish between normal, benign abnormalities, and cancerous tissues. We present the development and successful application of VHIS for imaging human ovarian tissue. Comparison of VHIS images with corresponding histopathology allowed for qualitatively distinguishing microstructural features unique to the studied tissue type and disease state. These results motivate the development of a laparoscopic VHIS for evaluating the surface and subsurface morphological alterations in ovarian cancer pathogenesis. PMID:24676382

Multi-modality optical imaging of ovarian cancer in a post-menopausal mouse model

NASA Astrophysics Data System (ADS)

Watson, Jennifer M.; Rice, Photini Faith; Marion, Samuel L.; Bentley, David L.; Brewer, Molly A.; Utzinger, Urs; Hoyer, Patricia B.; Barton, Jennifer K.

2011-03-01

Our goal is to use optical imaging to detect cancer development on the sub cellular scale. By determining the microscopic changes that precede ovarian cancer we hope to develop a minimally invasive screening test for high risk patients. A mouse ovarian cancer model has been developed by treating mice with 4-Vinylcyclohexene Diepoxide to induce ovarian failure and 7, 12-Dimethylbenz[a]anthracene (DMBA) to induce ovarian cancer. Using optical coherence tomography (OCT) and multiphoton microscopy (MPM) we have obtained co-registered en face images of sixty-seven mouse ovaries ex vivo and forty-two ovaries in vivo. Preliminary analysis indicates that OCT and MPM can visualize ovarian microstructure. During the next year we will be completing a long term survival study using post-menopausal mice that have been treated with DMBA to induce cancer and imaged in vivo at time points before and after treatment.

Sex differences in the metabolic dysfunction and insulin resistance of skeletal muscle glucose transport following high fructose ingestion.

PubMed

Rattanavichit, Yupaporn; Chukijrungroat, Natsasi; Saengsirisuwan, Vitoon

2016-12-01

The role of high fructose ingestion (HFI) in the development of conditions mimicking human metabolic syndrome has mostly been demonstrated in male animals; however, the extent of HFI-induced metabolic alterations in females remains unclear. The present study investigated whether HFI-induced metabolic perturbations differ between sexes and whether HFI aggravates the metabolic disturbances under ovarian hormone deprivation. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were given either water or liquid fructose (10% wt/vol) for 6 wk. Blood pressure, glucose tolerance, insulin-stimulated glucose transport activity and signaling proteins, including insulin receptor (IR), insulin receptor substrate 1 (IRS-1), Akt, Akt substrate of 160 kDa (AS160), AMPKα, JNK, p38 MAPK, angiotensin-converting enzyme (ACE), ANG II type 1 receptor (AT 1 R), ACE2, and Mas receptor (MasR) in skeletal muscle, were evaluated. We found that HFI led to glucose intolerance and hypertension in male and OVX rats but not in female rats with intact ovaries. Moreover, HFI did not induce insulin resistance in the skeletal muscle of female and OVX rats but impaired the insulin-stimulated glucose transport activity in the skeletal muscle of male rats, which was accompanied by lower insulin-stimulated IRS-1 Tyr 989 (44%), Akt Ser 473 (30%), and AS160 Ser 588 (43%), and increases in insulin-stimulated IRS-1 Ser 307 (78%), JNK Thr 183 /Tyr 185 (69%), and p38 MAPK Thr 180 /Tyr 182 (81%). The results from the present study show sex differences in the development of metabolic syndrome-like conditions and indicate the protective role of female sex hormones against HFI-induced cardiometabolic abnormalities. Copyright © 2016 the American Physiological Society.

Effects of environmental lighting and tryptophan devoid diet on the rat vaginal cycle.

PubMed

Giammanco, S; Ernandes, M; La Guardia, M

1997-09-01

Cerebral serotonin level influences luteinizing hormone release and, consequently, ovulation. The present study evaluated the effects of precooked maize meal (polenta), a diet almost devoid of tryptophan the serotonin precursor on the alterations of the estrus cycle as measured by vaginal smears analysis in Wistar rats. Several conditions of environmental lighting were used in order to modify ovarian cycle: 1) natural alternating light/dark cycle; 2) continuous darkness; 3) continuous light by sodium steams: 4) continuous light by fluorescent neon tubes. Rats bred in continuous lighting showed estrus-proestrus rate significantly greater than rats bred in normal lighting or in continuous darkness. The feeding with precooked maize meal suppressed persistent estrus in rats bred in continuous lighting, and significantly cut down the estrus-proestrus frequency in any condition of environmental lighting. Our results lead to hypothesize that polenta diet, for its low tryptophan content, cutting down both tryptophan plasma content and serotonin neuronal synthesis, promotes luteinizing hormone peak.

Immunohistochemical evaluation of proliferation, apoptosis and steroidogenic enzymes in the ovary of rats with polycystic ovary.

PubMed

Lombardi, Leonardo Augusto; Simões, Ricardo Santos; Maganhin, Carla Cristina; Baracat, Maria Cândida Pinheiro; Silva-Sasso, Gisela Rodrigues; Florencio-Silva, Rinaldo; Soares, José Maria; Baracat, Edmund Chada

2014-07-01

to evaluate the immunohistochemical expression of proliferative, apoptotic and steroidogenic enzyme markers in the ovaries of rats with polycystic ovary syndrome (PCOS). twenty rats were divided into two groups: GCtrl - estrous phase, and PCOS - with polycystic ovaries. The GCtrl animals were subjected to a lighting period from 7 am to 7 pm, while the animals with PCOS group remained with continuous lighting for 60 days. Subsequently, the animals were anesthetized, the ovaries were removed and fixed in 10% formaldehyde, prior to paraffin embedding. Sections were stained using H.E. or subjected to immunohistochemical methods for the detection of Ki-67, cleaved caspase-3, CYP11A1, CYP17A1 and CYP19A1. The results were analyzed using Student's t-test (p < 0,05). morphological results showed evidence of interstitial cells originating from the inner theca cells of degenerating ovarian cysts in PCOS. Immunoexpression of Ki-67 was higher in the granulosa cells in GCtrl, and the theca interna cells in PCOS, while cleaved caspase-3 was higher in granulosa cells of ovarian cysts from PCOS and in the theca interna cells of GCtrl. Immunoreactivity of CYP11A1 in the theca interna, granulosa and interstitial cells was similar between the two groups, while CYP17A1 and CYP19A1 were higher in the granulosa and interstitial cells in the PCOS group. the results indicate that the interstitial cells are derived from the theca interna and that enzymatic changes occur in the theca interna and interstitial cells in ovaries of rats with PCOS, responsible for the high levels of androgens and estradiol.

Enhanced insulin sensitivity and acute regulation of metabolic genes and signaling pathways after a single electrical or manual acupuncture session in female insulin-resistant rats.

PubMed

Benrick, Anna; Maliqueo, Manuel; Johansson, Julia; Sun, Miao; Wu, Xiaoke; Mannerås-Holm, Louise; Stener-Victorin, Elisabet

2014-12-01

To compare the effect of a single session of acupuncture with either low-frequency electrical or manual stimulation on insulin sensitivity and molecular pathways in the insulin-resistant dihydrotestosterone-induced rat polycystic ovary syndrome (PCOS) model. Both stimulations cause activation of afferent nerve fibers. In addition, electrical stimulation causes muscle contractions, enabling us to differentiate changes induced by activation of sensory afferents from contraction-induced changes. Control and PCOS rats were divided into no-stimulation, manual-, and electrical stimulation groups and insulin sensitivity was measured by euglycemic hyperinsulinemic clamp. Manually stimulated needles were rotated 180° ten times every 5 min, or low-frequency electrical stimulation was applied to evoke muscle twitches for 45 min. Gene and protein expression were analyzed by real-time PCR and Western blot. The glucose infusion rate (GIR) was lower in PCOS rats than in controls. Electrical stimulation was superior to manual stimulation during treatment but both methods increased GIR to the same extent in the post-stimulation period. Electrical stimulation decreased mRNA expression of Adipor2, Adrb1, Fndc5, Erk2, and Tfam in soleus muscle and increased ovarian Adrb2 and Pdf. Manual stimulation decreased ovarian mRNA expression of Erk2 and Sdnd. Electrical stimulation increased phosphorylated ERK levels in soleus muscle. One acupuncture session with electrical stimulation improves insulin sensitivity and modulates skeletal muscle gene and protein expression more than manual stimulation. Although electrical stimulation is superior to manual in enhancing insulin sensitivity during stimulation, they are equally effective after stimulation indicating that it is activation of sensory afferents rather than muscle contraction per se leading to the observed changes.

Ultrafine Angelica gigas Powder Normalizes Ovarian Hormone Levels and Has Antiosteoporosis Properties in Ovariectomized Rats: Particle Size Effect

PubMed Central

Choi, Kyeong-Ok; Lee, Inae; Paik, Sae-Yeol-Rim; Kim, Dong Eun; Lim, Jung Dae; Kang, Wie-Soo; Ko, Sanghoon

2012-01-01

Abstract The root of Angelica gigas (Korean angelica) is traditionally used to treat women's ailments that are caused by an impairment of menstrual blood flow and cycle irregularities. This study evaluated the effect particle size of Korean angelica powder on its efficacy for treating estrogen-related symptoms of menopause. Initially, Korean angelica roots were pulverized into ultrafine powder, and orally administered to the rats at a concentration of 500 mg/kg body weight for 8 weeks. The effects of Korean angelica powder particle size on extraction yield, contents of bioactive compounds (decursin and decursinol angelate), levels of serum ovarian hormones (estradiol and progesterone), reproductive hormones (luteinizing hormone and follicle-stimulating hormone), and experimental osteoporosis parameters (mineral density, strength, and histological features) were determined. A significant increase (fivefold) in the contents of decursin and decursinol angelate in the extract of the ultrafine Korean angelica powder was observed compared to coarse Korean angelica powder. Rats were divided into sham-operated or ovariectomized (OVX) groups that were fed coarse (CRS) or ultrafine (UF) ground Korean angelica root. The serum levels of estradiol in the OVX_UF group were 19.2% and 54.1% higher than that of OVX_CRS group. Serum bone-alkaline phosphatase/total-alkaline phosphatase index in the OVX_UF group was half that of the OVX_CRS group. In addition, less trabecular bone loss and thick cortical areas were observed in rats administered ultrafine powder. Therefore, ultrafine grinding may enhance the bioactivity of herbal medicines and be especially useful when their extracted forms lose bioactivity during processing, storage, and oral intake. PMID:23039111

Effect of Citrullus colocynthis hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOs rats model: An experimental study.

PubMed

Barzegar, Mohammad Hossein; Khazali, Homayoun; Kalantar, Seyyed Mehdi; Khoradmehr, Arezoo

2017-10-01

Citrullus colocynthis (CCT) is used as the anti-diabetic and antioxidant agent. Polycystic ovarian syndrome (PCOS) is a reproductive disorder which level of gonadotropins and sexual hormones are imbalanced. We evaluated the effect of CCT hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOs rats' model. 40 female adult Wistar rats divided into five groups (n=8each: Group I (control) only injected by sesame oil as estradiol valerate solvent, group II (Sham) was orally received normal saline after estradiol valerate- induced polycystic ovarian syndrome (4 mg/rat estradiol valerate, intramuscularly), and three experimental groups, that after induction of PCOS within 60 days, received orally 50 mg/kg CCT extract (group III), 50mg/kg metformin (group IV), and CCT extract+ metformin (group V) for 20 days. The serum concentration level of luteinizing, testosterone and follicle stimulating hormones were measured using ELISA method and the serum concentration level of glucose were measured using the oxidative method (glucose meter). Histological study of ovary tissue carried out by hematoxylin-eosin staining. There was a significant reduction in luteinizing hormone and testosterone in III-V groups compared to Sham group, whereas follicle stimulating hormone in III-V groups was not significantly changed in comparison with Sham group. Histological investigations showed a significant increase in number of preantral and antral follicles and corpus luteum in the experimental groups compared to group II. Marked improvement in hormonal and histological symptoms of PCOS may be due to CCT effects hence, CCT can potentially be considered as an effective drug for treatment of PCOS.

Incidence of ovarian cancer after hysterectomy: a nationwide controlled follow up.

PubMed

Loft, A; Lidegaard, O; Tabor, A

1997-11-01

To estimate the risk of developing ovarian cancer after abdominal (total or subtotal) hysterectomy on benign indication. Prospective historical cohort study with 12.5 years of follow up. Denmark, nationwide. All Danish women (aged 0 to 99 years) having undergone hysterectomy with conservation of at least one ovary for a benign indication from 1977 to 1981 (n = 22,135). Follow up was conducted from 1977 to 1991. The reference group included all Danish women who had not undergone hysterectomy, age-standardised according to the hysterectomy group (n = 2,554,872). Registry data derived from the Danish National Register of Patients (diagnoses and operation codes) and the Civil Registration System (information about general population, including time of death). Incidence rate of ovarian cancer, lifetime risk of ovarian cancer, relative risk of ovarian cancer. Seventy-one women developed ovarian cancer on average 7.0 years after hysterectomy and 10,659 women in the reference group had ovarian cancer diagnosed after on average 6.4 years. The incidence rate of ovarian cancer was 0.27 per 1000 person-years in the group that had undergone hysterectomy and 0.34 per 1000 person-years in the general population (age-standardised). The extrapolated lifetime risk of developing ovarian cancer was 2.1% after hysterectomy and 2.7% in the general population (RR 0.78; 95% CI 0.60-0.96). The risk of ovarian cancer is lower among women who have undergone hysterectomy compared with those who have not. The protection seems to decrease with time.

Concomitant Alterations of Desmosomes, Adhesiveness, and Diffusion through Gap Junction Channels in a Rat Ovarian Transformation Model System

DTIC Science & Technology

1993-01-01

while using a sterile glass slide, held parallel to the monolayer, as a MATERIALS AND METHODS straight edge. Cultures were photographed using phase...contrastmicrosoyo tonoa~r movng ofi I spheria mi rocr rie bed ntI h CEILL CELIL CONTACT AND DIFFU SION 23 and cytokeratin 8 antibodies (refer to Figs. 4a

Studies on the ovarian motility of small laboratory rodents.

PubMed

Gimeno, M F; Gimeno, A L

1975-01-01

Guinea pig ovaries were isolated and immersed in Krebs-Ringer bicarbonate solution, gassed with carbogen and added with glucose as the substrate. The experiments were carried out at 37 degrees C and the preparations were subjected to a basal tension of 500 mg. The spontaneous motility (contractile tension and frequency) of guinea pig ovaries obtained in late proestrus was significantly greater than that of the estrus or early proestrus. The influence of oxytocin on ovarian motility was significantly more marked in late proestrus than in estrus or early proestrus. Both the spontaneous and induced mortility of guinea pig ovaries are augmented in the immediate prevoulatory moment. In isolated rat ovaries, the isometric contractile tension and the frequency of contractions increased as the estral cycle progressed. During late proestrus, left ovaries had a contractile activity of greater intensity and frequency than the right ones, whereas during early proestrus the magnitudes were comparable. Oxytocin elicited greater responses in left than right ovaries of the late proestrus, the effect becoming similar in estrus and early proestrus. Rat ovaries obtained immediately before ovulation are specifically sensitized to the influence of oxytocin and not to other smooth muscle stimulants.

[Effects of hypothalamic microinjections of 6-hydroxydopamine (6-OHDA) on estral cycle and morphology of the genital tract in the female rat (author's transl)].

PubMed

Sala, M A; Oteui, J T; Benedetti, W I

1975-01-01

To determine whether central catecholaminergic pathways are involved in the neural contral of gonadotrophin secretion, they were interrupted at the hypothalamic level by microinjections of 6-hydroxydopamine (6-OHDA). The effects on ovulation, estral cycle and ovarian and uterine histology were studied. Microinjections of 50 mug of 6-OHDA hydrobromyde were made bilaterally into the anterolateral hypothalamus in a group of rats. Another group was injected with 25 mug of 6-OHDA, while a control group recieved an equivalent volume (5 mul) of saline with ascorbic acid. Animals injected with 50 mug of 6-OHDA showed blockade of ovulation, vaginal cytology characteristics of persistent estrous, polyfollicular ovaries and enlarged uteri with hypertrophic endometrial glands. In the group injected with 25 mug, similiar effects were demonstrated, but the number of affected animals was smaller than that in the 50 mug group. Control animals dit not show modifications, either in estral cycle or in ovarian and uterine histology. These results suggest that 6-OHDA injected into the anterolateral hypothalmus interferes with catecholaminergic pathways that participate in the neural control of ovulation.

Evidence that the subunit structure of gonadotropin receptor is preserved during regression of rat corpus luteum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, J.; Menon, K.N.J.

1986-05-29

The level of hCG/LH receptor has been shown to undergo marked changes during the life span of rat corpus luteum. To evaluate whether these fluctuations are due to changes in the receptor subunit structure or receptor protein content, the /sup 125/I-hCG binding activity and the receptor subunit structure were determined during different time periods of pseudopregnancy. The maximum /sup 125/I-hCG binding activity was observed on day 7, after which it decreased by 20 and 45% on day 11 and day 14, respectively. The Scatchard analysis of /sup 125/I-hCG binding data showed that the decrease in binding activity was caused bymore » a change in the number of binding sites rather than a change in the binding affinity. The LH/hCG receptor in ovarian membranes obtained on days 7, 11 and 14 were characterized by the method of affinity cross-linking. All four subunits of the LH/hCG receptor were detected in the ovarian membranes at all stages while the intensity decreased parallel to a decrease in hCG binding from day 7 to day 14.« less

Co-existence of breast and ovarian cancers in BRCA germ-line mutation carriers

PubMed Central

Dilawari, A; Cangiarella, J; Smith, J; Huang, A; Downey, A; Muggia, F

2008-01-01

The co-existence of breast and ovarian cancers in the same individual should raise suspicion of a hereditary process. Patients with either BRCA1 or BRCA2 germ-line mutations have an average risk of 39% and 11% respectively of developing ovarian cancer by the age of 70; they have a risk of 35–85% of developing breast cancer in their lifetime. We report here unusual pathologic features in a BRCA2 germ-line mutation carrier recently diagnosed with synchronous breast and ovarian cancers, and summarize the findings in six other women who were diagnosed with ovarian cancer either simultaneously with the diagnosis of breast cancer or at varying times after the diagnosis. While in most instances this may be a coincidental occurrence in highly susceptible individuals, the patient we highlight raises the provocative hypothesis that at times breast cancer metastasizes to the ovaries of mutation carriers and stimulates the development of an ovarian cancer as well as other cancers. In addition, these ovarian cancers may have different mechanisms of metastases predisposing them to travel to unusual sites. PMID:22275985

Endogenous estrogen status, but not genistein supplementation, modulates 7,12-dimethylbenz[a]anthracene-induced mutation in the liver cII gene of transgenic big blue rats.

PubMed

Chen, Tao; Hutts, Robert C; Mei, Nan; Liu, Xiaoli; Bishop, Michelle E; Shelton, Sharon; Manjanatha, Mugimane G; Aidoo, Anane

2005-06-01

A growing number of studies suggest that isoflavones found in soybeans have estrogenic activity and may safely alleviate the symptoms of menopause. One of these isoflavones, genistein, is commonly used by postmenopausal women as an alternative to hormone replacement therapy. Although sex hormones have been implicated as an important risk factor for the development of hepatocellular carcinoma, there are limited data on the potential effects of the estrogens, including phytoestrogens, on chemical mutagenesis in liver. Because of the association between mutation induction and the carcinogenesis process, we investigated whether endogenous estrogen and supplemental genistein affect 7,12-dimethylbenz[a]anthracene (DMBA)-induced mutagenesis in rat liver. Intact and ovariectomized female Big Blue rats were treated with 80 mg DMBA/kg body weight. Some of the rats also received a supplement of 1,000 ppm genistein. Sixteen weeks after the carcinogen treatment, the rats were sacrificed, their livers were removed, and mutant frequencies (MFs) and types of mutations were determined in the liver cII gene. DMBA significantly increased the MFs in liver for both the intact and ovariectomized rats. While there was no significant difference in MF between the ovariectomized and intact control animals, the mutation induction by DMBA in the ovariectomized groups was significantly higher than that in the intact groups. Dietary genistein did not alter these responses. Molecular analysis of the mutants showed that DMBA induced chemical-specific types of mutations in the liver cII gene. These results suggest that endogenous ovarian hormones have an inhibitory effect on liver mutagenesis by DMBA, whereas dietary genistein does not modulate spontaneous or DMBA-induced mutagenesis in either intact or ovariectomized rats.

Risk of breast cancer after a diagnosis of ovarian cancer in BRCA mutation carriers: Is preventive mastectomy warranted?

PubMed

McGee, Jacob; Giannakeas, Vasily; Karlan, Beth; Lubinski, Jan; Gronwald, Jacek; Rosen, Barry; McLaughlin, John; Risch, Harvey; Sun, Ping; Foulkes, William D; Neuhausen, Susan L; Kotsopoulos, Joanne; Narod, Steven A

2017-05-01

Preventive breast surgery and MRI screening are offered to unaffected BRCA mutation carriers. The clinical benefit of these two modalities has not been evaluated among mutation carriers with a history of ovarian cancer. Thus, we sought to determine whether or not BRCA mutation carriers with ovarian cancer would benefit from preventive mastectomy or from MRI screening. First, the annual mortality rate for ovarian cancer patients was estimated for a cohort of 178 BRCA mutation carriers from Ontario, Canada. Next, the actuarial risk of developing breast cancer was estimated using an international registry of 509 BRCA mutation carriers with ovarian cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) associated with mastectomy and with MRI-based breast surveillance. Cox proportional hazards models were used to evaluate the impacts of mastectomy and MRI screening on breast cancer incidence as well as on all-cause mortality. Twenty (3.9%) of the 509 patients developed breast cancer within ten years following ovarian cancer diagnosis. The actuarial risk of developing breast cancer at ten years post-diagnosis, conditional on survival from ovarian cancer and other causes of mortality was 7.8%. Based on our simulation results, among all BRCA mutation-carrying patients diagnosed with stage III/IV ovarian cancer at age 50, the chance of dying before age 80 was reduced by less than 1% with MRI and by less than 2% with mastectomy. Greater improvements in survival with MRI or mastectomy were observed for women who had already survived 10years after ovarian cancer, and for women with stage I or II ovarian cancer. Among BRCA mutation-carrying ovarian cancer patients without a personal history of breast cancer, neither preventive mastectomy nor MRI screening is warranted, except for those who have survived ovarian cancer without recurrence for ten years and for those with early stage ovarian cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of a Mouse Model of Menopausal Ovarian Cancer

PubMed Central

Smith, Elizabeth R.; Wang, Ying; Xu, Xiang-Xi

2014-01-01

Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology. A potentially useful model is the germ cell-deficient Wv (white spotting variant) mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1–5% (it is not a null mutation). Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer. Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention. PMID:24616881

Evaluation of ovotoxicity induced by 7, 12-dimethylbenz[a]anthracene and its 3,4-diol metabolite utilizing a rat in vitro ovarian culture system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Igawa, Yoshiyuki; BioPharma Center, Asubio Pharma Co., Ltd., Gunma; Keating, Aileen F.

The polycyclic aromatic hydrocarbon 7, 12-dimethylbenz[a]anthracene, (DMBA), targets and destroys all follicle types in rat and mouse ovaries. DMBA requires bioactivation to DMBA-3,4-diol-1,2-epoxide for ovotoxicity via formation of the intermediate, DMBA-3,4-diol (catalyzed by microsomal epoxide hydrolase; mEH). mEH was shown to be involved in DMBA bioactivation for ovotoxicity induction in B6C3F{sub 1} mouse ovaries. The current study compared DMBA and DMBA-3,4-diol mediated ovotoxicity, and investigated mEH involvement in DMBA-3,4-diol bioactivation in Fischer 344 (F344) rat ovary. F344 postnatal day (PND) 4 rat ovaries were cultured in vehicle control or media containing 1) DMBA or DMBA-3,4-diol (12.5 nM - 1 {mu}M;more » 15 days); 2) DMBA (1 {mu}M; 6 h - 15 days); and 3) DMBA (1 {mu}M) or DMBA-3,4-diol (75 nM) {+-} the mEH activity inhibitor cyclohexene oxide (CHO; 2 mM; 4 days). Ovaries were histologically evaluated and mEH mRNA and protein were measured by reverse transcriptase PCR or Western blotting, respectively. Ovotoxicity following 15 days of culture occurred (P < 0.05) at lower concentrations of DMBA-3,4-diol (12.5 nM - primordial; 75 nM - primary) than DMBA (75 nM - primordial; 375 nM - primary). The temporal pattern of mEH expression following DMBA exposure showed mRNA up-regulation (P < 0.05) on day 2, with increased protein (P < 0.05) on day 4, the earliest time of observed follicle loss (P < 0.05). mEH inhibition prevented DMBA-induced, but not DMBA-3,4-diol-induced ovotoxicity. These results demonstrate a conserved response in mice and rats for ovarian mEH involvement in DMBA bioactivation to its ovotoxic, 3,4-diol-1,2-epoxide form.« less

Molecular mechanisms associated with 46,XX disorders of sex development.

PubMed

Knarston, Ingrid; Ayers, Katie; Sinclair, Andrew

2016-03-01

In the female gonad, distinct signalling pathways activate ovarian differentiation while repressing the formation of testes. Human disorders of sex development (DSDs), such as 46,XX DSDs, can arise when this signalling is aberrant. Here we review the current understanding of the genetic mechanisms that control gonadal development, with particular emphasis on those that drive or inhibit ovarian differentiation. We discuss how disruption to these molecular pathways can lead to 46,XX disorders of ovarian development. Finally, we look at recently characterized novel genes and pathways that contribute and speculate how advances in technology will aid in further characterization of normal and disrupted human ovarian development. © 2016 Authors; published by Portland Press Limited.

Time course of the estradiol-dependent induction of oxytocin receptor binding in the ventromedial hypothalamic nucleus of the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, A.E.; Ball, G.F.; Coirini, H.

