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Sample records for endometrial progesterone resistance

  1. Metformin targeting autophagy overcomes progesterone resistance in endometrial carcinoma.

    PubMed

    Zhuo, Zhihong; Wang, Aiming; Yu, Huimin

    2016-11-01

    Metformin is the most prescribed anti-diabetic medication worldwide because of its proven efficacy and limited side effects. In this study, the significant anticancer effect of metformin was investigated in both endometrial carcinoma and progesterone-resistant endometrial carcinoma cells. We tested the growth inhibition assay using MTT cell proliferation, cell cycle assay, apoptosis assessment with flow cytometry using propidium iodide and Annexin V, and autophagy protein expression with western blot analysis. Metformin inhibited the growth of cancer cells with different concentrations in a dose- and time-dependent manner. Moreover, the inhibition properties observed as a function of increased concentrations of metformin were markedly augmented when the medication was administered in the progesterone-resistant Ishikawa cells, even with a dose as low as 10 mM. The early and late phases of apoptosis were enhanced in the metformin-treated tumour cells that were analyzed. For the Ishikawa cells, the expression of p-AMPK, LC-3, and beclin1 was upregulated after treatment, whereas the AMPK levels were not modulated. Furthermore, for the Ishikawa-PR cells, the protein levels were similarly upregulated. Finally, we observed that the three proteins showed much more variability in Ishikawa-PR cells than in Ishikawa cells. The application of metformin to target autophagy in endometrial cancer cells provides a new potential treatment for progesterone-resistant endometrial carcinoma.

  2. Cholesterol Synthetase DHCR24 Induced by Insulin Aggravates Cancer Invasion and Progesterone Resistance in Endometrial Carcinoma

    PubMed Central

    Dai, Miao; Zhu, Xiao-Lu; Liu, Fei; Xu, Qin-Yang; Ge, Qiu-Lin; Jiang, Shu-Heng; Yang, Xiao-Mei; Li, Jun; Wang, Ya-Hui; Wu, Qing-Kai; Ai, Zhi-Hong; Teng, Yin-Cheng; Zhang, Zhi-Gang

    2017-01-01

    3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss. PMID:28112250

  3. Human Endometrial Fibroblasts Derived from Mesenchymal Progenitors Inherit Progesterone Resistance and Acquire an Inflammatory Phenotype in the Endometrial Niche in Endometriosis1

    PubMed Central

    Barragan, Fatima; Irwin, Juan C.; Balayan, Shaina; Erikson, David W.; Chen, Joseph C.; Houshdaran, Sahar; Piltonen, Terhi T.; Spitzer, Trimble L.B.; George, Ashley; Rabban, Joseph T.; Nezhat, Camran; Giudice, Linda C.

    2016-01-01

    Human endometrium undergoes cyclic regeneration involving stem/progenitor cells, but the role of resident endometrial mesenchymal stem cells (eMSC) as progenitors of endometrial stromal fibroblasts (eSF) has not been definitively demonstrated. In endometriosis, eSF display progesterone (P4) resistance with impaired decidualization in vivo and in vitro. To investigate eMSC as precursors of eSF and whether endometriosis P4 resistance is inherited from eMSC, we analyzed transcriptomes of eutopic endometrium eMSC and eSF isolated by fluorescence-activated cell sorting (FACS) from endometriosis (eMSCendo, eSFendo) and controls (eMSCcontrol, eSFcontrol) and their derived primary cultures. Differentially expressed lineage-associated genes (LG) of FACS-isolated eMSC and eSF were largely conserved in endometriosis. In culture, eSFcontrol maintained in vitro expression of a subset of eSF LG and decidualized in vitro with P4. The eMSCcontrol cultures differentiated in vitro to eSF lineage, down-regulating eMSC LG and up-regulating eSF LG, showing minimal transcriptome differences versus eSFcontrol cultures and decidualizing in vitro. Cultured eSFendo displayed less in vitro LG stability and did not decidualize in vitro. In vitro, eMSCendo differentiated to eSF lineage but showed more differentially expressed genes versus eSFendo cultures, and did not decidualize in vitro, demonstrating P4 resistance inherited from eMSCendo. Compared to controls, cultures from tissue-derived eSFendo uniquely had a pro-inflammatory phenotype not present in eMSCendo differentiated to eSF in vitro, suggesting divergent niche effects for in vivo versus in vitro lineage differentiation. These findings substantiate eMSC as progenitors of eSF and reveal eSF in endometriosis as having P4 resistance inherited from eMSC and a pro-inflammatory phenotype acquired within the endometrial niche. PMID:27075616

  4. Influence of AKT on Progesterone Action in Endometrial Diseases1

    PubMed Central

    Lee, Irene I.; Kim, J. Julie

    2014-01-01

    ABSTRACT Progesterone plays an essential role in the maintenance of the endometrium; it prepares the endometrium for pregnancy, promotes decidualization, and inhibits estrogen-dependent proliferation. Progesterone function is often dysregulated in endometrial disease states. In addition, the PI3K/AKT signaling pathway is often overactive in endometrial pathologies and promotes the survival and proliferation of the diseased cells. Understanding how AKT influences progesterone action is critical in improving hormone-based therapies in endometrial pathologies. Here, we summarize recent studies investigating the crosstalk between the AKT pathway and progesterone receptor function in endometriosis and endometrial cancer. PMID:25100707

  5. Progesterone Receptor Action in Leiomyoma and Endometrial Cancer

    PubMed Central

    Kim, J. Julie; Sefton, Elizabeth C.; Bulun, Serdar E.

    2013-01-01

    Progesterone is a key hormone in the regulation of uterine function. In the normal physiological context, progesterone is primarily involved in remodeling of the endometrium and maintaining a quiescent myometrium. When pathologies of the uterus develop, specifically, endometrial cancer and uterine leiomyoma, response to progesterone is usually altered. Progesterone acts through mainly two isoforms of the progesterone receptor (PR), PRA and PRB which have been reported to exhibit different transcriptional activities. Studies examining the expression and function of the PRs in the normal endometrium and myometrium as well as in endometrial cancer and uterine leiomyoma are summarized here. The clinical use of progestins and the transcriptional activity of the PR on genes specific to endometrial cancer and leiomyoma are described. An increased understanding of the differential expression of PRs and response to progesterone in these two diseases is critical in order to develop more efficient and targeted therapies. PMID:20374701

  6. Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer.

    PubMed

    Kim, J Julie; Kurita, Takeshi; Bulun, Serdar E

    2013-02-01

    Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases.

  7. Progesterone Action in Endometrial Cancer, Endometriosis, Uterine Fibroids, and Breast Cancer

    PubMed Central

    Kim, J. Julie; Kurita, Takeshi

    2013-01-01

    Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases. PMID:23303565

  8. Progesterone resistance in endometriosis: origins, consequences and interventions.

    PubMed

    Patel, Bansari G; Rudnicki, Martin; Yu, Jie; Shu, Yimin; Taylor, Robert N

    2017-06-01

    Endometriosis is a common cause of pelvic pain and affects up to 10% of women of reproductive age. Aberrant progesterone signaling in the endometrium plays a significant role in impaired decidualization and establishment of ectopic endometrial implants. Eutopic endometrial cells from women with endometriosis fail to downregulate genes needed for decidualization, such as those involved in cell cycle regulation, leading to unbridled proliferation. Several causes of progesterone resistance in the endometrium have been postulated, including congenital "preconditioning", whereby the in utero environment renders infants susceptible to neonatal uterine bleeding and endometriosis. Progesterone action is crucial to decreasing inflammation in the endometrium, and deviant progesterone signaling results in a proinflammatory phenotype. Conversely, chronic inflammation can induce a progesterone-resistant state. Repetitive retrograde endometrial shedding begets chronic peritoneal inflammation, which further exacerbates progesterone resistance. Genetic causes of progesterone resistance include progesterone receptor gene polymorphisms, altered microRNA expression, and epigenetic modifications to progesterone receptors and their targets. Environmental toxins such as dioxin play a possible role in the genesis of endometriosis by permitting an inflammatory milieu. A consequence of impaired progesterone action is that hormonal therapy is rendered ineffective for a subset of women with endometriosis. Synthetic progestins, such as dienogest, may overcome this phenomenon by increasing progesterone receptor expression and decreasing proinflammatory cytokines. Other modalities include high dose depot formulations of progestins, medicated intrauterine devices and the likely advent of oral GnRH antagonists. Unearthing root causes of progesterone inaction in endometriosis will aid in the development of novel therapeutics geared toward prevention and treatment. © 2017 Nordic Federation of

  9. Effect of progesterone on the release of arachidonic acid from human endometrial cells stimulated by histamine

    SciTech Connect

    Wilson, T.; Liggins, G.C.; Aimer, G.P.; Watkins, E.J.

    1986-02-01

    Progesterone at concentrations of 10(-7)M and 10(-8)M inhibits release of (/sup 3/H)-arachidonic acid from stimulated, perfused, endometrial cells. The effect is independent of the mechanism of stimulation. Cortisol (10(-5)M but not 10(-7)M) has a similar effect in this system but estradiol (10(-7)M) is without effect. There was a positive correlation (p less than 0.05) between the magnitude of inhibition by progesterone and the day of cycle. The inhibitory action of progesterone on the release of arachidonic acid was greater in endometrial cells than in decidual cells and was apparent after fifteen minutes. The activities of commercial and endometrial cell-free preparations of phospholipase A2 and phospholipase C were unaffected by the presence of progesterone. We conclude that progesterone modulates release of (/sup 3/H)-arachidonic acid from endometrial cells by a rapid, indirect action on phospholipase activity.

  10. Progesterone resistance in endometriosis: link to failure to metabolize estradiol.

    PubMed

    Bulun, Serdar E; Cheng, You-Hong; Yin, Ping; Imir, Gonca; Utsunomiya, Hiroki; Attar, Erkut; Innes, Joy; Julie Kim, J

    2006-03-27

    Endometriosis is the most common cause of pelvic pain and affects an estimated 5 million women in the US. The biologically active estrogen estradiol (E2) is the best-defined mitogen for the growth and inflammation processes in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Progesterone and progestins may relieve pain by limiting growth and inflammation in endometriosis but a portion of patients with endometriosis and pelvic pain do not respond to treatment with progestins. Moreover, progesterone-induced molecular changes in the eutopic (intrauterine) endometrial tissue of women with endometriosis are either blunted or undetectable. These in vivo observations are indicative of resistance to progesterone action in endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptors (PRs) and the lack of the PR isoform named progesterone receptor B (PR-B). In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factor(s). These unknown factor(s) act on neighboring epithelial cells to induce the expression of the enzyme 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD-2), which metabolizes the biologically active estrogen E2 to estrone (E1). In endometriotic tissue, progesterone does not induce epithelial 17beta-HSD-2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate 17beta-HSD-2 may be due to the lack of PR-B and very low levels of progesterone receptor A (PR-A) observed in vivo in endometriotic tissue. The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this local mitogen. The cellular and molecular mechanisms underlying progesterone resistance and failure to metabolize E2 in endometriosis are reviewed.

  11. Endometrial receptivity profile in patients with premature progesterone elevation on the day of HCG administration.

    PubMed

    Haouzi, Delphine; Bissonnette, Laurence; Gala, Anna; Assou, Said; Entezami, Frida; Perrochia, Hélène; Dechaud, Hervé; Hugues, Jean-Noel; Hamamah, Samir

    2014-01-01

    The impact of a premature elevation of serum progesterone level, the day of hCG administration in patients under controlled ovarian stimulation during IVF procedure, on human endometrial receptivity is still debated. In the present study, we investigated the endometrial gene expression profile shifts during the prereceptive and receptive secretory stage in patients with normal and elevated serum progesterone level on the day of hCG administration in fifteen patients under stimulated cycles. Then, specific biomarkers of endometrial receptivity in these two groups of patients were tested. Endometrial biopsies were performed on oocyte retrieval day and on day 3 of embryo transfer, respectively, for each patient. Samples were analysed using DNA microarrays and qRT-PCR. The endometrial gene expression shift from the prereceptive to the receptive stage was altered in patients with high serum progesterone level (>1.5 ng/mL) on hCG day, suggesting accelerated endometrial maturation during the periovulation period. This was confirmed by the functional annotation of the differentially expressed genes as it showed downregulation of cell cycle-related genes. Conversely, the profile of endometrial receptivity was comparable in both groups. Premature progesterone rise alters the endometrial gene expression shift between the prereceptive and the receptive stage but does not affect endometrial receptivity.

  12. Distribution of estrogen and progesterone receptors isoforms in endometrial cancer

    PubMed Central

    2014-01-01

    Background 70–80% of sporadic endometrial carcinomas are defined as endometrioid carcinoma (EC). Early-stage, well differentiated endometrial carcinomas usually retain expression of estrogen and progesterone receptors (ER and PR, respectively), as advanced stage, poorly differentiated tumors often lack one or both of these receptors. Well-described EC prognosis includes tumor characteristics, such as depth of myometrial invasion. Therefore, in the current study, we evaluated the expression profile of ER and PR isoforms, including ER-α, PR-A and PR–B, in correlation to EC tumor histological depth. Methods Using immunohistochemistry and image analysis software, the expression of ER-α, PR-A, PR–B and Ki67 was assessed in endometrial stroma and epithelial glands of superficial, deep and extra-tumoral sections of 15 paraffin embedded EC specimens, and compared to 5 biopsies of non-malignant endometrium. Results Expression of PR-A and ER-α was found to be lower in EC compared to nonmalignant tissue, as the stromal expression was dramatically reduced compared to epithelial cells. Expression ratios of both receptors were significantly high in superficial and deep portions of EC; in non-tumoral portion of EC were close to the ratios of nonmalignant endometrium. PR-B expression was low in epithelial glands of EC superficial and deep portions, and high in the extra-tumoral region. Elevated PR-B expression was found in stroma of EC, as well. Conclusions The ratio of ER-α and PR-A expression in the epithelial glands and the stroma of EC biopsies may serve as an additional parameter in the histological evaluation of EC tumor. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1155060506119016 PMID:24684970

  13. Photoaffinity labeling of the progesterone receptor from human endometrial carcinoma

    SciTech Connect

    Clarke, C.L.; Satyaswaroop, P.G.

    1985-11-01

    A nude mouse model for the growth of human endometrial carcinoma and hormonal modulation of the progesterone receptor (PR) was established previously. This study describes the effect of 17 beta-estradiol and tamoxifen (TAM) on growth rate and PR concentration in a hormonally responsive human endometrial tumor (EnCa 101) grown in this experimental system and presents the first characterization of human endometrial carcinoma PR. EnCa 101 was transplanted subcutaneously into ovariectomized, BALB/c, nu/nu athymic mice and grown under 17 beta-estradiol-stimulated, TAM-stimulated, and control conditions. Both 17 beta-estradiol and TAM increased the growth rate of EnCa 101 in nude mice, and a parallel increase in the cytosol PR concentration was observed. PR was partially purified by phosphocellulose and DEAE cellulose chromatography, and the DEAE eluate was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and photoaffinity labeling with (17 alpha-methyl-TH)promegestone ((TH)R5020). Two PR-negative tumors (EnCa K and EnCa V) were also examined in parallel. Photolabeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of EnCa 101 grown in the presence of 17 beta-estradiol or TAM revealed incorporation of (3H)R5020 into proteins of molecular weight approximately 116,000 and 85,000. Labeled proteins of molecular weight 66,000, 45,000, and 35,000 were also observed. No incorporation of (TH)R5020 was observed in EnCa 101 grown in the absence of estrogen, nor was any observed in EnCa K or EnCa V.

  14. Delineating the prime mover action of progesterone for endometrial receptivity in primates.

    PubMed

    Ghosh, D; Sengupta, J

    2014-11-01

    Progesterone is essential for endometrial receptivity in primates. It is now evident that embryo-derived signal influences implantation stage endometrium under progesterone dominance, and collectively results in endometrial receptivity to implanting blastocyst. Previously, a few studies were performed using global gene profiling based on microarray technology to identify changes in gene expression between early luteal phase and mid luteal phase endometrium, however, the issue of combinatorial regulation by progesterone-dependent regulation and by embryo-derived signal on transcripts profiles during endometrial differentiation toward receptivity for blastocyst implantation in primates has not been addressed. the present review summarizes a few issues, specifically that of transforming growth factor β-tumour necrosis factor α (TGFβ-TNFα) pathways and signal transducer and activator of transcription (STAT) signalling system related to luteal phase progesterone action on endometrial receptivity in terms of its transcriptomic expression using a potent antiprogestin (mifepristone) in conception cycles of the rhesus monkey as a non-human primate model.

  15. A gata2-dependent transcription network regulates uterine progesterone responsiveness and endometrial function

    USDA-ARS?s Scientific Manuscript database

    Altered progesterone responsiveness leads to female infertility and cancer, but underlying mechanisms remain unclear. Mice with uterine-specific ablation of GATA binding protein 2 (Gata2) are infertile, showing failures in embryo implantation, endometrial decidualization, and uninhibited estrogen si...

  16. Infertility associated with the absence of endometrial progesterone receptors in a bitch.

    PubMed

    Dockweiler, J C; Cossic, B; Donnelly, C G; Gilbert, R O; Buckles, E; Cheong, S H

    2017-02-01

    A three-year-old intact female Old English sheepdog was presented for evaluation of infertility. A uterine biopsy was performed during dioestrus, and the microscopic appearance was inconsistent with progesterone stimulation; the glands were sparse, simple and failed to show coiling, while the glandular epithelium was cuboidal instead of columnar. There was very little evidence of glandular activity. Due to the inappropriate appearance of the glands for the stage of the cycle, immunohistochemistry for progesterone receptors was performed. No progesterone receptor-positive immunoreactivity was identified in the endometrial luminal epithelium, glandular epithelium or stroma. Weak intranuclear immunoreactivity was identified within the smooth muscle cells of the myometrium. The absence of progesterone receptors within the endometrial glands is the most likely explanation for the abnormal appearance of the endometrium and for this bitch's infertility. To our knowledge, this is the first report of endometrial progesterone receptor absence in a bitch. © 2016 Blackwell Verlag GmbH.

  17. Differential regulation of glucose transporter expression by estrogen and progesterone in Ishikawa endometrial cancer cells.