1989-09-01

Oxytocin (OT) transmission is involved in the steroid-dependent display of sexual receptivity in rats. One of the biochemical processes stimulated by the ovarian steroid 17 beta-estradiol (E2) that is relevant to reproduction is the induction of OT receptor binding in the ventromedial hypothalamic nucleus (VMN). The purpose of these experiments was to determine if E2-induced changes in OT receptor binding in the VMN occur within a time frame relevant to cyclic changes in ovarian steroid secretion. OT receptor binding was measured in the VMN of ovariectomized rats implanted for 0-96 h with E2-containing Silastic capsules. The rate of decay ofmore » OT receptor binding was measured in another group of animals 6-48 h after capsule removal. Receptors were labeled with the specific OT receptor antagonist ({sup 125}I)d(CH2)5(Tyr(Me)2,Thr4,Tyr-NH2(9))OVT, and binding was measured with quantitative autoradiographic methods. In addition, plasma E2 levels and uterine weights were assessed in animals from each treatment condition. Significant increases in E2-dependent OT receptor binding and uterine weight occurred within 24 h of steroid treatment. After E2 withdrawal, OT receptor binding and uterine weight decreased significantly within 24 h. These results are consistent with the hypothesis that steroid modulation of OT receptor binding is necessary for the induction of sexual receptivity.« less

Manifestation of Hyperandrogenism in the Continuous Light Exposure-Induced PCOS Rat Model

PubMed Central

Kang, Xuezhi; Jia, Lina; Shen, Xueyong

2015-01-01

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, and its pathogenesis has yet to be completely clarified. A fully convincing animal model has not been established for PCOS. In earlier studies, researchers have shown that the exposure of rats to continuous light can induce PCOS; nevertheless, hyperandrogenism, a key characteristic observed in human PCOS, has not been reported previously. In the present study, we found that (1) body weights decreased in female rats in a continuous light environment with both ovarian and uterine augmentation; (2) the estrous cycle in rats under continuous light environment was disordered, and polycystic ovary-like changes occurred, accompanied with fur loss and lethargy; and (3) serum testosterone levels in rats in a continuous light environment significantly increased. Our data suggest that continuous light can lead to the occurrence of PCOS in female rats without the need for drugs; this is a reasonable PCOS animal model that is more consistent with the natural disease state in humans; and poor sleep habits or negligence of sleep hygiene may be an important lifestyle factor in pathogenesis of PCOS. PMID:26064969

Penetration of chemicals into the oocyte, uterine fluid, and preimplantation blastocyst

PubMed Central

Fabro, Sergio

1978-01-01

Chemicals, including commonly used drugs (e.g., penicillin, meprobamate, pyridium, and mercaptomerin) penetrate and persist for some time in the ovarian follicular fluid at concentrations approximately similar to that of the serum. Information as to the penetration of chemicals into the granulosa cells and into the oocyte is scanty, although there are some indications that these structures are also permeable to foreign chemicals. Similarly, caffeine, nicotine, thiopental, salicylic acid, antipyrine, barbital, and isoniazid enter the uterine secretion and penetrate the preimplantation blastocyst of mice, rats and rabbits. The pattern of distribution of compounds among ovarian follicular fluid, uterine luminal fluid, blastocyst and plasma varies from compound to compound and appears to be related to the molecular weight and degree of ionization of the compound and differs in pregnant and nonpregnant animals. Thus, nicotine and DDT accumulate in the uterine luminal fluid of pregnant but not in that of nonpregnant rabbits. The penetration of foreign chemicals into the oocyte, uterine luminal fluid, and preimplantation blastocyst may exert adverse effects on fertilization, implantation, and/or further development of the conceptus. The possible toxicological importance of this process to eutherian reproduction is discussed. PMID:17539150

An imbalance between apoptosis and proliferation contributes to follicular persistence in polycystic ovaries in rats

PubMed Central

Salvetti, Natalia R; Panzani, Carolina G; Gimeno, Eduardo J; Neme, Leandro G; Alfaro, Natalia S; Ortega, Hugo H

2009-01-01

Background Cystic ovarian disease is an important cause of infertility that affects bovine, ovine, caprine and porcine species and even human beings. Alterations in the ovarian micro-environment of females with follicular cysts could alter the normal processes of proliferation and programmed cell death in ovarian cells. Thus, our objective was to evaluate apoptosis and proliferation in ovarian cystic follicles in rats in order to investigate the cause of cystic follicle formation and persistence. Methods We compared the number of in situ apoptotic cells by TUNEL assay, expression of active caspase-3 and members of Bcl-2 family by immunohistochemistry; and cell proliferation by the expression of the proliferation markers: PCNA and Ki-67. Results The proliferation index was low in granulosa of tertiary and cystic follicles of light exposed rats when compared with tertiary follicles of control animals, while in theca interna only cystic follicles presented low proliferation index when compared with tertiary follicles (p < 0.05). The granulosa of cysts exhibited a similar cell DNA fragmentation to early atretic follicles. In the granulosa and theca interna, active caspase-3 shown similar immunostaining levels in tertiary and cystic follicles (p < 0.05). The granulosa cells presented high expression of Bcl-2, Bcl-xL and Bcl-w in the tertiary and cystic follicles with diminishing intensity in the atretic follicles, except with Bcl-w where the intensity was maintained in the atretic follicles (p < 0.05). The expression of Bax was weak in the healthy and cystic follicles. In the theca interna, Bcl-2 expression was the same as the pattern found in the granulosa; no differences were found between tertiary and cystic follicles from both groups for Bcl-xL and Bcl-w. The expression of Bax in this layer was higher in the tertiary follicles of the treated animals (p < 0.05) while the values for cystic follicles were similar to those in the tertiary follicles of controls. The theca externa showed low expression of the pro and anti-apoptotic proteins. Conclusion These results show that the combination of weak proliferation indices and low apoptosis observed in follicular cysts, could explain the cause of the slow growth of cystic follicles and the maintenance of a static condition without degeneration, which leads to their persistence. These alterations may be due to structural and functional modifications that take place in these cells and could be related to hormonal changes in animals with this condition. PMID:19570211

Familial association of specific histologic types of ovarian malignancy with other malignancies.

PubMed

Lorenzo Bermejo, Justo; Rawal, Rajesh; Hemminki, Kari

2004-04-01

Population-based data on the familial association of specific histologic types of ovarian malignancy with other malignancies are limited. Such data may help to elucidate etiologic differences among histologic types of ovarian malignancy. The nationwide Swedish Family-Cancer Database, which includes 10.3 million individuals and 20,974 ovarian carcinomas, was used to calculate standardized incidence ratios and 95% confidence intervals for age- and histology-specific ovarian malignancies in women whose parents or siblings were affected with malignancies at the most common disease sites. Ovarian malignancy was found to be associated with ovarian, laryngeal, breast, endometrial, liver, and colon carcinoma, as well as myeloma; epithelial ovarian malignancy was found to be associated with ovarian, endometrial, and skin malignancies and with melanoma and myeloma; papillary serous cystadenocarcinoma was found to be associated with ovarian and skin malignancies and with myeloma; and endometrioid carcinoma was found to be associated with endometrial, ovarian, and prostate malignancies and with melanoma. For younger women (ages 40-45 years) whose mothers were affected with endometrial malignancies, the risk of developing endometrioid carcinoma was slightly greater than the risk of developing papillary serous cystadenocarcinoma. Specific types of ovarian malignancy may be associated with specific familial disease sites, with such associations depending on age at diagnosis; the strength of the observed associations varied according to histology. Associations were found between endometrioid carcinoma and endometrial malignancy and between serous carcinoma and Hodgkin disease. Copyright 2004 American Cancer Society.

Towards prevention of ovarian cancer.

PubMed

Ali, Aus Tariq

2018-01-01

Ovarian cancer is the leading cause of death of all gynaecological cancers. To date, there is no reliable, specific screening procedure for detecting ovarian cancer. The risk factors of ovarian cancer include modifiable and non-modifiable factors. The main goal of the ovarian cancer prevention program is to significantly reduce the risk of development of ovarian cancer and other cancers such as breast and/or peritoneal cancer. The application of non-surgical preventive approaches such as oral contraceptives, parity and breastfeeding has been shown to be highly protective against ovarian cancer development. Targeting inflammation has been also reported to be associated with a protective trend against ovarian cancer and can be achieved through either non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin or lifestyle modifications or both. Lifestyle modification that includes regular exercise, healthy diet supplemented with anti-oxidants and anti-inflammatory elements reduces the risk of the disease even further. Surgical protective approaches include; tubal ligation, hysterectomy and prophylactic bilateral salpingo-oophorectomy and the former is the most effective approach to protect against ovarian cancer. A better understanding of the risk factors of ovarian cancer and the current approaches to prevent it may increase the awareness and help to decrease the incidence of ovarian cancer, increase the five-year survival rate and decrease the mortality rate significantly in the general population especially among those at high risk for ovarian cancer. This review is an attempt to outline a potential program of ovarian cancer prevention and the potential challenges. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Elucidation of the mechanism of fertilization and clinical application of assisted reproductive technology].

PubMed

Hiroi, M

1996-08-01

Fertilization is the process including many events such as maturation of egg and sperm, attachment, binding, acrosomal reaction, penetration, fusion, cortical reaction, zona reaction and nuclear fusion of both gamete, whereby individual gametes from the female and male unite to create offspring. Although the reason for mechanism of fertilization is still not clearly understood, this process may accelerate the rate adaptation in evolution. In this special lecture, I would like to present our experimental and clinical results especially concerning with morphological, physiological, biochemical and molecular approach on the mechanism of fertilization. 1. Development and maturation of follicles and oocytes. It is well known that pituitary FSH, LH control the ovarian function. Follicular development and ovum maturation are also controlled by both pituitary gonadotropins and local factors such as autocrine and paracrine agents. When hMG is injected during 1-6 day of menstrual cycle, several dominant follicles are developed. If hMG is injected after selection of dominant follicles, only one dominant follicle develop in the ovary. When PMS-treated immature rats were injected with immature or mature follicle fluids, rats injected with mature follicular fluid showed strongly suppress in the ovarian weights and numbers of ovulated follicles. Also mature follicle suppress aromatization from and androstenedione to estradiol. These findings mean that mature follicular fluid contains inhibitory factors. Apoptosis of granulosa cells and follicular steroids are related to fertilization. 2. Intracellular calcium of oocyte. Intracellular calcium concentration is known to start to increase in a periodic manner after fertilization in oocytes of mammalians. In 65% of tested mouse oocytes, fertilization occurred during 4 hours observation after sperm insemination in vitro. An initial long lasting intracellular calcium concentration was observed and followed by periodic manner. This calcium oscillation is inhibited by calcium blockers such as verpamil and nifedipine, but increased by high concentration of extracellular calcium concentration in the medium. Role of increase of intracellular calcium are understood to prevent polysperm and activate metabolism of oocytes. 3. Glucose metabolism of oocytes. Mouse embryo utilizes pyruvate as an essential nutrient until the 8-cell stage, and glucose thereafter. We have devised non-radiometrie and enzymatic microassay method to measure glucose, deoxyglucose, deoxyglucose 6-phosphate incorporated into individual mouse oocytes and preimplantation embryo. In parallel, the activities of several enzymes of glycolytic pathway were also determined. In this study, glucose metabolism is necessary to develop in fertilized ova with changing activity of enzymes. 4. Molecular bases of ovarian fluid. The zona pellucida ZP is involved in a number of events in fertilization, all these fertilization events occur in the oviduct. Oviductal glycoprotein 200-240 KD has been identified from oviductal zona pellucida. Monoclonal antibody of oviductal glycoprotein reacted with ZP of oviductal egg but not with the ovarian egg. Anti-ZPO antibody inhibit to bind sperm to ZP. Sequences in mouse and hamster oviduct specific glycoprotein are estimated, this glycoprotein mRNA was observed in only oviduct by northern blotting method. These molecular gene expression was observed by in situ hybridization in the oviduct of estrous cycle of hamster. 5. Microinsemination of sperm. Microinsemination of sperm into oocyte is widely used in clinical medicine. Sperm penetration assay (hamster test) is useful method to estimate fertilization capacity of sperm. But immotile sperm cannot estimate it. So modified micro sperm penetration assay was established to estimate fertilization capacity of sperm by using micro-manipulator. Subzonal sperm injection (SUZI) and intracytoplasmic sperm injection (ICSI) promotes fertilization and cleavage rate in immotile

Diagnostic tool for early detection of ovarian cancers using Raman spectroscopy

NASA Astrophysics Data System (ADS)

Lieber, Chad A.; Molpus, Kelly; Brader, Kevin; Mahadevan-Jansen, Anita

2000-05-01

With an overall survival rate of about 35 percent, ovarian cancer claims more than 13,000 women in the US each year. It is estimated that roughly 1 in 70 women will develop ovarian cancer. Current screening techniques are challenged due to cost-effectiveness, variable false-positive results, and the asymptomatic nature of the early stages of ovarian cancer. The predominant screening method for ovarian cancers is transvaginal sonography (TVS). TVS is fairly accomplished at ovarian cancer detection, however it is inefficient in distinguishing between benign and malignant masses. Accurate diagnosis of the ovarian tumor relies on exploratory laparotomy, thus increasing the cost and hazard of false- positive screening methods. Raman spectroscopy has been sued successfully as a diagnostic tool in several organ systems in vitro. These studies have shown that Raman spectroscopy can be used to provide diagnosis of subtle changes in tissue pathology with high accuracy. Based on this success, we have developed a Raman spectroscopic system for application in the ovary. Using this system, the Raman signatures of normal and various types of non-normal human ovarian tissues were characterized in vitro. Raman spectra are being analyzed, and empirical as well as multivariate discriminatory algorithms developed. Based on the result of this study, a strategy for in vivo trials will be planned.

Photoaffinity-labeling and fluorescence-distribution studies of gonadotropin-releasing hormone receptors in ovarian granulosa cells.

PubMed Central

Hazum, E; Nimrod, A

1982-01-01

Photoaffinity labeling of rat ovarian granulosa cells and membrane preparations with a bioactive photoaffinity derivative of gonadotropin-releasing hormone resulted in identification of two specific components with apparent molecular weights of 60,000 and 54,000. Fluorescent visualization of gonadotropin-releasing hormone receptors in these cells, by using a bioactive rhodamine derivative of the hormone, indicated that the fluorescently labeled receptors were initially distributed uniformly on the cell surface and then formed patches that subsequently internalized (at 37 degrees C) into endocytic vesicles. These processes were dependent on specific binding sites for the rhodamine-labeled peptide on the granulosa cells. These studies may provide an experimental basis for understanding the molecular events involved in the action of the hormone in the ovary. Images PMID:6281784

[Age-related characteristics of structural support for ovarian function].

PubMed

Koval'skiĭ, G B

1984-12-01

Histoenzymological assay was used to investigate various structures of the ovaries of rats of two groups aged 3-4 and 12-14 months during estral cycle. The activity of 3 beta-, 17 beta- and 20 alpha-steroid dehydrogenases, glucose-6-phosphate dehydrogenase, NAD and NADP-diaphorases, esterase, acid and alkaline phosphatases was studied. It has been shown that transport alterations in the microcirculation including the hematofollicular barrier play, the leading part in age-dependent depression of reproductive and endocrine functions. Ageing rats demonstrated no linkage between endothelial, thecal and granular cells, which points to the injury of the histophysiological mechanisms of the follicular system integration.

Follicle dynamics: visualization and analysis of follicle growth and maturation using murine ovarian tissue culture.

PubMed

Murase, Tomohiko; Iwase, Akira; Komatsu, Kouji; Bayasula; Nakamura, Tomoko; Osuka, Satoko; Takikawa, Sachiko; Goto, Maki; Kotani, Tomomi; Kikkawa, Fumitaka

2018-02-01

To visualize and analyze follicle development in ovarian tissue culture using physiological concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in order to establish an ovarian tissue culture system that enables efficient in vitro growth of follicles. Ovarian tissues from 4-week-old female ICR mice were sliced and cultured. Images of ovarian tissues in culture were obtained at 24-h or 30-min intervals by using a microscope. The area of each follicle observed in the ovarian tissue slices was tracked and analyzed in association with oocyte maturation. We were able to track the development of each follicle using this culture system. Follicle growth was associated with oocyte maturation. Meiotically matured oocytes (MII) were obtained from 33% of all follicles investigated. Approximately, a quarter of follicles (24%) did not grow and resulted in atresia. Follicle dynamics were successfully visualized and analyzed in murine ovarian tissue culture. We were able to obtain mature oocytes from the fully grown follicles in vitro. This culture system would be helpful for efficient in vitro culturing of ovarian tissues.

Tetraploid cells from cytokinesis failure induce aneuploidy and spontaneous transformation of mouse ovarian surface epithelial cells.

PubMed

Lv, Lei; Zhang, Tianwei; Yi, Qiyi; Huang, Yun; Wang, Zheng; Hou, Heli; Zhang, Huan; Zheng, Wei; Hao, Qiaomei; Guo, Zongyou; Cooke, Howard J; Shi, Qinghua

2012-08-01

Most ovarian cancers originate from the ovarian surface epithelium and are characterized by aneuploid karyotypes. Aneuploidy, a consequence of chromosome instability, is an early event during the development of ovarian cancers. However, how aneuploid cells are evolved from normal diploid cells in ovarian cancers remains unknown. In the present study, cytogenetic analyses of a mouse syngeneic ovarian cancer model revealed that diploid mouse ovarian surface epithelial cells (MOSECs) experienced an intermediate tetraploid cell stage, before evolving to aneuploid (mainly near-tetraploid) cells. Using long-term live-cell imaging followed by fluorescence in situ hybridization (FISH), we demonstrated that tetraploid cells originally arose from cytokinesis failure of bipolar mitosis in diploid cells, and gave rise to aneuploid cells through chromosome mis-segregation during both bipolar and multipolar mitoses. Injection of the late passage aneuploid MOSECs resulted in tumor formation in C57BL/6 mice. Therefore, we reveal a pathway for the evolution of diploid to aneuploid MOSECs and elucidate a mechanism for the development of near-tetraploid ovarian cancer cells.

Advancing ovarian folliculometry with selective plane illumination microscopy

NASA Astrophysics Data System (ADS)

Lin, Hsiao-Chun Amy; Dutta, Rahul; Mandal, Subhamoy; Kind, Alexander; Schnieke, Angelika; Razansky, Daniel

2016-12-01

Determination of ovarian status and follicle monitoring are common methods of diagnosing female infertility. We evaluated the suitability of selective plane illumination microscopy (SPIM) for the study of ovarian follicles. The large field of view and fast acquisition speed of our SPIM system enables rendering of volumetric image stacks from intact whole porcine ovarian follicles, clearly visualizing follicular features including follicle volume and average diameter (70 μm-2.5 mm), their spherical asymmetry parameters, size of developing cumulus oophorus complexes (40 μm-110 μm), and follicular wall thickness (90 μm-120 μm). Follicles at all developmental stages were identified. A distribution of the theca thickness was measured for each follicle, and a relationship between these distributions and the stages of follicular development was discerned. The ability of the system to non-destructively generate sub-cellular resolution 3D images of developing follicles, with excellent image contrast and high throughput capacity compared to conventional histology, suggests that it can be used to monitor follicular development and identify structural abnormalities indicative of ovarian ailments. Accurate folliculometric measurements provided by SPIM images can immensely help the understanding of ovarian physiology and provide important information for the proper management of ovarian diseases.

Omega-3 polyunsaturated fatty acid docosahexaenoic acid and its role in exhaustive-exercise-induced changes in female rat ovulatory cycle.

PubMed

Mostafa, Abeer F; Samir, Shereen M; Nagib, R M

2018-04-01

Exhaustive exercises can cause delayed menarche or menstrual cycle irregularities in females. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are incorporated into a wide range of benefits in many physiological systems. Our work aimed to assess the role of ω-3 PUFA docosahexaenoic acid (DHA) on the deleterious effects of exhaustive exercise on the female reproductive system in rats. Virgin female rats were randomly divided into 4 groups (12 rats in each): control group, omega-3 group treated with DHA, exhaustive exercise group, and exhaustive exercised rats treated with DHA. Omega-3 was given orally to the rats once daily for 4 estrous cycles. Exhaustive exercises revealed lower levels in progesterone and gonadotropins together with histopathological decrease in number of growing follicles and corpora lutea. Moreover, the exercised rats showed low levels of ovarian antioxidants with high level of caspase-3 and plasma cortisol level that lead to disruption of hypothalamic-pituitary-gonadal axis. ω-3 PUFA DHA has beneficial effects on the number of newly growing follicles in both sedentary and exercised rats with decreasing the level of caspase-3 and increasing the antioxidant activity in ovaries. Exhaustive exercises can cause ovulatory problems in female rats that can be improved by ω-3 supplementation.

Ovarian steroids act as respiratory stimulant and antioxidant against the causes and consequences of sleep-apnea in women.

PubMed

Boukari, Ryma; Laouafa, Sofien; Ribon-Demars, Alexandra; Bairam, Aida; Joseph, Vincent

2017-05-01

Evidence supports the importance of ovarian hormones as potential tools against sleep apneas in women. On one hand, progesterone is largely acknowledged as being a respiratory stimulant that reduces the frequency of apneas, but the underlying mechanisms remain poorly understood. Recent studies in mice showed that the respiratory effects of progesterone are mediated by at least two classes of progesterone receptors, including the nuclear (nPR) and membrane receptors (mPR). Some of these receptors (nPR) have sex-specific effects on the frequency of apneas recorded during sleep in mice, while mPRβ acts in males as well as in females. Moreover, sleep apnea is a condition that induces an "oxidative stress" response in several tissues, and this contributes to the deleterious consequences of sleep apneas, including the development of hypertension. While estradiol is recognized as an antioxidant hormone, its potential protective role has remained mostly ignored in the field. We will review recent data supporting an antioxidant role of estradiol in female rats exposed to intermittent hypoxia, a reliable animal model of sleep apnea. Since estradiol has two main receptors (ERα and ERβ) we will discuss their relative implications, and present new data showing a key role for ERα to prevent the hypertension induced by intermittent hypoxia. Overall this review highlights the fact that ovarian hormones could potentially be used as efficient tools against the causes (i.e. instabilities of the respiratory control system) and consequences (oxidative stress) of sleep apnea. Copyright © 2017 Elsevier B.V. All rights reserved.

Expression of Progesterone Receptor Membrane Component-2 Within the Immature Rat Ovary and Its Role in Regulating Mitosis and Apoptosis of Spontaneously Immortalized Granulosa Cells1

PubMed Central

Griffin, Daniel; Liu, Xiufang; Pru, Cindy; Pru, James K.; Peluso, John J.

2014-01-01

ABSTRACT Progesterone receptor membrane component 2 (Pgrmc2) mRNA was detected in the immature rat ovary. By 48 h after eCG, Pgrmc2 mRNA levels decreased by 40% and were maintained at 48 h post-hCG. Immunohistochemical studies detected PGRMC2 in oocytes and ovarian surface epithelial, interstitial, thecal, granulosa, and luteal cells. PGRMC2 was also present in spontaneously immortalized granulosa cells, localizing to the cytoplasm of interphase cells and apparently to the mitotic spindle of cells in metaphase. Interestingly, PGRMC2 levels appeared to decrease during the G1 stage of the cell cycle. Moreover, overexpression of PGRMC2 suppressed entry into the cell cycle, possibly by binding the p58 form of cyclin dependent kinase 11b. Conversely, Pgrmc2 small interfering RNA (siRNA) treatment increased the percentage of cells in G1 and M stage but did not increase the number of cells, which was likely due to an increase in apoptosis. Depleting PGRMC2 did not inhibit cellular 3H-progesterone binding, but attenuated the ability of progesterone to suppress mitosis and apoptosis. Taken together these studies suggest that PGRMC2 affects granulosa cell mitosis by acting at two specific stages of the cell cycle. First, PGRMC2 regulates the progression from the G0 into the G1 stage of the cell cycle. Second, PGRMC2 appears to localize to the mitotic spindle, where it likely promotes the final stages of mitosis. Finally, siRNA knockdown studies indicate that PGRMC2 is required for progesterone to slow the rate of granulosa cell mitosis and apoptosis. These findings support a role for PGRMC2 in ovarian follicle development. PMID:24990806

Oriental Medicine Kyung-Ok-Ko Prevents and Alleviates Dehydroepiandrosterone-Induced Polycystic Ovarian Syndrome in Rats

PubMed Central

Lee, Jin Moo; Bae, Chun-Sik; Kim, Sung-Hoon; Ryu, Jong Hoon; Cho, Ik-Hyun

2014-01-01

Kyung-Ok-Ko (KOK), a traditional herbal prescription composed of Rehmannia glutinosa Liboschitz var. purpurae, Lycium chinense, Aquillaria agallocha, Poria cocos, Panax ginseng, and honey, has been widely used in traditional Oriental medicine as a vitalizing medicine or as the prescription for patients with age-associated disorders such as amnesia and stroke. However, the potential protective value of KOK for the treatment of polycystic ovarian syndrome (PCOS) is largely unknown. We investigated whether pre-administration (daily from 2 hours before PCOS induction) and post-administration (daily after induction of PCOS) of KOK (0.5, 1.0, and 2.0 g/kg/day, p.o.) could have a protective effect in a dehydroepiandrosterone (DHEA, s.c.)-induced PCOS rat model. Pre-administration of KOK significantly decreased the elevated body weight and ovary weight, elevated size and number of follicular cysts, elevated level of serum glucose, and estradiol after DHEA injection. KOK reduced the elevated percentage of CD8 (+) T lymphocytes in lymph nodes, the elevated mRNA expression of CD11b and CD3 in ovaries, and infiltration of macrophages in ovarian tissue with PCOS. KOK diminished the increased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), chemokines (IL-8, MCP-1), and iNOS in the ovaries, and increased the reduced mRNA expression of growth factors (EGF, TGF-β) by DHEA injection. Post-administration of KOK also improved the DHEA-induced PCOS-like symptoms, generally similar to those evident from pre-administration of KOK. KOK may effectively prevent and improve DHEA-induced PCOS via anti-inflammatory action, indicating its preventive and therapeutic potential for suppressing PCOS. PMID:24520334

Oriental medicine Kyung-Ok-Ko prevents and alleviates dehydroepiandrosterone-induced polycystic ovarian syndrome in rats.

PubMed

Jang, Minhee; Lee, Min Jung; Lee, Jin Moo; Bae, Chun-Sik; Kim, Sung-Hoon; Ryu, Jong Hoon; Cho, Ik-Hyun

2014-01-01

Kyung-Ok-Ko (KOK), a traditional herbal prescription composed of Rehmannia glutinosa Liboschitz var. purpurae, Lycium chinense, Aquillaria agallocha, Poria cocos, Panax ginseng, and honey, has been widely used in traditional Oriental medicine as a vitalizing medicine or as the prescription for patients with age-associated disorders such as amnesia and stroke. However, the potential protective value of KOK for the treatment of polycystic ovarian syndrome (PCOS) is largely unknown. We investigated whether pre-administration (daily from 2 hours before PCOS induction) and post-administration (daily after induction of PCOS) of KOK (0.5, 1.0, and 2.0 g/kg/day, p.o.) could have a protective effect in a dehydroepiandrosterone (DHEA, s.c.)-induced PCOS rat model. Pre-administration of KOK significantly decreased the elevated body weight and ovary weight, elevated size and number of follicular cysts, elevated level of serum glucose, and estradiol after DHEA injection. KOK reduced the elevated percentage of CD8 (+) T lymphocytes in lymph nodes, the elevated mRNA expression of CD11b and CD3 in ovaries, and infiltration of macrophages in ovarian tissue with PCOS. KOK diminished the increased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), chemokines (IL-8, MCP-1), and iNOS in the ovaries, and increased the reduced mRNA expression of growth factors (EGF, TGF-β) by DHEA injection. Post-administration of KOK also improved the DHEA-induced PCOS-like symptoms, generally similar to those evident from pre-administration of KOK. KOK may effectively prevent and improve DHEA-induced PCOS via anti-inflammatory action, indicating its preventive and therapeutic potential for suppressing PCOS.

Hormonal Contraception, Body Water Balance and Thermoregulation

DTIC Science & Technology

1997-10-01

Schreiber, and M. D. Lindheimer. Effect of ovarian sex steroids on osmoregulation and vasopressin secretion in the rat. Am. J. Physiol. 250 (Endocrinol...two widely used oral contraceptive preparations differ significantly in their estrogenicity. Estrogens have potent effects on the regulation of body...water balance (1, 4), so these two forms of oral contraceptive pills may differ in their effects on water regulation, and hence on physical performance

Alterations in ovarian follicular progesterone secretion by elevated exposures to the drinking water disinfection by-product dibromoacetic acid: examination of the potential site(s) of impact along the steroidogenic pathway

EPA Science Inventory

Previous data from our laboratory indicated that the drinking water disinfection by-product, dibromoacetic acid (DBA), when applied in vitro to rat preovulatory follicles at a concentration consistent with blood levels found to disrupt estrous cyclicity, was able to block the sti...

Hypericin-loaded nanoparticles for the photodynamic treatment of ovarian cancer.

PubMed

Zeisser-Labouèbe, Magali; Lange, Norbert; Gurny, Robert; Delie, Florence

2006-12-01

A photodynamic approach has been suggested to improve diagnosis and therapy of ovarian cancer. As Hypericin (Hy), a natural photosensitizer (PS) extracted from Hypericum perforatum, has been shown to be efficient in vitro and in vivo for the detection or treatment of other cancers, Hy could also be a potent tool for the treatment and detection of ovarian cancer. Due to its hydrophobicity, systemic administration of Hy is problematic. Thus, polymeric nanoparticles (NPs) of polylactic acid (PLA) or polylactic-co-glycolic acid (PLGA) were used as a drug delivery system. Hy-loaded NPs were produced with the following characteristics: (i) size in the 200-300 nm range, (ii) negative zeta potential, (iii) low residual PVAL and (iv) drug loading from 0.03 to 0.15% (w/w). Their in vitro photoactivity was investigated on the NuTu-19 ovarian cancer cell model derived from Fischer 344 rats and compared to free drug. Hy-loaded PLA NPs exhibited a higher photoactivity than free drug. Increasing light dose or incubation time with cells induced an enhanced activity of Hy-loaded PLA NPs. Increased NP drug loading had a negative effect on their photoactivity on NuTu-19 cells: at the same Hy concentration, the higher was the drug loading, the lower was the phototoxic effect. The influence of NP drug loading on the Hy release from NPs was also investigated.

Relationship between Numerous Mast Cells and Early Follicular Development in Neonatal MRL/MpJ Mouse Ovaries

PubMed Central

Nakamura, Teppei; Otsuka, Saori; Ichii, Osamu; Sakata, Yuko; Nagasaki, Ken-Ichi; Hashimoto, Yoshiharu; Kon, Yasuhiro

2013-01-01

In the neonatal mouse ovary, clusters of oocytes called nests break into smaller cysts and subsequently form individual follicles. During this period, we found numerous mast cells in the ovary of MRL/MpJ mice and investigated their appearance and morphology with follicular development. The ovarian mast cells, which were already present at postnatal day 0, tended to localize adjacent to the surface epithelium. Among 11 different mouse strains, MRL/MpJ mice possessed the greatest number of ovarian mast cells. Ovarian mast cells were also found in DBA/1, BALB/c, NZW, and DBA/2 mice but rarely in C57BL/6, NZB, AKR, C3H/He, CBA, and ICR mice. The ovarian mast cells expressed connective tissue mast cell markers, although mast cells around the surface epithelium also expressed a mucosal mast cell marker in MRL/MpJ mice. Some ovarian mast cells migrated into the oocyte nests and directly contacted the compressed and degenerated oocytes. In MRL/MpJ mice, the number of oocytes in the nest was significantly lower than in the other strains, and the number of oocytes showed a positive correlation with the number of ovarian mast cells. The gene expression of a mast cell marker also correlated with the expression of an oocyte nest marker, suggesting a link between the appearance of ovarian ? 4mast cells and early follicular development. Furthermore, the expression of follicle developmental markers was significantly higher in MRL/MpJ mice than in C57BL/6 mice. These results indicate that the appearance of ovarian mast cells is a unique phenotype of neonatal MRL/MpJ mice, and that ovarian mast cells participate in early follicular development, especially nest breakdown. PMID:24124609

CYP1B1, Oxidative Stress, and Inflammation in the Etiology of Ovarian Epithelial Cancer Using an Avian Model of Ovarian Carcinoma

DTIC Science & Technology

2007-11-01

information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services , Directorate for Information...ovarian cancer in Women and Hens”. First AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development, Sep 12-15, 2006...associated with ovarian cancer in humans and hens“ Presented at the 1st International Aegean conference on Ovarian Cancer, June 2006,Crete, Greece 4

CRTC2 and Nedd4 ligase involvement in FSH and TGFβ1 upregulation of connexin43 gap junction.

PubMed

Fang, Wei-Ling; Lai, Si-Yi; Lai, Wei-An; Lee, Ming-Ting; Liao, Ching-Fong; Ke, Ferng-Chun; Hwang, Jiuan-Jiuan

2015-12-01

The major mission of the ovarian follicle is the timely production of the mature fertilizable oocyte, and this is achieved by gonadotropin-regulated, gap junction-mediated cell-cell communication between the oocyte and surrounding nurturing granulosa cells. We have demonstrated that FSH and transforming growth factor beta 1 (TGFβ1) stimulate Gja1 gene-encoded connexin43 (Cx43) gap junction formation/function in rat ovarian granulosa cells is important for their induction of steroidogenesis; additionally, cAMP-protein kinase A (PKA)- and calcium-calcineurin-sensitive cAMP response element-binding (CREB) coactivator CRTC2 plays a crucial role during steroidogenesis. This study was to explore the potential molecular mechanism whereby FSH and TGFβ1 regulate Cx43 synthesis and degradation, particularly the involvement of CRTC2 and ubiquitin ligase Nedd4. Primary culture of granulosa cells from ovarian antral follicles of gonadotropin-primed immature rats was used. At 48 h post-treatment, FSH plus TGFβ1 increased Cx43 level and gap junction function in a PKA- and calcineurin-dependent manner, and TGFβ1 acting through its type I receptor modulated FSH action. Chromatin-immunoprecipitation analysis reveals FSH induced an early-phase (45 min) and FSH+TGFβ1 further elicited a late-phase (24 h) increase in CRTC2, CREB and CBP binding to the Gja1 promoter. Additionally, FSH+TGFβ1 increased the half-life of hyper-phosphorylated Cx43 (Cx43-P2). Also, the proteasome inhibitor MG132 prevented the brefeldin A (blocker of protein transport through Golgi)-reduced Cx43-P2 level and membrane Cx43 gap junction plaque. This is associated with FSH+TGFβ1-attenuated Cx43 interaction with Nedd4 and Cx43 ubiquitination. In all, this study uncovers that FSH and TGFβ1 upregulation of Cx43 gap junctions in ovarian granulosa cells critically involves enhancing CRTC2/CREB/CBP-mediated Cx43 expression and attenuating ubiquitin ligase Nedd4-mediated proteosomal degradation of Cx43 protein. © 2015 Society for Endocrinology.

Immunotherapy for Ovarian Cancer: What's Next?

PubMed Central

Kandalaft, Lana E.; Powell, Daniel J.; Singh, Nathan; Coukos, George

2011-01-01

In the past decade, we have witnessed important gains in the treatment of ovarian cancer; however, additional advances are required to reduce mortality. With compelling evidence that ovarian cancers are immunogenic tumors, immunotherapy should be further pursued and optimized. The dramatic advances in laboratory and clinical procedures in cellular immunotherapy, along with the development of powerful immunomodulatory antibodies, create new opportunities in ovarian cancer therapeutics. Herein, we review current progress and future prospects in vaccine and adoptive T-cell therapy development as well as immunomodulatory therapy tools available for immediate clinical testing. PMID:21079136

Ovarian cancer stem cells more questions than answers.

PubMed

Ottevanger, Petronella Beatrix

2017-06-01

Epithelial ovarian cancer is a highly lethal disease, which is usually diagnosed at a late stage with extensive metastases in the abdominal cavity. Ovarian cancer either develops from the ovarian surface epithelium (OSE) or from serous intra-epithelial carcinoma (STIC). Primary therapy consists of debulking surgery and platinum based chemotherapy. The success of debulking surgery depends on surgical skills but also on the gene signature of the tumour. Debulking surgery combined with first line platinum based chemotherapy, frequently leads to complete remission. However, most ovarian cancers relapse. Once the disease has relapsed, the interval between subsequent therapies decreases steadily due to rapid progression and therapy resistance. Research on therapy resistance of ovarian cancer is frequently devoted to genetic alterations in cancer cells, leading to drug inactivation, enhanced DNA repair mechanisms and intracellular pathway derangements. However the knowledge of ovarian cancer stem cells (OCSC) and the role they play in the development of cancer and therapy resistance is sparse. In this review current knowledge on the characteristics of OCSCs and the micro environmental mechanisms leading to the development or activation of OCSCs resulting in ovarian cancer is reviewed. Moreover the role of OCSC in both surgical and systemic therapy resistance and the relation with epithelial mesenchymal transformation (EMT) is discussed, as are micro-environmental signals leading to OCSC or EMT activation. Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.

Follicle Depletion Provides a Permissive Environment for Ovarian Carcinogenesis

PubMed Central

Wang, Ying; Cai, Kathy Qi; Smith, Elizabeth R.; Yeasky, Toni M.; Moore, Robert; Ganjei-Azar, Parvin; Klein-Szanto, Andres J.; Godwin, Andrew K.; Hamilton, Thomas C.

2016-01-01

We modeled the etiology of postmenopausal biology on ovarian cancer risk using germ cell-deficient white-spotting variant (Wv) mice, incorporating oncogenic mutations. Ovarian cancer incidence is highest in peri- and postmenopausal women, and epidemiological studies have established the impact of reproductive factors on ovarian cancer risk. Menopause as a result of ovarian follicle depletion is thought to contribute to higher cancer risk. As a consequence of follicle depletion, female Wv mice develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis frequently found in postmenopausal human ovaries. Lineage tracing using MISR2-Cre indicated that the tubular adenomas that developed in Wv mice were largely derived from the MISR2 lineage, which marked only a fraction of ovarian surface and oviduct epithelial cells in wild-type tissues. Deletion of p27, either heterozygous or homozygous, was able to convert the benign tubular adenomas into more proliferative tumors. Restricted deletion of p53 in Wv/Wv mice by either intrabursal injection of adenoviral Cre or inclusion of the MISR2-Cre transgene also resulted in augmented tumor growth. This finding suggests that follicle depletion provides a permissive ovarian environment for oncogenic transformation of epithelial cells, presenting a mechanism for the increased ovarian cancer risk in postmenopausal women. PMID:27354067

Individualized controlled ovarian stimulation in expected poor-responders: an update.

PubMed

Haahr, Thor; Esteves, Sandro C; Humaidan, Peter

2018-03-09

Controlled ovarian stimulation with subsequent multi-follicular development continues to be a keystone in ART. Evidence supports an individualized approach to ovarian stimulation, usually involving combinations of ovarian reserve tests, body mass index and age to tailor the exogenous gonadotropin dose, and potentially adjuvant treatment aiming for high safety and a shortening of time to live birth. While stimulation and trigger concepts have been developed successfully in normo- and hyperresponder patients, the poor responder patient remains difficult to manage. However, recent advances in definition and classification of the expected poor ovarian responder patient might enable a more accurate and clinically useful interpretation of new treatment concepts in a more homogenous study population. In the present review, we discuss the classification of the expected poor ovarian responder patient as well as clinically useful measurements of efficacy for controlled ovarian stimulation, and finally, we discuss the evidence for clinical management of patients with expected poor ovarian response, including adjuvant treatments such as growth hormone, androgens, and LH activity.In conclusion, the best available evidence supports that the treatment of the expected poor ovarian response patient should be individualized in all steps of ART, including the choice of GnRH analogue, the gonadotropin type and dose, ovulation trigger, and the possible use of adjuvant therapies.

Regulation of Ovarian Cancer Stem Cells or Tumor-Initiating Cells

PubMed Central

Kwon, Mi Jeong; Shin, Young Kee

2013-01-01

Cancer stem cells or tumor-initiating cells (CSC/TICs), which can undergo self-renewal and differentiation, are thought to play critical roles in tumorigenesis, therapy resistance, tumor recurrence and metastasis. Tumor recurrence and chemoresistance are major causes of poor survival rates of ovarian cancer patients, which may be due in part to the existence of CSC/TICs. Therefore, elucidating the molecular mechanisms responsible for the ovarian CSC/TICs is required to develop a cure for this malignancy. Recent studies have indicated that the properties of CSC/TICs can be regulated by microRNAs, genes and signaling pathways which also function in normal stem cells. Moreover, emerging evidence suggests that the tumor microenvironments surrounding CSC/TICs are crucial for the maintenance of these cells. Similarly, efforts are now being made to unravel the mechanism involved in the regulation of ovarian CSC/TICs, although much work is still needed. This review considers recent advances in identifying the genes and pathways involved in the regulation of ovarian CSC/TICs. Furthermore, current approaches targeting ovarian CSC/TICs are described. Targeting both CSC/TICs and bulk tumor cells is suggested as a more effective approach to eliminating ovarian tumors. Better understanding of the regulation of ovarian CSC/TICs might facilitate the development of improved therapeutic strategies for recurrent ovarian cancer. PMID:23528891

Social interactions and their connection to aggression and ovarian development in orphaned worker bumblebees (Bombus impatiens).

PubMed

Sibbald, E D; Plowright, C M S

2014-03-01

This study examines the social dynamics of reproductive conflict. Orphaned worker bumblebees (Bombus impatiens) with comparatively high or low levels of social activity were paired to determine whether aggression and reproduction could be traced to earlier social interactions. The workers were paired according to their levels of social activity (a socially active+another socially active worker, socially active+socially inactive, and two socially inactive workers). The presence or absence of brood was also manipulated. The absence of brood increased both aggression and ovarian development, suggesting that aggression and reproduction are associated or that there is a third variable that affects both. Socially active pairs were significantly more aggressive: here, social activity can be taken as an early indicator of aggression. No such effect, however, was obtained on ovarian development as the socially active pairs did not differ on their degree of ovarian development compared to the others. Within the socially active+socially inactive pairs, the socially active worker did not have more developed ovaries and was not more aggressive than her socially inactive partner. Results highlight that environmental conditions (the absence of brood) can predict ovarian development and although social activity can be observed prior to aggression, differences in aggression do not translate into differences in ovarian development under these conditions. Copyright © 2013 Elsevier B.V. All rights reserved.

Normal female phenotype and ovarian development despite the ovarian expression of the sex-determining region of Y chromosome (SRY) in a 46,XX/69,XXY diploid/triploid mosaic child conceived after in vitro fertilization-intracytoplasmic sperm injection.

PubMed

Oktem, Ozgur; Paduch, Darius A; Xu, Kangpu; Mielnik, Anna; Oktay, Kutluk

2007-03-01

Diploid/triploid mosaicism (mixoploidy) is a rare chromosomal abnormality characterized by mental and growth retardation, hypotonia, and dysmorphic features such as facial asymmetry, low-set ears, and syndactyly. All 46,XX/69,XXY cases fall into three phenotypic groups: male with testicular development, ovotestis disorder of sex development (DSD), or undervirilized male DSD. All phenotypic females with diploid/triploid mosaic reported so far had 46,XX/69,XXX karyotype. We report an 8-year-old girl conceived after in vitro fertilization-intracytoplasmic sperm injection with normal internal/external genital and ovarian development despite 46,XX/69,XXY mosaicism and normal expression of sex-determining region of Y chromosome (SRY) in her gonads. Because of the increased risk of gonadoblastoma resulting from Y chromosome mosaicism, her ovaries were removed by laparoscopy. Ovarian tissue was analyzed histologically as well as by fluorescence in situ hybridization, PCR, and RT-PCR amplification to determine the localization of Y chromosome and expression of SRY and DAX1 mRNA. Methylation-specific PCR was used to assess the inactivation pattern of X chromosomes. By laparoscopy, internal female genital anatomy appeared to be normal. Cytogenetic and molecular methods confirmed the presence of intact and functionally active Y chromosome in the ovary. Strikingly, histological assessment of the gonads showed normal ovarian architecture with abundant primordial follicles despite the presence of the Y chromosome in ovarian follicles and the expression of SRY mRNA in gonadal tissue. This case illustrates that normal ovarian development is possible in the presence of Y chromosome in ovarian follicles and despite the expression of SRY in ovarian tissue. Furthermore, this is the first documented case of mixoploidy after in vitro fertilization-intracytoplasmic sperm injection and the only phenotypic female with 46,XX/69,XXY karyotype.

Role of chemokine network in the development and progression of ovarian cancer: a potential novel pharmacological target.

PubMed

Barbieri, Federica; Bajetto, Adriana; Florio, Tullio

2010-01-01

Ovarian cancer is the most common type of gynecologic malignancy. Despite advances in surgery and chemotherapy, the survival rate is still low since most ovarian cancers relapse and become drug-resistant. Chemokines are small chemoattractant peptides mainly involved in the immune responses. More recently, chemokines were also demonstrated to regulate extra-immunological functions. It was shown that the chemokine network plays crucial functions in the tumorigenesis in several tissues. In particular the imbalanced or aberrant expression of CXCL12 and its receptor CXCR4 strongly affects cancer cell proliferation, recruitment of immunosuppressive cells, neovascularization, and metastasization. In the last years, several molecules able to target CXCR4 or CXCL12 have been developed to interfere with tumor growth, including pharmacological inhibitors, antagonists, and specific antibodies. This chemokine ligand/receptor pair was also proposed to represent an innovative therapeutic target for the treatment of ovarian cancer. Thus, a thorough understanding of ovarian cancer biology, and how chemokines may control these different biological activities might lead to the development of more effective therapies. This paper will focus on the current biology of CXCL12/CXCR4 axis in the context of understanding their potential role in ovarian cancer development.

Long non-coding RNA ZFAS1 interacts with miR-150-5p to regulate Sp1 expression and ovarian cancer cell malignancy.

PubMed

Xia, Bairong; Hou, Yan; Chen, Hong; Yang, Shanshan; Liu, Tianbo; Lin, Mei; Lou, Ge

2017-03-21

We reported that long non-coding RNA ZFAS1 was upregulated in epithelial ovarian cancer tissues, and was negatively correlated to the overall survival rate of patients with epithelial ovarian cancer in this study. While depletion of ZFAS1 inhibited proliferation, migration, and development of chemoresistance, overexpression of ZFAS1 exhibited an even higher proliferation rate, migration activity, and chemoresistance in epithelial ovarian cancer cell lines. We further found miR-150-5p was a potential target of ZFAS1, which was downregulated in epithelial ovarian cancer tissue. MiR-150-5p subsequently inhibited expression of transcription factor Sp1, as evidence by luciferase assays. Inhibition of miR-150-5p rescued the suppressed proliferation and migration induced by depletion of ZFAS1 in epithelial ovarian cancer cells, at least in part. Taken together, our findings revealed a critical role of ZFAS1/miR-150-5p/Sp1 axis in promoting proliferation rate, migration activity, and development of chemoresistance in epithelial ovarian cancer. And ZFAS1/miR-150-5p may serve as novel markers and therapeutic targets of epithelial ovarian cancer.

7,12-Dimethylbenz[a]anthracene-Induced Malignancies in a Mouse Model of Menopause

PubMed Central

Marion, Samuel L; Watson, Jennifer; Sen, Nivedita; Brewer, Molly A; Barton, Jennifer K; Hoyer, Patricia B

2013-01-01

Ovarian cancer has a high mortality rate because there are few symptoms in early disease development. The incidence of ovarian cancer increases in women after menopause. Understanding early events in this disease can best be achieved by using animal models. Therefore, the objective of this study was to develop and track the onset of ovarian tumorigenesis in mice mimicking characteristics of postmenopausal epithelial cancer in women. Female B6C3F1 mice (age, 28 d) received 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg IV daily for 20 d) to cause ovarian failure. Four months after VCD treatment, via surgical intervention, each mouse received a single injection of 7,12-dimethylbenz[a]anthracene (DMBA) or vehicle control (sesame oil) under the bursa of the right ovary to cause ovarian neoplasms. The experimental groups were untreated controls (Con–Con), DMBA-treatment only (Con–DMBA), VCD treatment only (VCD–Con), and VCD+DMBA-treated (VCD+DMBA) mice. At 3, 5, 7, and 9 mo after DMBA injection, ovaries were collected for histologic and immunohistochemical evaluation. No tumors developed in Con–Con mice. All VCD-treated mice (with or without DMBA) exhibited ovarian failure. Mice that received both VCD and DMBA exhibited tumors at 3 mo (50%), 5 mo (14%), 7 mo (90%), and 9 mo (57%) after DMBA treatment; 31% of the tumors were epithelial in origin. Our findings confirm that inducing ovarian tumors in mice by chemical means is an effective method for studying early stages of tumor development that may be relevant to epithelial ovarian cancers that arise in postmenopausal women. PMID:23561932

7,12-dimethylbenz[a]anthracene-induced malignancies in a mouse model of menopause.

PubMed

Marion, Samuel L; Watson, Jennifer; Sen, Nivedita; Brewer, Molly A; Barton, Jennifer K; Hoyer, Patricia B

2013-02-01

Ovarian cancer has a high mortality rate because there are few symptoms in early disease development. The incidence of ovarian cancer increases in women after menopause. Understanding early events in this disease can best be achieved by using animal models. Therefore, the objective of this study was to develop and track the onset of ovarian tumorigenesis in mice mimicking characteristics of postmenopausal epithelial cancer in women. Female B6C3F1 mice (age, 28 d) received 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg IV daily for 20 d) to cause ovarian failure. Four months after VCD treatment, via surgical intervention, each mouse received a single injection of 7,12-dimethylbenz[a]anthracene (DMBA) or vehicle control (sesame oil) under the bursa of the right ovary to cause ovarian neoplasms. The experimental groups were untreated controls (Con-Con), DMBA-treatment only (Con-DMBA), VCD treatment only (VCD-Con), and VCD+DMBA-treated (VCD+DMBA) mice. At 3, 5, 7, and 9 mo after DMBA injection, ovaries were collected for histologic and immunohistochemical evaluation. No tumors developed in Con-Con mice. All VCD-treated mice (with or without DMBA) exhibited ovarian failure. Mice that received both VCD and DMBA exhibited tumors at 3 mo (50%), 5 mo (14%), 7 mo (90%), and 9 mo (57%) after DMBA treatment; 31% of the tumors were epithelial in origin. Our findings confirm that inducing ovarian tumors in mice by chemical means is an effective method for studying early stages of tumor development that may be relevant to epithelial ovarian cancers that arise in postmenopausal women.

Ovarian and cervical cancer awareness: development of two validated measurement tools.

PubMed

Simon, Alice E; Wardle, Jane; Grimmett, Chloe; Power, Emily; Corker, Elizabeth; Menon, Usha; Matheson, Lauren; Waller, Jo

2012-07-01

The aim of the study was to develop and validate measures of awareness of symptoms and risk factors for ovarian and cervical cancer (Ovarian and Cervical Cancer Awareness Measures). Potentially relevant items were extracted from the literature and generated by experts. Four validation studies were carried out to establish reliability and validity. Women aged 21-67 years (n=146) and ovarian and cervical cancer experts (n=32) were included in the studies. Internal reliability was assessed psychometrically. Test-retest reliability was assessed over a 1-week interval. To establish construct validity, Cancer Awareness Measure (CAM) scores of cancer experts were compared with equally well-educated comparison groups. Sensitivity to change was tested by randomly assigning participants to read either a leaflet giving information about ovarian/cervical cancer or a leaflet with control information, and then completing the ovarian/cervical CAM. Internal reliability (Cronbach's α=0.88 for the ovarian CAM and α=0.84 for the cervical CAM) and test-retest reliability (r=0.84 and r=0.77 for the ovarian and cervical CAMs, respectively) were both high. Validity was demonstrated with cancer experts achieving higher scores than controls [ovarian CAM: t(36)= -5.6, p<0.001; cervical CAM: t(38)= -3.7, p=0.001], and volunteers who were randomised to read a cancer leaflet scored higher than those who received a control leaflet [ovarian CAM: t(49)=7.5, p<0.001; cervical CAM: t(48)= -5.5, p<0.001]. This study demonstrates the psychometric properties of the ovarian and cervical CAMs and supports their utility in assessing ovarian and cervical cancer awareness in the general population.

Ovarian and cervical cancer awareness: development of two validated measurement tools

PubMed Central

Simon, Alice E; Wardle, Jane; Grimmett, Chloe; Power, Emily; Corker, Elizabeth; Menon, Usha; Matheson, Lauren; Waller, Jo

2012-01-01

Background The aim of the study was to develop and validate measures of awareness of symptoms and risk factors for ovarian and cervical cancer (Ovarian and Cervical Cancer Awareness Measures). Methods Potentially relevant items were extracted from the literature and generated by experts. Four validation studies were carried out to establish reliability and validity. Women aged 21–67 years (n=146) and ovarian and cervical cancer experts (n=32) were included in the studies. Internal reliability was assessed psychometrically. Test-retest reliability was assessed over a 1-week interval. To establish construct validity, Cancer Awareness Measure (CAM) scores of cancer experts were compared with equally well-educated comparison groups. Sensitivity to change was tested by randomly assigning participants to read either a leaflet giving information about ovarian/cervical cancer or a leaflet with control information, and then completing the ovarian/cervical CAM. Results Internal reliability (Cronbach's α=0.88 for the ovarian CAM and α=0.84 for the cervical CAM) and test-retest reliability (r=0.84 and r=0.77 for the ovarian and cervical CAMs, respectively) were both high. Validity was demonstrated with cancer experts achieving higher scores than controls [ovarian CAM: t(36)= –5.6, p<0.001; cervical CAM: t(38)= –3.7, p=0.001], and volunteers who were randomised to read a cancer leaflet scored higher than those who received a control leaflet [ovarian CAM: t(49)=7.5, p<0.001; cervical CAM: t(48)= –5.5, p<0.001]. Conclusions This study demonstrates the psychometric properties of the ovarian and cervical CAMs and supports their utility in assessing ovarian and cervical cancer awareness in the general population. PMID:21933805

Proceedings of the 2010 National Toxicology Program Satellite Symposium

PubMed Central

Adams, E. Terence; Auerbach, Scott; Blackshear, Pamela E.; Bradley, Alys; Gruebbel, Margarita M.; Little, Peter B.; Malarkey, David; Maronpot, Robert; McKay, Jennifer S.; Miller, Rodney A.; Moore, Rebecca R.; Morrison, James P.; Nyska, Abraham; Ramot, Yuval; Rao, Deepa; Suttie, Andrew; Wells, Monique Y.; Willson, Gabrielle A.; Elmore, Susan A.

2011-01-01

The 2010 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri,” was held in Chicago, Illinois, in advance of the scientific symposium sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The goal of the annual NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for voting or discussion. Some topics covered during the symposium included a comparison of rat and mouse hepatocholangiocarcinoma, a comparison of cholangiofibrosis and cholangiocarcinoma in rats, a mixed pancreatic neoplasm with acinar and islet cell components, an unusual preputial gland tumor, renal hyaline glomerulopathy in rats and mice, eosinophilic substance in the nasal septum of mice, INHAND nomenclature for proliferative and nonproliferative lesions of the CNS/PNS, retinal gliosis in a rat, fibroadnexal hamartoma in rats, intramural plaque in a mouse, a treatment-related chloracne-like lesion in mice, and an overview of mouse ovarian tumors. PMID:21177527

New models of hematogenous ovarian cancer metastasis demonstrate preferential spread to the ovary and a requirement for the ovary for abdominal dissemination.

PubMed

Coffman, Lan G; Burgos-Ojeda, Daniela; Wu, Rong; Cho, Kathleen; Bai, Shoumei; Buckanovich, Ronald J

2016-09-01

Emerging evidence suggest that many high-grade serous "ovarian" cancers (HGSOC) start in the fallopian tube. Cancer cells are then recruited to the ovary and then spread diffusely through the abdomen. The mechanism of ovarian cancer spread was thought to be largely due to direct shedding of tumor cells into the peritoneal cavity with vascular spread being of limited importance. Recent work challenges this dogma, suggesting hematogenous spread of ovarian cancer may play a larger role in ovarian cancer cell metastasis than previously thought. One reason the role of vascular spread of ovarian cancer has not been fully elucidated is the lack of easily accessible models of vascular ovarian cancer metastasis. Here, we present 3 metastatic models of ovarian cancer which confirm the ability of ovarian cancer to hematogenously spread. Strikingly, we observe a high rate of metastasis to the ovary with the development of ascites in these models. Interestingly, oophorectomy resulted in a complete loss of peritoneal metastases and ascites. Taken together, our data indicate that hematogenously disseminated HGSOC cells have a unique tropism for the ovary and that hematogenous spread in ovarian cancer may be more common than appreciated. Furthermore, our studies support a critical role for the ovary in promoting HGSOC cell metastasis to the abdomen. The models developed here represent important new tools to evaluate both the mechanism of cancer cell recruitment to the ovary and understand and target key steps in ovarian cancer metastasis. Copyright © 2016 Elsevier Inc. All rights reserved.