    PubMed

    Medina, Rodolfo A; Meneses, Ana Maria; Vera, Juan Carlos; Gúzman, Catherine; Nualart, Francisco; Rodriguez, Federico; de los Angeles Garcia, Maria; Kato, Sumie; Espinoza, Natalia; Monsó, Carolina; Carvajal, Andres; Pinto, Mauricio; Owen, Gareth I

    2004-09-01

    Estrogen replacement therapy and other unopposed estrogen treatments increase the incidence of endometrial abnormalities, including cancer. However, this effect is counteracted by the co-administration of progesterone. In the endometrium, glucose transporter (GLUT) expression and glucose transport are known to fluctuate throughout the menstrual cycle. Here, we determined the effect of estrogen and progesterone on the expression of GLUT1-4 and on the transport of deoxyglucose in Ishikawa endometrial cancer cells. Cells were incubated with estrogen, progesterone or combined estrogen and progesterone for 24 h and the effect on the expression of GLUT1-4 and on deoxyglucose transport was determined. We show that GLUT1 expression is upregulated by estrogen and progesterone individually, but that combined estrogen and progesterone treatment reverses this increase. Hormonal treatments do not affect GLUT2, GLUT3 or GLUT4 expression. Transport studies demonstrate that estrogen increases deoxyglucose transport at Michaelis-Menten constants (Kms) corresponding to GLUT1/4, an effect which disappears when progesterone is added concomitantly. These data demonstrate that different hormonal treatments differentially regulate GLUT expression and glucose transport in this endometrial cancer cell line. This regulation mirrors the role played by estrogen and progesterone on the incidence of cancer in this tissue and suggests that GLUT1 may be utilized by endometrial cancer cells to fuel their demand for increased energy requirement.

  18. Correlation between endometrial biopsy and serum progesterone level in prediction of corpus luteum function.

    PubMed

    El-hefnawi, N; Abou-gabal, A; El-etriby, A; Maged, M; Wafa, G; Ragab, I

    1987-01-01

    This study aimed to determine the correlation between endometrial biopsy and serum progesterone level in prediction of corpus luteum function in regularly menstruating women. Endometrial biopsy specimens were obtained from 40 women 20-25 years old with unproven fertility 2-3 days before the anticipated onset of menses. A simultaneous blood sample was obtained for measurement of serum progesterone levels using a radioimmunoassay technique. 27 biopsies were considered to be in-phase (IP) by histologic criteria, and the remaining 13 were out-of-phase (OOP). The mean serum progesterone level obtained from women with OOP biopsies 3-4 days before onset of menses was significantly lower than that obtained 1-2 days before the onset of menses. Menstruation occurred in women with OOP biopsies at a time when serum progesterone level was apparently rising. On the other hand, values were too small to identify any significant difference between groups of women with IP and OOP biopsies when these biopsies were performed very late in the cycle. The author states the importance of evaluating both serum progesterone and endometrial biopsy dating in the late luteal phase of the menstrual cycle. Serum progesterone was easy to perform, while endometrial biopsy showed the end result.

  19. [Pregnancy outcome of frozen-thawed embryo transfers in different endometrial progesterone preparation time].

    PubMed

    Lu, Jin; Zhang, Cuilian; Zhang, Shaodi; Geng, Jiaxuan; Zhang, Yixuan

    2014-06-01

    To investigate the pregnancy outcome of frozen-thawed embryos transfer in different endometrial progesterone preparation time. From January to December 2012, pregnant outcome of 1 103 frozen-thawed embryo transfer cycles using artificial periodic endometrial preparation were studied retrospectively in Reproductive Medical Center of Henan Provincial People's Hospital. It was divided into 4 groups: group 3-3 (n = 543, 3 days after endometrial progesterone preparation and transfer D3 embryo), group 4-3(n = 330, 4 days after endometrial progesterone preparation and transfer D3 embryo), group 5-5 (n = 150, 5 days after endometrial progesterone preparation and transfer D5 blastula), group 6-5 (n = 80, 6 days after endometrial progesterone preparation and transfer D5 blastula). The rate of implantation, pregnancy, ectopic pregnancy, multiple pregnancy, and first trimester abortion were compared among those groups. (1) With the different endometrial progesterone preparation methods and transfer D3 embryos, implantation rate [group 3-3:39.9% (429/1 074); group 4-3:44.1% (286/648)], pregnancy rate [group 3-3:56.0% (304/543); group 4-3:59.4% (196/330)], ectopic pregnancy rate [group 3-3:3.3% (10/304); group 4-3:2.6% (5/196)], multiple pregnancy rate[group 3-3: 38.5% (117/304) ; group 4-3: 43.4% (85/196)]and early abortion rate [group 3-3: 13.5% (41/304); group 4-3:13.3% (26/196)] had no significant differences between group 3-3 and group 4-3 (all P > 0.05). (2) With the different endometrial progesterone preparation methods and transfer D5 blastocysts, implantation rate [group 5-5:64.7% (191/295) ; group 6-5:69.4% (100/144)], pregnancy rate [group 5-5:80.7% (121/150) ; group 6-5:78.8% (63/80)], ectopic pregnancy rate [group 5-5:2.5% (3/121); group 6-5:0], multiple pregnancy rate[group 5-5:55.4% (67/121); group 6-5: 46.3% (37/80)] and early abortion rate [group 5-5: 5.8% (7/121); group 6-5:7.9% (5/63)]. However, there were no significantly differences between group 5-5 and

  20. Decreased Progesterone Receptor B/A Ratio in Endometrial Cells by Tumor Necrosis Factor-Alpha and Peritoneal Fluid from Patients with Endometriosis.

    PubMed

    Chae, Uisoo; Min, Jin Young; Kim, Sung Hoon; Ihm, Hyo Jin; Oh, Young Sang; Park, So Yun; Chae, Hee Dong; Kim, Chung Hoon; Kang, Byung Moon

    2016-11-01

    Progesterone resistance is thought to be a major factor that contributes to progression of endometriosis. However, it is not clear what causes progesterone resistance in endometriosis. This study aimed to assess whether cytokines or peritoneal fluid can affect progesterone receptor (PR) expression in endometrial cells and to verify whether PR expression is reduced in endometriosis. The PR-B/A ratio was measured via real-time polymerase chain reaction after in vitro culture, in which endometrial cells were treated with either tumor necrosis factor-alpha (TNF-α), interleukin-1 beta, or peritoneal fluid obtained from women with advanced-stage endometriosis. Immunohistochemistry was performed to compare PR-B expression between eutopic and ectopic endometrial tissues from women with and without advanced-stage endometriosis. The PR-B/A ratio was significantly decreased by treatment with either TNF-α (p=0.011) or peritoneal fluid from women with advanced-stage endometriosis (p=0.027). Immunoreactivity of PR-B expression was significantly lower during the secretory phase than during the proliferative phase in endometrial tissues from control subjects (p<0.001). PR-B expression was significantly reduced in the eutopic endometrium (p=0.031) and ovarian endometrioma (p=0.036) from women with advanced-stage endometriosis compared with eutopic endometrium tissues from control subjects. Progesterone resistance in endometriosis may be caused by proinflammatory conditions in the pelvic peritoneal microenvironment.

  1. Effect of progesterone elevation in follicular phase of IVF-cycles on the endometrial receptivity.

    PubMed

    Lawrenz, B; Fatemi, H M

    2017-04-01

    The premature rise of progesterone during the late follicular phase in stimulated IVF cycles is a frequent event, and emerging evidence shows that premature progesterone rise does negatively affect the outcome of assisted reproductive techniques. The effect of elevated peripheral progesterone levels in the late follicular phase seems to be on the endometrium and the window of implantation, which may lead to asynchrony between the endometrium and the developing embryo. In stimulated cycles, endometrial maturation is advanced on the day of oocyte retrieval, and patients with a progesterone level above 1.5 ng/ml on the day of final oocyte maturation have different endometrial gene expression profiles. This progesterone level seems to represent the critical threshold, at which a negative effect on the ongoing pregnancy rate in fresh IVF cycles can be observed. Moreover, no association exists between progesterone elevation in the fresh cycle, and the probability of pregnancy after transfer of frozen-thawed embryos, originating from that cycle. The causes of premature progesterone elevation during ovarian stimulation are still unclear; however, recent studies point towards enhanced FSH-stimulation as a cause for progesterone elevation.

  2. Systematic dissection of the mechanisms underlying progesterone receptor downregulation in endometrial cancer

    PubMed Central

    Yang, Shujie; Jia, Yichen; Liu, Xiaoyue; Winters, Christopher; Wang, Xinjun; Zhang, Yuping; Devor, Eric J.; Hovey, Adriann M.; Reyes, Henry D.; Xiao, Xue; Xu, Yang; Dai, Donghai; Meng, Xiangbing; Thiel, Kristina W.; Domann, Frederick E.; Leslie, Kimberly K.

    2014-01-01

    Progesterone, acting through its receptor, PR (progesterone receptor), is the natural inhibitor of uterine endometrial carcinogenesis by inducing differentiation. PR is downregulated in more advanced cases of endometrial cancer, thereby limiting the effectiveness of hormonal therapy. Our objective was to understand and reverse the mechanisms underlying loss of PR expression in order to improve therapeutic outcomes. Using endometrial cancer cell lines and data from The Cancer Genome Atlas, our findings demonstrate that PR expression is downregulated at four distinct levels. In well-differentiated cancers, ligand-induced receptor activation and downregulation are intact. miRNAs mediate fine tuning of PR levels. As differentiation is lost, PR silencing is primarily at the epigenetic level. Initially, recruitment of the polycomb repressor complex 2 to the PR promoter suppresses transcription. Subsequently, DNA methylation prevents PR expression. Appropriate epigenetic modulators reverse these mechanisms. These data provide a rationale for combining epigenetic modulators with progestins as a therapeutic strategy for endometrial cancer. Significance: Traditional hormonal therapy for women with endometrial cancer can be molecularly enhanced by combining progestins with epigenetic modulators, thereby increasing progesterone receptor expression and significantly improving treatment efficacy. PMID:25229191

  3. Androgens Upregulate Endometrial Epithelial Progesterone Receptor Expression: Potential Implications for Endometriosis.

    PubMed

    Babayev, Samir N; Park, Chan Woo; Keller, Patrick W; Carr, Bruce R; Word, Ruth A; Bukulmez, Orhan

    2017-10-01

    Androgenic compounds have been implicated in induction of endometrial atrophy yet the mechanisms of androgen effects on human endometrium have not been well studied. We hypothesized that androgens may promote their endometrial effects via modulation of progesterone receptor (PR) expression. Proliferative phase endometrial samples were collected at the time of hysterectomy. We evaluated the effect of the potent androgen 5α-dihydrotestosterone (DHT) on endometrial PR expression by treating human endometrial explants, endometrial stromal cells, and Ishikawa cells with DHT. Ishikawa cells were also treated with DHT ± the androgen receptor (AR) blocker flutamide. The PR-B, total PR messenger RNA (mRNA), and PR protein expression were assessed. Expression of cyclin D1 and D2 was checked as markers of cell proliferation. As expected, estradiol induced PR expression in isolated stromal cells, endometrial epithelial cells, and tissue explants. The DHT treatment also resulted in increased PR expression in endometrial explants and Ishikawa cells but not in stromal cells. Further, protein levels of both nuclear PR isoforms (PR-A and PR-B) were induced with the DHT treatment. Although flutamide treatment alone did not affect PR expression, flutamide diminished androgen-induced upregulation of PR in both endometrial explants and Ishikawa cells. Although estradiol induced both cyclin D1 and cyclin D2 mRNA, DHT did not induce these markers of cell proliferation. Androgens may mediate endometrial effects through upregulation of PR gene and protein expression. Endometrial PR upregulation by androgens is mediated, at least in part, through AR.

  4. Overexpression of progesterone receptor A isoform in mice leads to endometrial hyperproliferation, hyperplasia and atypia.

    PubMed

    Fleisch, M C; Chou, Y C; Cardiff, Robert D; Asaithambi, A; Shyamala, G

    2009-04-01

    A delicate balance in estrogen and progesterone signaling through their cognate receptors is characteristic for the physiologic state of the endometrium, and a shift in receptor isotype expression can be frequently found in human endometrial pathology. In this study, using a transgenic mouse model, we examined the mechanisms whereby alterations in progesterone receptor (PR) isotype expression leads to endometrial pathology. For an experimental model, we used transgenic mice (PR-A transgenics) carrying an imbalance in the native ratio of the two PR isoforms A and B (PR-A and PR-B) through the expression of additional A form and examined their uterine phenotype under different hormonal regimens, using various criteria. Uterine epithelial cell proliferation was augmented in PR-A transgenics and was abolished by PR antagonists. In particular, proliferative response to progesterone, independent of signaling through estrogen, was enhanced. Upon continuous exposure to estradiol and progesterone, the uteri in PR-A transgenics displayed gross enlargement, endometrial hyperplasia including atypical lesions, endometritis and pelvic inflammatory disease. Imbalanced expression of the two isoforms of PR in a transgenic model reveals multiple derangements in the regulation of uterine physiology, resulting in various pathologies including hyperplasias.

  5. Endometrial response to concurrent treatment with vaginal progesterone and transdermal estradiol.

    PubMed

    Fernández-Murga, L; Hermenegildo, C; Tarín, J J; García-Pérez, M-Á; Cano, A

    2012-10-01

    ABSTRACT Objective To describe the effect of the intermittent administration of vaginal progesterone and a low-dose estradiol patch on endometrial stability, as assessed by the rate of amenorrhea and endometrial stimulation. Methods This was an open study in which 64 moderately symptomatic, postmenopausal women were treated in the outpatient clinic of our University Hospital for different intervals up to 1 year. The treatment consisted of a combination of patches delivering 25 µg/day estradiol and intravaginal pills containing 100 mg of micronized progesterone. Patches and pills were administered concomitantly in a twice-a-week protocol. The endometrial response was assessed by endovaginal ultrasound completed with suction biopsy when required. Results Both cumulative amenorrhea and no-bleeding rates increased progressively and reached 88.9% and 100.0%, respectively, by the 12th month. Isolated or repetitive episodes of bleeding, bleeding and spotting, or only spotting were reported by three, four, and 12 women, respectively. Endometrial thickness remained unaltered. Endometrium was atrophic in the seven women in whom a biopsy was performed. Conclusion The substantially reduced progestogen load determined by this combination achieved an acceptable incidence of spotting or bleeding when associated with a low estrogenic dose. There was no apparent endometrial stimulation. Additional studies are required to confirm this observation.

  6. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity.

    PubMed

    Young, Steven L

    2013-11-01

    Embryo attachment and implantation is critical to successful reproduction of all eutherian mammals, including humans; a better understanding of these processes could lead to improved infertility treatments and novel contraceptive methods. Experience with assisted reproduction, especially oocyte donation cycles, has established that despite the diverse set of hormones produced by the ovary in a cycle-dependent fashion, the sequential actions of only two of them, oestrogen and progesterone, are sufficient to prepare a highly receptive endometrium in humans. Further investigation on the endometrial actions of these two hormones is currently providing significant insight into the implantation process in women, strongly suggesting that an abnormal response to progesterone underlies infertility in some patients.

  7. Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis.

    PubMed

    Aghajanova, L; Tatsumi, K; Horcajadas, J A; Zamah, A M; Esteban, F J; Herndon, C N; Conti, M; Giudice, L C

    2011-04-01

    Eutopic endometrium in endometriosis has molecular evidence of resistance to progesterone (P(4)) and activation of the PKA pathway in the stromal compartment. To investigate global and temporal responses of eutopic endometrium to P(4), we compared early (6-h), intermediate (48-h), and late (14-Day) transcriptomes, signaling pathways, and networks of human endometrial stromal fibroblasts (hESF) from women with endometriosis (hESF(endo)) with hESF from women without endometriosis (hESF(nonendo)). Endometrial biopsy samples were obtained from subjects with and without mild peritoneal endometriosis (n = 4 per group), and hESF were isolated and treated with P(4) (1 μM) plus estradiol (E(2)) (10 nM), E(2) alone (10 nM), or vehicle for up to 14 days. Total RNA was subjected to microarray analysis using a Gene 1.0 ST (Affymetrix) platform and analyzed by using bioinformatic algorithms, and data were validated by quantitative real-time PCR and ELISA. Results revealed unique kinetic expression of specific genes and unique pathways, distinct biological and molecular processes, and signaling pathways and networks during the early, intermediate, and late responses to P(4) in both hESF(nonendo) and hESF(endo), although a blunted response to P(4) was observed in the latter. The normal response of hESF to P(4) involves a tightly regulated kinetic cascade involving key components in the P(4) receptor and MAPK signaling pathways that results in inhibition of E(2)-mediated proliferation and eventual differentiation to the decidual phenotype, but this was not established in the hESF(endo) early response to P(4). The abnormal response of this cell type to P(4) may contribute to compromised embryonic implantation and infertility in women with endometriosis.

  8. ATM may be a protective factor in endometrial carcinogenesis with the progesterone pathway.

    PubMed

    Shan, Weiwei; Wang, Chao; Zhang, Zhenbo; Luo, Xuezhen; Ning, Chengcheng; Yu, Yinhua; Feng, Youji; Gu, Chao; Chen, Xiaojun

    2015-03-01

    The purpose of the study was to explore the role and mechanism of ataxia-telangiectasia mutated (ATM) protein in endometrial carcinogenesis. A reverse-phase protein array (RPPA) was used to analyze the expression of ATM signal pathway proteins in Ishikawa and progesterone-insensitive Ishikawa. ATM expression was detected in endometrium specimens by immunohistochemistry, including 8 cases with proliferative endometrium, 6 cases with secretory endometrium, 10 cases with simple hyperplasia (SH), 13 cases of complex hyperplasia (CH), 11 cases of endometrial atypical hyperplasia (EAH), and 83 cases with type I endometrial cancer. The relationship between ATM expression and other clinicopathological indicators was also examined in type I endometrial cancer patients. The mechanisms of ATM were explored in vitro with the endometrial cell lines Ishikawa and RL95-2. A cell counting kit-8 (CCK-8) test and Western blot analysis were performed to test proliferation and protein expression. Statistical analysis was performed with SPSS19.0. The significance level was set at 0.05. ATM was increased with medroxyprogesterone acetate (MPA) stimulation in Ishikawa in RPPA. ATM expression gradually decreased in endometrial hyperplasic lesions compared with the normal proliferative and secretory endometrium and was the lowest in type I endometrial cancer. ATM expression was negatively correlated with pathological grades in type I endometrial cancer. In vitro, ATM silencing retarded proliferation inhibition in Ishikawa and RL95-2 treated with MPA. ATM silencing could down-regulate the MPA-stimulated signal proteins, including Chk2, P53, and caspase-3 in vitro. MPA might exert its role through activating the ATM-associated pathway, ATM-Chk2-P53-caspase-3 (active), preserving normal endometrium and protecting it from malignancies. ATM might be a promising indicator for endometrial hyperplasia and cancer.