Ovarian aging: latest thoughts on assessment and management.

PubMed

Younis, Johnny S

2011-12-01

In the past few decades, women have been intentionally delaying pregnancy and ovarian aging has become one of the most detrimental factors of pregnancy achievement. This review will discuss contemporary methods of ovarian aging assessment and present an overview of current management strategies. Antimullerian hormone (AMH) and antral follicle count (AFC) seem to be the most reliable predictors of ovarian aging appraisal. Nevertheless, they have not been shown to predict pregnancy achievement in assisted reproduction. Heritability has a high impact on ovarian aging. Employing several genetic approaches, it is now being widely investigated, but the task is far from being accomplished. Although multivariate models have not been proven to be superior to AFC, new data support the notion that chronological age and genetic markers inclusion may increase their reliability. Several strategies have been suggested to treat ovarian aging in assisted reproductive technology (ART) settings. None of the stimulation protocol manipulations have been found to be advantageous and individualization of treatment is still recommended. Ovarian priming by different androgen preparations has been shown to be promising but more randomized controlled trials are needed to support these findings. Except for oocyte donation other ART strategies have not shown a convincing benefit for ovarian aging. The new development of oocyte vitrification may well introduce opportunities for fertility preservation to women at risk of ovarian aging. Proper assessment and detection of ovarian aging, employing current or developing predictors of ovarian reserve, especially genetic tests, may enable health providers to recommend, at appropriate biological time, early pregnancy achievement or fertility preservation in women at risk.

[Effect of agonist and antagonist of 5-HT(1A) receptors on learning in female rats during ovarian cycle].

PubMed

Fedotova, Iu O; Ordian, N E

2010-01-01

The involvement of 5-HT(1A) receptors in learning/memory processes during ovary cycle was assessed in the adult female rats. 8-OH-DPAT (0.05 mg/kg, s.c.), 5-HT(1A) receptor agonist and NAN-190 (0.1 mg/kg, i.p.), 5-HT(1A) receptor antagonist were injected chronically to adult female rats. Learning of these animals was assessed in different models: passive avoidance performance and Morris water maze. Chronic NAN-190 administration to females resulted in the appearance of the passive avoidance performance in proestrous and estrous, as distinct from the control animals, but failed to change the dynamics of spatial learning in Morris water maze. Chronic 8-OH-DPAT administration similarly impaired non-spatial and spatial learning in females during all phases of ovary cycle. The results of the study suggest modulating role of 5-HT(1A) receptors in learning/memory processes during ovary cycle in the adult female rats.

Maternal High-Fat Diet-Induced Loss of Fetal Oocytes Is Associated with Compromised Follicle Growth in Adult Rat Offspring1

PubMed Central

Tsoulis, Michael W.; Chang, Pauline E.; Moore, Caroline J.; Chan, Kaitlyn A.; Gohir, Wajiha; Petrik, James J.; Vickers, Mark H.; Connor, Kristin L.; Sloboda, Deborah M.

2016-01-01

Maternal obesity predisposes offspring to metabolic and reproductive dysfunction. We have shown previously that female rat offspring born to mothers fed a high-fat (HF) diet throughout pregnancy and lactation enter puberty early and display aberrant reproductive cyclicity. The mechanisms driving this reproductive phenotype are currently unknown thus we investigated whether changes in ovarian function were involved. Wistar rats were mated and randomized to: dams fed a control diet (CON) or dams fed a HF diet from conception until the end of lactation (HF). Ovaries were collected from fetuses at Embryonic Day (E) 20, and neonatal ovaries at Day 4 (P4), prepubertal ovaries at P27 and adult ovaries at P120. In a subset of offspring, the effects of a HF diet fed postweaning were evaluated. The present study shows that fetuses of mothers fed a HF diet had significantly fewer oocytes at E20, and in neonates, have reduced AMH signaling that may facilitate an increased number of assembled primordial follicles. Both prepubertally and in adulthood, ovaries show increased follicular atresia. As adults, offspring have reduced FSH responsiveness, low expression levels of estrogen receptor alpha (Eralpha), the oocyte-secreted factor, Gdf9, oocyte-specific RNA binding protein, Dazl, and high expression levels of the granulosa-cell derived factor, AMH, in antral follicles. Together, these data suggest that ovarian compromise in offspring born to HF-fed mothers may arise from changes already observable in the fetus and neonate and in the long term, associated with increased follicular atresia through adulthood. PMID:26962114

Tributyltin impairs the reproductive cycle in female rats.

PubMed

Lang Podratz, Priscila; Delgado Filho, Vicente Sathler; Lopes, Pedro Francisco Iguatemy; Cavati Sena, Gabriela; Matsumoto, Silvia Tamie; Samoto, Vivian Yochiko; Takiya, Christina Maeda; de Castro Miguel, Emilio; Silva, Ian Victor; Graceli, Jones Bernardes

2012-01-01

Triorganotins are environmental contaminants, commonly used in antifouling agents for boats, that bioaccumulate and thus are found in mammals and humans due to ingestion of contaminated seafood diets. The importance of triorganotins as environmental endocrine disruptors and consequent reproductive toxicity in different animal models is well known; however, the adverse effects on reproductive cycle are less well understood. The potential reproductive toxicity of tributyltin (TBT) on regular reproductive cycling of female rats was examined. Wistar female rats (12 wk old, weighing approximately 230 g) were divided into two groups: control (vehicle, ethanol 0.4%) and tributyltin (100 ng/kg/d, 7 d/wk, for 16 d by gavage). Tributyltin significantly decreased the cycle regularity (%), duration of the reproductive cycle, the proestrus and diestrus phases, and number of epithelial cell in proestrus phase. TBT also increased the duration of metestrus and the number of cornified cells in this phase. Ovary weight and serum 17β-estradiol levels decreased markedly, accompanied by a significant increase in progesterone levels. Histological analysis showed apoptotic cells in corpus luteum and granulosa cells layer, with cystic follicles after TBT exposure. Tributyltin also elevated number of atretic follicles and corpoa lutea. The micronucleus (MN) test, using Chinese hamster ovary cells, demonstrated a concentration-dependent mutagenic effect of TBT, and at 2.0 × 10(-2)ng/ml most of the cells were nonviable. The toxic potential of TBT over the reproductive cycle may be attributed to changes found in the ovarian weight, unbalanced levels of sexual female hormones, and number of ovarian follicles and corpora lutea.

Uptake and selective partitioning of dietary lipids to ovarian and muscle tissue of maturing female coho salmon, Oncorhynchus kisutch, during secondary oocyte growth.

PubMed

Johnson, Ronald B; Kroeger, Eric L; Reichert, William L; Carter, Cameron S; Rust, Michael B

2017-06-01

Female coho salmon, Oncorhynchus kisutch, were fed one of two experimental feeds containing lipids with markedly different stable 13 C isotope signatures during the late cortical alveolus, lipid droplet, and vitellogenesis stages of secondary oocyte growth. Ovarian and muscle lipids fatty acid concentrations were significantly affected by treatment during all three stages of development. Stable 13 C isotope analyses confirmed that dietary lipids were incorporated into both ovarian and muscle lipids during all three stages and revealed that ovarian lipids were more affected than muscle lipids during vitellogenesis. Arachidonic acid (ARA) was incorporated into ovarian lipids at the highest rate of all fatty acids examined with the greatest uptake observed during the cortical alveolus and lipid droplet stages of development. Docosahexaenoic acid (DHA) was incorporated into ovarian lipids at the next highest rate with the greatest uptake observed during the lipid droplet stage of development. The presence of an ovary specific, fatty acid transfer mechanism is proposed. Results from this study demonstrate the ability to greatly alter the fatty acid composition of ovarian lipids through a dietary change during secondary oocyte growth and may be of great interest to producers of farmed salmon and salmon broodstock programs. Published by Elsevier Inc.

Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian cancer

PubMed Central

Gao, Yan; Foster, Rosemary; Yang, Xiaoqian; Feng, Yong; Shen, Jacson K.; Mankin, Henry J.; Hornicek, Francis J.; Amiji, Mansoor M.; Duan, Zhenfeng

2015-01-01

The clinical significance of Cluster of Differentiation 44 (CD44) remains controversial in human ovarian cancer. The aim of this study is to evaluate the clinical significance of CD44 expression by using a unique tissue microarray, and then to determine the biological functions of CD44 in ovarian cancer. In this study, a unique ovarian cancer tissue microarray (TMA) was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. CD44 expression in TMA was assessed by immunohistochemistry. Both the metastatic and recurrent ovarian cancer tissues expressed higher level of CD44 than the patient-matched primary tumor. A significant association has been shown between CD44 expression and both the disease free survival and overall survival. A strong increase of CD44 was found in the tumor recurrence of mouse model. Finally, when CD44 was knocked down, proliferation, migration/invasion activity, and spheroid formation were significantly suppressed, while drug sensitivity was enhanced. Thus, up-regulation of CD44 represents a crucial event in the development of metastasis, recurrence, and drug resistance to current treatments in ovarian cancer. Developing strategies to target CD44 may prevent metastasis, recurrence, and drug resistance in ovarian cancer. PMID:25823654

Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian cancer.

PubMed

Gao, Yan; Foster, Rosemary; Yang, Xiaoqian; Feng, Yong; Shen, Jacson K; Mankin, Henry J; Hornicek, Francis J; Amiji, Mansoor M; Duan, Zhenfeng

2015-04-20

The clinical significance of Cluster of Differentiation 44 (CD44) remains controversial in human ovarian cancer. The aim of this study is to evaluate the clinical significance of CD44 expression by using a unique tissue microarray, and then to determine the biological functions of CD44 in ovarian cancer. In this study, a unique ovarian cancer tissue microarray (TMA) was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. CD44 expression in TMA was assessed by immunohistochemistry. Both the metastatic and recurrent ovarian cancer tissues expressed higher level of CD44 than the patient-matched primary tumor. A significant association has been shown between CD44 expression and both the disease free survival and overall survival. A strong increase of CD44 was found in the tumor recurrence of mouse model. Finally, when CD44 was knocked down, proliferation, migration/invasion activity, and spheroid formation were significantly suppressed, while drug sensitivity was enhanced. Thus, up-regulation of CD44 represents a crucial event in the development of metastasis, recurrence, and drug resistance to current treatments in ovarian cancer. Developing strategies to target CD44 may prevent metastasis, recurrence, and drug resistance in ovarian cancer.

GONADOTROPIN RELEASING HORMONE (GNRH) PARTIALLY REVERSES THE INHIBITORY EFFECT OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ON OVULATION IN THE IMMATURE GONADOTROPIN-TREATED RAT. (R826132)

EPA Science Inventory

Abstract

Several studies have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has inhibitory effects on ovulation. This action may be the result of either direct effect(s) of TCDD on ovarian function or via altered secretion of pituitary luteinizing hormon...

Pharmacogenetic algorithm for individualized controlled ovarian stimulation (iCOS) in assisted reproductive technology cycles.

PubMed

Roque, Matheus; Bianco, Bianca; Christofolini, Denise M; Cordts, Emerson B; Vilarino, Fabia L; Carvalho, Waldemar; Valle, Marcello; Sampaio, Marcos; Geber, Selmo; Esteves, Sandro C; Barbosa, Caio P

2018-06-14

Controlled ovarian stimulation (COS) is crucial for optimizing in vitro fertilization (IVF) / intracytoplasmic sperm injection (ICSI) success. Multiple factors influence the ovarian response to COS, making predictions about oocyte yields not so straightforward. As a result, the ovarian response may be poor or suboptimal, or even excessive, all of which have negative consequences for the affected patient. There is a group of patients that present with a suboptimal response to COS despite normal biomarkers of ovarian reserve, such as AFC and AMH. These patients have a lower number of retrieved oocytes than what was expected based on their ovarian reserve, thus showing the inadequacy of using only the traditional ovarian reserve biomarkers to predict the ovarian response. Suboptimal response to COS might be related to ovarian sensitivity to exogenous gonadotropins modulated by genetic factors. The understanding of the gene polymorphisms related to reproductive function can help to improve the clinical management of this patient population and to explain some of the individual patient variability in response to COS. The development of a pharmacogenetic approach concerning COS in the context of assisted reproduction seems attractive as it might help to understand the relationship between genetic variants and ovarian response to exogenous gonadotropins. The patient ́s genetic profile could be used to select the most appropriate gonadotropin type, predict the optimal dosage for each drug, develop a cost-effective treatment plan, maximize the success rates, and lastly, decrease the time-to-pregnancy.

Ovarian transposition in young women and fertility sparing.

PubMed

Mossa, B; Schimberni, M; Di Benedetto, L; Mossa, S

2015-09-01

Ovarian transposition is a highly effective surgical procedure used to preserve ovarian function in premenopausal patients with cancers requiring postoperative or primary pelvic radiotherapy. Pelvic irradiation determines severe damage of ovarian DNA and iatrogenic ovarian failure with premature menopause, necessity of long-term hormone replacement therapy and infertility. We conducted an extensive research of the literature in Medline between January 2000 and April 2015 using the key-words "ovarian transposition radiotherapy", "radiotherapy gonadal function", radiotherapy fertility sparing". The population included young women with normal ovarian function affected by cancers that required pelvic radiotherapy. We have examined 32 articles reporting on 1189 women undergoing ovarian transposition. Median age was 32.5 years, follow up was median 48 months. The procedure has been performed in patients less than 40 years of age. Surgery has been achieved by laparotomy or laparoscoy. We have analyzed effects of radiotherapy on ovarian function. The proportion of women treated by ovarian transposition preserved ovarian function was 70%. About 86% of patients did not develop ovarian cysts and in 98-99% of cases did not occur any metastatic disease. Ovarian transposition is associated with significant preservation of ovarian function and a low frequency of complications as cysts and metastasis. In 31% of cases the procedure can fail. Further studies are needed to evaluate the efficacy of ovarian transposition and the follow up. Ovarian transposition should be discussed at the time of cancer diagnosis in every premenopausal woman requiring pelvic radiotherapy.

Bisphenol A Exposure, Ovarian Follicle Numbers, and Female Sex Steroid Hormone Levels: Results From a CLARITY-BPA Study

PubMed Central

Patel, Shreya; Brehm, Emily; Gao, Liying; Rattan, Saniya; Ziv-Gal, Ayelet

2017-01-01

Bisphenol A (BPA) is an industrial chemical found in thermal receipts and food and beverage containers. Previous studies have shown that BPA can affect the numbers and health of ovarian follicles and the production of sex steroid hormones, but they often did not include a wide range of doses of BPA, used a small sample size, focused on relatively short-term exposures to BPA, and/or did not examine the consequences of chronic BPA exposure on the ovaries or steroid levels. Thus, this study was designed to examine the effects of a wide range of doses of BPA on ovarian morphology and sex steroid hormone production. Specifically, this study tested the hypothesis that prenatal and continuous BPA exposure reduces ovarian follicle numbers and sex steroid hormone levels. To test this hypothesis, rats were dosed with vehicle, ethinyl estradiol (0.05 and 0.5 μg/kg body weight/d), or BPA (2.5, 25, 250, 2500, and 25,000 μg/kg body weight/d) from gestation day 6 until 1 year as part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA). Ovaries and sera were collected on postnatal days 1, 21, and 90, and at 6 months and 1 year. The ovaries were subjected to histological evaluation of follicle numbers and the sera were subjected to measurements of estradiol and progesterone. Collectively, these data indicate that BPA exposure at some doses and time points affects ovarian follicle numbers and sex steroid levels, but these effects are different than those observed with ethinyl estradiol exposure and some previous studies on BPA. PMID:28324068

Bisphenol A Exposure, Ovarian Follicle Numbers, and Female Sex Steroid Hormone Levels: Results From a CLARITY-BPA Study.

PubMed

Patel, Shreya; Brehm, Emily; Gao, Liying; Rattan, Saniya; Ziv-Gal, Ayelet; Flaws, Jodi A

2017-06-01

Bisphenol A (BPA) is an industrial chemical found in thermal receipts and food and beverage containers. Previous studies have shown that BPA can affect the numbers and health of ovarian follicles and the production of sex steroid hormones, but they often did not include a wide range of doses of BPA, used a small sample size, focused on relatively short-term exposures to BPA, and/or did not examine the consequences of chronic BPA exposure on the ovaries or steroid levels. Thus, this study was designed to examine the effects of a wide range of doses of BPA on ovarian morphology and sex steroid hormone production. Specifically, this study tested the hypothesis that prenatal and continuous BPA exposure reduces ovarian follicle numbers and sex steroid hormone levels. To test this hypothesis, rats were dosed with vehicle, ethinyl estradiol (0.05 and 0.5 μg/kg body weight/d), or BPA (2.5, 25, 250, 2500, and 25,000 μg/kg body weight/d) from gestation day 6 until 1 year as part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA). Ovaries and sera were collected on postnatal days 1, 21, and 90, and at 6 months and 1 year. The ovaries were subjected to histological evaluation of follicle numbers and the sera were subjected to measurements of estradiol and progesterone. Collectively, these data indicate that BPA exposure at some doses and time points affects ovarian follicle numbers and sex steroid levels, but these effects are different than those observed with ethinyl estradiol exposure and some previous studies on BPA. Copyright © 2017 Endocrine Society.

Proteomics of ovarian cancer: functional insights and clinical applications

DOE PAGES

Elzek, Mohamed A.; Rodland, Karin D.

2015-03-04

In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification ofmore » aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. In conclusion, we propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs.« less

In vitro fertilization surrogate pregnancy in a patient who underwent radical hysterectomy followed by ovarian transposition, lower abdominal wall radiotherapy, and chemotherapy.

PubMed

Steigrad, Stephen; Hacker, Neville F; Kolb, Bradford

2005-05-01

To describe an IVF surrogate pregnancy from a patient who had a radical hysterectomy followed by excision of a laparoscopic port site implantation with ovarian transposition followed by abdominal wall irradiation and chemotherapy, which resulted in premature ovarian failure from which there was partial recovery. Case report. Tertiary referral university women's hospital in Sydney, Australia and private reproductive medicine clinic in California. A 34-year-old woman who underwent laparoscopy for pelvic pain, shortly afterward followed by radical hysterectomy and pelvic lymph node dissection, who subsequently developed a laparoscopic port site recurrence, which was excised in association with ovarian transposition before abdominal wall irradiation and chemotherapy. Modified IVF treatment, transabdominal oocyte retrieval, embryo cryopreservation in Australia, and transfer to a surrogate mother in the United States. Pregnancy. Miscarriage in the second cycle and a twin pregnancy in the fourth cycle. This is the first case report of ovarian stimulation and oocyte retrieval performed on transposed ovaries after a patient developed premature ovarian failure after radiotherapy and chemotherapy with subsequent partial ovarian recovery.

Progesterone and estradiol plasma levels in neonatally irradiated cycling rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freud, A.; Sod-Moriah, U.A.

1990-01-01

Female rats which were exposed to a single low dose of gamma irradiation (6R or 15R) at the age of 8 days produce smaller litters when mature than untreated controls. The possibility that the impaired fertility resulted from altered ovarian activity as reflected by changes in plasma levels of progesterone or estardiol was investigated. Plasma levels of both steroids were determined throughout the day of proestrus. Progesterone level was also determined in 6R animals on the day of weaning. The maturity of such irradiated rats was assessed by observing the time of vaginal opening. The results indicated that the preovulatorymore » peak of progesterone was delayed in the 6R rats whereas in the 15R group its levels were significantly lower. On the other hand no differences in estradiol plasma levels were noticed between the groups. The higher level of progesterone in the 6R animals was not evident on the day of weaning and was even in both groups, but vaginal opening in the irradiated rats was significantly delayed. The elevated level of progesterone might be responsible, among other endocrine changes, for the lower fertility of neonatally irradiated mature female rats.« less

Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals.

PubMed

Kousta, Eleni; Papathanasiou, Asteroula; Skordis, Nicos

2010-01-01

There have been considerable advances concerning understanding of the early and later stages of ovarian development; a number of genes have been implicated and their mutations have been associated with developmental abnormalities. The most important genes controlling the initial phase of gonadal development, identical in females and males, are Wilms' tumor suppressor 1 (WT1) and steroidogenic factor 1 (SF1). Four genes are likely to be involved in the subsequent stages of ovarian development (WNT4, DAX1, FOXL2 and RSPO1), but none is yet proven to be the ovarian determining factor. Changes in nomenclature and classification were recently proposed in order to incorporate genetic advances and substitute gender-based diagnostic labels in terminology. The term "disorders of sex development" (DSD) is proposed to substitute the previous term "intersex disorders". Three main categories have been used to describe DSD in the 46,XX individual: 1) disorders of gonadal (ovarian) development: ovotesticular DSD, previously named true hermaphroditism, testicular DSD, previously named XX males, and gonadal dysgenesis; 2) disorders related to androgen excess (congenital adrenal hyperplasia, aromatase deficiency and P450 oxidoreductase deficiency); and 3) other rare disorders. In this mini-review, recent advances concerning development of the genital system in 46,XX individuals and related abnormalities are discussed. Basic embryology of the ovary and molecular pathways determining ovarian development are reviewed, focusing on mutations disrupting normal ovarian development. Disorders of sex development according to the revised nomenclature and classification in 46,XX individuals are summarized, including genetic progress in the field.

Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver.

PubMed

Chukijrungroat, Natsasi; Khamphaya, Tanaporn; Weerachayaphorn, Jittima; Songserm, Thaweesak; Saengsirisuwan, Vitoon

2017-08-01

The role of gender in the progression of fatty liver due to chronic high-fat high-fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were fed either a control diet or HFFD for 12 wk. Indexes of liver damage and hepatic steatosis were analyzed biochemically and histologically together with monitoring changes in hepatic gene and protein expression. HFFD induced a higher degree of hepatic steatosis in females, with significant increases in proteins involved in hepatic lipogenesis, whereas HFFD significantly induced liver injury, inflammation, and oxidative stress only in males. Interestingly, a significant increase in hepatic fibroblast growth factor 21 (FGF21) protein expression was observed in HFFD-fed males but not in HFFD-fed females. Ovarian hormone deprivation by itself led to a significant reduction in FGF21 with hepatic steatosis, and HFFD further aggravated hepatic fat accumulation in OVX rats. Importantly, estrogen replacement restored hepatic FGF21 levels and reduced hepatic steatosis in HFFD-fed OVX rats. Collectively, our results indicate that male rats are more susceptible to HFFD-induced hepatic inflammation and that the mechanism underlying this sex dimorphism is mediated through hepatic FGF21 expression. Our findings reveal sex differences in the development of HFFD-induced fatty liver and indicate the protective role of estrogen against HFFD-induced hepatic steatosis. Copyright © 2017 the American Physiological Society.

Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor.

PubMed

van de Lagemaat, R; Timmers, C M; Kelder, J; van Koppen, C; Mosselman, S; Hanssen, R G J M

2009-03-01

In assisted reproductive technology, human chorionic gonadotrophin (hCG) is administered subcutaneously for the induction of oocyte maturation and ovulation. Our efforts to develop orally bioavailable luteinizing hormone (LH) receptor agonists have led to the discovery of Org 43553, a low molecular weight (LMW) LH receptor (LH-R) agonist. Org 43553 was tested in vitro and in vivo in pre-clinical pharmacological models to demonstrate efficacy and oral availability. Org 43553 is a potent stimulator of the human LH-R in vitro (EC(50) 3.7 nM). In primary mouse Leydig cells, Org 43553 stimulated testosterone production. Pharmacokinetic analyses showed high oral bioavailability in rats (79%) and dogs (44%) with a shorter half-life compared with hCG (3.4 versus 5.6 h in the rat). Ovulation induction by Org 43553 was demonstrated in immature mice as well as in cyclic rats after single-dose oral administration (50 mg/kg). The ovulated oocytes were of good quality as demonstrated by successful fertilization and implantation of normal embryos. In male rats, testosterone production was substantially induced after oral administration. Org 43553 is the first LMW LH-R mimetic with demonstrated in vivo efficacy upon oral administration and could therefore replace subcutaneously administered hCG. The elimination half-life of Org 43553 is substantially shorter than hCG, which could potentially represent a clinical benefit in reducing the risk of ovarian hyperstimulation syndrome (OHSS).

Nedd4L expression is decreased in ovarian epithelial cancer tissues compared to ovarian non-cancer tissue.

PubMed

Yang, Qiuyun; Zhao, Jinghe; Cui, Manhua; Gi, Shuting; Wang, Wei; Han, Xiaole

2015-12-01

Recent studies have demonstrated that the neural precursor cell expressed, developmentally downregulated 4-like (Nedd4L) gene plays a role in the progression of various cancers. However, reports describing Nedd4L expression in ovarian cancer tissues are limited. A cohort (n = 117) of archival formalin-fixed, paraffin embedded resected normal ovarian epithelial tissues (n = 10), benign ovarian epithelial tumor tissues (n = 10), serous borderline ovarian epithelial tumor tissues (n = 14), mucous borderline ovarian epithelial tumor tissues (n = 11), and invasive ovarian epithelial cancer tissues (n = 72) were assessed for Nedd4L protein expression using immunohistochemistry. Nedd4L protein expression was significantly decreased in invasive ovarian epithelial cancer tissues compared to non-cancer tissues (P < 0.05). Decreased Nedd4L protein expression correlated with clinical stage, pathological grade, lymph node metastasis and survival (P < 0.05). Nedd4L protein expression may be an independent prognostic marker of ovarian cancer development. © 2015 Japan Society of Obstetrics and Gynecology.

A Mouse Model to Investigate Postmenopausal Biology as an Etiology of Ovarian Cancer Risk

DTIC Science & Technology

2007-11-01

1 mucinous adenocarcinomas 3 clear-cell carcinomas 1 malignant mixed mesodermal tumor 3 metastatic ovarian carcinomas 5 undifferentiated carcinomas 2...serous LMP tumors 2 mucinous LMP tumors 1 benign serous cystadenoma Ovarian tumor blocks 38 18 serous adenocarcinomas 5 mucinous adenocarcinomas 2...endometrioid adenocarcinomas 3 clear cell carcinomas 6 serous LMP 3 mucinous LMP 1 benign fibrous cystadenoma MMPs IN EARLY OVARIAN CANCER DEVELOPMENT

Role of Fallopian Tubes in the Development of Ovarian Cancer.

PubMed

Corzo, Camila; Iniesta, Maria D; Patrono, Maria Guadalupe; Lu, Karen H; Ramirez, Pedro T

2017-02-01

Ovarian cancer is the leading cause of death from gynecologic malignancy and the fifth cause of cancer death in women in the United States. The most common and lethal histologic subtype of epithelial ovarian cancer is high-grade serous carcinoma (HGSC), which generally presents at an advanced stage. HGSC may be associated with BRCA1 and BRCA2 mutations. Historically, HGSC was believed to originate from the ovarian epithelial cells. However, more recent evidence supports the idea that most ovarian cancers originate in the fallopian tube epithelium in both high-risk women and in the general population. Serous tubal intraepithelial carcinomas may ultimately evolve into ovarian or peritoneal cancer. As a result, prophylactic salpingectomy with conservation of the ovaries has become an increasingly more common practice for premenopausal women undergoing risk-reducing surgery. Because the fallopian tube is now recognized as the most common potential site of origin of ovarian carcinoma, there is ongoing research to explore molecular and genetic factors that may be critical in the development of this disease. Further research is needed to identify novel opportunities for early detection and screening of ovarian cancer with the ultimate goal of increasing overall survival. Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.