  9. Analysis of estrogen- and progesterone-receptor expression in endometrial polyps.

    PubMed

    Lopes, Reginaldo Guedes C; Baracat, Edmund Chada; de Albuquerque Neto, Luiz Cavalcanti; Ramos, José Francisco Dória; Yatabe, Salete; Depesr, Daniela Baptista; Lippi, Umberto Gazi

    2007-01-01

    To investigate the presence of estrogen receptors (ER) and progesterone receptors (PR) in the glandular epithelium and stroma of endometrial polyps in women who underwent hysteroscopic polypectomy. Prospective study (Canadian Task Force classification II-3. Hospital de Servidor Público Estadual de São Paulo "Francisco Morato de Oliveira." Forty-eight patients with a solitary endometrial polyp who underwent hysteroscopic polypectomy and resection of an endometrial fragment. The estrogen and progesterone receptor expression, in the polyp, was compared with the endometrial hormone expression of the same patients. The specimens were analyzed by immunohistochemistry. The percentage of staining cells was determined as follows: grade I, 0% to 25%; grade II, 26% to 50%; grade III, 51% to 75%; and grade IV, 76% to 100% of stained nuclei. The intensity of nuclear staining was classified as grade I, absent; grade II, weak; grade III, strong; and grade IV, very strong staining. The sum of both grades was the histochemical score. The total scores of polyp and endometrium were statistically compared. The total scores of ER of glandular epithelium were 258 in polyp and 211 in endometrium. As to stroma, it was 155 in polyp and 163 in endometrium. The total scores of PR of glandular epithelium were 286 in polyp and 211 in endometrium. As to stroma, the totals were 76 in polyp and 77 in endometrium. In immunohistochemistry, the concentrations of both ER and PR in glandular epithelium were significantly higher in endometrial polyp than in normal endometrium. The concentrations of ER and PR in the stroma were similar in the polyp and endometrium. The concentrations of these receptors in the glandular epithelium and stroma were similar in postmenopausal and premenopausal patients. The concentrations of ER and PR in glandular epithelium were significantly higher in endometrial polyp than in normal endometrium. The concentrations of these receptors in the glandular epithelium and

  10. Microarray Analysis on Gene Regulation by Estrogen, Progesterone and Tamoxifen in Human Endometrial Stromal Cells

    PubMed Central

    Ren, Chun-E; Zhu, Xueqiong; Li, Jinping; Lyle, Christian; Dowdy, Sean; Podratz, Karl C.; Byck, David; Chen, Hai-Bin; Jiang, Shi-Wen

    2015-01-01

    Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies. PMID:25782154

  11. Molecular mechanisms of treatment resistance in endometriosis: the role of progesterone-hox gene interactions.

    PubMed

    Cakmak, Hakan; Taylor, Hugh S

    2010-01-01

    HOX genes, encoding homeodomain transcription factors, are dynamically expressed in endometrium, where they are necessary for endometrial growth, differentiation, and implantation. In human endometrium, the expression of HOXA10 and HOXA11 is driven by sex steroids, with peak expression occurring at time of implantation in response to rising progesterone levels. However, the maximal HOXA10 and HOXA11 expression fails to occur in women with endometriosis. In endometriosis, altered progesterone receptor expression or diminished activity may lead to attenuated or dysregulated progesterone response and decreased expression of progesterone-responsive genes including HOX genes in the eutopic endometrium. In turn, other mediators of endometrial receptivity that are regulated by HOX genes, such as pinopodes, alphavbeta3 integrin, and IGFBP-1, are downregulated in endometriosis. HOXA10 hypermethylation has recently been demonstrated to silence HOXA10 gene expression and account for decreased HOXA10 in the endometrium of women with endometriosis. Silencing of progesterone target genes by methylation is an epigenetic mechanism that mediates progesterone resistance. The relatively permanent nature of methylation may explain the widespread failure of treatments for endometriosis-related infertility.

  12. Progesterone receptor (PROGINS) polymorphism and the risk of endometrial cancer development.

    PubMed

    Junqueira, M G; da Silva, I D C G; Nogueira-de-Souza, N C; Carvalho, C V; Leite, D B; Gomes, M T V; Baracat, E C; Lopes, L A F; Nicolau, S M; Gonçalves, W J

    2007-01-01

    The progesterone receptor gene (PROGINS) has been identified as a risk modifier for benign and malignant gynecological diseases. The present case-control study is to evaluate the role of the PROGINS polymorphisms, as risk factor, for endometrial cancer development and to investigate the association between these genetics variants and clinical/pathologic variables of endometrial cancer. PROGINS polymorphism was examined in a total of 121 patients with endometrial cancer and 282 population-based control subjects, all located at the same area in São Paulo, SP, Brazil. The genotyping of PROGINS polymorphism was determined by polymerase chain reaction. The frequencies of PROGINS polymorphism T1/T1, T1/T2, and T2/T2 were 82.6%, 14.9%, and 2.5% in the endometrial cancer patients and 78.4%, 21.6%, and 0% in the controls, respectively. The chi(2) test showed a higher incidence of the T2/T2 genotype in the endometrial cancer group subjects, these results were statistically different (P= 0.012). However, due to the fact that there were no women in the control group showing homozygosis for the allele T2, the correct evaluation of odds ratio could not be properly calculated. Regarding the clinical and pathologic findings observed within the group of patients with endometrial cancer, there was significant correlation between T1/T2 genotype and the presence of myoma (P= 0.048). No correlations were observed among the other variables. These data suggest that the PROGINS polymorphism T2/T2 genotype might be associated with an increased risk of endometrial cancer.

  13. Leptin receptor expression during the progression of endometrial carcinoma is correlated with estrogen and progesterone receptors

    PubMed Central

    Méndez-López, Luis Fernando; Zavala-Pompa, Angel; Cortés-Gutiérrez, Elva I.; Cerda-Flores, Ricardo M.

    2016-01-01

    Introduction The hormone leptin, which is produced in the adipose tissue, may influence tumorigenesis directly via its receptor (Ob-R). Thus, a role for Ob-R in endometrial carcinogenesis has been proposed. However, most studies neither included samples of the entire histological progression of endometrial carcinoma nor examined Ob-R jointly with the estrogen and progesterone receptors (ER and PR, respectively). Material and methods To determine the fluctuations of Ob-R, ER, and PR during the histological progression of endometrial carcinoma, we assessed their expression via immunohistochemistry (IHC) in six histological types of endometrium (proliferative, secretory, nonatypical and atypical hyperplasia, and endometrioid and nonendometrioid endometrial carcinoma), in which we performed histopathological and digital scoring for the quantification of receptors. Results We found that Ob-R expression was positively correlated with that of ER and PR (r = 1, p < 0.001; r = 0.943, p < 0.005, respectively), and there was a significant difference in Ob-R expression among proliferative normal endometrium, hyperplasias, and carcinomas, according to their relative digitally scored Ob-R expression (p < 0.001). In addition, we observed that Ob-R expression in the secretory endometrium was more similar to that of carcinomas than to its proliferative counterpart. Conclusions These results indicate that Ob-R expression fluctuates during endometrial carcinogenesis in correlation with ER and PR, suggesting that Ob-R expression in vivo is highly dependent on estrogen and progesterone activities in the endometrium and on its ER and PR status, as suggested previously by in vitro studies. PMID:28144276

  14. Neonatal Progesterone Programs Adult Uterine Responses to Progesterone and Susceptibility to Uterine Dysfunction

    PubMed Central

    Rumi, M. A. Karim; Kubota, Kaiyu; Chakraborty, Damayanti; Chien, Jeremy; Roby, Katherine F.

    2015-01-01

    In this report, we investigated the consequences of neonatal progesterone exposure on adult rat uterine function. Female pups were subcutaneously injected with vehicle or progesterone from postnatal days 3 to 9. Early progesterone exposure affected endometrial gland biogenesis, puberty, decidualization, and fertility. Because decidualization and pregnancy success are directly linked to progesterone action on the uterus, we investigated the responsiveness of the adult uterus to progesterone. We first identified progesterone-dependent uterine gene expression using RNA sequencing and quantitative RT-PCR in Holtzman Sprague-Dawley rats and progesterone-resistant Brown Norway rats. The impact of neonatal progesterone treatment on adult uterine progesterone responsiveness was next investigated using quantitative RT-PCR. Progesterone resistance affected the spectrum and total number of progesterone-responsive genes and the magnitude of uterine responses for a subset of progesterone targets. Several progesterone-responsive genes in adult uterus exhibited significantly dampened responses in neonatally progesterone-treated females compared with those of vehicle-treated controls, whereas other progesterone-responsive transcripts did not differ between female rats exposed to vehicle or progesterone as neonates. The organizational actions of progesterone on the uterus were dependent on signaling through the progesterone receptor but not estrogen receptor 1. To summarize, neonatal progesterone exposure leads to disturbances in endometrial gland biogenesis, progesterone resistance, and uterine dysfunction. Neonatal progesterone effectively programs adult uterine responsiveness to progesterone. PMID:26204463

  15. Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors

    PubMed Central

    Friel, Anne M.; Zhang, Ling; Pru, Cindy A.; Clark, Nicole C.; McCallum, Melissa L.; Blok, Leen J.; Shioda, Toshi; Peluso, John J.; Rueda, Bo R.; Pru, James K.

    2014-01-01

    Endometrial cancer is the leading gynecologic cancer in women in the United States with 52,630 women predicted to be diagnosed with the disease in 2014. The objective of this study was to determine if progesterone (P4) receptor membrane component 1 (PGRMC1) influenced endometrial cancer cell viability in response to chemotherapy in vitro and in vivo. A Jentiviral-based shRNA knockdown approach was used to generate stable PGRMC1-intact and PGRMC1-deplete Ishikawa endometrial cancer cell lines that also lacked expression of the classical progesterone receptor (PGR). Progesterone treatment inhibited mitosis of PGRMC1-intact, but not PGRMC1-deplete cells, suggesting that PGRMC1 mediates the anti-mitotic actions of P4.To test the hypothesis that PGRMC1 attenuates chemotherapy-induced apoptosis, PGRMC1-intact and PGRMC1-deplete cells were treated in vitro with vehicle, P4 (1 μM), doxorubicin (Dox. 2 μg/ml). or P4 + Dox for 48 h. Doxorubicin treatment of PGRMC1-intact cells resulted in a significant increase in cell death; however, co-treatment with P4 significantly attenuated Dex-induced cell death. This response to P4 was lost in PGRMC1-deplete cells. To extend these observations in vivo, a xenograft model was employed where PGRMC1-intact and PGRMC1-deplete endometrial tumors were generated following subcutaneous and intraperitonea l inoculation of immunocompromised NOD/SCIO and nude mice, respectively. Tumors derived from PGRMC1-deplete cells grew slower than tumors from PGRMC1-intact cells. Mice harboring endometrial tumors were then given three treatments of vehicle (1:1 cremophor EL: ethanol + 0.9% saline) or chemotherapy [Paclitaxel (15 mg/kg, i.p.) followed after an interval of 30 minutes by CARBOplatin (SO mg/kg)] at five day intervals. In response to chemotherapy, tumor volume decreased approximately four-fold more in PGRMC1-deplete tumors when compared with PGRMC1 intact control tumors, suggesting that PGRMC1 promotes tumor cell viability during

  16. Distinguishing features of endometrial pathology after exposure to the progesterone receptor modulator mifepristone.

    PubMed

    Fiscella, Julietta; Bonfiglio, Thomas; Winters, Paul; Eisinger, Steven H; Fiscella, Kevin

    2011-07-01

    There is growing interest in the use of progesterone receptor modulators such as mifepristone for treatment of gynecologic and other conditions, but interest in progesterone receptor modulators is dampened by the effects of the agents on the endometrium. In this study, we examined the endometria of women exposed to mifepristone for treatment of leiomyomas in doses of 2.5 and 5 mg and compared them to unexposed endometria. We assessed the reliability of these features by comparing agreement in ratings between pathologists who were blinded to each other's readings. We assessed distinguishing features between exposed and unexposed groups by comparing frequency of features between groups. We found that key features could be reliably assessed by pathologists experienced in endometrial pathology. We observed several features (nonsynchronous endometrium, large fluid filled glands, and abnormal blood vessels) that distinguished endometrial samples that were and were not exposed to the drug. These findings suggest several features that can be tracked during studies involving mifepristone and, potentially, other progesterone receptor modulators.

  17. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity

    PubMed Central

    Young, Steven L.

    2013-01-01

    Embryo attachment and implantation is critical to successful reproduction of all eutherian mammals, including humans; a better understanding of these processes could lead to improved infertility treatments and novel contraceptive methods. Experience with assisted reproduction, especially oocyte donation cycles, has established that despite the diverse set of hormones produced by the ovary in a cycle-dependent fashion, the sequential actions of only two of them, oestrogen and progesterone, are sufficient to prepare a highly receptive endometrium in humans. Further investigation on the endometrial actions of these two hormones is currently providing significant insight into the implantation process in women, strongly suggesting that an abnormal response to progesterone underlies infertility in some patients. PMID:23933037

  18. Is the positivity of estrogen receptor or progesterone receptor different between type 1 and type 2 endometrial cancer?

    PubMed Central

    Shen, Fang; Gao, Yifei; Ding, Jingxin; Chen, Qi

    2017-01-01

    Endometrial cancer is a major cancer in women and traditionally divided into type 1 and type 2. It is well known that type 2 endometrial cancer has a poor prognosis. Studies have suggested that estrogen receptor (ER) or progesterone receptor (PR) positive are positively associated with endometrial cancer survive. However whether the positivity of ER or PR is different between cancer types has not been investigated yet. In this retrospective study, the positivity of ER or PR was analysed in 1054 women with primary diagnosed endometrial cancer taking into account cancer types and menopausal status from the largest university teaching women's hospital in China. The positivity of ER or PR (over 90%) was significantly higher in type 1 compared to that in type 2 endometrial cancer (71% or 64%) in both premenopausal and postmenopausal women. There was no different in positivity of ER or PR in type 1 endometrial cancer between premenopausal and postmenopausal women. However, in type 2 endometrial cancer, the positivity of ER or PR in premenopausal women was significantly higher compared to that in postmenopausal women. Our data demonstrate that both ER and PR positivity are significantly higher in type 1 endometrial cancer (92%) compared to type 2 (72% ER positive, 65% PR positive). Menopausal status is not associated with the positivity of ER or PR in type 1 endometrial cancer. Our data may provide some novel insights why Asian women have better outcomes of endometrial cancer which was reported in the literature. PMID:27888807

  19. Is the positivity of estrogen receptor or progesterone receptor different between type 1 and type 2 endometrial cancer?

    PubMed

    Shen, Fang; Gao, Yifei; Ding, Jingxin; Chen, Qi

    2017-01-03

    Endometrial cancer is a major cancer in women and traditionally divided into type 1 and type 2. It is well known that type 2 endometrial cancer has a poor prognosis. Studies have suggested that estrogen receptor (ER) or progesterone receptor (PR) positive are positively associated with endometrial cancer survive. However whether the positivity of ER or PR is different between cancer types has not been investigated yet. In this retrospective study, the positivity of ER or PR was analysed in 1054 women with primary diagnosed endometrial cancer taking into account cancer types and menopausal status from the largest university teaching women's hospital in China. The positivity of ER or PR (over 90%) was significantly higher in type 1 compared to that in type 2 endometrial cancer (71% or 64%) in both premenopausal and postmenopausal women. There was no different in positivity of ER or PR in type 1 endometrial cancer between premenopausal and postmenopausal women. However, in type 2 endometrial cancer, the positivity of ER or PR in premenopausal women was significantly higher compared to that in postmenopausal women. Our data demonstrate that both ER and PR positivity are significantly higher in type 1 endometrial cancer (92%) compared to type 2 (72% ER positive, 65% PR positive). Menopausal status is not associated with the positivity of ER or PR in type 1 endometrial cancer. Our data may provide some novel insights why Asian women have better outcomes of endometrial cancer which was reported in the literature.

  20. Treatment of simple and complex endometrial non-atypical hyperplasia with natural progesterone: response rate to different doses.

    PubMed

    Marra, Chiara; Penati, Cristina; Ferrari, Luisa; Cantù, Maria Grazia; Bargossi, Lorena; Fruscio, Robert

    2014-01-01

    The aim of this study is to evaluate the response rate to natural progesterone in non-atypical endometrial hyperplasia and to identify the lowest effective dose. A total of 197 patients of childbearing age with simple or complex hyperplasia were retrospectively identified. The women were treated with a cyclic administration of progesterone at different dosages (100 versus 200 versus 300 mg daily). Endometrial biopsies were performed at 6, 12, 18 months. In comparing progesterone to a regimen of no therapy, a significantly higher remission rate was observed in the progesterone group than in the latter (95 versus 75%, p = 0.05 for simple hyperplasia; 89 versus 35%, p < 0.001 for complex hyperplasia). Out of 60 women with simple hyperplasia, remission was observed in 9/11 (81.8%), 40/41 (97.5%) and 8/8 (100%) patients treated, respectively, with progesterone 100, 200 and 300 mg daily. Out of 72 women with complex hyperplasia, remission was observed in 3/5 (60%), 49/53 (92.4%) and 12/14 (85.7%) patients treated with progesterone 100, 200 and 300 mg daily, respectively. There was no statistically significant difference in the response rate in the two groups, neither with simple nor with complex hyperplasia. In conclusion, progesterone increased the regression rate of both simple and complex hyperplasia.

  1. Prognostic significance of estrogen and progesterone receptor expression in LNG-IUS (Mirena) treatment of endometrial hyperplasia: an immunohistochemical study.