Fertility drug use and the risk of ovarian tumors in infertile women: a case-control study.

PubMed

Asante, Albert; Leonard, Phoebe H; Weaver, Amy L; Goode, Ellen L; Jensen, Jani R; Stewart, Elizabeth A; Coddington, Charles C

2013-06-01

To assess the influence of infertility and fertility drugs on risk of ovarian tumors. Case-control study (Mayo Clinic Ovarian Cancer Study). Ongoing academic study of ovarian cancer. A total of 1,900 women (1,028 with ovarian tumors and 872 controls, frequency matched on age and region of residence) who had provided complete information in a self-report questionnaire about history of infertility and fertility drug use. None. Effect of infertility history, use of fertility drugs and oral contraception, and gravidity on the risk of ovarian tumor development, after controlling for potential confounders. Among women who had a history of infertility, use of fertility drugs was reported by 44 (24%) of 182 controls and 38 (17%) of 226 cases. Infertile women who used fertility drugs were not at increased risk of developing ovarian tumors compared with infertile women who did not use fertility drugs; the adjusted odds ratio was 0.64 (95% CI, 0.37, 1.11). The findings were similar when stratified by gravidity and when analyzed separately for borderline versus invasive tumors. We found no statistically significant association between fertility drug use and risk of ovarian tumors. Further larger, prospective studies are needed to confirm this observation. Published by Elsevier Inc.

Role of Chemokine Network in the Development and Progression of Ovarian Cancer: A Potential Novel Pharmacological Target

PubMed Central

Barbieri, Federica; Bajetto, Adriana; Florio, Tullio

2010-01-01

Ovarian cancer is the most common type of gynecologic malignancy. Despite advances in surgery and chemotherapy, the survival rate is still low since most ovarian cancers relapse and become drug-resistant. Chemokines are small chemoattractant peptides mainly involved in the immune responses. More recently, chemokines were also demonstrated to regulate extra-immunological functions. It was shown that the chemokine network plays crucial functions in the tumorigenesis in several tissues. In particular the imbalanced or aberrant expression of CXCL12 and its receptor CXCR4 strongly affects cancer cell proliferation, recruitment of immunosuppressive cells, neovascularization, and metastasization. In the last years, several molecules able to target CXCR4 or CXCL12 have been developed to interfere with tumor growth, including pharmacological inhibitors, antagonists, and specific antibodies. This chemokine ligand/receptor pair was also proposed to represent an innovative therapeutic target for the treatment of ovarian cancer. Thus, a thorough understanding of ovarian cancer biology, and how chemokines may control these different biological activities might lead to the development of more effective therapies. This paper will focus on the current biology of CXCL12/CXCR4 axis in the context of understanding their potential role in ovarian cancer development. PMID:20049170

Improving efficacy of metastatic tumor segmentation to facilitate early prediction of ovarian cancer patients' response to chemotherapy

NASA Astrophysics Data System (ADS)

Danala, Gopichandh; Wang, Yunzhi; Thai, Theresa; Gunderson, Camille C.; Moxley, Katherine M.; Moore, Kathleen; Mannel, Robert S.; Cheng, Samuel; Liu, Hong; Zheng, Bin; Qiu, Yuchen

2017-02-01

Accurate tumor segmentation is a critical step in the development of the computer-aided detection (CAD) based quantitative image analysis scheme for early stage prognostic evaluation of ovarian cancer patients. The purpose of this investigation is to assess the efficacy of several different methods to segment the metastatic tumors occurred in different organs of ovarian cancer patients. In this study, we developed a segmentation scheme consisting of eight different algorithms, which can be divided into three groups: 1) Region growth based methods; 2) Canny operator based methods; and 3) Partial differential equation (PDE) based methods. A number of 138 tumors acquired from 30 ovarian cancer patients were used to test the performance of these eight segmentation algorithms. The results demonstrate each of the tested tumors can be successfully segmented by at least one of the eight algorithms without the manual boundary correction. Furthermore, modified region growth, classical Canny detector, and fast marching, and threshold level set algorithms are suggested in the future development of the ovarian cancer related CAD schemes. This study may provide meaningful reference for developing novel quantitative image feature analysis scheme to more accurately predict the response of ovarian cancer patients to the chemotherapy at early stage.

Light-sheet microscopy for quantitative ovarian folliculometry

NASA Astrophysics Data System (ADS)

Lin, Hsiao-Chun Amy; Dutta, Rahul; Mandal, Subhamoy; Kind, Alexander; Schnieke, Angelika; Razansky, Daniel

2017-02-01

Determination of ovarian status and follicle monitoring are common methods of diagnosing female infertility. We evaluated the suitability of selective plane illumination microscopy (SPIM) for the study of ovarian follicles. Owing to the large field of view and fast acquisition speed of our newly developed SPIM system, volumetric image stacks from entire intact samples of pig ovaries have been rendered demonstrating clearly discernible follicular features like follicle diameters (70 μm - 2.5 mm), size of developing Cumulus oophorus complexes (COC ) (40 μm - 110 μm), and follicular wall thicknesses (90 μm-120 μm). The observation of clearly distinguishable COCs protruding into the follicular antrum was also shown possible, and correlation with the developmental stage of the follicles was determined. Follicles of all developmental stages were identified, and even the small primordial follicle clusters forming the egg nest could be observed. The ability of the system to non-destructively generate sub-cellular resolution 3D images of developing follicles, with excellent image contrast and high throughput capacity compared to conventional histology, suggests that it can be used to monitor follicular development and identify structural abnormalities indicative of ovarian ailments. Accurate folliculometric measurements provided by SPIM images can immensely help the understanding of ovarian physiology and provide important information for the proper management of ovarian diseases.

Studies on gonadotropin receptor of rat ovary and testis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Q.

1989-01-01

The subunit structure of the testicular LH/hCG receptor was studied by a chemical cross-linking technique. Leydig cells isolated from rat testis were incubated with {sup 125}I-hCG, following which the bound {sup 125}I-hCG was covalently cross-linked to the receptor on the cell surface with a cleavable or a non-cleavable cross-linking reagent. The hormone-receptor complex was extracted and then either subjected to gel permeation chromatography under nondenaturing conditions, or resolved by SDS-polyacrylamide gel electrophoresis, followed by autoradiographic analysis. The ovarian LH/hCG receptor was studied with luteal cells from pseudopregnant rats. Purification of the receptor was achieved by ligand affinity chromatography following detergentmore » solubilization of the plasma membrane. The purified hCG receptor displayed properties identical to the membrane bound receptor with regard to binding specificity and affinity, and exhibited a molecular weight of approximately 130,000 dalton.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elzek, Mohamed A.; Rodland, Karin D.

In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification ofmore » aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. In conclusion, we propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs.« less

Ovarian developmental variation in the primitively eusocial wasp Ropalidia marginata suggests a gateway to worker ontogeny and the evolution of sociality.

PubMed

Shukla, Shantanu; Chandran, Swarnalatha; Gadagkar, Raghavendra

2013-01-15

Social insects are characterized by reproductive caste differentiation of colony members into one or a small number of fertile queens and a large number of sterile workers. The evolutionary origin and maintenance of such sterile workers remains an enduring puzzle in insect sociobiology. Here, we studied ovarian development in over 600 freshly eclosed, isolated, virgin female Ropalidia marginata wasps, maintained in the laboratory. The wasps differed greatly both in the time taken to develop their ovaries and in the magnitude of ovarian development despite having similar access to resources. All females started with no ovarian development at day zero, and the percentage of individuals with at least one oocyte at any stage of development increased gradually across age, reached 100% at 100 days and decreased slightly thereafter. Approximately 40% of the females failed to develop ovaries within the average ecological lifespan of the species. Age, body size and adult feeding rate, when considered together, were the most important factors governing ovarian development. We suggest that such flexibility and variation in the potential and timing of reproductive development may physiologically predispose females to accept worker roles and thus provide a gateway to worker ontogeny and the evolution of sociality.

Honeybee product therapeutic as stem cells homing for ovary failure.

PubMed

Safitri, Erma; Widiyatno, Thomas V; Prasetyo, R Heru

2016-11-01

Complexity of the method of isolation, cultivation in vitro and the expensive cost of transplantation process of stem cells, it would require an innovation to homing and differentiation of stem cells and increase folliculogenesis. The stem cells homing was achieved through the provision of food or beverages derived from natural materials like honeybee product. Through honeybee product, there will be homing of stem cells and accompany with the sources from the body itself will take place in regeneration of the ovary. Female rats model of degenerative ovary was obtained through food fasting but still have drinking water for 5 days. It caused malnutrition and damage of the ovarian tissue. The administration of 50% honeybee product (T1) was performed for 10 consecutive days, while the positive control group (T0+) was fasted and not given honeybee product and the negative control (T0-) not fasted and without honeybee product. Observations were taken for homing of stem cells, raised of folliculogenesis, differentiation of stem cells, and regeneration of the ovarian tissue using routine H&E staining. Homing of stem cells shown the vascular endothelial growth factor and granulocyte colony-stimulating factor expression; enhancement of folliculogenesis was indicated by an increase of follicle dee Graaf count; enhancement of differentiation of stem cells was indicated by growth differentiation factor-9 expression; and regeneration of ovarian tissue indicated by intact ovarian tissue with growing follicles. Honeybee product can be induced endogenous stem cells in regeneration of ovary failure due to malnutrition.

New models of hematogenous ovarian cancer metastasis demonstrate preferential spread to the ovary and a requirement for the ovary for abdominal dissemination

PubMed Central

Coffman, Lan G; Burgos-Ojeda, Daniela; Wu, Rong; Cho, Kathleen; Bai, Shoumei; Buckanovich, Ronald J

2016-01-01

Emerging evidence suggest that many high grade serous ‘ovarian’ cancers (HGSOC) start in the fallopian tube. Cancer cells are then recruited to the ovary and then spread diffusely through the abdomen. The mechanism of ovarian cancer spread was thought to be largely due to direct shedding of tumor cells into the peritoneal cavity with vascular spread being of limited importance. Recent work challenges this dogma, suggesting hematogenous spread of ovarian cancer may play a larger role in ovarian cancer cell metastasis than previously thought. One reason the role of vascular spread of ovarian cancer has not been fully elucidated is the lack of easily accessible models of vascular ovarian cancer metastasis. Here we present three metastatic models of ovarian cancer which confirm the ability of ovarian cancer to hematogenously spread. Strikingly, we observe a high rate of metastasis to the ovary with the development of ascites in these models. Interestingly, oophorectomy resulted in a complete loss of peritoneal metastases and ascites. Taken together our data indicates that hematogenously disseminated HGSOC cells have a unique tropism for the ovary and that hematogenous spread in ovarian cancer may be more common than appreciated. Furthermore our studies support a critical role for the ovary in promoting HGSOC cell metastasis to the abdomen. The models developed here represent important new tools to evaluate both the mechanism of cancer cell recruitment to the ovary and to understand and target key steps in ovarian cancer metastasis. PMID:27083386

Evidences for involvement of growth hormone and insulin-like growth factor in ovarian development of starry flounder (Platichthys stellatus).

PubMed

Xu, Yongjiang; Wang, Bin; Liu, Xuezhou; Shi, Bao; Zang, Kun

2017-04-01

Although gonadotrophins are major regulators of ovarian function in teleosts and other vertebrates, accumulating evidence indicates that the growth hormone (GH)-insulin-like growth factor (IGF) axis also plays an important role in fish reproduction. As a first step to understand the physiological role of the GH-IGF system in the ovarian development of starry flounder (Platichthys stellatus), the expression profiles of GH and IGF messenger RNAs (mRNAs) and plasma GH, IGF-I, estradiol-17β (E2), and testosterone (T) levels during the ovarian development were investigated. The developmental stages of ovaries were divided into five stages (II, III, IV, V, and VI) by histological analysis. The hepatosomatic index (HSI) and gonadosomatic index (GSI) values increased and peaked at stage IV and stage V, respectively, and then declined at stage VI. Pituitary GH mRNA levels decreased sharply at stage III and raised to top level at stage VI. The hepatic IGF-I mRNA levels ascended to maximum value at stage V and then declined significantly at stage VI. However, the hepatic IGF-II mRNA levels remained stable and increased significantly at stage VI. In contrast, the ovarian IGF-I mRNA levels increased gradually and peaked at stage VI. The ovarian IGF-II mRNA levels were initially stable and increased significantly at stage V until the top level at stage VI. Consistent with the pituitary GH mRNA levels, plasma GH levels reduced sharply at stage III and remained depressed until stage V and then raised remarkably at stage VI. Plasma IGF-I level peaked at stage V and then declined to initial level. Plasma E2 level peaked at stage IV and then dramatically descended to the basal level. Plasma T level peaked at stage V and then declined significantly back to the basal level. Based on statistical analysis, significant positive correlations between hepatic IGF-I mRNA and GSI, ovarian IGF-II mRNA and hepatic IGF-II mRNA, ovarian IGF-I mRNA and ovarian IGF-II mRNA, and plasma IGF-I and plasma T were observed, respectively. These results suggest that the GH-IGF system may be involved in the ovarian development of starry flounder; GH and IGFs appear to play distinct roles in the regulation of the ovarian development in paracrine/autocrine manners. These findings extend our knowledge of the roles of the GH-IGF axis on reproduction regulation in fish.

Association between average daily television viewing time and the incidence of ovarian cancer: findings from the Japan Collaborative Cohort Study.

PubMed

Ukawa, Shigekazu; Tamakoshi, Akiko; Mori, Mitsuru; Ikehara, Satoyo; Shirakawa, Toru; Yatsuya, Hiroshi; Iso, Hiroyasu

2018-02-01

Seventy-five percent of epidemiological studies have reported that sedentary behavior is associated with ovarian cancer incidence. Although Japan has one of the most sedentary populations, with median sitting times of 7 h/day, this association has not been investigated. This study aimed to elucidate the association between average daily television (TV) viewing time, which is a major sedentary behavior, and the incidence of ovarian cancer in a large-scale nationwide cohort study in Japan. A total of 34,758 female participants aged 40-79 years without a history of cancer at baseline were included in the study. The inverse probability weighted competing risk model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the incidence of ovarian cancer. During a median follow-up of 19.4 years, 59 participants developed ovarian cancer (ICD-10: C56), 2,706 participants developed other types of cancer, and 4,318 participants died. Participants who watched TV for ≥ 5 h/day were more likely to develop ovarian cancer than those who watched TV for < 2 h/day (HR 2.15; 95% CI 1.54-2.99). Our findings suggest that reducing the amount of time spent sedentarily may be beneficial for preventing ovarian cancer.

Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin

USDA-ARS?s Scientific Manuscript database

Ovarian cancer, the deadliest of gynecologic cancers, is usually diagnosed at advanced stage due to invalidated screening test and non-specific symptoms presented. Although carboplatin has been popular for treating ovarian cancer for decades, patients eventually develop resistance to this platinum-c...

Activated ovarian endothelial cells promote early follicular development and survival.

PubMed

Kedem, Alon; Aelion-Brauer, Anate; Guo, Peipei; Wen, Duancheng; Ding, Bi-Sen; Lis, Raphael; Cheng, Du; Sandler, Vladislav M; Rafii, Shahin; Rosenwaks, Zev

2017-09-19

New data suggests that endothelial cells (ECs) elaborate essential "angiocrine factors". The aim of this study is to investigate the role of activated ovarian endothelial cells in early in-vitro follicular development. Mouse ovarian ECs were isolated using magnetic cell sorting or by FACS and cultured in serum free media. After a constitutive activation of the Akt pathway was initiated, early follicles (50-150 um) were mechanically isolated from 8-day-old mice and co-cultured with these activated ovarian endothelial cells (AOEC) (n = 32), gel (n = 24) or within matrigel (n = 27) in serum free media for 14 days. Follicular growth, survival and function were assessed. After 6 passages, flow cytometry showed 93% of cells grown in serum-free culture were VE-cadherin positive, CD-31 positive and CD 45 negative, matching the known EC profile. Beginning on day 4 of culture, we observed significantly higher follicular and oocyte growth rates in follicles co-cultured with AOECs compared with follicles on gel or matrigel. After 14 days of culture, 73% of primary follicles and 83% of secondary follicles co-cultured with AOEC survived, whereas the majority of follicles cultured on gel or matrigel underwent atresia. This is the first report of successful isolation and culture of ovarian ECs. We suggest that co-culture with activated ovarian ECs promotes early follicular development and survival. This model is a novel platform for the in vitro maturation of early follicles and for the future exploration of endothelial-follicular communication. In vitro development of early follicles necessitates a complex interplay of growth factors and signals required for development. Endothelial cells (ECs) may elaborate essential "angiocrine factors" involved in organ regeneration. We demonstrate that co-culture with ovarian ECs enables culture of primary and early secondary mouse ovarian follicles.

[Investigation of risk factors for ovarian tumors with the "case-control" method followed by automated prognostication for ovarian oncopathology].

PubMed

Kulinich, S I; Gertsekovich, D A; Cherniak, E V

1994-01-01

The results of questionnaire-based case-control screening for ovarian oncopathology in 478 patients and 478 healthy females are presented. The two groups matched with respect to age and place of residence. An 82.4% effective mathematical decision rule developed. It can be used as a method of early diagnosis of ovarian tumors as well as in formation of groups at high risk.

Development of the Ovarian Cancer Cohort Consortium: Risk Factor Associations by Heterogeneity of Disease

DTIC Science & Technology

2014-10-01

we have received data. Analyses of primary ovarian cancer risk factors (e.g., oral contraceptive use, parity) by histology are complete and a...including (but not limited to) age, oral contraceptive use, tubal ligation, parity, postmenopausal hormone use, family history of ovarian cancer, body mass...of ovarian or breast cancers, menopausal status, postmenopausal hormone use (ever/never, duration, and type), use of oral contraceptives (ever/never

Prevention of Ovarian High Grade Serous Carcinoma by Elucidating Its Early Changes

DTIC Science & Technology

2016-10-01

tissue sections for studies related to study early tumor development in ovarian cancer. This information will be shared with science community. 15...fallopian tube. IMPACT ON SOCIETY BEYOND SCIENCE AND TECHNOLOGY: The findings will help to educate the society about the origins of ovarian...A Team-based Science Approach This project will help to plan the scientific and leadership aspects of the Ovarian Cancer Academy. It will also

Allograft en bloc vagino-utero-ovarian avascular transplant versus autograft implantation in rats.

PubMed

Salehian, Mohammad-Taghi; Salehian, Arash; Mossaffa, Nariman; Hadian, Mehrnaz; Eghtesadi-Araghi, Payam

2008-12-01

The aim of this study was to compare the results of an allograft en bloc vagino-uteroovarian avascular transplant with those of autograft implantation in rats. Thirty-four inbred adult virgin female Albino rats (age range, 10 - 12 weeks) were divided into 2 groups: the control group (autograft, n=11) and the study group (en bloc vagino-utero-ovariectomy, n=23). In the study group, the uterus and adnexa and the ovaries of the donor rat were transplanted to the recipient animal. Twenty-five to 30 days after that procedure, all rats were killed, and the samples were assessed histopathologically. No immunosuppressive drugs were used. Ten rats died during the postoperative period. In 16 rats, the transplanted system had survived completely at the conclusion of the study. In each of the study groups, complete survival of the uterus and ovaries was noted in 8 rats (34.8% in the study group and 72.8% in the control group). In all rats except 1, histopathologic examination did not reveal any signs of the classic criteria for tissue rejection reaction. The lack of revascularization, nonspecific signs of inflammation, and the presence of large granular lymphocytes and natural killer cells were reported. Our data indicated that the outcome of both allograft and homograft avascular en bloc transplant of vagino-utero-ovariectomy in rats was successful, and that immunologic rejection did not seem to have an important role in those procedures.

Bovine ovarian follicular growth and development correlate with lysophosphatidic acid expression.

PubMed

Sinderewicz, Emilia; Grycmacher, Katarzyna; Boruszewska, Dorota; Kowalczyk-Zięba, Ilona; Staszkiewicz, Joanna; Ślężak, Tomasz; Woclawek-Potocka, Izabela

2018-01-15

The basis of successful reproduction is proper ovarian follicular growth and development. In addition to prostaglandins and vascular endothelial growth factor, a number of novel factors are suggested as important regulators of follicular growth and development: PGES, TFG, CD36, RABGAP1, DBI and BTC. This study focuses on examining the expression of these factors in granulosa and thecal cells that originate from different ovarian follicle types and their link with the expression of lysophosphatidic acid (LPA), known local regulator of reproductive functions in the cow. Ovarian follicles were divided into healthy, transitional, and atretic categories. The mRNA expression levels for PGES, TFG, CD36, RABGAP1, DBI and BTC in granulosa and thecal cells in different follicle types were measured by real-time PCR. The correlations among expression of enzymes synthesizing LPA (autotaxin, phospholipase A2), receptors for LPA and examined factors were measured. Immunolocalization of PGES, TFG, CD36, RABGAP1, DBI and BTC was examined by immunohistochemistry. We investigated follicle-type dependent mRNA expression of factors potentially involved in ovarian follicular growth and development, both in granulosa and thecal cells of bovine ovarian follicles. Strong correlations among receptors for LPA, enzymes synthesizing LPA, and the examined factors in healthy and transitional follicles were observed, with its strongest interconnection with TFG, DBI and RABGAP1 in granulosa cells, and TFG in thecal cells; whereas no correlations in atretic follicles were detected. A greater number of correlations were found in thecal cells than in granulosa cells as well as in healthy follicles than in transitional follicles. These data indicate the role of LPA in the growth, development and physiology of the bovine ovarian follicle. Copyright © 2017 Elsevier Inc. All rights reserved.

Voluntary wheel running improves adipose tissue immunometabolism in ovariectomized low-fit rats.

PubMed

Zidon, Terese M; Park, Young-Min; Welly, Rebecca J; Woodford, Makenzie L; Scroggins, Rebecca J; Britton, Steven L; Koch, Lauren G; Booth, Frank W; Padilla, Jaume; Kanaley, Jill A; Vieira-Potter, Victoria J

2018-01-02

Loss of ovarian hormones is associated with increased adiposity, white adipose tissue (WAT) inflammation, and insulin resistance (IR). Previous work demonstrated ovariectomized (OVX) rats bred for high aerobic fitness (HCR) are protected against weight gain and IR compared to rats bred for low aerobic fitness (LCR) yet wheel running prevents OVX-induced IR in LCR rats. The purpose of this study was to determine whether adipose tissue immunometabolic characteristics from female HCR and LCR rats differs before or after OVX, and whether wheel running mitigates OVX-induced adipose tissue immunometabolic changes in LCR rats. Female OVX HCR and LCR rats were all fed a high fat diet (HFD) (n = 7-8/group) and randomized to either a running wheel or remain sedentary for 11 weeks. Ovary-intact rats (n = 7-12/group) were fed a standard chow diet with no wheel. Ovary-intact LCR rats had a greater visceral WAT inflammatory profile compared to HCR. Following OVX, sedentary LCR rats had greater serum leptin (p<0.001) and WAT inflammation (p<0.05) than sedentary HCR. Wheel running normalized the elevated serum leptin and reduced both visceral (p<0.05) and subcutaneous (p<0.03) WAT inflammatory markers in the LCR rats. Paradoxically, wheel running increased some markers of WAT inflammation in OVX HCR rats (p<0.05), which correlated with observed weight gain. Taken together, HCR rats appear to have a healthier WAT immune and metabolic profile compared to LCR, even following OVX. Wheel running improves WAT health in previously sedentary LCR rats. On the other hand, increased WAT inflammation is associated with adiposity gain despite a high volume of wheel running in HCR rats.

Progesterone signaling mediated through progesterone receptor membrane component-1 in ovarian cells with special emphasis on ovarian cancer.

PubMed

Peluso, John J

2011-08-01

Various ovarian cell types including granulosa cells and ovarian surface epithelial cells express the progesterone (P4) binding protein, progesterone receptor membrane component-1 (PGRMC1). PGRMC1 is also expressed in ovarian tumors. PGRMC1 plays an essential role in promoting the survival of both normal and cancerous ovarian cell in vitro. Given the clinical significance of factors that regulate the viability of ovarian cancer, this review will focus on the role of PGRMC1 in ovarian cancer, while drawing insights into the mechanism of PGRMC1's action from cell lines derived from healthy ovaries as well as ovarian tumors. Studies using PGRMC1siRNA demonstrated that P4's ability to inhibit ovarian cells from undergoing apoptosis in vitro is dependent on PGRMC1. To confirm the importance of PGRMC1, the ability of PGRMC1-deplete ovarian cancer cell lines to form tumors in intact nude mice was assessed. Compared to PGRMC1-expressing ovarian cancer cells, PGRMC1-deplete ovarian cancer cells formed tumors in fewer mice (80% compared to 100% for controls). Moreover, the number of tumors derived from PGRMC1-deplete ovarian cancer cells was 50% of that observed in controls. Finally, the tumors that formed from PGRMC1-deplete ovarian cancer cells were about a fourth the size of tumors derived from ovarian cancer cells with normal levels of PGRMC1. One reason for PGRMC1-deplete tumors being smaller is that they had a poorly developed microvasculature system. How PGRMC1 regulates cell viability and in turn tumor growth is not known but part of the mechanism likely involves the regulation of genes that promote cell survival and inhibit apoptosis. Copyright © 2011 Elsevier Inc. All rights reserved.

Imaging the ovary.

PubMed

Feng, Yi; Tamadon, Amin; Hsueh, Aaron J W

2018-05-01

During each reproductive cycle, the ovary exhibits tissue remodelling and cyclic vasculature changes associated with hormonally regulated folliculogenesis, follicle rupture, luteal formation and regression. However, the relationships among different types of follicles and corpora lutea are unclear, and the role of ovarian vasculature in folliculogenesis and luteal dynamics has not been extensively investigated. Understanding of ovarian physiology and pathophysiology relies upon elucidation of ovarian morphology and architecture. This paper summarizes the literature on traditional approaches to the imaging of ovarian structures and discusses recent advances in ovarian imaging. Traditional in-vivo ultrasound, together with histological and electron microscopic approaches provide detailed views of the ovary at organ, tissue and molecular levels. However, in-vivo imaging is limited to antral and larger follicles whereas histological imaging is mainly two-dimensional in nature. Also discussed are emerging approaches in the use of near-infrared fluorophores to image follicles in live animals to detect preantral follicles as well as visualizing ovarian structures using CLARITY in fixed whole ovaries to elucidate three-dimensional interrelationships among follicles, corpora lutea and ovarian vasculature. Advances in ovarian imaging techniques provide new understanding of ovarian physiology and allow for the development of better tools to diagnose ovarian pathophysiology. Copyright © 2018 Reproductive Healthcare Ltd. All rights reserved.

Environmental and developmental origins of ovarian reserve.

PubMed

Richardson, M C; Guo, M; Fauser, B C J M; Macklon, N S

2014-01-01

BACKGROUND Oocyte number is established early in life before a gradual loss of this ovarian reserve during reproductive life until oocyte availability becomes limiting at the menopause. Although there is a large genetic component to the ovarian reserve achieved before birth, other influences including the maternal endocrine and nutritional milieu, and environmental factors may represent important developmental determinants. Environmental and nutritional factors may also modify the downward trajectory of ovarian reserve in adult life. The combination of these early and later life influences has the potential to lead to diminished ovarian reserve, compromising fertility in later reproductive years and altering age at natural menopause. METHODS Literature searches of the ISI Web of Knowledge database were carried out using the main terms 'ovarian reserve' and 'menopause AND age' in conjunction with a range of other terms encompassing a variety of factors with potential effects on ovarian reserve. The various searches were inspected manually and the relevant papers selected for critical analysis and interpretation. RESULTS Evidence was identified supporting the view that elevated prenatal androgens have an adverse effect on the early establishment of ovarian reserve, although the implications for ovarian reserve in the polycystic ovary syndrome (which may also be programmed through prenatal androgen exposure) remain uncertain. Recent evidence is cited suggesting that effects of maternal nutrient restriction on ovarian reserve may also involve changes in prenatal androgen exposure. A general rationale is developed through examination of evidence which emphasizes the roles of the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) systems in ovarian reserve modulation. Because of their similarity to the natural ligands, many environmental compounds have the ability to bind to these receptors (albeit at lower affinities) and thereby have the potential to influence either the initial setting of ovarian reserve during development or the trajectory of ovarian reserve during adult life. For example, exposure to compounds in cigarette smoke may accelerate loss of ovarian reserve in smokers leading to diminished ovarian reserve, earlier age at last child and earlier menopause. Socioenocomic factors are clearly associated with age at natural menopause, with correlations with economic status and education level. However, such effects in western societies are in general small, and the underlying mechanisms remain unclear. CONCLUSIONS Exposure to many environmental compounds, particularly to those that leach from plastics and other synthetic materials, is commonplace in modern societies to the extent that many are found at measurable concentrations in body fluids within most of the population. Relating fluid levels of individual compounds to parameters reflecting ovarian reserve in selected populations appears to be an effective way forward and, indeed, some early-stage findings do show some cause for concern. There is a pressing need for the development of practical advice enabling women to minimize their intake of AHR/ER ligands, perhaps through dietary/cosmetic choices or improved food packaging.

Models of ovarian cancer metastasis: Murine models

PubMed Central

Šale, Sanja; Orsulic, Sandra

2008-01-01

Mice have mainly been used in ovarian cancer research as immunodeficient hosts for cell lines derived from the primary tumors and ascites of ovarian cancer patients. These xenograft models have provided a valuable system for pre-clinical trials, however, the genetic complexity of human tumors has precluded the understanding of key events that drive metastatic dissemination. Recently developed immunocompetent, genetically defined mouse models of epithelial ovarian cancer represent significant improvements in the modeling of metastatic disease. PMID:19337569

Fertility drugs and ovarian cancer.

PubMed

Ali, Aus Tariq

2017-06-20

The aetiology of ovarian cancer is multifactorial with both endogenous and exogenous risk factors playing an important role. The exact pathogenesis of ovarian cancer is still not well understood, despite the number of hypotheses published. Due to an increase in the number of women using fertility drugs, much attention has been focused on the long-term health effects of such drugs. Although fertility drugs facilitate the ovulation process, it is however associated with a significant increase in hormone concentrations, placing exposed women at increased risk of gynaecological cancer. Many clinical and epidemiological studies have examined the association between fertility drugs and ovarian cancer risk. Results from these studies have been contradictory, as some studies have reported an increased risk of ovarian cancer while others reported no increased risk. Nevertheless, recent studies have shown that women who used fertility drugs and did not conceive had a higher risk of developing ovarian cancer, compared to women who used fertility drugs and conceived and delivered successfully. This review discusses the effect of fertility drugs on the risk of developing ovarian cancer, providing details on four possible scenarios associated with fertility treatment. In addition, the limitations of previous studies and their impact on our understanding of the association between fertility drugs and ovarian cancer also have been highlighted. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Epigenetic down-regulated DDX10 promotes cell proliferation through Akt/NF-κB pathway in ovarian cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gai, Muhuizi; Bo, Qifang; Qi, Lixia, E-mail: lixiaqi_dph@sina.com

Ovarian cancer contributes to the majority of ovarian cancer, while the molecular mechanisms remain elusive. Recently, some DEAD box protein 1 has been reported play a tumor suppressor role in ovarian cancer progression. However, the functions of DEAD box protein (DDX) members in ovarian cancer development remain largely unknown. In current study, we retrieved GEO databases and surprisingly found that DDX10 is significantly down-regulated in ovarian cancer tissues compared with normal ovary. These findings suggest that DDX10 might also play a suppressive role in ovarian cancer. We then validated the down-regulated expression pattern of DDX10 in fresh ovarian cancer tissues.more » Furthermore, both loss- and gain-functions assays reveal that the down-regulated DDX10 could promote ovarian cancer proliferation in vitro and the xenograft subcutaneous tumor formation assays confirmed these findings in vivo. In addition, we found that DDX10 is epigenetic silenced by miR-155-5p in ovarian cancer. Moreover, we further preliminary illustrated that down-regulated DDX10 promotes ovarian cancer cell proliferation through Akt/NF-κB pathway. Taken together, in current study, we found a novel tumor suppressor, DDX10, is epigenetic silenced by miR-155-5p in ovarian cancer, and the down-regulated expression pattern of DDX10 promotes ovarian cancer proliferation through Akt/NF-κB pathway. Our findings shed the light that DDX families might be a novel for ovarian cancer treatment. - Highlights: • A novel DEAD box protein, DDX10 is significantly down-regulated in ovarian cancer tissues. • Down-regulated DDX10 promotes ovarian cancer cell proliferation and growth both in vitro and in vivo. • miR-155-5p is highly expressed in ovarian cancer tissues and epigenetically targets DDX10. • DDX10 and miR-155-5p regulates Akt/p65 axis in ovarian cancer cells.« less

Current state of biomarker development for clinical application in epithelial ovarian cancer

PubMed Central

Moore, Richard G.; MacLaughlan, Shannon; Bast, Robert C.

2011-01-01

Each year in the United States over 15,000 women die of epithelial ovarian cancer (EOC)and 22,000 are diagnosed with the disease. The incidence of ovarian cancer has remained stable over the past decade however, survival rates have improved steadily. Increases in survival rates can be attributed to the advances in surgical management, development of effective cytotoxic drugs and the route of administration of chemotherapy. Ovarian cancer survival rates could also be improved through screening and early detection. Disappointingly, effective screening methods have not been established and continue to be elusive. Historically the goal of a screening test was to achieve a positive predictive value (PPV) greater than 10% in order be considered cost effective and have an acceptable risk for the population being screened. Despite the inability of currently available screening algorithms to achieve the desired PPV there may be an advantage in producing a stage migration to lower stages at the time of diagnoses, thereby resulting in improved survival. Equally important recent studies have demonstrated that women who have their initial surgery performed by gynecologic oncologists, and women who have their surgeries at centers experienced in the treatment of ovarian cancer have higher survival rates. For these reasons it is essential that all women at high risk for ovarian cancer receive their initial care by gynecologic oncologists and at centers with multidisciplinary teams experienced in the optimal care of ovarian cancer patients. With this in mind, methods that facilitate the accurate triage of women who will ultimately be diagnosed with ovarian cancer could play a significant role in improving survival rates for these patients. This review article will examine the current state of biomarker use in ovarian cancer screening, risk assessment and for monitoring ovarian cancer patients. PMID:19879639

Cox-1 Suppression and Follicle Depletion in the Etiology of Menopause- Associated Ovarian Cancer

DTIC Science & Technology

2008-04-01

follicular function (2). Most oocytes are progressively lost by atresia, or apoptosis (3), and the ovary may develop a number of atrophic features...the risk of ovarian epithelial cancers, by far the most predominant form (14), and cause growth inhibition and apoptosis in ovarian cancer cell lines...1990;4:390-400. 8. Mintz B. Embryological development of primordial germ-cells in the mouse: influence of a new mutation, Wj. J Embryol Exp

Resveratrol Reduces Steroidogenesis in Rat Ovarian Theca-Interstitial Cells: The Role of Inhibition of Akt/PKB Signaling Pathway

PubMed Central

Ortega, Israel; Villanueva, Jesus A.; Wong, Donna H.; Cress, Amanda B.; Sokalska, Anna; Stanley, Scott D.

2012-01-01

Polycystic ovary syndrome is characterized by theca-interstitial hyperplasia and increased expression of steroidogenic genes, leading to excessive androgen production. Resveratrol, a natural polyphenol, promotes apoptosis and reduces rat theca-interstitial cell growth, in part by inhibiting the mevalonate pathway and decreasing the availability of substrates of isoprenylation [farnesyl-pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP)]. This study evaluated the effect of resveratrol on rat theca-interstitial cell steroidogenesis. Because resveratrol may activate sirtuins, this study also investigated whether steroidogenesis was affected by sirtuin inhibitors (nicotinamide, sirtinol). Theca-interstitial cells were cultured with or without resveratrol (1–10 μm), GGPP (30 μm), FPP (30 μm), nicotinamide (1 mm), and/or sirtinol (10 μm). Resveratrol did not affect progesterone levels but reduced androgen production in a concentration-dependent fashion (androstenedione by up to 78% and androsterone by up to 76%). This inhibitory effect correlated with a decrease in mRNA expression of genes regulating androgen production, especially Cyp17a1 (by up to 73%). GGPP and FPP had no effect on androgen levels and Cyp17a1 mRNA levels and did not alter the effects induced by resveratrol. Similarly, sirtuin inhibitors did not reverse resveratrol-induced inhibition of steroidogenesis. However, resveratrol decreased activity of serine-threonine kinase/protein kinase B pathway, a cell-signaling pathway involved in ovarian steroidogenesis. The present findings indicate that resveratrol reduces androgen production primarily by inhibiting Cyp17a1 mRNA expression, and this inhibition may be mediated, in part, by blocking the activity of the serine-threonine kinase/protein kinase B pathway. These findings may be of clinical relevance to conditions associated with excessive production of androgens by theca cells, such as polycystic ovary syndrome. PMID:22719052

Reprint of "Repeated adolescent activity-based anorexia influences central estrogen signaling and adulthood anxiety-like behaviors in rats".

PubMed

Lee, Tien-Jui; Kinzig, Kimberly P

2017-09-01

Anorexia nervosa (AN) typically presents in adolescence and is highly comorbid with anxiety and depression, which often persist after elimination of AN symptomology. The activity-based anorexia (ABA) paradigm allows for evaluation of behavioral and neuroendocrine consequences of AN-like behaviors, including voluntary anorexia, hyperactivity, and disruption of the hypothalamic-pituitary-gonadal (HPG) and the hypothalamic pituitary adrenal (HPA) axis. Because ABA in adolescent females results in increased anxiety-like behavior in adulthood and the estrogen signaling system has been shown to play a role in anxiety and food intake, we investigated the role of ovarian hormones in adolescent ABA-treated rats, and long-term effects of mid- and late adolescent ABA exposure on behavior and estrogen signaling. While previous research demonstrated that two bouts of ABA during adolescence resulted in decreased time in the open arm of the elevated plus maze (EPM) and increased activity of the HPA axis in response to a novel stressor, here we show that one bout of ABA in mid-or late-adolescence did not result in the same behavioral outcome. Two exposures to ABA during adolescence were necessary to produce long-term anxiety-like behavior on the EPM. Finally, removal of ovarian hormones by ovariectomy (OVX) prior to puberty did not attenuate long-term behavioral consequences of ABA in adolescence, and estrogen receptor β (ERβ) expression level in the amygdala of ABA rats was significantly lower than control subjects. Taken together, these studies identify enduring effects of ABA in adolescent females that may be mediated by ABA-induced changes to CNS ERβ signaling that increase anxiety-like behaviors. Copyright © 2017 Elsevier Inc. All rights reserved.

Plasma hormonal profiles and dendritic spine density and morphology in the hippocampal CA1 stratum radiatum, evidenced by light microscopy, of virgin and postpartum female rats.

PubMed

Brusco, Janaína; Wittmann, Raul; de Azevedo, Márcia S; Lucion, Aldo B; Franci, Celso R; Giovenardi, Márcia; Rasia-Filho, Alberto A

2008-06-27

Successful reproduction requires that changes in plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oxytocin (OT), estrogen (E(2)) and progesterone (P(4)) occur together with the display of maternal behaviors. Ovarian steroids and environmental stimuli can affect the dendritic spines in the rat hippocampus. Here, studying Wistar rats, it is described: (a) the sequential and concomitant changes in the hormonal profile of females at postpartum days (PP) 4, 8, 12, 16, 20 and 24, comparing to estrous cycle referential values; (b) the dendritic spine density in the stratum radiatum of CA1 (CA1-SR) Golgi-impregnated neurons in virgin females across the estrous cycle and in multiparous age-matched ones; and (c) the proportion of different types of spines in the CA1-SR of virgin and postpartum females, both in diestrus. Plasma levels of gonadotrophins and ovarian hormones remained low along PP while LH increased and PRL decreased near the end of the lactating period. The lowest dendritic spine density was found in virgin females in estrus when compared to diestrus and proestrus phases or to postpartum females in diestrus (p<0.03). Other comparisons among groups were not statistically significant (p>0.4). There were no differences in the proportions of the different spine types in nulliparous and postpartum females (p>0.2). Results suggest that medium layer CA1-SR spines undergo rapid modifications in Wistar females across the estrous cycle (not quite comparable to Sprague-Dawley data or to hormonal substitutive therapy following ovariectomy), but persistent effects of motherhood on dendritic spine density and morphology were not found in this area.

Effect of Citrullus colocynthis hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOs rats model: An experimental study

PubMed Central

Barzegar, Mohammad Hossein; Khazali, Homayoun; Kalantar, Seyyed Mehdi; Khoradmehr, Arezoo

2017-01-01

Background: Citrullus colocynthis (CCT) is used as the anti-diabetic and antioxidant agent. Polycystic ovarian syndrome (PCOS) is a reproductive disorder which level of gonadotropins and sexual hormones are imbalanced. Objective: We evaluated the effect of CCT hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOs rats’ model. Materials and Methods: 40 female adult Wistar rats divided into five groups (n=8each: Group I (control) only injected by sesame oil as estradiol valerate solvent, group II (Sham) was orally received normal saline after estradiol valerate- induced polycystic ovarian syndrome (4 mg/rat estradiol valerate, intramuscularly), and three experimental groups, that after induction of PCOS within 60 days, received orally 50 mg/kg CCT extract (group III), 50mg/kg metformin (group IV), and CCT extract+ metformin (group V) for 20 days. The serum concentration level of luteinizing, testosterone and follicle stimulating hormones were measured using ELISA method and the serum concentration level of glucose were measured using the oxidative method (glucose meter). Histological study of ovary tissue carried out by hematoxylin-eosin staining. Results: There was a significant reduction in luteinizing hormone and testosterone in III-V groups compared to Sham group, whereas follicle stimulating hormone in III-V groups was not significantly changed in comparison with Sham group. Histological investigations showed a significant increase in number of preantral and antral follicles and corpus luteum in the experimental groups compared to group II. Conclusion: Marked improvement in hormonal and histological symptoms of PCOS may be due to CCT effects hence, CCT can potentially be considered as an effective drug for treatment of PCOS. PMID:29387832

Comparison of early morphological and molecular changes induced by 17-alpha-methyltestosterone and estradiol benzoate in the rat ovary.

PubMed

Ferre, Céline; Belluco, Sara; Tinwell, Helen; Bars, Rémi; Benahmed, Mohamed; Rouquie, David; Schorsch, Frédéric

2013-05-01

Repeated exposure to 17-α-methyltestosterone (17MT) and estradiol benzoate (EB) for 28 or 90 days in rats induce similar ovarian atrophy. The objective of the present work was to identify and compare the early effects induced by 17MT and EB on the ovary using molecular and histopathological tools. Female rats were evaluated after 1, 3 or 7 days following an oral exposure by gavage at a daily dose of 600 mg/kg/day for 17MT and 5 mg/kg/day for EB. All animals were found to be acyclic after 3 or 7 days of treatment with 17MT and EB. Histopathological changes were present in the ovary, uterus, vagina and mammary gland after both treatments. Ovarian atrophy known as the long term effect of 17MT and EB was not yet detected after 7 days of treatment. But non regressive corpora lutea and cystic follicles were identically observed in the ovary of 17MT and EB treated females. Both compounds induced a decrease of LH transcripts together with an increase of plasma progesterone and prolactin levels. Differences in the profile of regulation of the aromatase were noted after 1 and 3 days of treatment in 17MT treated animals (upregulated) when compared to EB treated animals (downregulated). In summary, we have shown that despite the different nature of hormonal activity, EB and 17MT induce very early endocrine perturbation which presents several similarities. Our work indicated that the detection of early key hormonal markers in short term studies can help to predict the adverse long term effects on target tissues. Copyright © 2012 Elsevier GmbH. All rights reserved.

The orexigenic effect of melanin-concentrating hormone (MCH) is influenced by sex and stage of the estrous cycle

PubMed Central

Santollo, Jessica; Eckel, Lisa A.

2008-01-01

Recently, it was shown that that the orexigenic effect of melanin concentrating hormone (MCH) is attenuated by estradiol treatment in ovariectomized (OVX) rats. This suggests that female rats may be less responsive than male rats to the behavioral effects of MCH. To investigate this hypothesis, the effects of lateral ventricular infusions of MCH on food intake, water intake, meal patterns, and running wheel activity were examined in male and female rats. To further characterize the impact of estradiol on MCH-induced food intake, female rats were OVX and tested with and without 17-β-estradiol benzoate (EB) replacement. In support of our hypothesis, food and water intakes following MCH treatment were greater in male rats, relative to female rats. Specifically, the orexigenic effect of MCH was maximal in male rats and minimal in EB-treated OVX rats. In both sexes, the orexigenic effect of MCH was mediated by a selective increase in meal size, which was attenuated in EB-treated OVX rats. MCH induced a short-term (2 h) decrease in wheel running that, unlike its effects on ingestive behavior, was similar in males and females. Thus, estradiol decreases some, but not all, of the behavioral effects of MCH. To examine the influence of endogenous estradiol, food intake was monitored following MCH treatment in ovarian-intact, cycling rats. As predicted by our findings in OVX rats, the orexigenic effect of MCH was attenuated in estrous rats, relative to diestrous rats. We conclude that the female rat’s reduced sensitivity to the orexigenic effect of MCH may contribute to sex- and estrous cycle-related differences in food intake. PMID:18191424

Primary Ovarian Insufficiency Induced by Fanconi Anemia E Mutation in a Mouse Model.

PubMed

Fu, Chun; Begum, Khurshida; Overbeek, Paul A

2016-01-01

In most cases of primary ovarian insufficiency (POI), the cause of the depletion of ovarian follicles is unknown. Fanconi anemia (FA) proteins are known to play important roles in follicular development. Using random insertional mutagenesis with a lentiviral transgene, we identified a family with reduced fertility in the homozygous transgenic mice. We identified the integration site and found that the lentivirus had integrated into intron 8 of the Fanconi E gene (Fance). By RT-PCR and in situ hybridization, we found that Fance transcript levels were significantly reduced. The Fance homozygous mutant mice were assayed for changes in ovarian development, follicle numbers and estrous cycle. Ovarian dysplasias and a severe lack of follicles were seen in the mutant mice. In addition, the estrous cycle was disrupted in adult females. Our results suggest that POI has been induced by the Fance mutation in this new mouse model.

Premature ovarian insufficiency in young girls: repercussions on uterine volume and bone mineral density.

PubMed

Bakhsh, Hanadi; Dei, Metella; Bucciantini, Sandra; Balzi, Daniela; Bruni, Vincenzina

2015-01-01

To evaluate biological differences among young subjects with premature ovarian insufficiency (POI) commencing at different stages of life. Retrospective observational study. Careggi University Hospital Participants: One hundred sixty-two females aged between 15 and 29 years with premature ovarian insufficiency. Data were collected as a retrospective chart review of baseline evaluation at diagnosis of premature ovarian insufficiency (POI). About 162 participants were divided into four groups based on gynecological age. Two primary outcome variables (uterine development and bone mineral density (BMD)) were analyzed in terms of differences among groups and in a multivariate logistic regression analysis. Uterine development was clearly jeopardized when estrogen insufficiency started at a very young age. Total body BMD showed significant differences among the four groups studied, clearly corresponding to the duration of ovarian function. Data were discussed in relation to the choice of hormone replacement therapy regimens.

Coffee, tea, and caffeine consumption and risk of epithelial ovarian cancer and borderline ovarian tumors: Results from a Danish case-control study.

PubMed

Gosvig, Camilla F; Kjaer, Susanne K; Blaakær, Jan; Høgdall, Estrid; Høgdall, Claus; Jensen, Allan

2015-01-01

Epidemiological studies that have investigated the association between coffee, tea and caffeine consumption and ovarian cancer risk have produced conflicting results. Furthermore, only few studies have examined the role of coffee and tea consumption separately for borderline ovarian tumors. By use of data from a large Danish population-based case-control study, we examined the risk of ovarian tumors associated with coffee, tea, and caffeine consumption with a particular focus on characterizing risks by tumor behavior and histology. From 1995 through 1999, we included 267 women with ovarian cancer, 115 women with borderline ovarian tumors and 911 randomly selected control women. All women completed a beverage frequency questionnaire with detailed information on coffee and tea consumption. Analyses were performed using multiple logistic regression models. Both coffee (OR = 0.90; 95% CI 0.84-0.97 per cup/day) and total caffeine consumption from coffee and tea combined (OR = 0.93; 95% CI 0.88-0.98 per 100 mg/day) decreased the risk of ovarian cancer. These associations were significant only for the serous and "other" subtypes of ovarian cancer. No relation between tea consumption and ovarian cancer risk was observed. The risk estimates for borderline ovarian tumors resembled those observed for ovarian cancer, but did not reach statistical significance. Our results indicate that coffee consumption and total caffeine consumption from coffee and tea combined is associated with a modest decreased risk of ovarian cancer. However, more biological studies are needed to identify bioactive chemical compounds in coffee that potentially could affect ovarian cancer development.

Prolonged use of alendronate alters the biology of cranial repair in estrogen-deficient rats' associated simultaneous immunohistochemical expression of TGF-β1+, α-ER+, and BMPR1B.

PubMed

Giovanini, Allan Fernando; de Sousa Passoni, Giuliene Nunes; Göhringer, Isabella; Deliberador, Tatiana Miranda; Zielak, João Cesar; Storrer, Carmem Lucia Muller; Costa-Casagrande, Thais Andrade; Scariot, Rafaela

2018-06-01

TGF-β1 is a cytokine that may induce both osteoneogenesis through Runx-2 or fibrosis via the transcription of α-smooth muscle actin (α-SMA). Because it has been previously known that alendronate increases the level of TGF-β1 and that under the usual condition of bone metabolism the estrogen may prevent the fibrotic effect of TGF-β1, the aim of this study was to evaluate if alendronate alters the cellular differentiation process post calvarial surgery in estrogen-deficient specimens. A transosseous defect that was 5 mm in diameter was created on the calvarium of each of 32 female rats with previous ovarian-salpingo-oophorectomy. All defects were treated with autografts, and 16 rats received the administration of 1 mg/kg of alendronate three times a week until euthanasia on the 15th and 60th day post surgery. Histomorphometric and immunohistochemical analyses of the expression of TGF-β1, estrogen receptor alpha nuclear (α-ER), α-SMA, BMPR1B, and Runx-2 were performed, and ELISA was used to measure the level of estrogen. All animals demonstrated low levels of estrogen post ovarian-salpingo-oophorectomy. The histological results demonstrated larger bone matrix deposition in specimens treated with alendronate on the 15th day post surgery. The result was associated with a higher co-expression of TGF-β1, BMPR1B, and Runx-2 when compared with the control group. In addition, on the 60th day post surgery, the increase of bone matrix deposition from 15th to 60th day was discrete in specimens treated with alendronate compared with the control group. This result coincided with the intense simultaneous expression of TGF-β1, α-ER, and α-SMA, whereas the expression of BMPR1B and Runx-2 decreased. The prolonged administration of alendronate altered the cranial repair in ovarian-salpingo-oophorectomized specimens due to the simultaneous occurrence of low estrogen and the presence of TGF-β1+/α-ER+ inducing the presence of α-SMA + , whereas BMPR1B and Runx-2 were suppressed. The prolonged administration of alendronate alters osteoneogenesis and induces an unusual microenvironment in the bone that seems to imitate the physiological tissue damage that culminates in the loss of the functional layer of endometrium.

Neurotrophin NT3 promotes ovarian primordial to primary follicle transition

PubMed Central

Nilsson, Eric; Dole, Gretchen; Skinner, Michael K

2017-01-01

Neurotrophins are growth factors that are known to have a role in promoting cell survival and differentiation. The focus of the current study is to examine the role of neurotrophins in regulating ovarian primordial follicle development. Ovaries from 4-day old rats were placed into organ culture and cultured for 10 days in the absence or presence of neurotrophin-3 (NT3), brain-derived neurotrophic factor (BDNF), or nerve growth factor (NGF). Treatment of ovaries with NT3 resulted in a significant (P<0.01) increase in primordial follicle development (i.e. primordial to primary follicle transition). Treatment with BDNF at high doses of 100–250 ng/ml also significantly (P<0.01) increased primordial follicle development, but NGF had no effect. Immunohistochemical studies determined that NT3 was present in granulosa cells, interstitial tissue, and in the oocytes of primordial and primary follicles. The NT3 receptor NTRK3 was present in oocytes at all stages of development. Analysis of ovaries that contain predominantly primordial follicles demonstrated the transcripts for NT3, NTRK3, NGF, and the BDNF/neurotrophin-4 (NT4) receptor NTRK2 are expressed, while BDNF, NT4, and the NGF receptor NTRK1 are not detectable. Inhibition of the NTRK3 receptor with the tyrphostin AG 879 resulted in oocyte death and a significant (P<0.01) reduction in follicle pool size. Inhibition of the NTRK receptors with K252a slowed primordial to primary follicle transition. A microarray analysis demonstrated that a small number of genes were differentially expressed after NT3 treatment. Observations indicate that the neurotrophin NT3, acting through the NTRK3 receptor in oocytes, promotes the primordial to primary follicle transition. PMID:19584175

78 FR 54741 - National Ovarian Cancer Awareness Month, 2013

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-06

..., women with a family history of breast or ovarian cancer, and those who have had certain types of cancer... Proclamation Each September, America calls attention to a deadly disease that affects thousands of women across our country. This year, over 22,000 women will develop ovarian cancer, and more than half that number...

Hyberbaric oxygen increases atresia in normal & steroid induced PCO rat ovaries

PubMed Central

2012-01-01

Background In this study, we investigated the effect of hyperbaric oxygen therapy (HBOT) on the morphology of estradiol valerate (EV) induced polycystic ovary (PCO) to find a new treatment modality for improvement of PCO. Methods The rats were divided into four groups. Group1, control; group 2, PCO group; group 3, PCO with HBOT group and group 4, normal ovary with HBOT. PCO was induced by a single intramuscular injection of 4 mg EV in adult cycling rats. Other rats with normal ovaries had oil injection as placebo. HBOT was applied to third and fourth groups for six weeks. Histopathologic evaluation of ovaries of all groups were performed & compared. Results Six weeks of HBOT was resulted in increase in follicular atresia, decrease in the number of primary, secondary, tertiary follicles and decrease in the number of fresh corpus luteum in normal rat ovary. HBOT on polycystic rat ovary, resulted in significant increase in atretic follicles which were already present. Conclusions HBOT of six weeks itself, changed ovarian morphology in favor of atresia both in PCO group and control group. This result of aggravated follicular atresia after HBOT on EV induced PCO may be due to long-term exposure in our protocol which with this state seems to be inapplicable in the improvement of PCO morphology. PMID:22309835

Secondary Primary Malignancy Risk in Patients With Ovarian Cancer in Taiwan: A Nationwide Population-Based Study.