    PubMed

    Akesson, Emelie; Gallos, Ioannis D; Ganesan, Raji; Varma, Rajesh; Gupta, Janesh K

    2010-03-01

    We performed immunohistochemical analysis of estrogen (ERalpha) and progesterone receptors (PRA and PRB), phosphatase and tensin homolog (PTEN) and aromatase in endometrial hyperplasia treated with Mirena (levonorgestrel-releasing intrauterine system; LNG-IUS) and explored their prognostic significance. The baseline pre-treatment endometrial hyperplasia of a selected prospective cohort was analyzed [complex (n = 29) and atypical (n = 5)]. Study participants were categorized into those that showed endometrial regression (responders, n = 28) and those that showed non-regression or histological progression to atypia or malignancy (non-responders, n = 6). Immunohistochemical expression was expressed as a histological score (HS). Responders compared to non-responders showed significantly higher HSs for estrogen and progesterone receptors. Absence of estrogen and progesterone receptors predicted non-responder status with likelihood ratios of 9.33 (95% CI 2.19-39.81) and 2.92 (95% CI 1.47-5.79), respectively. Neither PTEN nor aromatase expression were associated with LNG-IUS therapy responsiveness. Responsiveness of endometrial hyperplasia to LNG-IUS therapy may be determined through analysis of baseline estrogen and progesterone receptors, but these exploratory findings require confirmation in a larger dataset.

  2. Transforming Growth Factor β1 (TGFβ1) and Progesterone Regulate Matrix Metalloproteinases (MMP) in Human Endometrial Stromal Cells

    PubMed Central

    Itoh, Hiroko; Kishore, Annavarapu Hari; Lindqvist, Annika; Rogers, David E.

    2012-01-01

    Context: Menstruation is preceded by progesterone withdrawal and endometrial matrix remodeling predominantly through induction of matrix metalloproteinases (MMP) and recruitment of invading neutrophils. Design: Using endometrial tissues from women during various phases of the menstrual cycle, we found that MMP2, MMP9, and MMP11 were up-regulated in the late secretory phase/premenstrual phase. Because TGFβ-responsive genes were also up-regulated in endometrium during this time, we tested the hypothesis that TGFβ1 and progesterone regulate expression of MMP in human endometrial stromal cells (HESC). Results: Treatment of HESC with TGFβ1 resulted in marked increases in MMP2 and MMP11 mRNA and pro- and active MMP2 activity. Progesterone inhibited TGFβ1-induced stimulation of MMP2 and MMP11 through its nuclear hormone receptors. Interestingly, TGFβ1 also decreased progesterone receptor (PR)-A and PR-B in HESC with a more pronounced effect on PR-A. Conclusions: These data support the hypothesis that TGFβ1 has endogenous anti-progestational effects in HESC and that the opposing effects of progesterone and TGFβ1 are important in regulation of matrix integrity in human endometrium. PMID:22466340

  3. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis.

    PubMed

    Bulun, Serdar E; Cheng, You-Hong; Pavone, Mary Ellen; Xue, Qing; Attar, Erkut; Trukhacheva, Elena; Tokunaga, Hideki; Utsunomiya, Hiroki; Yin, Ping; Luo, Xia; Lin, Zhihong; Imir, Gonca; Thung, Stephen; Su, Emily J; Kim, J Julie

    2010-01-01

    Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease. In endometriotic stromal cells, the levels of progesterone receptor (PR), particularly the PR-B isoform, are significantly decreased, leading to a loss of paracrine signaling. PR deficiency likely underlies the development of progesterone resistance in women with endometriosis who no longer respond to progestin therapy. Here we review the complex epigenetic and transcriptional mechanisms leading to PR deficiency. The initial event may involve deficient methylation of the estrogen receptor (ER)beta promoter resulting in pathologic overexpression of ERbeta in endometriotic stromal cells. We speculate that alterations in the relative levels of ERbeta and ERalpha in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERalpha-tauomicron-ERbeta ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERbeta and ERalpha leading to PR loss and progesterone resistance in endometriosis.

  4. Biomarkers of progestin therapy resistance and endometrial hyperplasia progression

    PubMed Central

    Upson, Kristen; Allison, Kimberly H.; Reed, Susan D.; Jordan, Carolyn D.; Newton, Katherine M.; Swisher, Elizabeth M.; Doherty, Jennifer A.; Garcia, Rochelle L.

    2012-01-01

    Objective To identify biomarkers associated with progestin therapy resistance and persistence/progression of endometrial hyperplasia. Study Design We performed a nested case-control study among women with complex (n=73) and atypical (n=41) hyperplasia treated with oral progestin, followed 2–6 months for persistence/progression. We evaluated index endometrial protein expression for progesterone receptors A (PRA) and B (PRB), PTEN, Pax-2 and Bcl-2. Odds ratios and 95% confidence intervals were estimated. Results Among women with atypical hyperplasia, high PRB expression was associated with 90% decreased risk of persistence/progression (95% CI: 0.01–0.8). High expression of PRA and PRB suggested decreased risk of persistence/ progression (OR=0.1, 95% CI: 0.02–1.0). These findings were not observed among women with complex hyperplasia. No associations were found with PTEN, Pax-2, and Bcl-2 protein expression. Conclusions PRB expression shows promise as a biomarker of progestin response. Further research is warranted to understand how PRB expression may guide treatment decisions. PMID:22727345

  5. Mig-6 regulates endometrial genes involved in cell cycle and progesterone signaling

    PubMed Central

    Yoo, Jung-Yoon; Kim, Tae Hoon; Lee, Jae Hee; Dunwoodie, Sally L.; Ku, Bon Jeong; Jeong, Jae-Wook

    2015-01-01

    Mitogen inducible gene 6 (Mig-6) is an important mediator of progesterone (P4) signaling to inhibit estrogen (E2) signaling in the uterus. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and E2-induced endometrial cancer. To identify the molecular pathways regulated by Mig-6, we performed microarray analysis on the uterus of ovariectomized Mig-6f/f and PGRcre/+ Mig-6f/f (Mig-6d/d) mice treated with vehicle or P4 for 6 hours. The results revealed that 772 transcripts were significantly regulated in the Mig-6d/d uterus treated with vehicle as compared with Mig-6f/f mice. The pathway analysis showed that Mig-6 suppressed the expression of gene-related cell cycle regulation in the absence of ovarian steroid hormone. The epithelium of Mig-6d/d mice showed a significant increase in the number of proliferative cells compared to Mig-6f/f mice. This microarray analysis also revealed that 324 genes are regulated by P4 as well as Mig-6. Cited2, the developmentally important transcription factor, was identified as being regulated by the P4-Mig-6 axis. To determine the role of Cited2 in the uterus, we used the mice with Cited2 that were conditionally ablated in progesterone receptor-positive cells (PGRcre/+ Cited2f/f; Cited2d/d). Ablation of Cited2 in the uterus resulted in a significant reduction in the ability of the uterus to undergo a hormonally induced decidual reaction. Identification and analysis of these responsive genes will help define the role of P4 as well as Mig-6 in regulating uterine biology. PMID:25976672

  6. Mig-6 regulates endometrial genes involved in cell cycle and progesterone signaling.

    PubMed

    Yoo, Jung-Yoon; Kim, Tae Hoon; Lee, Jae Hee; Dunwoodie, Sally L; Ku, Bon Jeong; Jeong, Jae-Wook

    2015-07-10

    Mitogen inducible gene 6 (Mig-6) is an important mediator of progesterone (P4) signaling to inhibit estrogen (E2) signaling in the uterus. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and E2-induced endometrial cancer. To identify the molecular pathways regulated by Mig-6, we performed microarray analysis on the uterus of ovariectomized Mig-6(f/f) and PGR(cre/+)Mig-6(f/f) (Mig-6(d/d)) mice treated with vehicle or P4 for 6 h. The results revealed that 772 transcripts were significantly regulated in the Mig-6(d/d) uterus treated with vehicle as compared with Mig-6(f/f) mice. The pathway analysis showed that Mig-6 suppressed the expression of gene-related cell cycle regulation in the absence of ovarian steroid hormone. The epithelium of Mig-6(d/d) mice showed a significant increase in the number of proliferative cells compared to Mig-6(f/f) mice. This microarray analysis also revealed that 324 genes are regulated by P4 as well as Mig-6. Cited2, the developmentally important transcription factor, was identified as being regulated by the P4-Mig-6 axis. To determine the role of Cited2 in the uterus, we used the mice with Cited2 that were conditionally ablated in progesterone receptor-positive cells (PGR(cre/+)Cited2(f/f); Cited2(d/d)). Ablation of Cited2 in the uterus resulted in a significant reduction in the ability of the uterus to undergo a hormonally induced decidual reaction. Identification and analysis of these responsive genes will help define the role of P4 as well as Mig-6 in regulating uterine biology. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. DISTINGUISHING FEATURES OF ENDOMETRIAL PATHOLOGY FOLLOWING EXPOSURE TO THE PROGESTERONE RECEPTOR MODULATOR MIFEPRISTONE

    PubMed Central

    Fiscella, Julietta; Bonfiglio, Thomas; Winters, Paul; Eisinger, Steven H; Fiscella, Kevin

    2011-01-01

    There is growing interest in use of progesterone receptor modulators (PRM) such as mifepristone for treatment of gynecological and other conditions, but interest in PRMs is dampened by effects of the agents on the endometrium. In this study, we examined the endometria of women exposed to mifepristone for treatment of leiomyomas in doses of 2.5 mg and 5 mg and compared them to unexposed endometria. We assessed the reliability of these features by comparing agreement in ratings between pathologists who were blinded to each other's readings. We assessed distinguishing features between exposed and unexposed groups by comparing frequency of features between groups. We found that key features could be reliably assessed by pathologists experienced in endometrial pathology. We observed several features (non synchronous endometrium, large fluid filled glands and abnormal blood vessels) that distinguished endometrial samples that were and were not exposed to the drug. These findings suggest several features that can be tracked during studies involving mifepristone and potentially other PRMs. PMID:21315422

  8. Effect of a povidone-iodine intrauterine infusion on progesterone levels and endometrial steroid receptor expression in mares

    PubMed Central

    2010-01-01

    Background Intrauterine infusions have been widely used for the treatment of endometritis in the mare. Nevertheless, their consequences on endocrine and endometrial molecular aspects are unknown. We studied the effect of a 1% povidone-iodine solution intrauterine infusion on progesterone levels, endometrial histology and estrogen (ERα) and progesterone (PR) receptor distribution by immunohistochemistry. Methods Fourteen healthy mares were used in this study. Estruses were synchronized and seven mares were treated with intrauterine infusions at days 0 and 2 post ovulation of two consecutive estrous cycles. Uterine biopsy samples were taken on days 6 and 15 post ovulation. Results The treatment did not induce an inflammatory response indicating endometritis, neither affected the ERα. However, it reduced the percentage of PR positive cells (PPC) on day 6 (deep glandular epithelium, control: 95.7 vs. infused: 61.5, P < 0.05). Treated mares tended to have lower progesterone levels on day 2 (3.9 ng/ml vs. 6.6 ng/ml, P = 0.07), and higher levels on day 15 compared with controls (4.4 ng/ml vs. 1.3 ng/ml, P = 0.07). Conclusion a 1% povidone-iodine infusion during days 0 and 2 post ovulation in healthy mares did not induce histological changes indicating endometritis, but altered progesterone concentrations and reduced the expression of endometrial PR at day 6 without affecting the ERα. These changes could reduce embryo survival. PMID:21162724

  9. All-cause mortality in young women with endometrial cancer receiving progesterone therapy.

    PubMed

    Ruiz, Maria P; Huang, Yongmei; Hou, June Y; Tergas, Ana I; Burke, William M; Ananth, Cande V; Neugut, Alfred I; Hershman, Dawn L; Wright, Jason D

    2017-08-24

    Uterine-preserving therapy with progesterone may be used in young women with endometrial cancer who desire fertility preservation. Such therapy delays definitive treatment with hysterectomy. We examined the use and safety of progestational therapy in young women with endometrial cancer. The primary outcome of the analysis was overall survival. We identified women ≤49 years of age with stage I endometrial cancer in the National Cancer Database from 2004 through 2014. Women treated with hormonal therapy with or without hysterectomy were compared to women treated with hysterectomy. After propensity score weighting, overall survival was examined using proportional hazards models. A total of 23,231 patients, including 872 (3.8%) women treated with hormonal therapy were identified. Use of hormonal therapy was 2.4% (95% confidence interval, 1.8-3.3%) in 2004 and increased over time to 5.9% (95% confidence interval, 5.0-6.9%) by 2014 (P < .0001). Use of hormonal therapy decreased with older age, higher substage, and increasing grade. Black women were more likely to receive hormonal therapy while Medicaid recipients were less likely to receive hormonal therapy. The 5-year survival for patients treated with hormonal therapy was 96.4% (95% confidence interval, 94.3-98.0%) compared to 97.2% (95% confidence interval, 96.9-97.4%) for hysterectomy. In a multivariable model, women treated with hormonal therapy were 92% (hazard ratio, 1.92; 95% confidence interval, 1.15-3.19) more likely to die compared to women who underwent primary hysterectomy. When stratified by stage, hormonal therapy was associated with increased mortality in women with stage IB and I-not otherwise specified tumors but not for stage IA neoplasms. Use of progestational therapy is increasing. Its use was associated with decreased survival, particularly in women with stage IB tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Disrupted Cell Cycle Control in Cultured Endometrial Cells from Patients with Endometriosis Harboring the Progesterone Receptor Polymorphism PROGINS

    PubMed Central

    D'Amora, Paulo; Maciel, Thiago Trovati; Tambellini, Rodrigo; Mori, Marcelo A.; Pesquero, João Bosco; Sato, Helio; Girão, Manoel João Batista Castello; Guerreiro da Silva, Ismael Dale Cotrim; Schor, Eduardo

    2009-01-01

    Presently, little is understood about how endometriosis is established or maintained, or how genetic factors can predispose women to the disease. Because of the crucial role that the progesterone receptor polymorphism PROGINS plays in predisposing women to the development of endometriosis, we hypothesized that this variant may influence critical steps during endometrial cell metabolism that are involved in the pathogenesis of endometriosis. Eutopic endometria were collected from three sources: women with endometriosis who had a single PROGINS allele (from the progesterone receptor gene); women with endometriosis who had the wild-type progesterone receptor allele; and women without endometriosis who had the wild-type allele. Cells prepared from the eutopic endometria of these women were stimulated with both estradiol and progesterone, and then examined for cell proliferation, viability, and apoptosis. The cells from women with endometriosis that carried the PROGINS allele demonstrated increased proliferation, greater viability, and decreased apoptosis following progesterone treatment. In general, these parameters were very different as compared with those of women with endometriosis but without the PROGINS allele and women in the control group. This result indicates there is a reduced level of progesterone responsiveness in women who carry the PROGINS polymorphism. Because progesterone responsiveness is known to be an important characteristic of women with endometriosis, these data support the contention that the PROGINS polymorphism enhances the endometriosis phenotype. PMID:19497994

  11. Disrupted cell cycle control in cultured endometrial cells from patients with endometriosis harboring the progesterone receptor polymorphism PROGINS.

    PubMed

    D'Amora, Paulo; Maciel, Thiago Trovati; Tambellini, Rodrigo; Mori, Marcelo A; Pesquero, João Bosco; Sato, Helio; Girão, Manoel João Batista Castello; Guerreiro da Silva, Ismael Dale Cotrim; Schor, Eduardo

    2009-07-01

    Presently, little is understood about how endometriosis is established or maintained, or how genetic factors can predispose women to the disease. Because of the crucial role that the progesterone receptor polymorphism PROGINS plays in predisposing women to the development of endometriosis, we hypothesized that this variant may influence critical steps during endometrial cell metabolism that are involved in the pathogenesis of endometriosis. Eutopic endometria were collected from three sources: women with endometriosis who had a single PROGINS allele (from the progesterone receptor gene); women with endometriosis who had the wild-type progesterone receptor allele; and women without endometriosis who had the wild-type allele. Cells prepared from the eutopic endometria of these women were stimulated with both estradiol and progesterone, and then examined for cell proliferation, viability, and apoptosis. The cells from women with endometriosis that carried the PROGINS allele demonstrated increased proliferation, greater viability, and decreased apoptosis following progesterone treatment. In general, these parameters were very different as compared with those of women with endometriosis but without the PROGINS allele and women in the control group. This result indicates there is a reduced level of progesterone responsiveness in women who carry the PROGINS polymorphism. Because progesterone responsiveness is known to be an important characteristic of women with endometriosis, these data support the contention that the PROGINS polymorphism enhances the endometriosis phenotype.

  12. Progesterone potentiates the growth inhibitory effects of calcitriol in endometrial cancer via suppression of CYP24A1

    PubMed Central

    Bokhari, Amber A.; Lee, Laura R.; Raboteau, Dewayne; Turbov, Jane; Rodriguez, Isabel V.; Pike, John Wesley; Hamilton, Chad A.; Maxwell, George Larry; Rodriguez, Gustavo C.; Syed, Viqar

    2016-01-01

    Here, we evaluated the expression of CYP24A1, a protein that inactivates vitamin D in tissues. CYP24A1 expression was increased in advanced-stage endometrial tumors compared to normal tissues. Similarly, endometrial cancer cells expressed higher levels of CYP24A1 than immortalized endometrial epithelial cells. RT-PCR and Western blotting were used to examine CYP24A1 mRNA and protein levels in endometrial cancer cells after 8, 24, 72, and 120 h of exposure to progesterone, progestin derivatives and calcitriol, either alone or in combination. Progestins inhibited calcitriol-induced expression of CYP24A1 and splice variant CYP24SV mRNA and protein in cancer cells. Furthermore, actinomycin D, but not cycloheximide, blocked calcitriol-induced CYP24A1 splicing. siRNA-induced knockdown of CYP24A1 expression sensitized endometrial cancer cells to calcitriol-induced growth inhibition. These data suggest that CYP24A1 overexpression reduces the antitumor effects of calcitriol in cancer cells and that progestins may be beneficial for maintaining calcitriol's anti-endometrial cancer activity. PMID:27769055

  13. Persistence of an intact endometrial matrix and vessels structure in women exposed to VA-2914, a selective progesterone receptor modulator.

    PubMed

    Ravet, S; Munaut, C; Blacher, S; Brichant, G; Labied, S; Beliard, A; Chabbert-Buffet, N; Bouchard, P; Foidart, J-M; Pintiaux, A

    2008-11-01

    VA-2914 is a selective progesterone receptor modulator with potential contraceptive activity that induces amenorrhea, whereas progestins cause endometrial spotting and bleeding. This abnormal bleeding due to progestins is a consequence of focal stromal proteolysis by an increase in naked vessel size and density. Our objective was to quantify the effects of VA-2914 on endometrial vascularization, fibrillar matrix, and vascular endothelial growth factor (VEGF)-A expression in endometrial biopsies from 41 women before and after 12 wk daily treatment with a placebo, or 2.5, 5, or 10 mg VA-2914. Collagen fibrillar network was stained by silver impregnation. Vessel area, density, and structure were quantified with a computer-assisted image analysis system after double immunostaining using an anti-von Willebrand factor (endothelial cells) and an anti-alpha smooth muscle actin (vascular smooth muscle cells) marker antibody. VEGF-A mRNAs were quantified by RT-PCR and localized by immunohistochemistry. The endometrial vessels, collagen network, and mRNA levels of VEGF-A were identical during the luteal phase at baseline and in VA-2914 treated women. VEGF-A distribution was unchanged. VA-2914 does not alter the endometrial matrix and cells, and does not modify the endometrial vessel morphology as compared with baseline biopsies.