PubMed

Hung, Yi-Ping; Liu, Chia-Jen; Hu, Yu-Wen; Chen, Min-Huang; Li, Chun-Pin; Yeh, Chiu-Mei; Chiou, Tzeon-Jye; Chen, Tzeng-Ji; Yang, Muh-Hwa; Chao, Yee

2015-09-01

To evaluate the incidence of secondary primary malignancy (SPM) in patients with ovarian cancer using a nationwide retrospective population-based dataset. Patients newly diagnosed with ovarian cancer between 1997 and 2010 were identified using Taiwan's National Health Insurance database. Patients with antecedent malignancies were excluded. Standardized incidence ratios (SIRs) for SPM were calculated and compared with the cancer incidence in the general population. Risk factors for cancer development were analyzed using Cox proportional hazard models. Effects of surgery, chemotherapy, and radiotherapy after ovarian cancer diagnosis were regarded as time-dependent variables to prevent immortal time bias. During the 14-year study period (follow-up of 56,214 person-years), 707 cancers developed in 12,127 patients with ovarian cancer. The SIR for all cancers was 2.78 (95% confidence interval 2.58-3.00). SIRs for follow-up periods of >5, 1-5, and <1 year were 1.87, 2.04, and 6.40, respectively. After the exclusion of SPM occurring within 1 year of ovarian cancer diagnosis, SIRs were significantly higher for cancers of the colon, rectum, and anus (2.14); lung and mediastinum (1.58); breast (1.68); cervix (1.65); uterus (7.96); bladder (3.17), and thyroid (2.23); as well as for leukemia (3.98) and others (3.83). Multivariate analysis showed that age ≥ 50 years was a significant SPM risk factor (hazard ratio [HR] 1.60). Different treatments for ovarian cancer, including radiotherapy (HR 2.07) and chemotherapy (HR 1.27), had different impacts on SPM risk. Patients with ovarian cancer are at increased risk of SPM development. Age ≥ 50 years, radiotherapy, and chemotherapy are independent risk factors. Close surveillance of patients at high risk should be considered for the early detection of SPM.

Ovarian sensitivity index is strongly related to circulating AMH and may be used to predict ovarian response to exogenous gonadotropins in IVF

PubMed Central

2011-01-01

Background Serum anti-Mullerian hormone (AMH) is currently considered the best marker of ovarian reserve and of ovarian responsiveness to gonadotropins in in-vitro fertilization (IVF). AMH assay, however, is not available in all IVF Units and is quite expensive, a reason that limits its use in developing countries. The aim of this study is to assess whether the "ovarian sensitivity index" precisely reflects AMH so that this index may be used as a surrogate for AMH in prediction of ovarian response during an IVF cycle. Methods AMH serum levels were measured in 61 patients undergoing IVF with a "long" stimulation protocol including the GnRH agonist buserelin and recombinant follicle-stimulating hormone (rFSH). Patients were divided into four subgroups according to the percentile of serum AMH and their ovarian stimulation was prospectively followed. Ovarian sensitivity index (OSI) was calculated dividing the total administered FSH dose by the number of retrieved oocytes. Results AMH and OSI show a highly significant negative correlation (r = -0.67; p = 0.0001) that is stronger than the one between AMH and the total number of retrieved oocytes and than the one between AMH and the total FSH dose. Conclusions OSI reflects quite satisfactory the AMH level and may be proposed as a surrogate of AMH assay in predicting ovarian responsiveness to FSH in IVF. Being very easy to calculate and costless, its use could be proposed where AMH measurement is not available or in developing countries where limiting costs is of primary importance. PMID:21824441

Screening for ovarian cancer in women with varying levels of risk, using annual tests, results in high recall for repeat screening tests

PubMed Central

2011-01-01

Background We assessed ovarian cancer screening outcomes in women with a positive family history of ovarian cancer divided into a low-, moderate- or high-risk group for development of ovarian cancer. Methods 545 women with a positive family history of ovarian cancer referred to the Ovarian Screening Service at the Royal Marsden Hospital, London from January 2000- December 2008 were included. They were stratified into three risk-groups according to family history (high-, moderate- and low-risk) of developing ovarian cancer and offered annual serum CA 125 and transvaginal ultrasound screening. The high-risk group was offered genetic testing. Results The median age at entry was 44 years. The number of women in the high, moderate and low-risk groups was 397, 112, and 36, respectively. During 2266 women years of follow-up two ovarian cancer cases were found: one advanced stage at her fourth annual screening, and one early stage at prophylactic bilateral salpingo-oophorectomy (BSO). Prophylactic BSO was performed in 138 women (25.3%). Forty-three women had an abnormal CA125, resulting in 59 repeat tests. The re-call rate in the high, moderate and low-risk group was 14%, 3% and 6%. Equivocal transvaginal ultrasound results required 108 recalls in 71 women. The re-call rate in the high, moderate, and low-risk group was 25%, 6% and 17%. Conclusion No early stage ovarian cancer was picked up at annual screening and a significant number of re-calls for repeat screening tests was identified. PMID:22112691

Cytotoxic T cell clones isolated from ovarian tumor-infiltrating lymphocytes recognize multiple antigenic epitopes on autologous tumor cells.

PubMed

Ioannides, C G; Freedman, R S; Platsoucas, C D; Rashed, S; Kim, Y P

1991-03-01

CTL clones were developed from tumor infiltrating lymphocytes (TIL) from the ascites of a patient with ovarian carcinoma by coculture of TIL with autologous tumor cells and subsequent cloning in the presence of autologous tumor cells. These CTL clones expressed preferential cytolytic activity against autologous tumor cells but not against allogeneic ovarian tumor cells and the NK-sensitive cell line K562. The cytolytic activity of these CTL against autologous tumors was inhibited by anti-TCR (WT31 mAb), anti-HLA class I, and anti-CD3 mAb but not by the NK function antibody Leu 11b. Cloning of the autologous tumor cells in vitro revealed that the CTL clones of the ovarian TIL expressed differential abilities to lyse autologous tumor cell clones. The specificity analysis of these autologous tumor specific CTL suggested that they recognize several antigenic determinants present on the ovarian tumor cells. Our results indicate the presence of at least three antigenic epitopes on the tumor cells (designated OVA-1A, OVA-1B, and OVA-1C), one of which (OVA-1C) is unstable. These determinants are present either simultaneously or separately, and six types of ovarian clones can be distinguished on the basis of their expression. These results indicate that CTL of the TIL detect intratumor antigenic heterogeneity. The novel heterogeneity identified within the ovarian tumor cells in this report may be of significance for understanding cellular immunity in ovarian cancer and developing adoptive specific immunotherapeutic approaches in ovarian cancer.

FOXL2 activates P450 aromatase gene transcription: towards a better characterization of the early steps of mammalian ovarian development.

PubMed

Pannetier, Maëlle; Fabre, Stéphane; Batista, Frank; Kocer, Ayhan; Renault, Lauriane; Jolivet, Geneviève; Mandon-Pépin, Béatrice; Cotinot, Corinne; Veitia, Reiner; Pailhoux, Eric

2006-06-01

Previous studies have equated FOXL2 as a crucial actor in the ovarian differentiation process in different vertebrate species. Its transcriptional extinction in the polled intersex syndrome (PIS) leads primarily to a drastic decrease of aromatase (CYP19) expression in the first steps of goat ovarian development. In this study, we provide a better characterization of early ovarian development in goat, and we provide experimental evidence demonstrating that FOXL2 represents a direct transcriptional activator of the CYP19 gene through its ovarian-specific promoter 2. Moreover, the ovarian location of FOXL2 and CYP19 proteins, together with their expression profiles in the female gonads, stress the involvement of FOXL2 co-factor(s) for regulating CYP19 transcription. Expressional analyses show that activin-betaA can be considered as a strong candidate for being one of these FOXL2 co-factors. Finally, we discuss evidence for a role of activin and estrogens in somatic and germinal cell proliferation occurring before germ cell meiosis. This period, of 20 days in goat, seems to have no equivalent in mouse. This species-specific difference could explain the phenotype discrepancy observed between XX goat PIS(-/-) and XX mouse Foxl2(-/-).

Hawaii natural compounds are promising to reduce ovarian cancer deaths.

PubMed

Fei-Zhang, David J; Li, Chunshun; Cao, Shugeng

2016-07-02

The low survival rate of patients with ovarian cancer largely results from the advanced ovarian tumors as well as tumor resistance to chemotherapy, leading to metastasis and recurrence. However, it is missing as to an effective therapeutic approach that focuses on these aspects to prolong progression-free survival and to decrease mortality in ovarian cancer patients. Here, based on our cancer drug discovery studies, we provide prospective insights into the development of a future line of drugs to effectively reduce ovarian cancer deaths. Pathways that increase the probability of cancer, such as the defective Fanconi anemia (FA) pathway, may render cancer cells more sensitive to new drug targeting.

Identification of miRNA Signatures Associated with Epithelial Ovarian Cancer Chemoresistance with Further Biological and Functional Validation of Identified Key miRNAS

DTIC Science & Technology

2016-04-01

hindered by the unreliable analytical results owing largely to biocompatibility problems induced by sensorimplantation (e.g., inflammatory/foreign body...sensors with outer polymeric coatings that slowlygenerate low levels of nitric oxide (NO). Release of NO has been shown to enhance the biocompatibility ...Preliminary biocompatibility experimentssuggested that RSNO levels within the SQ fluid of rats may be sufficient to generate enough local NO to

GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile.

PubMed

Chaudhari, Nirja; Dawalbhakta, Mitali; Nampoothiri, Laxmipriya

2018-04-11

GnRH is the master molecule of reproduction that is influenced by several intrinsic and extrinsic factors such as neurotransmitters and neuropeptides. Any alteration in these regulatory loops may result in reproductive-endocrine dysfunction such as the polycystic ovarian syndrome (PCOS). Although low dopaminergic tone has been associated with PCOS, the role of neurotransmitters in PCOS remains unknown. The present study was therefore aimed at understanding the status of GnRH regulatory neurotransmitters to decipher the neuroendocrine pathology in PCOS. PCOS was induced in rats by oral administration of letrozole (aromatase inhibitor). Following PCOS validation, animals were assessed for gonadotropin levels and their mRNA expression. Neurotrasnmitter status was evaluated by estimating their levels, their metabolism and their receptor expression in hypothalamus, pituitary, hippocampus and frontal cortex of PCOS rat model. We demonstrate that GnRH and LH inhibitory neurotransmitters - serotonin, dopamine, GABA and acetylcholine - are reduced while glutamate, a major stimulator of GnRH and LH release, is increased in the PCOS condition. Concomitant changes were observed for neurotransmitter metabolising enzymes and their receptors as well. Our results reveal that increased GnRH and LH pulsatility in PCOS condition likely result from the cumulative effect of altered GnRH stimulatory and inhibitory neurotransmitters in hypothalamic-pituitary centre. This, we hypothesise, is responsible for the depression and anxiety-like mood disorders commonly seen in PCOS women.

Protective effects of D-Trp6-luteinising hormone-releasing hormone microcapsules against cyclophosphamide-induced gonadotoxicity in female rats.

PubMed

Bokser, L; Szende, B; Schally, A V

1990-06-01

The possible protective effect of an agonist of luteinising hormone-releasing hormone (LH-RH) against the ovarian damage caused by cyclophosphamide was investigated in rats. D-Trp6-LH-RH microcapsules were injected once a month for 3 months, in a dose calculated to release 25 micrograms day-1. Control animals received the injection vehicle. Sixty days after the first injection of microcapsules, cyclophosphamide was given at a loading dose of 50 mg kg-1 followed by 5 mg kg-1 day-1 for 30 days, while the treatment with D-Trp6-LH-RH was continued. When the ovaries were examined 3 months and 5 months after discontinuation of treatment, a significant reduction in the total number of follicles (P less than 0.01) was found in non-pretreated animals given cyclophosphamide. This reduction affected mainly follicles larger than 100 microns. An irreversible disintegration and destruction of granulosa cells was also observed in this group. In animals pretreated with D-Trp6-LH-RH, administration of cyclophosphamide caused no reduction in the number and diameter of follicles. Thus, the treatment with D-Trp6-LH-RH microcapsules before and during chemotherapy prevented the ovarian injury inflicted by cyclophosphamide. The suppression of gonadal function by LH-RH analogues could be possibly utilised for the protection of the ovaries against damage caused by cytotoxic drugs.

Protective effects of D-Trp6-luteinising hormone-releasing hormone microcapsules against cyclophosphamide-induced gonadotoxicity in female rats.

PubMed Central

Bokser, L.; Szende, B.; Schally, A. V.

1990-01-01

The possible protective effect of an agonist of luteinising hormone-releasing hormone (LH-RH) against the ovarian damage caused by cyclophosphamide was investigated in rats. D-Trp6-LH-RH microcapsules were injected once a month for 3 months, in a dose calculated to release 25 micrograms day-1. Control animals received the injection vehicle. Sixty days after the first injection of microcapsules, cyclophosphamide was given at a loading dose of 50 mg kg-1 followed by 5 mg kg-1 day-1 for 30 days, while the treatment with D-Trp6-LH-RH was continued. When the ovaries were examined 3 months and 5 months after discontinuation of treatment, a significant reduction in the total number of follicles (P less than 0.01) was found in non-pretreated animals given cyclophosphamide. This reduction affected mainly follicles larger than 100 microns. An irreversible disintegration and destruction of granulosa cells was also observed in this group. In animals pretreated with D-Trp6-LH-RH, administration of cyclophosphamide caused no reduction in the number and diameter of follicles. Thus, the treatment with D-Trp6-LH-RH microcapsules before and during chemotherapy prevented the ovarian injury inflicted by cyclophosphamide. The suppression of gonadal function by LH-RH analogues could be possibly utilised for the protection of the ovaries against damage caused by cytotoxic drugs. Images Figure 2 PMID:2142603

Effects of thermal regime on ovarian maturation and plasma sex steroids in farmed white sturgeon, Acipenser transmontanus

USGS Publications Warehouse

Webb, M.A.H.; Van Eenennaam, J. P.; Feist, G.W.; Linares-Casenave, J.; Fitzpatrick, M.S.; Schreck, C.B.; Doroshov, S.I.

2001-01-01

Recently, commercial aquaculture farms in Northern California have exposed gravid, cultured white sturgeon females to cold water (12 ?? 1??C) throughout the late phase of vitellogenesis and ovarian follicle maturation resulting in improved ovulation rates and egg quality. However, the optimum timing for transfer of broodfish to the cold water and the capacity of transferred broodfish to maintain reproductive competence over an extended time in cold water had not been evaluated. Gravid white sturgeon females that have been raised at water temperatures of 16-20??C were transported to either cold water (12 ?? 1??C; Group 1) in November 1997 or maintained in ambient water temperatures (10-19??C; Group 2) until early spring. In March 1998, half of the fish in Group 2 had regressed ovaries, but the remaining females had intact ovarian follicles and were transported to the cold water. Ovarian follicles and blood were collected from females until they reached the stage of spawning readiness (determined by germinal vesicle position and an oocyte maturation assay) or underwent ovarian regression. Exposure of gravid sturgeon females to ambient water temperatures (14.5 ?? 2.3??C, mean ?? S.D.) from October to March led to a decrease in plasma sex steroids and a high incidence of ovarian regression in fish with a more advanced stage of oocyte development. Transfer of females with intact ovarian follicles to cold water (12 ?? 1??C) in the fall or early spring resulted in normal ovarian development in the majority of females. Holding females in cold water does not seem to override their endogenous reproductive rhythms but extends their capacity to maintain oocyte maturational competence over a longer period of time. A temperature-sensitive phase in ovarian development may occur during the transition from vitellogenic growth to oocyte maturation, and the degree and timing of sensitivity to environmental temperature are dependent on the female's endogenous reproductive rhythm. ?? 2001 Elsevier Science B.V. All Rights reserved.

Regulatory considerations on endpoints in ovarian cancer drug development.

PubMed

Balasubramaniam, Sanjeeve; Kim, Geoffrey S; McKee, Amy E; Pazdur, Richard

2017-07-15

Ovarian cancer remains a disease entity that is responsible for considerable morbidity and mortality among women worldwide. Modern drug research pipelines and accelerated drug development timelines applied to other disease entities have begun to make an impact on treatment options for patients with advanced ovarian cancer, as exemplified by the recent accelerated approval of 2 agents for this disease as the forerunners of a growing number of registrational trials. Regulatory flexibility for this serious and life-threatening condition spurs the consideration of intermediate endpoints for regulatory trial design, including potential applications in the development of newer therapeutic classes such as targeted therapies and immunotherapies for patients with advanced ovarian cancer. Cancer 2017;123:2604-8. © 2017 American Cancer Society. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Premature ovarian insufficiency: Pathogenesis and management

PubMed Central

Fenton, Anna J.

2015-01-01

The term premature ovarian insufficiency (POI) describes a continuum of declining ovarian function in a young woman, resulting in an earlier than average menopause. It is a term that reflects the variable nature of the condition and is substantially less emotive than the formerly used “premature ovarian failure” which signaled a single event in time. Contrary to the decline in the age of menarche seen over the last 3-4 decades there has been no similar change in the age of menopause. In developed nations, the average age for cessation of menstrual cycles is 50-52 years. The age is younger among women from developing nations. Much has been written about POI despite a lack of good data on the incidence of this condition. It is believed that 1% of women under the age of 40 years and 0.1% under the age of 30 years will develop POI. Research is increasingly providing information about the pathogenesis and treatments are being developed to better preserve ovarian function during cancer treatment and to improve fertility options. This narrative review summarizes the current literature to provide an approach to best practice management of POI. PMID:26903753

Tissue factor expression as a possible determinant of thromboembolism in ovarian cancer

PubMed Central

Uno, K; Homma, S; Satoh, T; Nakanishi, K; Abe, D; Matsumoto, K; Oki, A; Tsunoda, H; Yamaguchi, I; Nagasawa, T; Yoshikawa, H; Aonuma, K

2007-01-01

Ovarian cancer, and clear cell carcinoma in particular, reportedly increases the risk of venous thromboembolism (VTE). However, the mechanisms remain unclear. Tissue factor (TF) supposedly represents a major factor in the procoagulant activities of cancer cells. The present study examined the involvement of TF expression in VTE for patients with ovarian cancer. Subjects comprised 32 consecutive patients (mean age 49.8 years) with histologically confirmed ovarian cancer. Presence of VTE was examined using a combination of clinical features, D-dimer levels and venous ultrasonography. Immunohistochemical analysis was used to evaluate TF expression into 4 degrees. Venous thromboembolism was identified in 10 of the 32 patients (31%), including five of the 11 patients with clear cell carcinoma. Tissue factor expression was detected in cancer tissues from 24 patients and displayed significant correlations with VTE development (P=0.0003), D-dimer concentration (P=0.003) and clear cell carcinoma (P<0.05). Multivariate analysis identified TF expression as an independent predictive factor of VTE development (P<0.05). Tissue factor (TF) expression is a possible determinant of VTE development in ovarian cancer. In particular, clear cell carcinoma may produce excessive levels of TF and is more likely to develop VTE. PMID:17211468

Expression and clinical significance of the HIF-1a/ET-2 signaling pathway during the development and treatment of polycystic ovary syndrome.

PubMed

Wang, Fan; Zhang, Zhenghong; Wang, Zhaokai; Xiao, Kaizhuan; Wang, Qing; Su, Jingqian; Wang, Zhengchao

2015-04-01

Polycystic ovary syndrome (PCOS) is a major health problem in reproductive-aged women worldwide, but the precise pathogenesis of PCOS remains unclear. Our previous study revealed that hypoxia-inducible factor (HIF)-1a mediated endothelin (ET)-2 signaling plays an important role in ovulation in rats. Therefore, the present study used a PCOS rat model to test the hypotheses that HIF-1a signaling is expressed and inhibited in ovaries during PCOS formation and that the HIF-1a/ET-2 signaling pathway is a target of dimethyldiguanide (DMBG) in the clinical treatment of PCOS. First, the development of a PCOS model and the effect of DMBG treatment were examined through ovarian histology and serum hormone levels, which were consistent with previous reports. Second, HIF-1a and ET-2 expression were detected by immunohistochemistry and western blot. The results showed decreased HIF-1a/ET-2 expression in the ovaries of PCOS rats, whereas DMBG treatment reversed the protein decreases and improved the PCOS symptoms. Third, to understand the molecular mechanism, HIF-1a/ET-2 mRNA expression was also examined. Interestingly, HIF-1a mRNA increased in the ovaries of PCOS rats, while ET-2 mRNA decreased, indicating that HIF-1a protein degradation may be involved in POCS development and treatment. Finally, HIF prolyl hydroxylase (PHD) activity was examined to further clarify the contribution of HIF-1a signaling to the development and treatment of PCOS. The results suggested that the inhibition of HIF-1a/ET-2 signaling may be caused by increased PHD activity in PCOS. DMBG-treated PCOS may further activate HIF-1a signaling at least partly through inhibiting PHD activity. Taken together, these results indicate that HIF-1a signaling is inhibited in a PCOS rat model through increasing PHD activity. DMBG treatment improved PCOS by rescuing this pathway, suggesting that HIF-1a signaling plays an important role in the development and treatment of PCOS. This HIF-1a-mediated ET-2 signaling pathway may be an important mechanism regulating PCOS formation and treatment in mammalian ovaries in vivo and should be a new clinical target for PCOS prevention and treatment in the future.

Modulation of ovarian steroidogenesis by adiponectin during delayed embryonic development of Cynopterus sphinx.

PubMed

Anuradha; Krishna, Amitabh

2014-09-01

The aim of present study was to evaluate role of adiponectin in ovarian steroidogenesis during delayed embryonic development of Cynopterus sphinx. This study showed significantly low circulating adiponectin level and a decline in expression of adiponectin receptor 1 (AdipoR1) in the ovary during the period of delayed embryonic development as compared with the normal development. The adiponectin treatment in vivo during the period of delayed development caused significantly increased in circulating progesterone and estradiol levels together with increased expression of AdipoR1 in the ovary. The in vitro study confirmed the stimulatory effect of adiponectin on progesterone synthesis. Both in vivo and in vitro studies showed that the effects of adiponectin on ovarian steroidogenesis were mediated through increased expression of luteinizing hormone-receptor, steroidogenic acute regulatory protein and 3β-hydroxyl steroid dehydrogenase enzyme. The adiponectin treatment may also promote progesterone synthesis by modulating ovarian angiogenesis, cell survival and rate of apoptosis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Role of juvenile hormone and allatotropin on nutrient allocation, ovarian development and survivorship in mosquitoes

PubMed Central

Hernández-Martínez, Salvador; Mayoral, Jaime G.; Li, Yiping; Noriega, Fernando G.

2009-01-01

Teneral reserves are utilized to initiate previtellogenic ovarian development in mosquitoes. Females having emerged with low teneral reserves have reduced juvenile hormone (JH) synthesis and previtellogenic development. We investigated what role JH, allatotropin (AT) and other head-factors play in the regulation of previtellogenic ovarian development and adult survivorship. Factors from the head are essential for corpora allata (CA) activation and reproductive maturation. We have shown that decapitation of females within 9–12 h after adult ecdysis prevented normal development of the previtellogenic follicles; however maximum previtellogenic ovarian development could be induced in decapitated females by topically applying a JH analog. When females were decapitated 12 or more hours after emergence nutritional resources had been committed to ovarian development and survivorship was significantly reduced. To study if allatotropin levels correlated with teneral reserves, we measured AT titers in the heads of two adult phenotypes (large and small females) generated by raising larvae under different nutritional diets. In large mosquitoes AT levels increased to a maximum of 45 fmol in day 4; in contrast, the levels of allatotropin in the heads of small mosquitoes remained below 9 fmol during the 7 days evaluated. These results suggest that only when nutrients are appropriate, factors released from the brain induce the CA to synthesize enough JH to activate reproductive maturation. PMID:17070832

Methoxyphenyl chalcone sensitizes aggressive epithelial cancer to cisplatin through apoptosis induction and cancer stem cell eradication.

PubMed

Su, Yu-Kai; Huang, Wen-Chien; Lee, Wei-Hwa; Bamodu, Oluwaseun Adebayo; Zucha, Muhammad Ary; Astuti, Indwiani; Suwito, Heri; Yeh, Chi-Tai; Lin, Chien-Min

2017-05-01

Current standard chemotherapy for late stage ovarian cancer is found unsuccessful due to relapse after completing the regimens. After completing platinum-based chemotherapy, 70% of patients develop relapse and resistance. Recent evidence proves ovarian cancer stem cells as the source of resistance. Therefore, treatment strategy to target both cancer stem cells and normal stem cells is essential. In this study, we developed a novel chalcone derivative as novel drug candidate for ovarian cancer treatment. We found that methoxyphenyl chalcone was effective to eliminate ovarian cancer cells when given either as monotherapy or in combination with cisplatin. We found that cell viability of ovarian cancer cells was decreased through apoptosis induction. Dephosphorylation of Bcl2-associated agonist of cell death protein was increased after methoxyphenyl chalcone treatment that led to activation of caspases. Interestingly, this drug also worked as a G2/M checkpoint modulator with alternative ways of DNA damage signal-evoking potential that might work to increase response after cisplatin treatment. In addition, methoxyphenyl chalcone was able to suppress autophagic flux and stemness regulator in ovarian spheroids that decreased their survival. Therefore, combination of methoxyphenyl chalcone and cisplatin showed synergistic effects. Taken together, we believe that our novel compound is a promising novel therapeutic agent for effective clinical treatment of ovarian cancer.

Focused glycomic analysis of the N-linked glycan biosynthetic pathway in ovarian cancer

PubMed Central

Abbott, Karen L.; Nairn, Alison V.; Hall, Erica M.; Horton, Marc B.; McDonald, John F.; Moremen, Kelley W.; Dinulescu, Daniela M.; Pierce, Michael

2014-01-01

Epithelial ovarian cancer is the deadliest female reproductive tract malignancy in Western countries. Less than 25% of cases are diagnosed when the cancer is confined, however, pointing to the critical need for early diagnostics for ovarian cancer. Identifying the changes that occur in the glycome of ovarian cancer cells may provide an avenue to develop a new generation of potential biomarkers for early detection of this disease. We performed a glycotranscriptomic analysis of endometrioid ovarian carcinoma using human tissue, as well as a newly developed mouse model that mimics this disease. Our results show that the N-linked glycans expressed in both non-diseased mouse and human ovarian tissues are similar; moreover, malignant changes in the expression of N-linked glycans in both mouse and human endometrioid ovarian carcinoma are qualitatively similar. Lectin reactivity was used as a means for rapid validation of glycan structural changes in the carcinomas that were predicted by the glycotranscriptome analysis. Among several changes in glycan expression noted, the increase of bisected N-linked glycans and the transcripts of the enzyme responsible for its biosynthesis, GnT-III, was the most significant. This study provides evidence that glycotranscriptome analysis can be an important tool in identifying potential cancer biomarkers. PMID:18690643

Ovarian Cancer Risk Prediction Models

Cancer.gov

Developing statistical models that estimate the probability of developing ovarian cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

Differential Expression of microRNAs in the Ovaries from Letrozole-Induced Rat Model of Polycystic Ovary Syndrome.

PubMed

Li, Dandan; Li, Chunjin; Xu, Ying; Xu, Duo; Li, Hongjiao; Gao, Liwei; Chen, Shuxiong; Fu, Lulu; Xu, Xin; Liu, Yongzheng; Zhang, Xueying; Zhang, Jingshun; Ming, Hao; Zheng, Lianwen

2016-04-01

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disorder. To understand the pathogenesis of PCOS, we established rat models of PCOS induced by letrozole and employed deep sequencing to screen the differential expression of microRNAs (miRNAs) in PCOS rats and control rats. We observed vaginal smear and detected ovarian pathological alteration and hormone level changes in PCOS rats. Deep sequencing showed that a total of 129 miRNAs were differentially expressed in the ovaries from letrozole-induced rat model compared with the control, including 49 miRNAs upregulated and 80 miRNAs downregulated. Furthermore, the differential expression of miR-201-5p, miR-34b-5p, miR-141-3p, and miR-200a-3p were confirmed by real-time polymerase chain reaction. Bioinformatic analysis revealed that these four miRNAs were predicted to target a large set of genes with different functions. Pathway analysis supported that the miRNAs regulate oocyte meiosis, mitogen-activated protein kinase (MAPK) signaling, phosphoinositide 3-kinase/Akt (PI3K-Akt) signaling, Rap1 signaling, and Notch signaling. These data indicate that miRNAs are differentially expressed in rat PCOS model and the differentially expressed miRNA are involved in the etiology and pathophysiology of PCOS. Our findings will help identify miRNAs as novel diagnostic markers and therapeutic targets for PCOS.

Metabolites from invasive pests inhibit mitochondrial complex II: A potential strategy for the treatment of human ovarian carcinoma?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferramosca, Alessandra, E-mail: alessandra.ferramosca@unisalento.it; Conte, Annalea; Guerra, Flora

The red pigment caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea can be accumulated and transferred along the trophic chain, with detrimental consequences on biodiversity and ecosystem functioning. Despite increasing research efforts to understand how caulerpin modifies fish physiology, little is known on the effects of algal metabolites on mammalian cells. Here we report for the first time the mitochondrial targeting activity of both caulerpin, and its closely related derivative caulerpinic acid, by using as experimental model rat liver mitochondria, a system in which bioenergetics mechanisms are not altered. Mitochondrial function was tested by polarographic andmore » spectrophotometric methods. Both compounds were found to selectively inhibit respiratory complex II activity, while complexes I, III, and IV remained functional. These results led us to hypothesize that both algal metabolites could be used as antitumor agents in cell lines with defects in mitochondrial complex I. Ovarian cancer cisplatin-resistant cells are a good example of cell lines with a defective complex I function on which these molecules seem to have a toxic effect on proliferation. This provided novel insight toward the potential use of metabolites from invasive Caulerpa species for the treatment of human ovarian carcinoma cisplatin-resistant cells. -- Highlights: •Novel insight toward the potential use of the algal metabolites for the treatment of human diseases. •Caulerpin and caulerpinic acid inhibit respiratory complex II activity. •Both algal metabolites could be used as antitumor agents in ovarian cancer cisplatin-resistant cells.« less

Preclinical activity of melflufen (J1) in ovarian cancer.

PubMed

Carlier, Charlotte; Strese, Sara; Viktorsson, Kristina; Velander, Ebba; Nygren, Peter; Uustalu, Maria; Juntti, Therese; Lewensohn, Rolf; Larsson, Rolf; Spira, Jack; De Vlieghere, Elly; Ceelen, Wim P; Gullbo, Joachim

2016-09-13

Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.

Preclinical activity of melflufen (J1) in ovarian cancer

PubMed Central

Viktorsson, Kristina; Velander, Ebba; Nygren, Peter; Uustalu, Maria; Juntti, Therese; Lewensohn, Rolf; Larsson, Rolf; Spira, Jack; De Vlieghere, Elly; Ceelen, Wim P.; Gullbo, Joachim

2016-01-01

Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration. PMID:27528037

Origins based clinical and molecular complexities of epithelial ovarian cancer.

PubMed

Muinao, Thingreila; Pal, Mintu; Boruah, Hari Prasanna Deka

2018-06-08

Ovarian cancer is the most lethal of all common gynaecological malignancies in women worldwide. Ovarian cancer comprises of >15 distinct tumor types and subtypes characterized by histopathological features, environmental and genetic risk factors, precursor lesions and molecular events during oncogenesis. Recent studies on gene signatures profiling of different subtypes of ovarian cancer have revealed significant genetic heterogeneity between and within each ovarian cancer histological subtype. Thus, an immense interest have shown towards a more personalized medicine for understanding the clinical and molecular complexities of four major types of epithelial ovarian cancer (serous, endometrioid, clear cell, and mucinous). As such, further in depth studies are needed for identification of molecular signalling network complexities associated with effective prognostication and targeted therapies to prevent or treat metastasis. Therefore, understanding the metastatic potential of primary ovarian cancer and therapeutic interventions against lethal ovarian cancer for the development of personalized therapies is very much indispensable. Consequently, in this review we have updated the key dysregulated genes of four major subtypes of epithelial carcinomas. We have also highlighted the recent advances and current challenges in unravelling the complexities of the origin of tumor as well as genetic heterogeneity of ovarian cancer. Copyright © 2017. Published by Elsevier B.V.

Immunohistochemical localization of HE4 in benign, borderline, and malignant lesions of the ovary.

PubMed

Georgakopoulos, Penelope; Mehmood, Saira; Akalin, Ali; Shroyer, Kenneth R

2012-11-01

Despite advances in the development of novel methods to improve treatment, ovarian carcinoma is still the leading cause of gynecologic cancer death in the United States and other industrialized nations. Improvements in the clinical outcome of ovarian cancer will be achieved if methods can be developed to enable the detection of these tumors at the earliest possible stage. Thus, it is critically important to identify and validate new biomarkers of ovarian cancer. HE4 expression was defined by immunohistochemical analysis of a wide range of benign, borderline, and malignant ovarian lesions, including serous, endometrioid, mucinous, and clear cell lesions of the ovary and in primary tubal carcinomas and the normal fallopian tube. At the cellular level, HE4 was highly expressed in malignant ovarian tumors and in a wide range of benign and borderline ovarian lesions. In addition, HE4 was highly expressed in primary fallopian tube carcinomas and benign fallopian tubal epithelial cells. These results support the conclusion that HE4 is widely expressed in most benign, borderline, and malignant lesions of the ovary and the fallopian tube. The detection of HE4 expression at high levels in some benign lesions and normal tissues suggests that HE4 could have limited specificity as a marker of ovarian or tubal carcinoma. Furthermore, the relatively weak expression that was observed in many ovarian carcinomas indicates that HE4 could fail to detect some cases of primary or recurrent disease.

Expression of motility-related molecule Cdc42 in endometrial tissue in women with adenomyosis and ovarian endometriomata.

PubMed

Goteri, Gaia; Ciavattini, Andrea; Lucarini, Guendalina; Montik, Nina; Filosa, Alessandra; Stramazzotti, Daniela; Biagini, Graziella; Tranquilli, Andrea Luigi

2006-09-01

To evaluate Cdc42 expression in eutopic and ectopic endometrial tissue in patients with adenomyosis and ovarian endometriotic cysts compared with patients without endometriosis. Experimental retrospective study. University hospital. Twenty-four patients with adenomyosis, 19 with ovarian endometriomata, and 9 with fibroids or benign ovarian cysts. Hysterectomy and bilateral oophorectomy. Immunostaining for Cdc42 of eutopic and ectopic endometrial tissues. In eutopic endometrium of patients with adenomyosis and with fibroids or benign ovarian cysts, the intensity of Cdc42 immunostaining was weaker, especially in the specialized stromal cells, compared with cases with ovarian endometriosis (chi(2) test, P=.003). Expression of Cdc42 in eutopic endometrium showed a trend to be higher in the secretory than in the proliferative phase and in patients with ovarian endometriotic cysts compared with patients with adenomyosis (unpaired t test, P=.005), especially in the proliferative phase. An abnormally high expression of Cdc42 in eutopic endometrium in the secretory phase may contribute to the development of ovarian endometriosis, but it does not seem to be involved in the pathogenesis of adenomyosis.

Prohibitin (PHB) inhibits apoptosis in rat granulosa cells (GCs) through the extracellular signal-regulated kinase 1/2 (ERK1/2) and the Bcl family of proteins.

PubMed

Chowdhury, Indrajit; Thompson, Winston E; Welch, Crystal; Thomas, Kelwyn; Matthews, Roland

2013-12-01

Mammalian ovarian follicular development is tightly regulated by crosstalk between cell death and survival signals, which include both endocrine and intra-ovarian regulators. Whether the follicle ultimately ovulates or undergoes atresia is dependent on the expression and actions of factors promoting follicular cell proliferation, differentiation or apoptosis. Prohibitin (PHB) is a highly conserved, ubiquitous protein that is abundantly expressed in granulosa cells (GCs) and associated with GC differentiation and apoptosis. The current study was designed to characterize the regulation of anti-apoptotic and pro-apoptotic factors in undifferentiated rat GCs (gonadotropin independent phase) governed by PHB. Microarray technology was initially employed to identify potential apoptosis-related genes, whose expression levels within GCs were altered by either staurosporine (STS) alone or STS in presence of ectopically over-expressed PHB. Next, immunoblot studies were performed to examine the expression patterns of selective Bcl-2 family members identified by the microarray analysis, which are commonly regulated in the intrinsic-apoptotic pathway. These studies were designed to measure protein levels of Bcl2 family in relation to expression of the acidic isoform (phosphorylated) PHB and the components of MEK-Erk1/2 pathway. These studies indicated that over-expression of PHB in undifferentiated GCs inhibit apoptosis which concomitantly results in an increased level of the anti-apoptotic proteins Bcl2 and Bclxl, reduced release of cytochrome c from mitochondria and inhibition of caspase-3 activity. In contrast, silencing of PHB expression resulted in change of mitochondrial morphology from the regular reticular network to a fragmented form, which enhanced sensitization of these GCs to the induction of apoptosis. Collectively, these studies have provided new insights on the PHB-mediated anti-apoptotic mechanism, which occurs in undifferentiated GCs through a PHB → Mek-Erk1/2 → Bcl/Bcl-xL pathway and may have important clinical implications.

Expression of progesterone receptor membrane component-2 within the immature rat ovary and its role in regulating mitosis and apoptosis of spontaneously immortalized granulosa cells.

PubMed

Griffin, Daniel; Liu, Xiufang; Pru, Cindy; Pru, James K; Peluso, John J

2014-08-01

Progesterone receptor membrane component 2 (Pgrmc2) mRNA was detected in the immature rat ovary. By 48 h after eCG, Pgrmc2 mRNA levels decreased by 40% and were maintained at 48 h post-hCG. Immunohistochemical studies detected PGRMC2 in oocytes and ovarian surface epithelial, interstitial, thecal, granulosa, and luteal cells. PGRMC2 was also present in spontaneously immortalized granulosa cells, localizing to the cytoplasm of interphase cells and apparently to the mitotic spindle of cells in metaphase. Interestingly, PGRMC2 levels appeared to decrease during the G1 stage of the cell cycle. Moreover, overexpression of PGRMC2 suppressed entry into the cell cycle, possibly by binding the p58 form of cyclin dependent kinase 11b. Conversely, Pgrmc2 small interfering RNA (siRNA) treatment increased the percentage of cells in G1 and M stage but did not increase the number of cells, which was likely due to an increase in apoptosis. Depleting PGRMC2 did not inhibit cellular (3)H-progesterone binding, but attenuated the ability of progesterone to suppress mitosis and apoptosis. Taken together these studies suggest that PGRMC2 affects granulosa cell mitosis by acting at two specific stages of the cell cycle. First, PGRMC2 regulates the progression from the G0 into the G1 stage of the cell cycle. Second, PGRMC2 appears to localize to the mitotic spindle, where it likely promotes the final stages of mitosis. Finally, siRNA knockdown studies indicate that PGRMC2 is required for progesterone to slow the rate of granulosa cell mitosis and apoptosis. These findings support a role for PGRMC2 in ovarian follicle development. © 2014 by the Society for the Study of Reproduction, Inc.

An Electron Microscope Study of the Rat Ovum

PubMed Central

Sotelo, J. Roberto; Porter, Keith R.

1959-01-01

This paper reports on the fine structure of rat oocytes at stages before ovulation, during maturation, fertilization, and early cleavage. The study includes parallel observations on light and electron microscope preparations with attempted correlations. The follicular cells of the ovarian egg are described as sending long processes through the zona pellucida to the egg surface where they mingle with thin projections from the egg itself. No open communication between follicle cell cytoplasm and egg cytoplasm was observed. During maturation and fertilization both types of processes are withdrawn from the zona. The germinal vesicle and later the pronuclei of the fertilized egg are characterized by numerous large nucleoli. These have the form of thick walled vesicles with diameters as great as 8 to 10 µ. The wall is dense in the EM image and appears to consist in part of small granules. The cytoplasm shows several inclusions including mitochondria of usual form and a Golgi component which has the typical fine structure and the distribution described by earlier light studies. Small dense particles, presumably RNP particles, are distributed throughout the cytoplasmic matrix and show no preference for membranes. The endoplasmic reticulum of the oocyte is represented by a scattering only of vesicles, but begins a more extensive and elaborate development with the onset of segmentation. One inclusion of the ooplasm, similar in size to mitochondria, receives special attention. It is a vesicular structure, containing a large number of small vesicles (10 to 50 mµ in diameter) and frequently a central density or nucleoid. They are referred to as multivesicular bodies. Such bodies are found in small number in the ovarian egg, but increase greatly in number during maturation and fertilization. It appears from the micrographs of eggs in these latter stages that these vesicular bodies break down and liberate their content of small vesicles to the surrounding ooplasm. Comments are provided on the apparent significance of the various observations. PMID:13654454

The rise of genomic profiling in ovarian cancer

PubMed Central

Previs, Rebecca A.; Sood, Anil K.; Mills, Gordon B.; Westin, Shannon N.

2017-01-01

Introduction Next-generation sequencing and advances in ‘omics technology have rapidly increased our understanding of the molecular landscape of epithelial ovarian cancers. Areas covered Once characterized only by histologic appearance and clinical behavior, we now understand many of the molecular phenotypes that underlie the different ovarian cancer subtypes. While the current approach to treatment involves standard cytotoxic therapies after cytoreductive surgery for all ovarian cancers regardless of histologic or molecular characteristics, focus has shifted beyond a ‘one size fits all’ approach to ovarian cancer. Expert commentary Genomic profiling offers potentially ‘actionable’ opportunities for development of targeted therapies and a more individualized approach to treatment with concomitant improved outcomes and decreased toxicity. PMID:27828713

Genetically engineered mouse models for epithelial ovarian cancer: are we there yet?

PubMed

Howell, Viive M

2014-03-01

The development of preclinical spontaneous genetically engineered mouse models (GEMMs) requires an understanding of the genetic basis of the human disease. Such robust models have proven invaluable for increasing understanding of human malignancies as well as identifying new biomarkers and testing new therapies for these diseases. While GEMMs have been reported for ovarian cancer, the majority have proven disappointing overall in their recapitulation of paired genetic and histological features especially for serous ovarian epithelial cancer. This review describes GEMMs for ovarian cancer, in particular, high grade serous ovarian cancer and assesses these in light of recent changes in our understanding of the human malignancy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of neonatal litter size and age on ovarian gene expression and follicular development in gilts

USDA-ARS?s Scientific Manuscript database

Gilts raised in small litters have greater ovulation rate, stay in the herd longer and produce more pigs. The objective was to understand how neonatal litter size affects gilt development. The hypothesis is that gilts reared in smaller litters have greater ovarian follicular development. Within 24 h...

Recent Progress in the Diagnosis and Treatment of Ovarian Cancer

PubMed Central

Jelovac, Danijela; Armstrong, Deborah K.

2013-01-01

Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Screening strategies using ultrasound and the cancer antigen (CA) 125 tumor marker are currently under study and may lower stage at diagnosis but have not yet been shown to improve survival. Women who have inherited a deleterious mutation in the BRCA1 or BRCA2 gene and those with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have the highest risk of developing ovarian cancer but account for only approximately 10% of those with the disease. Other less common and less well-defined genetic syndromes may increase the risk of ovarian cancer, but their contribution to genetic risk is small. A clear etiology for sporadic ovarian cancer has not been identified, but risk is affected by reproductive and hormonal factors. Surgery has a unique role in ovarian cancer, as it is used not only for diagnosis and staging but also therapeutically, even in patients with widely disseminated, advanced disease. Ovarian cancer is highly sensitive to chemotherapy drugs, particularly the platinum agents, and most patients will attain a remission with initial treatment. Recent advances in the delivery of chemotherapy using the intraperitoneal route have further improved survival after initial therapy. Although the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately develop disease recurrence. Chemotherapy for recurrent disease includes platinum-based, multiagent regimens for women whose disease recurs more than 6 to 12 months after the completion of initial therapy and sequential single agents for those whose disease recurs earlier. New targeted biologic agents, particularly those involved with the vascular endothelial growth factor pathway and those targeting the poly (ADP-ribose) polymerase (PARP) enzyme, hold great promise for improving the outcome of ovarian cancer. PMID:21521830

Temporary ovarian suppression during chemotherapy to preserve ovarian function and fertility in breast cancer patients: A GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.

PubMed

Lambertini, Matteo; Cinquini, Michela; Moschetti, Ivan; Peccatori, Fedro A; Anserini, Paola; Valenzano Menada, Mario; Tomirotti, Maurizio; Del Mastro, Lucia

2017-01-01

The development of premature ovarian failure and subsequent infertility are possible consequences of chemotherapy use in pre-menopausal women with early-stage breast cancer. Among the available strategies for fertility preservation, pharmacological protection of the ovaries using luteinising hormone-releasing hormone analogues (LHRHa) during chemotherapy has the potential to restore ovarian function and fertility after anticancer treatments; however, the possible efficacy and clinical application of this strategy has been highly debated in the last years. Following the availability of new data on this controversial topic, the Panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guideline on fertility preservation in cancer patients decided to apply the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology around the relevant and current question on the clinical utility of temporary ovarian suppression with LHRHa during chemotherapy as a strategy to preserve ovarian function and fertility in breast cancer patients. To answer this question, preservation of ovarian function and fertility were judged as critical outcomes for the decision-making. Three possible outcomes of harm were identified: LHRHa-associated toxicities, potential antagonism between concurrent LHRHa and chemotherapy, and lack of the prognostic impact of chemotherapy-induced premature ovarian failure. According to the GRADE evaluation conducted, the result was a strong positive recommendation in favour of using this option to preserve ovarian function and fertility in breast cancer patients. The present manuscript aims to update and summarise the evidence for the use of this strategy in light of the new data published up to January 2016, according to the GRADE process. Copyright © 2016 Elsevier Ltd. All rights reserved.

Impact of obesity on 7,12-dimethylbenz[a]anthracene-induced altered ovarian connexin gap junction proteins in female mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Nteeba, Jackson, E-mail: nteeba@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

The ovarian gap junction proteins alpha 4 (GJA4 or connexin 37; CX37), alpha 1 (GJA1 or connexin 43; CX43) and gamma 1 (GJC1 or connexin 45; CX45) are involved in cell communication and folliculogenesis. 7,12-dimethylbenz[a]anthracene (DMBA) alters Cx37 and Cx43 expression in cultured neonatal rat ovaries. Additionally, obesity has an additive effect on DMBA-induced ovarian cell death and follicle depletion, thus, we investigated in vivo impacts of obesity and DMBA on CX protein levels. Ovaries were collected from lean and obese mice aged 6, 12, 18, or 24 wks. A subset of 18 wk old mice (lean and obese) weremore » dosed with sesame oil or DMBA (1 mg/kg; ip) for 14 days and ovaries collected 3 days thereafter. Cx43 and Cx45 mRNA and protein levels decreased (P < 0.05) after 18 wks while Cx37 mRNA and protein levels decreased (P < 0.05) after 24 wks in obese ovaries. Cx37 mRNA and antral follicle protein staining intensity were reduced (P < 0.05) by obesity while total CX37 protein was reduced (P < 0.05) in DMBA exposed obese ovaries. Cx43 mRNA and total protein levels were decreased (P < 0.05) by DMBA in both lean and obese ovaries while basal protein staining intensity was reduced (P < 0.05) in obese controls. Cx45 mRNA, total protein and protein staining intensity level were decreased (P < 0.05) by obesity. These data support that obesity temporally alters gap junction protein expression and that DMBA-induced ovotoxicity may involve reduced gap junction protein function. - Highlights: • Ovarian gap junction proteins are affected by ovarian aging and obesity. • DMBA exposure negatively impacts gap junction proteins. • Altered gap junction proteins may contribute to infertility.« less

Hirsutism, virilism, polycystic ovarian disease, and the steroid-gonadotropin-feedback system: a career retrospective.

PubMed

Mahesh, Virendra B

2012-01-01

This career retrospective describes how the initial work on the mechanism of hormone action provided the tools for the study of hirsutism, virilism, and polycystic ovarian disease. After excessive ovarian and or adrenal androgen secretion in polycystic ovarian disease had been established, the question whether the disease was genetic or acquired, methods to manage hirsutism and methods for the induction of ovulation were addressed. Recognizing that steroid gonadotropin feedback was an important regulatory factor, initial studies were done on the secretion of LH and FSH in the ovulatory cycle. This was followed by the study of basic mechanisms of steroid-gonadotropin feedback system, using castration and steroid replacement and the events surrounding the natural onset of puberty. Studies in ovariectomized rats showed that progesterone was a pivotal enhancer of estrogen-induced gonadotropin release, thus accounting for the preovulatory gonadotropin surge. The effects of progesterone were manifested by depletion of the occupied estrogen receptors of the anterior pituitary, release of hypothalamic LHRH, and inhibition of enzymes that degrade LHRH. Progesterone also promoted the synthesis of FSH in the pituitary. The 3α,5α-reduced metabolite of progesterone brought about selective LH release and acted using the GABA(A) receptor system. The 5α-reduced metabolite of progesterone brought about selective FSH release; the ability of progesterone to bring about FSH release was dependent on its 5α-reduction. The GnRH neuron does not have steroid receptors; the steroid effect was shown to be mediated through the excitatory amino acid glutamate, which in turn stimulated nitric oxide. These observations led to the replacement of the long-accepted belief that ovarian steroids acted directly on the GnRH neuron by the novel concept that the steroid feedback effect was exerted at the glutamatergic neuron, which in turn regulated the GnRH neuron. The neuroprotective effects of estrogens on brain neurons are of considerable interest.

Altered Stem Cell Receptor Activity in the Ovarian Surface Epithelium by Exogenous Zinc and/or Progesterone.

PubMed

Oktem, G; Sahin, C; Dilsiz, O Y; Demiray, S B; Goker, E N T; Tavmergen, E

2015-05-01

Ovarian surface epithelium (OSE) has the characteristics of a stem cell and the potential for differentiation. Previous studies on this subject have succeeded in deriving oocytes from OSE stem cells, leading to the belief that OSE could be used for infertility treatment. Each rat (n = 10) was subjected to zinc and/or progesterone injection for 5 days after conception. After a 6-day implantation period, ovarian tissues were removed and comprehensive immunohistochemical analysis of stem cell markers was conducted: Sox2, Klf4, Oct3/4, c-Myc, CD117, CD90, SSEA-1 and Notch pathway analysis; Notch1, Jagged1, and Delta1 in the OSE and ovarian stromal cells were evaluated after treatment with zinc, progesterone, or both. Progesterone moderately affected Sox2 expression (p < 0.001), while zinc application strongly affected Klf4 and Oct3/4 and immunoreactivity (p < 0.001). CD90 immunoreactivity was decreased in the OSE and stroma of the progesterone group (p = 0.006) compared with the zinc (p = 0.244) and zinc/progesterone groups (p = 0.910). On the other hand, SSEA-1 showed moderate staining in the OSE and weak staining in stromal cells in animals treated with zinc (p = 0.727), progesterone (p = 0.626), and zinc/progesterone (p = 0.371), with no differences compared with control. Zinc application affected Notch pathway immunoreactivity, with a significant increase in Notch1 (p = 0.0015) and Jagged1 (p < 0.001). The expression of putative stem cell markers in the OSE was verified and stem cell receptor activity was raised in the OSE and ovarian stromal cells by zinc and progesterone. Thus, this increased expression allows the therapeutic use of zinc and progesterone in ovary-related infertility and brings a different perspective to reproductive medicine. © Georg Thieme Verlag KG Stuttgart · New York.

The presence of an insulin-like androgenic gland factor (IAG) and insulin-like peptide binding protein (ILPBP) in the ovary of the blue crab, Callinectes sapidus and their roles in ovarian development.

PubMed

Huang, Xiaoshuai; Ye, Haihui; Chung, J Sook

2017-08-01

Insulin-like androgenic gland factor (IAG) that is produced by the male androgenic gland (AG), plays a role in sexual differentiation and maintenance of male secondary sex characteristics in decapod crustaceans. With an earlier finding of IAG expression in a female Callinectes sapidus ovary, we aimed to examine a putative role of IAG during the ovarian development of this species. To this end, the full-length cDNA sequence of the ovarian CasIAG (termed CasIAG-ova) has been isolated. The predicted mature peptide sequence of CasIAG-ova is identical to that of the IAG from the AG, except in their signal peptide regions. The CasIAG-ova contains an alternative initiation codon (UUG) as the start codon, which suggests that the translational regulation of CasIAG-ova may differ from that of the IAG from AG. To define the function of CasIAG-ova, the expressions of CasIAG-ova as well as its putative binding protein, insulin-like peptide binding protein (ILPBP), are measured in the ovaries at various developmental stages obtained from different seasons. Season affects both CasIAG and ILPBP expression in the ovary. Overall, summer females at earlier ovarian stages contain high levels of CasIAG and ILPBP than spring or fall females. These findings indicate that CasIAG-ova and CasILPBP may be involved in the ovarian development. When comparing the levels of CasIAG and CasILPBP in the ovary, the latter are much higher (∼10-10000 fold) than the former. Expression patterns of CasILPBP differ from those of CasIAG-ova during ovarian development and by season, suggesting that ILPBP may have an additional role in ovarian development rather than a function of a putative binding protein of IAG. Copyright © 2017 Elsevier Inc. All rights reserved.

The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment

PubMed Central

Mitwally, Mohamed FM; Casper, Robert F; Diamond, Michael P

2005-01-01

Clinical utilization of ovulation stimulation to facilitate the ability of a couple to conceive has not only provided a valuable therapeutic approach, but has also yielded extensive information on the physiology of ovarian follicular recruitment, endometrial receptivity and early embryo competency. One of the consequences of the use of fertility enhancing agents for ovarian stimulation has been the creation of a hyperestrogenic state, which may influence each of these parameters. Use of aromatase inhibitors reduces hyperestrogenism inevitably attained during ovarian stimulation. In addition, the adjunct use of aromatase inhibitors during ovarian stimulation reduces amount of gonadotropins required for optimum stimulation. The unique approach of reducing hyperestrogenism, as well as lowering amount of gonadotropins without affecting the number of mature ovarian follicles is an exciting strategy that could result in improvement in the treatment outcome by ameliorating the deleterious effects of the ovarian stimulation on follicular development, endometrial receptivity, as well as oocyte and embryo quality. PMID:16202169

Peroxisome proliferator-activated receptors (PPARs) and ovarian function – implications for regulating steroidogenesis, differentiation, and tissue remodeling

PubMed Central

Komar, Carolyn M

2005-01-01

The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors involved in varied and diverse processes such as steroidogenesis, angiogenesis, tissue remodeling, cell cycle, apoptosis, and lipid metabolism. These processes are critical for normal ovarian function, and all three PPAR family members – alpha, delta, and gamma, are expressed in the ovary. Most notably, the expression of PPARgamma is limited primarily to granulosa cells in developing follicles, and is regulated by luteinizing hormone (LH). Although much has been learned about the PPARs since their initial discovery, very little is known regarding their function in ovarian tissue. This review highlights what is known about the roles of PPARs in ovarian cells, and discusses potential mechanisms by which PPARs could influence ovarian function. Because PPARs are activated by drugs currently in clinical use (fibrates and thiazolidinediones), it is important to understand their role in the ovary, and how manipulation of their activity may impact ovarian physiology as well as ovarian pathology. PMID:16131403