  14. Mig-6 regulates endometrial genes involved in cell cycle and progesterone signaling

    SciTech Connect

    Yoo, Jung-Yoon; Kim, Tae Hoon; Lee, Jae Hee; Dunwoodie, Sally L.; Ku, Bon Jeong; Jeong, Jae-Wook

    2015-07-10

    Mitogen inducible gene 6 (Mig-6) is an important mediator of progesterone (P4) signaling to inhibit estrogen (E2) signaling in the uterus. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and E2-induced endometrial cancer. To identify the molecular pathways regulated by Mig-6, we performed microarray analysis on the uterus of ovariectomized Mig-6{sup f/f} and PGR{sup cre/+}Mig-6{sup f/f} (Mig-6{sup d/d}) mice treated with vehicle or P4 for 6 h. The results revealed that 772 transcripts were significantly regulated in the Mig-6{sup d/d} uterus treated with vehicle as compared with Mig-6{sup f/f} mice. The pathway analysis showed that Mig-6 suppressed the expression of gene-related cell cycle regulation in the absence of ovarian steroid hormone. The epithelium of Mig-6{sup d/d} mice showed a significant increase in the number of proliferative cells compared to Mig-6{sup f/f} mice. This microarray analysis also revealed that 324 genes are regulated by P4 as well as Mig-6. Cited2, the developmentally important transcription factor, was identified as being regulated by the P4-Mig-6 axis. To determine the role of Cited2 in the uterus, we used the mice with Cited2 that were conditionally ablated in progesterone receptor-positive cells (PGR{sup cre/+}Cited2{sup f/f}; Cited2{sup d/d}). Ablation of Cited2 in the uterus resulted in a significant reduction in the ability of the uterus to undergo a hormonally induced decidual reaction. Identification and analysis of these responsive genes will help define the role of P4 as well as Mig-6 in regulating uterine biology. - Highlights: • We identify Mig-6- and P4-regulated uterine genes by microarray analysis. • Mig-6 suppresses cell cycle progression and epithelial cell proliferation in uterus. • We identify the Mig-6 dependent induced genes by P4. • Cited2 plays an important role for decidualization as a P4 and Mig-6 target gene.

  15. Endometrial stromal progesterone receptor-A/progesterone receptor-B ratio: no difference between women with and without endometriosis.

    PubMed

    Gentilini, Davide; Vigano, Paola; Vignali, Michele; Busacca, Mauro; Panina-Bordignon, Paola; Caporizzo, Elvira; Di Blasio, Anna Maria

    2010-09-01

    The aim of the present study was to investigate whether alterations of the P receptor-A/P receptor-B ratio could be considered an etiopathogenetic factor for endometriosis. We failed to observe statistically significant differences in both P receptor-A/P receptor-B messenger RNA and protein ratio between endometrial stromal cells derived from women with and without endometriosis.

  16. Progesterone resistance in a baboon model of endometriosis.

    PubMed

    Fazleabas, Asgerally T

    2010-01-01

    The development of a baboon model of induced endometriosis, which recapitulates the retrograde menstruation hypothesis, has greatly facilitated our understanding of the early events associated with the disease process. Sequential analysis of the eutopic endometrium following the establishment of disease suggests that the development of progesterone resistance is a gradual process and becomes evident after 6 months of disease induction. This resistance is manifested by a decreased responsiveness of the progesterone receptor and its chaperone immunophilins as well as epigenetic modifications of progesterone-regulated genes. In comparative studies, the time-dependent changes observed in the baboon eutopic endometrium are similar to those that have been reported to be altered in women with endometriosis. The baboon model therefore provides insight into the potential mechanisms by which genes in the eutopic endometrium are dysregulated and how this alteration results in infertility that is associated with endometriosis.

  17. The relationship of cerb B 2 expression with estrogen receptor and progesterone receptor and prognostic parameters in endometrial carcinomas

    PubMed Central

    2010-01-01

    Background Endometrial carcinoma (EC) is the most common malignancy of the female genital tract. Gene alterations and overexpression of various oncogenes are important in tumor development. The human HER 2 neu (c-erbB-2) gene product is a transmembrane receptor with an intracellular tyrosine kinase that plays an important role in coordinating the endometrial growth factor receptor signaling network. The aim of this study was to investigate the expression of c-erbB-2 in endometrial cancer, to study its correlation to established prognostic parameters and estrogen receptor (ER) and progesterone receptor (PR) status. Methods Immunohistochemical (IHC) analyses of ER, PR and c-erbB-2 were performed in 72 EC cases. Results We detected a positive staining with c erbB 2 in 18.1% of the cases and determined a statistically significant relation between c-erbB-2 and PR. We could not find a statistically significant relation between c-erbB-2 staining and ER. There was not a statistically significant difference between c-erbB-2 and histological grade. The highest level of c-erbB-2 was found in grade 2 cases. There was not any statistically significant relation between c-erbB-2 and menstrual status, myometrial invasion, lymph node status, stage and survival. Conclusions Although our study provides additional evidence of the potential prognostic role of c-erbB-2, further prospective and controlled studies are required to validate their clinical usefulness. PMID:20167054

  18. Identification of TRIM22 as a progesterone-responsive gene in Ishikawa endometrial cancer cells.

    PubMed

    Saito-Kanatani, Mayuko; Urano, Tomohiko; Hiroi, Hisahiko; Momoeda, Mikio; Ito, Masanori; Fujii, Tomoyuki; Inoue, Satoshi

    2015-11-01

    Progesterone plays important roles in implantation and maintains pregnancy. It antagonizes estrogen-mediated cell proliferation and promotes differentiation in the uterus. The action of progesterone is mediated by specific receptors, namely, the progesterone receptors (PRs). We generated two Ishikawa cell clones stably expressing PR isoform A (PR-A) and identified progesterone-responsive genes using cDNA microarray analysis. Fifteen genes were identified as progesterone-responsive gene candidates by microarray analysis and their progesterone-responsiveness was shown by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis. Out of these 15 genes, we focused on TRIM22. A database search revealed a progesterone response element (PRE) located from the -25 to -11 bp region upstream of TRIM22 exon 1. This PRE had a 1-bp mismatch in the consensus PRE sequence. A chromatin immunoprecipitation assay revealed that the interaction of PR with the TRIM22 PRE region increased in a hormone-dependent manner. The progesterone-dependent enhancer activity of TRIM22 PRE was demonstrated using a luciferase assay. Based on these results, we propose that TRIM22 is a direct target gene of PR and that it can mediate progesterone actions in uterine cells.

  19. Activity of phospholipase C and release of prostaglandin F2 alpha by endometrial tissue from ovariectomized ewes receiving progesterone and estradiol.

    PubMed

    Raw, R E; Silvia, W J

    1991-03-01

    Progesterone and estradiol interact to regulate secretion of prostaglandin (PG) F2 alpha from the ovine endometrium in response to oxytocin. Two experiments were conducted to determine if these effects were due to changes in activity of phospholipase C or in the second messenger responsive pathways that regulate production of PGF2 alpha. In both experiments, ovariectomized ewes were assigned to one of four treatment groups (control, estradiol, progesterone, progesterone and estradiol). Steroids were administered, in vivo, to mimic the changes that occur during the estrous cycle. On Day 16 of steroid treatment, endometrial tissue was collected and incubated, in vitro, to measure activity of phospholipase C and release of PGF2 alpha. Treatment with progesterone, in vivo, enhanced basal and oxytocin-induced activity of phospholipase C and release of PGF2 alpha, in vitro. Estradiol suppressed oxytocin-induced activity of phospholipase C, both in the presence and absence of progesterone. In contrast to its effects on phospholipase C, estradiol inhibited basal and oxytocin-induced release of PGF2 alpha when administered alone, but not when administered with progesterone. Steroids had similar effects on the release of PGF2 alpha induced by phorbol 12-myristate 13-acetate and A23187. It was concluded that progesterone and estradiol regulate endometrial release of PGF2 alpha by affecting both the activity of phospholipase C and its associated second messenger responsive pathways that may regulate production of PGF2 alpha.

  20. The slow growing embryo and premature progesterone elevation: compounding factors for embryo-endometrial asynchrony.

    PubMed

    Healy, Mae Wu; Yamasaki, Meghan; Patounakis, George; Richter, Kevin S; Devine, Kate; DeCherney, Alan H; Hill, Micah J

    2017-02-01

    Is there an association of progesterone (P4) on the day of trigger with live birth in autologous ART transfer cycles on day 5 versus day 6? P4 had a greater negative effect on live birth in day 6 fresh transfers compared to day 5 fresh transfers. Premature P4 elevation is associated with lower live birth rates in fresh autologous ART cycles, likely due to worsened endometrial-embryo asynchrony. Few studies have evaluated whether the effect of an elevated P4 on the day of trigger is different on live birth rates with a day 5 compared to a day 6 embryo transfer. This was a retrospective cohort study with autologous IVF cycles with fresh embryo transfers on day 5 and day 6 from 2011 to 2014. A total of 4120 day 5 and 230 day 6 fresh autologous embryo transfers were included. The primary outcome was live birth, defined as a live born baby at 24 weeks gestation or later. Patients from a large private ART practice were included. Analysis was performed with generalized estimating equations (GEE) modeling and receiver operating characteristic (ROC) curves. Day 6 transfers were less likely to have good quality embryos (73% versus 83%, P < 0.001) but the cohorts had similar rates of blastocyst stage transfer (92% versus 91%, P = 0.92). Live birth was less likely in fresh day 6 versus day 5 embryo transfers (34% versus 46%, P = 0.01) even when controlling for embryo confounders. In adjusted GEE models, the effect of P4 as a continuous variable on live birth was more pronounced on day 6 (P < 0.001). Similarly, the effect of P4 > 1.5 ng/ml on day of trigger was more pronounced on day 6 than day 5 (P < 0.001). Day 6 live birth rates were 8% lower than day 5 when P4 was in the normal range (P = 0.04), but became 17% lower when P4 was > 1.5 ng/ml (P < 0.01). ROC curves for P4 predicting live birth demonstrated a greater AUC in day 6 transfers (AUC 0.59, 95% CI 0.51-0.66) than day 5 (AUC 0.54, 95% CI 0.52-0.55). Interaction testing of P4 × day of embryo transfer was highly

  1. Progesterone acts via progesterone receptors A and B to regulate breast cancer resistance protein expression.

    PubMed

    Vore, Mary; Leggas, Markos

    2008-03-01

    The breast cancer resistance protein (BCRP; ABCG2) is an ATP-dependent efflux multidrug transporter that belongs to the G family of half-transporters that consist of six transmembrane-spanning domains and must homodimerize to form the active membrane transporter. It is expressed in the apical plasma membrane domain of the small intestine, endothelium, and liver, where it has been shown to play an important role in limiting drug absorption and distribution and in enhancing drug clearance, respectively. BCRP is also expressed in the apical membrane of mammary alveolar epithelia, where it mediates efflux of substrates into milk, and in the placental syncytiotro-phoblasts, where it reduces fetal exposure to these substrates. BCRP substrates include numerous drugs (topotecan, nitrofurantoin, cimetidine) as well as food carcinogens (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) and the vitamins riboflavin and folic acid. BCRP expression is regulated by a number of nuclear transcription factors, including the peroxisome proliferator-activated receptor-gamma and Hif-1. This issue of Molecular Pharmacology includes a study (p. 845) now conclusively demonstrating that progesterone acts via the progesterone A and B receptors to regulate BCRP expression in a placental cell line.

  2. Endometrial stromal fibroblasts from women with polycystic ovary syndrome have impaired progesterone-mediated decidualization, aberrant cytokine profiles and promote enhanced immune cell migration in vitro

    PubMed Central

    Piltonen, T.T.; Chen, J.C.; Khatun, M.; Kangasniemi, M.; Liakka, A.; Spitzer, T.; Tran, N.; Huddleston, H.; Irwin, J.C.; Giudice, L.C.

    2015-01-01

    STUDY QUESTION Do endometrial stromal fibroblasts (eSF) in women with polycystic ovary syndrome (PCOS) (eSFpcos) exhibit altered estrogen and/or progesterone (P4) responses, which may explain some of the adverse reproductive outcomes and endometrial pathologies in these women? SUMMARY ANSWER In vitro, eSF from women with PCOS exhibit an aberrant decidualization response and concomitant changes in pro-inflammatory cytokine, chemokine and matrix metalloproteinase (MMP) release and immune cell chemoattraction. In vivo these aberrations may result in suboptimal implantation and predisposition to endometrial cancer. WHAT IS KNOWN ALREADY The endometrium in women with PCOS has several abnormalities including progesterone (P4) resistance at the gene expression level, likely contributing to subfertility, pregnancy complications and increased endometrial cancer risk in PCOS women. STUDY DESIGN, SIZE, DURATION Prospective, university-based, case–control, in vitro study. PARTICIPANTS/MATERIALS, SETTING, METHODS Cultures of eSFPCOS (n = 12, Rotterdam and NIH criteria) and eSFControl (Ctrl) (n = 6, regular cycle length, no signs of hyperandrogenism) were treated with vehicle, estradiol (E2, 10 nM) or E2P4 (10 nM/1 μM) for 14 days. Progesterone receptor (PGR) mRNA was assessed with quantitative real-time PCR (qRT–PCR) and eSF decidualization was confirmed by insulin-like growth factor-binding protein-1 (IGFBP-1) transcript and protein expression. Fractalkine (CX3CL1), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL) 6, 8 and 11, macrophage chemoattractant protein (MCP) 1 and 3, CCL5 (RANTES) and MMPs (MMP1, 2, 3, 7, 9, 10 and 12) were measured in conditioned media by Luminex multiplex assays, and chemotactic activity of the conditioned media was tested in a migration assay using CD14+ monocyte and CD4+ T-cell migration assay. Effects of IL-6 (0.02, 0.2, 2 or 20 ng/ml) or IL-8 (0.04, 0.4, 4, or 40 ng/ml) or combination (0.2 ng/ml IL-6 and 4.0 ng

  3. Ultrasound assessment of endometrial cavity in perimenopausal women on oral progesterone for abnormal uterine bleeding: comparison of diagnostic accuracy of imaging with hysteroscopy-guided biopsy.

    PubMed

    Dasgupta, Subhankar; Dasgupta, Shyamal; Sharma, Partha Pratim; Mukherjee, Amitabha; Ghosh, Tarun Kumar

    2011-11-01

    To investigate the effect of oral progesterone on the accuracy of imaging studies performed to detect endometrial pathology in comparison to hysteroscopy-guided biopsy in perimenopausal women on progesterone treatment for abnormal uterine bleeding. The study population comprised of women aged 40-55 years with complaints of abnormal uterine bleeding who were also undergoing oral progesterone therapy. Women with a uterus ≥ 12 weeks' gestation size, previous abnormal endometrial biopsy, cervical lesion on speculum examination, abnormal Pap smear, active pelvic infection, adnexal mass on clinical examination or during ultrasound scan and a positive pregnancy test were excluded. A transvaginal ultrasound followed by saline infusion sonography were done. On the following day, a hysteroscopy followed by a guided biopsy of the endometrium or any endometrial lesion was performed. Comparison between the results of the imaging study with the hysteroscopy and guided biopsy was done. The final analysis included 83 patients. For detection of overall pathology, polyp and fibroid transvaginal ultrasound had a positive likelihood ratio of 1.65, 5.45 and 5.4, respectively, and a negative likelihood ratio of 0.47, 0.6 and 0.43, respectively. For detection of overall pathology, polyp and fibroid saline infusion sonography had a positive likelihood ratio of 4.4, 5.35 and 11.8, respectively, and a negative likelihood ratio of 0.3, 0.2 and 0.15, respectively. In perimenopausal women on oral progesterone therapy for abnormal uterine bleeding, imaging studies cannot be considered as an accurate method for diagnosing endometrial pathology when compared to hysteroscopy and guided biopsy. © 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.

  4. Progesterone metabolism in bovine endometrial cells and the effect of metabolites on the responsiveness of the cells to OT-stimulation of PGF2alpha.

    PubMed

    Jamshidi, Ahmad A; Girard, Dominique; Beaudry, Francis; Goff, Alan K

    2007-11-01

    Oxytocin receptor (OTR) expression is suppressed by progesterone (P4) during the luteal phase of the estrous cycle and then it increases at the time of luteolysis, but its regulation is still not completely understood. The objective of this work was to characterize P4 metabolism by endometrial cells in vitro and determine if metabolites were able to modify prostaglandin secretion in response to oxytocin (OT). Endometrial epithelial and stromal cells were incubated with 3H-P4 or 3H-pregnenolone (P5) for 6 or 24 h. Metabolites in the medium were separated by HPLC. The results showed that P4 and P5 were converted to two major polar metabolites and a less polar metabolite that was identified as 5alpha- or 5beta-pregnanedione by LC/MS. Progesterone metabolism was similar in both stromal and epithelial cells. To determine if 5alpha- or 5beta-pregnanedione were able to modify PGF(2)alpha synthesis, cells were cultured with P4, 5alpha- or 5beta-pregnanedione (100 ng ml(-1)) for 48 h and then each group of cells was incubated for a further 4-6 h with or without OT (200 ng ml(-1)). Results showed that only P4 caused significant (P<0.001) increase in basal, but not OT-stimulated, PGF(2)alpha synthesis. OT binding assays showed no significant effect of progesterone or its metabolites on OTR concentration. In conclusion, bovine endometrial cells are able to metabolize pregnenolone and progesterone but neither 5alpha- nor 5beta-pregnanedione altered prostaglandin synthesis or OTR number in endometrial epithelial cells. These data suggest that 5-pregnanediones do not play a role in the regulation OT-stimulated PGF(2)alpha secretion during the bovine estrous cycle.

  5. Quantitative analysis of expression level of estrogen and progesterone receptors and VEGF genes in human endometrial stromal cells after treatment with nicotine.

    PubMed

    Totonchi, Hamidreza; Miladpour, Behnoosh; Mostafavi-Pour, Zohreh; Khademi, Fatemeh; Kasraeian, Maryam; Zal, Fatemeh

    2016-10-01

    Cigarette smoke is a complex mixture of toxic chemicals, including nicotine, carbon monoxide, and several recognized carcinogens and mutagens. Nicotine has a direct disturbing influence on steroid hormones (estrogen and progesterone), which are essential components of the female reproductive system, but the effect of nicotine on the hormone receptors is not yet clear. The aim of this study was to elucidate the effect of nicotine on the expression of estrogen receptor (ER), progesterone receptor (PR), and vascular endothelial growth factor (VEGF) in endometrial stromal cells. Expression levels of PR, ER, and VEGF in human endometrial stromal primary cells treated with nicotine (0, 10(-11), 10(-8), and 10(-6 )μM) for 24 h were measured by quantitative real-time PCR. MTT assay demonstrated that nicotine decreased cell viability in a dose-dependent manner. Real-time PCR data showed that despite decrease in ER expression in the nicotine-treated groups compared with the control, nicotine exerted an increased inhibitory effect on PR expression compared to that on ER expression. VEGF mRNA expression in nicotine-treated endometrial stromal cells was increased. The results from this study provide novel evidence for inhibitory effects of nicotine on steroid hormones receptor expression in human primary endometrial cells. Also, our data suggest that nicotine might have angiogenesis effects on these cells.

  6. The endometrial and breast safety of menopausal hormone therapy containing micronised progesterone: A short review.

    PubMed

    Eden, John

    2017-02-01

    For a significant minority of women, menopausal symptoms can be very unpleasant; however, many are worried about taking menopausal hormone therapy (MHT) for fear of causing breast cancer. Micronised progesterone (mP4) has been available in Europe since the 1990s and clinical trials have shown that 100 mg oral daily, 200 mg oral sequentially or 100 mg vaginal every second day effectively protect the endometrium from the stimulatory effects of oestrogen. MHT containing mP4 has a significantly lower breast cancer risk than those containing progestins. Micronised progesterone does not appear to attenuate the cardiovascular benefits of oestrogen. Pharmaceutical grade, body identical MHT is now available in Australia.

  7. Oestrogen and Progesterone Receptors and COX-2 Expression in Endometrial Biopsy Samples During Maternal Recognition of Pregnancy in Llamas (Lama glama).

    PubMed

    Bianchi, C P; Meikle, A; Benavente, M A; Álvarez, M A; Trasorras, V L; Miragaya, M H; Rodríguez, E; Aba, M A

    2015-12-01

    Endometrial expression of oestrogen receptor-α (ERα), progesterone receptor (PR) and cyclooxigenase-2 (COX-2) was evaluated in non-pregnant and pregnant llamas during the period when luteolysis/maternal recognition of pregnancy is expected to occur. Females (n = 28) were divided into two groups: non-pregnant llamas were induced to ovulate with a Buserelin injection, and endometrial biopsies were obtained on day 8 (n = 5) or 12 (n = 5) post-induction of ovulation. Animals of the pregnant group (n = 18) were mated with a fertile male. Pregnancy was confirmed by the visualization of the embryo collected by transcervical flushing in 5 of 9 animals on day 8 post-mating and by progesterone profile on day 12 post-mating in 4 of 9 animals, when endometrial biopsies were obtained. An immunohistochemical technique was used to evaluate receptors population and COX-2 expression. Pregnant llamas showed a higher percentage of positive cells and stronger intensity for ERα than for non-pregnant llamas in stroma on day 8 and in the luminal epithelium on day 12 post-induction of ovulation, while a deep decrease in endometrial PR population was reported in pregnant llamas on that day in luminal and glandular epithelia and stroma. In the luminal epithelium, COX-2 expression was lower in pregnant than in non-pregnant animals. Briefly, the increase of ERα in pregnant llamas gives further support to the hypothesis that oestrogens are involved in the mechanism of maternal recognition of pregnancy. Endometrial PR decrease in pregnant llamas might be a necessary event to allow the expression of proteins involved in conceptus attachment, a mechanism widely accepted in other species. Moreover, embryo seems to attenuate maternal PGF(2α) secretion during early pregnancy by decreasing the endometrial expression of COX-2 in the luminal epithelium of pregnant llamas.

  8. Changes in the endometrial transcriptome during the bovine estrous cycle: effect of low circulating progesterone and consequences for conceptus elongation.

    PubMed

    Forde, N; Beltman, M E; Duffy, G B; Duffy, P; Mehta, J P; O'Gaora, P; Roche, J F; Lonergan, P; Crowe, M A

    2011-02-01

    In cattle, elevated concentrations of circulating progesterone (P4) in the immediate postconception period are associated with advanced conceptus development, while low P4 is implicated as a causative factor in low pregnancy rates observed in dairy cows. This study aimed to: 1) describe the transcriptional changes that occur in the bovine endometrium during the estrous cycle, 2) determine how elevated P4 affects these changes, 3) identify if low P4 alters the expression of these genes, and 4) assess the impact that low P4 has on conceptus development. Relatively few differences occurred in endometrial gene expression during the early luteal phase of the estrous cycle (Day 5 vs. 7), but comparison of endometria from more distant stages of the luteal phase (Day 7 vs. 13) revealed large transcriptional changes, which were significantly altered by exogenous supplementation of P4. Induction of low circulating P4 altered the normal temporal changes in gene expression, and these changes were coordinate with a delay in the down-regulation of the PGR from the LE and GE. Altered endometrial gene expression induced by low P4 was associated with a reduced capacity of the uterus to support conceptus development after embryo transfer on Day 7. In conclusion, the present study provides clear evidence that the temporal changes in the transcriptome of the endometrium of cyclic heifers are sensitive to circulating P4 concentrations in the first few days after estrus. Under low P4 conditions, a suboptimal uterine environment with reduced ability to support conceptus elongation is observed.

  9. Endometrial response of beef heifers on day 7 following insemination to supraphysiological concentrations of progesterone associated with superovulation.

    PubMed

    Forde, N; Carter, F; di Francesco, S; Mehta, J P; Garcia-Herreros, M; Gad, A; Tesfaye, D; Hoelker, M; Schellander, K; Lonergan, P

    2012-11-15

    Ovarian stimulation is a routine procedure in assisted reproduction to stimulate the growth of multiple follicles in naturally single-ovulating species including cattle and humans. The aim of this study was to analyze the changes induced in the endometrial transcriptome associated with superovulation in cattle and place these observations in the context of our previous data on changes in the endometrial transcriptome associated with elevated progesterone (P4) concentrations within the physiological range and those changes induced in the embryo due to superovulation. Mean serum P4 concentrations were significantly higher from day 4 to day 7 in superovulated compared with unstimulated control heifers (P < 0.05). Between-group analysis revealed a clear separation in the overall transcriptional profile of endometria from unstimulated control heifers (n = 5) compared with superovulated heifers (n = 5). This was reflected in the number of differentially expressed genes (DEGs) identified between the two groups with 795 up- and 440 downregulated in superovulated endometria. Ten times more genes were altered by superovulation (n = 1,234) compared with the number altered due to elevated P4 within physiological ranges by insertion of a P4-releasing intravaginal device (n = 124) with only 22 DEGs common to both models of P4 manipulation. Fewer genes were affected by superovulation in the embryo compared with the endometrium, (443 vs. 1,234 DEGs, respectively), and the manner in which genes were altered was different with 64.5% of genes up- and 35.5% of genes downregulated in the endometrium, compared with the 98.9% of DEGs upregulated in the embryo. In conclusion, superovulation induces significant changes in the transcriptome of the endometrium which are distinct from those in the embryo.

  10. [Study on effect of total matrines and extracts from Periplaneta americana on negative endometrial cancer cell JEC of progesterone receptors].

    PubMed

    Zhang, Xiao-wei; Zhu, Yan

    2015-06-01

    To study the effect of total matrines and extracts from Periplaneta americana on negative endometrial cancer cell JEC of progesterone receptors. After detecting the effect of total matrine, extracts from P. americana and their combination on JEC cells' growth inhibition, cell cycle, P53 and c-erbB-2 gene protein expressions through MTT, flow cytometry instrument and Western blot method, the author found that, (1) MTT: total matrines and extracts from P. americana could inhibit the growth of JEC cell, with significant increase in the inhibitory effect in the combination group. (2) Flow cytometry instrument: the cell cycle at G0/G1 increased after the treatment with total matrines, the cell cycle at G2/M increased after the treatment with extracts from periplaneta americana, and the ratio of G0/G1 cell cycle in the combination group was significantly higher than the other groups, with inhibition in cell growth and statistical difference in inter-group comparison (P < 0.05). (3) Western blot: the expression level of P53 increased and c-erbB-2 decreased after the treatment with total matrines, extracts from P. americana and their combination on JEC cell, with statistical difference in inter-group comparison (P < 0.05). The above results suggested that total matrines, extracts from P. americana and their combination could induce cell cycle arrest and inhibit the growth of JEC cell by up-regulating P53 and down-regulating the c-erbB-2 level.

  11. Modulation of endometrial transformation in gonadotrophin-stimulated and unstimulated pseudo-pregnant rabbits: studies with the progesterone receptor antagonist, onapristone.

    PubMed

    Krusche, C A; Herrler, A; Classen-Linke, I; Hegele-Hartung, C; von Rango, U; Beier, H M

    2000-08-01

    Advanced endometrial transformation often occurs in IVF and embryo transfer therapy after ovarian stimulation with gonadotrophins. One reason is probably the early rise in peripheral progesterone concentration after ovulation induction. Consequently, we studied in a rabbit model, whether the post-ovulatory application of the progesterone receptor antagonist, onapristone, could prevent such an advancement of endometrial transformation after stimulation with different gonadotrophin preparations. The inhibitory effect of onapristone on the endometrium is dependent upon the strength of ovarian stimulation. In unstimulated animals or animals treated with recombinant LH (nine corpora lutea/animal in both groups), secretory differentiation and proliferation of the endometrium was strongly inhibited by onapristone. After weak ovarian stimulation with a 3:1 mixture of FSH and LH (22 corpora lutea/animal), secretory differentiation was strongly inhibited, while proliferation was enhanced. After strong stimulation with either a 1:1 mixture of FSH and LH, or human menopausal gonadotrophin (HMG; >40 corpora lutea/animal), only limited inhibitory effects of onapristone on secretory transformation or proliferation could be detected. In conclusion, these graded effects of onapristone after stimulation with gonadotrophins, resemble the basic observations from which a therapeutic strategy emerges, to modulate the advanced endometrial transformation which occurs in many IVF patients after ovarian stimulation.

  12. Subfertility linked to combined luteal insufficiency and uterine progesterone resistance.

    PubMed

    Konno, Toshihiro; Graham, Amanda R; Rempel, Lea A; Ho-Chen, Jennifer K; Alam, S M Khorshed; Bu, Pengli; Rumi, M A Karim; Soares, Michael J

    2010-09-01

    Early pregnancy loss is common and can be caused by a range of factors. The Brown Norway (BN) rat exhibits reproductive dysfunction characterized by small litter size and pregnancy failure and represents a model for investigating early pregnancy loss. In this study, we investigated the establishment of pregnancy in the BN rat and gained insight into mechanisms causing its subfertility. Early stages of BN uteroplacental organization are unique. The BN primordial placenta is restricted in its development and correlates with limited BN uterine decidual development. BN uterine decidua was shown to be both structurally and functionally distinct and correlated with decreased circulating progesterone (P4) levels. Ovarian anomalies were also apparent in BN rats and included decreased ovulation rates and decreased transcript levels for some steroidogenic enzymes. Attempts to rescue the BN uterine decidual phenotype with steroid hormone therapy were ineffective. BN uteri were shown to exhibit reduced responsiveness to P4 but not to 17beta-estradiol. P4 resistance was associated with decreased transcript levels for the P4 receptor (Pgr), a P4 receptor chaperone (Fkbp4), and P4 receptor coactivators (Ncoa1 and Ncoa2). In summary, the BN rat exhibits luteal insufficiency and uterine P4 resistance, which profoundly affects its ability to reproduce.

  13. Oestrogen, progesterone and oxytocin receptors and COX-2 expression in endometrial biopsy samples from the induction of ovulation to luteolysis in llamas (Lama glama).

    PubMed

    Bianchi, C P; Meikle, A; Alvarez, M A; Benavente, M A; Cavilla, M V; Rodríguez, E; Aba, M A

    2013-08-01

    Endometrial expression of oestrogen (ERα), progesterone (PR) and oxytocin receptor (OR) and cyclooxygenase-2 (COX-2) was evaluated from the induction of ovulation to luteolysis in llamas. Ovarian activity was daily assessed by ultrasonography in five females. Ovulation was induced immediately after the detection of an ovulatory follicle by a GnRH injection (Day 0). Endometrial samples were obtained by transcervical biopsies from the left and right horns on day 0 and days 4, 8, 10 and 12 post-GnRH. Blood samples were collected daily for progesterone and estradiol-17β determinations by RIA. An immunohistochemical technique was used to study receptors population and COX-2 expression which were then evaluated by two independent observers. The expression of ERα and PR was highest on day 0 in the luminal epithelium and stroma in association with high plasma estradiol-17β concentrations. Thereafter, a decrease in ERα population was registered on day 4 and a new increase of its expression was observed between days 8 and 12 in those cell types. Conversely, PR population was gradually down-regulated until its lowest expression was reached on day 10 post-GnRH in the luminal epithelium. Content of OR was similar throughout the study in all cell types. The expression of COX-2 was highest from day 8 to 12 post-GnRH in the luminal epithelium, in relation to the time of maximal PGF2α release. Both steroid receptors populations and COX-2 expression were similar between horns. Meanwhile, OR expression was higher in the right than in the left uterine horn. In summary, this study showed that the loss of endometrium sensitivity to progesterone by days 8-10 post-induction of ovulation and the concomitant increase of COX-2 expression could play a key role in the mechanism of luteolysis and somehow be related to the short corpus luteum lifespan of llamas. © 2013 Blackwell Verlag GmbH.

  14. Response-specific progestin resistance in a newly characterized Ishikawa human endometrial cancer subcell line resulting from long-term exposure to medroxyprogesterone acetate.

    PubMed

    Zhao, Shunjun; Li, Genxia; Yang, Li; Li, Lei; Li, Hongyu

    2013-01-01

    Progestins, particularly medroxyprogesterone acetate (MPA), have for a long time been used as conservative treatment for young patients with clinical stage I, grade I endometrial carcinoma. However, more than 30% of patients with endometrial adenocarcinoma display resistance to endocrine therapies at the time of presentation and most cancer patients that initially respond to progestin treatment will at some point develop resistance, resulting in tumor progression. The cellular mechanisms underlying acquired resistance to progestin are poorly understood. In order to investigate the molecular mechanisms whereby human endometrial adenocarcinoma develops resistance to progestin therapy, we have undertaken to develop human endometrial adenocarcinoma cell lines that are resistant to the growth-inhibitory effects of progestins in vitro. A progestin-resistant subcell line of Ishikawa cells was developed from Ishikawa human endometrial adenocarcinoma cells by stepwise selection in increasing concentrations of the synthetic progestin, MPA, over ten months. The doubling time of the progestin-resistant cells (34.18±3.15 h) grown routinely in the medium containing 10 μM MPA was not significantly different from the doubling time of the parent Ishikawa cells (35.14±2.68 h) grown in the absence of MPA (t=-0.331, P=0.762). Moreover, the effect of treatment with MPA shifted from suppression of growth and invasiveness, as observed in the parent Ishikawa cells, to stimulation of growth and invasiveness in the progestin-resistant Ishikawa cells. The positive rates of estrogen receptor a (ERα) and progesterone receptor B (PRB) of the progestin-resistant Ishikawa cells were significantly reduced, whilst the positive rate of ERβ was significantly enhanced compared to the parent Ishikawa cells. These differences were statistically significant (P<0.05). Our results indicate that long-term treatment with MPA in Ishikawa cells may give rise to a resistance effect to MPA. When the

  15. Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding.

    PubMed

    Guzeloglu Kayisli, Ozlem; Kayisli, Umit A; Basar, Murat; Semerci, Nihan; Schatz, Frederick; Lockwood, Charles J

    2015-01-01

    Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+ medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+ progesterone (P4) were analyzed by quantitative Real-time (q)-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depot MPA (DMPA) treated women and ovariectomized guinea pigs (GPs) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as one of upstream regulators of the 235 MPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR-mediated transcription

  16. Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-survivin pathway

    PubMed Central

    Fan, Rujia; Wang, Yiying; Wang, Yue; Wei, Li; Zheng, Wenxin

    2017-01-01

    Progestin is commonly used for young patients suffering from endometrial hyperplasia or cancer. However, there is approximately 30% failure rate with unclear mechanism. We investigated if Nrf2-survivin pathway contributes the progestin resistance (PR) in this setting. Current study detected Nrf2 and survivin protein expression in post progestin treated endometrial tissue samples by using immunohistochemistry. Transfection of Nrf2 and survivin into endometrial cancer cells in vitro was done to determine the roles of Nrf2 and survivin in progestin resistance. Silence of survivin was then performed to explore if Nrf2-driven progestin resistance is mediated by survivin. Medorxyprogesterone acetate (MPA) and metformin were applied to examine the cellular proliferations under the controlled conditions. Overexpression of survivin and Nrf2 were found in progestin-resistant endometrial samples as well as in those areas with only partial responses after MPA treatment. In contrast, all responded endometrial tissue with complete decidualization showed negative expression of these two biomarkers. Exogenous overexpression of Nrf2 and survivin resulted in progestin resistance. In addition, reduction of survivin in endometrial cancer cells overcame the Nrf2 overexpression induced progestin resistance. Furthermore, Nrf2 and survivin expressions were effectively suppressed after withdrawal of MPA. Interestingly, metformin increased the progestin sensitivity by down regulation of Nrf2 and survivin. The findings suggest that dysregulation of Nrf2-survivin may represent part of the molecular mechanisms of progestin resistance in endometrial cancer. Detecting survivin and Nrf2 may predict progestin resistance, while targeting Nrf2 and survivin may represent a promising prevention and treatment strategy for endometrial cancer. PMID:28386373

  17. Changes in the Transcriptome of the Human Endometrial Ishikawa Cancer Cell Line Induced by Estrogen, Progesterone, Tamoxifen, and Mifepristone (RU486) as Detected by RNA-Sequencing

    PubMed Central

    Tamm-Rosenstein, Karin; Simm, Jaak; Suhorutshenko, Marina; Salumets, Andres; Metsis, Madis

    2013-01-01

    Background Estrogen (E2) and progesterone (P4) are key players in the maturation of the human endometrium. The corresponding steroid hormone modulators, tamoxifen (TAM) and mifepristone (RU486) are widely used in breast cancer therapy and for contraception purposes, respectively. Methodology/Principal findings Gene expression profiling of the human endometrial Ishikawa cancer cell line treated with E2 and P4 for 3 h and 12 h, and TAM and RU486 for 12 h, was performed using RNA-sequencing. High levels of mRNA were detected for genes, including PSAP, ATP5G2, ATP5H, and GNB2L1 following E2 or P4 treatment. A total of 82 biomarkers for endometrial biology were identified among E2 induced genes, and 93 among P4 responsive genes. Identified biomarkers included: EZH2, MDK, MUC1, SLIT2, and IL6ST, which are genes previously associated with endometrial receptivity. Moreover, 98.8% and 98.6% of E2 and P4 responsive genes in Ishikawa cells, respectively, were also detected in two human mid-secretory endometrial biopsy samples. TAM treatment exhibited both antagonistic and agonistic effects of E2, and also regulated a subset of genes independently. The cell cycle regulator cyclin D1 (CCND1) showed significant up-regulation following treatment with TAM. RU486 did not appear to act as a pure antagonist of P4 and a functional analysis of RU486 response identified genes related to adhesion and apoptosis, including down-regulated genes associated with cell-cell contacts and adhesion as CTNND1, JUP, CDH2, IQGAP1, and COL2A1. Conclusions Significant changes in gene expression by the Ishikawa cell line were detected after treatments with E2, P4, TAM, and RU486. These transcriptome data provide valuable insight into potential biomarkers related to endometrial receptivity, and also facilitate an understanding of the molecular changes that take place in the endometrium in the early stages of breast cancer treatment and contraception usage. PMID:23874806

  18. 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis.

    PubMed

    Bulun, Serdar E; Cheng, You-Hong; Pavone, Mary Ellen; Yin, Ping; Imir, Gonca; Utsunomiya, Hiroki; Thung, Stephen; Xue, Qing; Marsh, Erica E; Tokunaga, Hideki; Ishikawa, Hiroshi; Kurita, Takeshi; Su, Emily J

    2010-01-01

    Estradiol (E2) stimulates the growth and inflammation in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Several clinical and laboratory-based observations are indicative of resistance to progesterone action in endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptor (PR). In normal endometrium, progesterone acts via PR on stromal cells to induce secretion of paracrine factor(s) that in turn stimulate neighboring epithelial cells to express the enzyme 17beta-hydroxysteroid dehydrogenase type 2 (HSD17B2). HSD17B2 is an extremely efficient enzyme and rapidly metabolizes the biologically potent estrogen E2 to weakly estrogenic estrone. In endometriotic tissue, progesterone is incapable of inducing epithelial HSD17B2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate HSD17B2 may be due to the very low levels of PR observed in vivo in endometriotic tissue. The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this mitogen. The molecular details of this physiological paracrine interaction between the stroma and epithelium in normal endometrium and its lack thereof in endometriosis are discussed.

  19. Coordinate patterns of estrogen receptor, progesterone receptor, and Wilms tumor 1 expression in the histopathologic distinction of ovarian from endometrial serous adenocarcinomas.

    PubMed

    Fadare, Oluwole; James, Samuel; Desouki, Mohamed M; Khabele, Dineo

    2013-10-01

    The purpose of this study is to assess whether composite or coordinate immunoexpression patterns of estrogen receptor (ER), progesterone receptor (PR), and Wilms tumor 1 (WT1) gene can significantly distinguish between endometrial serous carcinoma (ESC) and ovarian serous carcinoma (OSC). Immunohistochemical analyses were performed on whole tissue sections from 22 uterus-confined ESCs and on a tissue microarray of 140 high-grade, pan-stage OSCs, using antibodies to ER, PR, and WT-1. Estrogen receptor, PR, and WT1 expressions were present in 37%, 49%, and 81% of OSC, respectively, but these markers were also present in 18%, 27%, and 36% of ESC. The ER+/PR+/WT1+ coordinate profile was identified in 33.6% of OSC but in none of ESC (P = .0006), resulting in a calculated sensitivity and specificity of this profile for OSC of 33.6% and 100%, respectively. By contrast, the ER-/PR-/WT1- coordinate profile was identified in 41% of ESC but in only 6.4% of OSC (P = .0001), resulting in a calculated sensitivity and specificity of this profile for ESC of 50% and 94%. In summary, in the differential diagnosis between OSC and ESC, positivity for all 3 markers favors an extrauterine origin, whereas negativity for all 3 markers is supportive of an endometrial origin. The use of single markers for this purpose is not recommended, as each lacks optimal discriminatory power. Coordinate profiles, in general, have a high specificity but low sensitivity in this differential diagnosis.

  20. Stromal Clues in Endometrial Carcinoma: Loss of Expression of β-Catenin, Epithelial-Mesenchymal Transition Regulators, and Estrogen-Progesterone Receptor

    PubMed Central

    Sayar, Ilyas; Ceyran, Ayse B.; Ibiloglu, Ibrahim; Akalin, Ibrahim; Firat, Ugur; Kosemetin, Duygu; Engin Zerk, Pinar; Aydin, Abdullah

    2016-01-01

    Epithelial-stroma interactions in the endometrium are known to be responsible for physiological functions and emergence of several pathologic lesions. Periglandular stromal cells act on endometrial cells in a paracrine manner through sex hormones. In this study, we immunohistochemically evaluated the expression of epithelial-mesenchymal transition regulators (SNAIL/SLUG, TWIST, ZEB1), adhesion molecules (β-catenin and E-cadhenin), estrogen (ER)-progesterone (PR) receptor and their correlation with each other in 30 benign, 148 hyperplastic (EH), and 101 endometrioid-type endometrial carcinoma (EC) endometria. In the epithelial component, loss of expression in E-cadherin, ER and PR, and overexpression of TWIST and ZEB1 were significantly higher in EC than in EH (P<0.01). In the periglandular stromal component, β-catenin and SNAIL/SLUG expression were significantly higher in normal endometrium and simple without atypical EH compared with complex atypical EH and EC (P<0.01). In addition, periglandular stromal TWIST expression was significantly higher in EH group compared with EC (P<0.05). There was significantly negative correlation between β-catenin and ER, TWIST and ER, and TWIST and PR in hyperplastic and carcinomatous glandular epithelium, whereas there was a significantly positive correlation between β-catenin and SNAIL-SLUG, β-catenin and TWIST, β-catenin and ER, β-catenin and PR, SNAIL-SLUG and ER, SNAIL-SLUG and PR, TWIST and ER, TWIST and PR, in periglandular/cancer-associated stromal cells (P<0.01). In conclusion, the pattern of positive and negative correlations in the expression of epithelial-mesenchymal transition regulators (SNAIL-SLUG and TWIST), sex hormone receptors (ER and PR), and β-catenin between ECs and hyperplasia, as well as between epithelium and stroma herein, is suggestive of a significant role for these proteins and their underlying molecular processes in the development of endometrial carcinomas. PMID:26367784

  1. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis.

    PubMed

    Burney, Richard O; Talbi, Said; Hamilton, Amy E; Vo, Kim Chi; Nyegaard, Mette; Nezhat, Camran R; Lessey, Bruce A; Giudice, Linda C

    2007-08-01

    The identification of molecular differences in the endometrium of women with endometriosis is an important step toward understanding the pathogenesis of this condition and toward developing novel strategies for the treatment of associated infertility and pain. In this study, we conducted global gene expression analysis of endometrium from women with and without moderate/severe stage endometriosis and compared the gene expression signatures across various phases of the menstrual cycle. The transcriptome analysis revealed molecular dysregulation of the proliferative-to-secretory transition in endometrium of women with endometriosis. Paralleled gene expression analysis of endometrial specimens obtained during the early secretory phase demonstrated a signature of enhanced cellular survival and persistent expression of genes involved in DNA synthesis and cellular mitosis in the setting of endometriosis. Comparative gene expression analysis of progesterone-regulated genes in secretory phase endometrium confirmed the observation of attenuated progesterone response. Additionally, interesting candidate susceptibility genes were identified that may be associated with this disorder, including FOXO1A, MIG6, and CYP26A1. Collectively these findings provide a framework for further investigations on causality and mechanisms underlying attenuated progesterone response in endometrium of women with endometriosis.

  2. hCG activates Epac-Erk1/2 signaling regulating Progesterone Receptor expression and function in human endometrial stromal cells.

    PubMed

    Tapia-Pizarro, Alejandro; Archiles, Sebastián; Argandoña, Felipe; Valencia, Cecilia; Zavaleta, Keyla; Cecilia Johnson, M; González-Ramos, Reinaldo; Devoto, Luigi

    2017-06-01

    How does hCG signal in human endometrial stromal cells (ESCs) and what is its role in regulating ESC function? hCG signaling in ESCs activates the extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) pathway through exchange protein activated by cyclic AMP (cAMP) (Epac) and transiently increases progesterone receptor (PR) transcript and protein expression and its transcriptional function. hCG is one of the earliest embryo-derived secreted signals in the endometrium, which abundantly expresses LH/hCG receptors. hCG signals through cAMP/protein kinase A (PKA) in gonadal cells, but in endometrial epithelial cells, hCG induces Erk1/2 activation independent of the cAMP/PKA pathway. Few data exist concerning the signal transduction pathways triggered by hCG in ESCs and their role in regulation of ESC function. This is an in vitro study comprising patients undergoing benign gynecological surgery (n = 46). Endometrial samples were collected from normal cycling women during the mid-secretory phase for ESCs isolation. The study conducted in an academic research laboratory within a tertiary-care hospital. The activation of the Erk1/2 signal transduction pathway elicited by hCG was evaluated in ESC. Signaling pathway inhibitors were used to examine the roles of PKA, PI3K, PKC, adenylyl cyclase and Epac on the hCG-stimulated up-regulation of phospho-Erk1/2 (pErk1/2). Erk1/2 phosphorylation was determined by immunoblot. siRNA targeting Epac was used to investigate the molecular mechanisms. To assess the role of Erk1/2 signaling induced by hCG on ESC function, gene expression regulation was examined by immunofluorescence and real-time quantitative PCR. The role of PR on the regulation of transcript levels was studied using progesterone and the PR antagonist RU486. All experiments were conducted using at least three different cell culture preparations in triplicate. Addition of hCG to ESCs in vitro induced the phosphorylation of Erk1/2 through cAMP accumulation. Such

  3. Endometrial receptivity: lessons from systems biology and candidate gene studies of endometriosis.

    PubMed

    Mathyk, Begum; Adams, Nyssa; Young, Steven L

    2017-02-01

    Endometrial receptivity is essential for embryo implantation and ongoing successful pregnancy. The temporal "window" during which the endometrium allows implantation, known as window of implantation (WOI), which is, characterized alteration of many genes. Transcriptomic changes at the time of implantation let us discover many genes and their protein products whose altered expression effects endometrial receptivity. New omics technologies helped us to understand the complex dynamics of endometrium. Progesterone is responsible for decidualization and establishment of implantation. In women with endometriosis progesterone resistance might impair decidualization and subsequent implantation in different ways. We summarized the effects of progesterone resistance on genes, transcription factors, proteins and inflammatory mediators. Understanding the effects of progesterone resistance on genes and downstream targets will highlight future treatments in patients with endometriosis.

  4. Association of insulin resistance with breast, ovarian, endometrial and cervical cancers in non-diabetic women.

    PubMed

    Sun, Wanwan; Lu, Jieli; Wu, Shengli; Bi, Yufang; Mu, Yiming; Zhao, Jiajun; Liu, Chao; Chen, Lulu; Shi, Lixin; Li, Qiang; Yang, Tao; Yan, Li; Wan, Qin; Liu, Yan; Wang, Guixia; Luo, Zuojie; Tang, Xulei; Chen, Gang; Huo, Yanan; Gao, Zhengnan; Su, Qing; Ye, Zhen; Wang, Youmin; Qin, Guijun; Deng, Huacong; Yu, Xuefeng; Shen, Feixia; Chen, Li; Zhao, Liebin; Wang, Tiange; Sun, Jichao; Xu, Min; Xu, Yu; Chen, Yuhong; Dai, Meng; Zhang, Jie; Zhang, Di; Lai, Shenghan; Li, Donghui; Ning, Guang; Wang, Weiqing

    2016-01-01

    Hyperinsulinemia and insulin resistance were reported to play a crucial role in diabetes-cancer relationship. This study aimed to explore the associations between insulin resistance and several female cancers in a non-diabetic population. This cross-sectional study was conducted in 121,230 middle-aged and elderly non-diabetic women. Cancer diagnosis was self-reported and further validated by medical records. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.50. The prevalence of both premenopausal and postmenopausal breast cancer, postmenopausal ovarian cancer and premenopausal endometrial cancer were higher in insulin-resistant participants than in insulin-sensitive participants (premenopausal breast cancer, 0.45 vs 0.28%; postmenopausal breast cancer, 0.86 vs 0.63%; postmenopausal ovarian cancer, 0.17 vs 0.09%; premenopausal endometrial cancer, 0.43 vs 0.25%, respectively, all P < 0.05). Individuals with insulin resistance had higher odds ratio (OR) of breast cancer, both premenopausal and postmenopausal (OR 1.98, 95% confidence interval (CI) 1.19-3.32; OR 1.29, 95% CI 1.01-1.63), postmenopausal ovarian cancer (OR 2.17, 95% CI 1.10-3.40) as well as total endometrial cancer (OR 1.47, 95% CI 1.02-2.12). Subgroup analysis revealed that the possitive association between insulin resistance and risk of prevalent breast cancer was observed in popualtion with younger age, overweight or obesity, higher education and impaired glucose tolerance (IGR). No relationships were observed for the risk of prevalent cervical cancers with insulin resistance. Non-diabetic women with insulin resistance had higher risk of prevalent breast, ovarian and endomatrial cancer, which suggests special attentions to these female cancer screening and prevention.

  5. Association of insulin resistance with breast, ovarian, endometrial and cervical cancers in non-diabetic women

    PubMed Central

    Sun, Wanwan; Lu, Jieli; Wu, Shengli; Bi, Yufang; Mu, Yiming; Zhao, Jiajun; Liu, Chao; Chen, Lulu; Shi, Lixin; Li, Qiang; Yang, Tao; Yan, Li; Wan, Qin; Liu, Yan; Wang, Guixia; Luo, Zuojie; Tang, Xulei; Chen, Gang; Huo, Yanan; Gao, Zhengnan; Su, Qing; Ye, Zhen; Wang, Youmin; Qin, Guijun; Deng, Huacong; Yu, Xuefeng; Shen, Feixia; Chen, Li; Zhao, Liebin; Wang, Tiange; Sun, Jichao; Xu, Min; Xu, Yu; Chen, Yuhong; Dai, Meng; Zhang, Jie; Zhang, Di; Lai, Shenghan; Li, Donghui; Ning, Guang; Wang, Weiqing

    2016-01-01

    Hyperinsulinemia and insulin resistance were reported to play a crucial role in diabetes-cancer relationship. This study aimed to explore the associations between insulin resistance and several female cancers in a non-diabetic population. This cross-sectional study was conducted in 121,230 middle-aged and elderly non-diabetic women. Cancer diagnosis was self-reported and further validated by medical records. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.50. The prevalence of both premenopausal and postmenopausal breast cancer, postmenopausal ovarian cancer and premenopausal endometrial cancer were higher in insulin-resistant participants than in insulin-sensitive participants (premenopausal breast cancer, 0.45 vs 0.28%; postmenopausal breast cancer, 0.86 vs 0.63%; postmenopausal ovarian cancer, 0.17 vs 0.09%; premenopausal endometrial cancer, 0.43 vs 0.25%, respectively, all P < 0.05). Individuals with insulin resistance had higher odds ratio (OR) of breast cancer, both premenopausal and postmenopausal (OR 1.98, 95% confidence interval (CI) 1.19-3.32; OR 1.29, 95% CI 1.01-1.63), postmenopausal ovarian cancer (OR 2.17, 95% CI 1.10-3.40) as well as total endometrial cancer (OR 1.47, 95% CI 1.02-2.12). Subgroup analysis revealed that the possitive association between insulin resistance and risk of prevalent breast cancer was observed in popualtion with younger age, overweight or obesity, higher education and impaired glucose tolerance (IGR). No relationships were observed for the risk of prevalent cervical cancers with insulin resistance. Non-diabetic women with insulin resistance had higher risk of prevalent breast, ovarian and endomatrial cancer, which suggests special attentions to these female cancer screening and prevention. PMID:27822422

  6. Endometrial Adenocarcinoma in a 27-Year-Old Woman

    PubMed Central

    Fadhlaoui, Anis; Ben Hassouna, Jamel; Khrouf, Mohamed; Zhioua, Fethi; Chaker, Anis

    2010-01-01

    Background Endometrial adenocarcinoma usually occurs after menopause, but in 2%–14% of cases, it occurs in young patients (less than 40 years of age) who are eager to preserve their fertility. Its treatment includes hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy, and, in some cases, radiation therapy. Aim To describe a case of endometrial adenocarcinoma occurring in a young woman and to undertake a literature review of risk factors and therapeutic options proposed for young women wishing to preserve their fertility. Case We report a case of endometrial cancer in a 27-year-old woman treated for resistant menorrhagia and cared for in our department as well as in the Salah Azaiez Institute. Conclusion Endometrial adenocarcinoma rarely occurs in young women. In such cases, other therapeutic options can be proposed: progesterone therapy and LH-RH (Luteinzing-Hormone-Releasing-Hormone) agonists therapy in order to preserve fertility in younger patients. PMID:21769252

  7. Bioadhesive emulsions for control release of progesterone resistant to vaginal fluids clearance.

    PubMed

    Campaña-Seoane, Maria; Peleteiro, Aaron; Laguna, Reyes; Otero-Espinar, Francisco J

    2014-12-30

    The aim of this study is to propose that mucoadhesive vaginal emulsions can be able to resist the clearance effect of vaginal fluid and to have an effective control release of progesterone. With this goal, silicon derivative, cyclomethicone pentamer, was selected as the bioadhesive and water resistant material. In order to obtain a system which is insensitive to the dilution of aqueous fluids, water in silicone (W/S) emulsions were prepared and different proportions of cyclomethicone as well as 8% or 15% w/w of progesterone were employed. The rheological, mechanical and mucoadhesive properties of emulsions were characterized and the drug release was measured for each formulation. Mucoadhesive behavior was determined and the influence of simulated vaginal fluid (SVF) at bioadhesion was assessed using three commercial mucoadhesive vaginal gels (Crinone(®), K-Y jelly(®) and Zidoval(®)) as the bioadhesive references. All assayed emulsions have good rheological and mechanical properties and their consistence and viscosity increase when the proportion of the internal phase increases. Related to mucoadhesion, in the absence of SVF, W/S emulsions showed similar bioadhesive levels like the commercial formulations. However, in the presence of SVF, W/S emulsions are able to keep their mucoadhesive properties while the marketed references drastically lose their consistency and adherence to the vaginal mucosa. Drug release profiles from W/S emulsion show that progesterone is released with pseudo-order zero kinetics and a constant release rate is maintained for at least two weeks. The results of the in vivo studies developed in rats show that after a single vaginal administration, bioadhesive W/S emulsions increase the uterine tissue progesterone levels in young and postmenopausal rats. Moreover in postmenopausal rats, they provide high uterine levels of progesterone compared to the bioadhesive-marketed gel used as a reference. Therefore, W/S emulsions have an interesting

  8. Homeostasis imbalance in the endometrium of women with implantation defects: the role of estrogen and progesterone.

    PubMed

    Lessey, Bruce A; Young, Steven L

    2014-09-01

    Embryo implantation is regulated by an inflammatory process in response to sequential exposure to estrogen and progesterone, followed by resolution and repair. The actions of estrogen and progesterone on these inflammatory processes are tightly and reciprocally controlled through regulated expression of steroid receptors, cofactors, chaperone proteins, and downstream signaling components. In endometriosis, the inflammatory cascades, normally seen at menstruation, are prematurely activated and endogenous endometrial mechanisms of inflammation resolution appear defective. The temporally abnormally inflammation is also associated with an imbalance between estrogen and progesterone actions; the normal luteal-phase dominance of progesterone action appears to be lost and is replaced by progesterone resistance and estrogen dominance. In this review, we examine these relationships in greater detail and argue that estrogen action is a prime target for future therapeutic solutions to endometriosis and implantation failure that result from this chronic, inflammatory disease.

  9. Lipocalin 2 Enhances Migration and Resistance against Cisplatin in Endometrial Carcinoma Cells

    PubMed Central

    Kashima, Hiroyasu; Yamada, Yasushi; Kobara, Hisanori; Asaka, Ryoichi; Ando, Hirofumi; Higuchi, Shotaro; Ida, Koichi; Mvunta, David Hamisi; Shiozawa, Tanri

    2016-01-01

    Purpose Lipocalin 2 (LCN2) is a secretory protein that is involved in various physiological processes including iron transport. We previously identified LCN2 as an up-regulated gene in endometrial carcinoma, and found that the overexpression of LCN2 and its receptor, SLC22A17, was associated with a poor prognosis. However, the functions and mechanism of action of LCN2 currently remain unclear. Methods The LCN2-overexpressing endometrial carcinoma cell lines, HHUA and RL95-2, and LCN2-low-expressing one, HEC1B, were used. The effects of LCN2 on cell migration, cell viability, and apoptosis under various stresses, including ultraviolet (UV) irradiation and cisplatin treatment, were examined using the scratch wound healing assay, WST-1 assay, and Apostrand assay, respectively. Results LCN2-silencing using shRNA method significantly reduced the migration ability of cells (p<0.05). Cytotoxic stresses significantly decreased the viability of LCN2-silenced cells more than that of control cells. In contrast, LCN2 overexpression was significantly increased cisplatin resistance. These effects were canceled by the addition of the iron chelator, deferoxamine. After UV irradiation, the expression of phosphorylated Akt (pAkt) was decreased in LCN2-silenced cells, and the PI3K inhibitor canceled the difference induced in UV sensitivity by LCN2. The cisplatin-induced expression of pAkt was not affected by LCN2; however, the expression of p53 and p21 was increased by LCN2-silencing. Conclusions These results indicated that LCN2 was involved in the migration and survival of endometrial carcinoma cells under various stresses in an iron-dependent manner. The survival function of LCN2 may be exerted through the PI3K pathway and suppression of the p53-p21 pathway. These functions of LCN2 may increase the malignant potential of endometrial carcinoma cells. PMID:27168162

  10. Endometrial ablation

    MedlinePlus

    Hysteroscopy-endometrial ablation; Laser thermal ablation; Endometrial ablation-radiofrequency; Endometrial ablation-thermal balloon ablation; Rollerball ablation; Hydrothermal ablation; Novasure ablation

  11. Progesterone Resistance in Endometriosis Is Modulated by the Altered Expression of MicroRNA-29c and FKBP4.

    PubMed

    Joshi, Niraj R; Miyadahira, Eduardo H; Afshar, Yalda; Jeong, Jae-Wook; Young, Steven L; Lessey, Bruce A; Serafini, Paulo C; Fazleabas, Asgerally T

    2017-01-01

    Endometriosis results in aberrant gene expression in the eutopic endometrium (EuE) and subsequent progesterone resistance. MicroRNA (miR) microarray data in a baboon model of endometriosis showed an increased expression of miR-29c. To explore the role of miR-29c in progesterone resistance in a subset of women with endometriosis. MiR-29c expression was analyzed in the endometrium of baboons and women with or without endometriosis. The role in progesterone resistance and decidualization was analyzed by transfecting human uterine fibroblast cells with miR-29c. Subjects diagnosed with deep infiltrative endometriosis (DIE) by transvaginal ultrasound with bowel preparation underwent surgical excision of endometriosis. Eutopic secretory endometrium was collected pre- and postoperatively. Women with normal EuE and without DIE served as controls. Quantitative reverse transcription polymerase chain reaction demonstrated that miR-29c expression increased, while the transcript levels of its target, FK506-binding protein 4 (FKBP4), decreased in the EuE of baboons following the induction of endometriosis. FKBP4 messenger RNA and decidual markers were statistically significantly decreased in decidualized human uterine fibroblast cells transfected with a miR-29c mimic compared with controls. Human data corroborated our baboon data and demonstrated higher expression of miR-29c in endometriosis EuE compared with normal EuE. MiR-29c was significantly decreased in endometriosis EuE postoperatively compared with preoperative tissues, and FKBP4 showed an inverse trend following radical laparoscopic resection surgery. We demonstrate that miR-29c expression is increased in EuE of baboons and women with endometriosis, which might contribute to a compromised progesterone response by diminishing the levels of FKBP4. Resection of DIE is likely to reverse the progesterone resistance associated with endometriosis in women.

  12. Endometrial proteins: a reappraisal.

    PubMed

    Seppälä, M; Julkunen, M; Riittinen, L; Koistinen, R

    1992-06-01

    Uterine factors influence reproduction at the macro-anatomy level, and the effects of hormonal steroids on endometrial morphology are well recognized in the histopathological diagnosis of dysfunctional bleeding and infertility. During the past decade, attention has been paid to endometrial protein synthesis and secretion with respect to endocrine stimuli and implantation, and to the paracrine/autocrine effects of endometrial peptide growth factors, their binding proteins and other factors. The emphasis of this presentation is on protein secretion of the secretory endometrium, in which progesterone plays a pivotal role. Insulin-like growth factors have receptors on the endometrium, and IGF-binding proteins, stimulated by progesterone, modulate the effects of IGFs locally. Also other protein products of the secretory endometrium have been reviewed in this communication, with special emphasis on studies of a progesterone-associated endometrial protein which has many names in the literature, such as PEP, PP14, alpha 2-PEG and AUP. Extensive studies are ongoing in many laboratories to elucidate the regulation, function, interplay at tissue and cellular levels, and clinical significance of these proteins.

  13. FKBP52 deficiency–conferred uterine progesterone resistance is genetic background and pregnancy stage specific

    PubMed Central

    Tranguch, Susanne; Wang, Haibin; Daikoku, Takiko; Xie, Huirong; Smith, David F.; Dey, Sudhansu K.

    2007-01-01

    Immunophilin FKBP52 serves as a cochaperone to govern normal progesterone (P4) receptor (PR) function. Using Fkbp52–/– mice, we show intriguing aspects of uterine P4/PR signaling during pregnancy. Implantation failure is the major phenotype found in these null females, which is conserved on both C57BL6/129 and CD1 backgrounds. However, P4 supplementation rescued implantation and subsequent decidualization in CD1, but not C57BL6/129, null females. Surprisingly, experimentally induced decidualization in the absence of blastocysts failed in Fkbp52–/– mice on either background even with P4 supplementation, suggesting that embryonic signals complement uterine signaling for this event. Another interesting finding was that while P4 at higher than normal pregnancy levels conferred PR signaling sufficient for implantation in CD1 null females, these levels were inefficient in maintaining pregnancy to full term. However, elevating P4 levels further restored PR signaling to a level optimal for successful term pregnancy with normal litter size. Collectively, the results show that the indispensability of FKBP52 in uterine P4/PR signaling is a function of genetic disparity and is pregnancy stage specific. Since there is evidence for a correlation between P4 supplementation and reduced risks of P4-resistant recurrent miscarriages and remission of endometriosis, these findings have clinical implications for genetically diverse populations of women. PMID:17571166

  14. Obesity and Endometrial Cancer.

    PubMed

    Shaw, Eileen; Farris, Megan; McNeil, Jessica; Friedenreich, Christine

    Endometrial cancer is the sixth most common cancer in women worldwide and the most common gynecologic malignancy in the developed world. This chapter explores the current epidemiologic evidence on the association between obesity and endometrial cancer risk and mortality. Using body mass index (BMI) as a measure of obesity, we found that obesity (defined as BMI > 30 and < 35 kg/m(2)) was associated with a 2.6-fold increase in endometrial cancer risk, while severe obesity (BMI > 35 kg/m(2)) was associated with a 4.7-fold increase compared to normal-weight women (BMI < 25 kg/m(2)). Increased central adiposity also increased endometrial cancer risk by 1.5- to twofold. Among both healthy and endometrial cancer patient populations, obesity was associated with a roughly twofold increase in endometrial cancer-specific mortality. This risk reduction was also observed for obesity and all-cause mortality among endometrial cancer patients. In the few studies that assessed risk associated with weight change, an increased endometrial cancer risk with weight gain and weight cycling was observed, whereas some evidence for a protective effect of weight loss was found. Furthermore, early-life obesity was associated with a moderately increased risk of endometrial cancer later in life. There are several mechanisms whereby obesity is hypothesized to increase endometrial cancer risk, including increased endogenous sex steroid hormones, insulin resistance, chronic inflammation and adipokines. Further research should focus on histological subtypes or molecular phenotypes of endometrial tumors and population subgroups that could be at an increased risk of obesity-associated endometrial cancer. Additionally, studies on weight gain, loss or cycling and weight loss interventions can provide mechanistic insight into the obesity-endometrial cancer association. Sufficient evidence exists to recommend avoiding obesity to reduce endometrial cancer risk.

  15. The impact of micronized progesterone on the endometrium: a systematic review.

    PubMed

    Stute, P; Neulen, J; Wildt, L

    2016-08-01

    Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. International guidelines on menopausal hormone therapy (MHT) do not specify on progestogen type, dosage, route of application and duration of safe use. At the same time, the debate on bioidentical hormones including micronized progesterone increases. Based on a systematic literature review on micronized progesterone for endometrial protection, an international expert panel's recommendations on MHT containing micronized progesterone are as follows: (1) oral micronized progesterone provides endometrial protection if applied sequentially for 12-14 days/month at 200 mg/day for up to 5 years; (2) vaginal micronized progesterone may provide endometrial protection if applied sequentially for at least 10 days/month at 4% (45 mg/day) or every other day at 100 mg/day for up to 3-5 years (off-label use); (3) transdermal micronized progesterone does not provide endometrial protection.

  16. Insulin resistance and endometrial cancer risk: A systematic review and meta-analysis.

    PubMed

    Hernandez, Adrian V; Pasupuleti, Vinay; Benites-Zapata, Vicente A; Thota, Priyaleela; Deshpande, Abhishek; Perez-Lopez, Faustino R

    2015-12-01

    It has been suggested that chronic hyperinsulinemia from insulin resistance is involved in the etiology of endometrial cancer (EC). We performed a systematic review and meta-analysis to assess whether insulin resistance is associated with the risk of EC. We searched PubMed-Medline, Embase, Scopus, and Web of Science for articles published from database inception through 30th September 2014. We included all observational studies evaluating components defining insulin resistance in women with and without EC. Quality of the included studies was assessed by Newcastle-Ottawa scale. Random-effects models and inverse variance method were used to meta-analyze the association between insulin resistance components and EC. Twenty-five studies satisfied our inclusion criteria. Fasting insulin levels (13 studies, n = 4088) were higher in women with EC (mean difference [MD] 33.94 pmol/L, 95% confidence interval [CI] 15.04-52.85, p = 0.0004). No differences were seen in postmenopausal versus pre- and postmenopausal subgroup analysis. Similarly, non-fasting/fasting C-peptide levels (five studies, n = 1938) were also higher in women with EC (MD 0.14 nmol/L, 95% CI 0.08-0.21, p < 0.00001). Homeostatic model assessment - insulin resistance (HOMA-IR) values (six studies, n = 1859) in EC patients were significantly higher than in women without EC (MD 1.13, 95% CI 0.20-2.06, p = 0.02). There was moderate-to-high heterogeneity among the included studies. Currently available epidemiologic evidence is suggestive of significantly higher risk of EC in women with high fasting insulin, non-fasting/fasting C-peptide and HOMA-IR values. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. The progesterone receptor coactivator Hic-5 is involved in the pathophysiology of endometriosis.

    PubMed

    Aghajanova, Lusine; Velarde, Michael C; Giudice, Linda C

    2009-08-01

    Endometriosis is an estrogen-dependent disorder primarily associated with pelvic pain and infertility in up to 10% of women of reproductive age. Recent studies suggest that resistance to progesterone action may contribute to the development and pathophysiology of this disorder. In this study we examined the in vivo and in vitro expression and function of one progesterone receptor (PR) coactivator, Hic-5, in human endometrium and endometrial stromal fibroblasts (hESFs) from 29 women with and 30 (control) women without endometriosis. Hic-5 was highly expressed in stromal, but not epithelial, cells in women without endometriosis, in a cycle-dependent manner. In contrast, Hic-5 expression was not regulated during the menstrual cycle in hESFs from women with endometriosis and was significantly reduced in hESFs from women with vs. without disease. Hic-5 mRNA expression throughout the cycle in endometrium from control women, but not those with endometriosis, correlated with expression of PR. Hic-5 mRNA in hESFs was significantly up-regulated in control but not endometriosis hESFs after treatment in vitro with 8-bromoadenosine-cAMP for 96 h but only modestly after 14 d of progesterone treatment. Hic-5 silencing did not influence cAMP-regulated gene expression but affected genes regulated solely by progesterone (e.g. DKK1 and calcitonin). Together the data suggest that the proposed progesterone resistance in endometrium from women with endometriosis derives, in part, from impaired expression of the PR coactivator, Hic-5, in endometrial tissue and cultured endometrial stromal fibroblasts.

  18. Progesterone Test

    MedlinePlus

    ... of infertility . Since progesterone levels vary throughout the menstrual cycle, multiple (serial) measurements can be used for this ... be ordered a few times during a woman's menstrual cycle to evaluate the change in progesterone concentrations. When ...

  19. Upregulation of TrkB promotes epithelial-mesenchymal transition and anoikis resistance in endometrial carcinoma.

    PubMed

    Bao, Wei; Qiu, Haifeng; Yang, Tingting; Luo, Xin; Zhang, Huijuan; Wan, Xiaoping

    2013-01-01

    Mechanisms governing the metastasis of endometrial carcinoma (EC) are poorly defined. Recent data support a role for the cell surface receptor tyrosine kinase TrkB in the progression of several human tumors. Here we present evidence for a direct role of TrkB in human EC. Immunohistochemical analysis revealed that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are more highly expressed in EC than in normal endometrium. High TrkB levels correlated with lymph node metastasis (p<0.05) and lymphovascular space involvement (p<0.05) in EC. Depletion of TrkB by stable shRNA-mediated knockdown decreased the migratory and invasive capacity of cancer cell lines in vitro and resulted in anoikis in suspended cells. Conversely, exogenous expression of TrkB increased cell migration and invasion and promoted anoikis resistance in suspension culture. Furthermore, over-expression of TrkB or stimulation by BDNF resulted in altered the expression of molecular mediators of the epithelial-to-mesenchymal transition (EMT). RNA interference (RNAi)-mediated depletion of the downstream regulator, Twist, blocked TrkB-induced EMT-like transformation. The use of in vivo models revealed decreased peritoneal dissemination in TrkB-depleted EC cells. Additionally, TrkB-depleted EC cells underwent mesenchymal-to-epithelial transition and anoikis in vivo. Our data support a novel function for TrkB in promoting EMT and resistance to anoikis. Thus, TrkB may constitute a potential therapeutic target in human EC.

  20. From endometrial hyperplasia to endometrial cancer: insight into the biology and possible medical preventive measures.

    PubMed

    Boruban, Melih C; Altundag, Kadri; Kilic, Gokhan S; Blankstein, Josef

    2008-04-01

    Controversies are still seen in the histological differential diagnosis of hyperplasia and well-differentiated endometrial carcinoma. Prediction of endometrial cancer in patients with hyperplasia with atypia, with the available markers has not been reliable yet. Hence these patients require more attention in the clinical management. Endometrial hyperplasia is proliferation of endometrial glands resulting in a higher gland : stroma ratio. Cytological atypia, which may progress to or co-exist with endometrial cancer and other pathological changes, result from estrogen stimulation unopposed by progesterone. Biomarkers whose expression is altered in cases of endometrial hyperplasia or cancer such as progesterone receptor, insulin-like growth factor I, retinaldehyde dehydrogenase type II, and secreted frizzled-related protein 4, seem to be promising to use as early-stage tumor markers. Mutation of PTEN is present in 83% of endometrial adenocarcinoma cases, making it the most frequent early molecular genetic alteration in type 1 endometrial tumors, which are generally associated with hyperplasia. p53 gene mutation is not found in endometrial hyperplasia, but researchers have detected this mutation in 20% of cases of endometrial carcinoma and 90% of cases of serous endometrial tumors. Cyclooxygenase-2 is important in tumorogenic transformation of hyperplasia. Expression of cyclooxygenase-2 decreases apoptosis, increases angiogenesis, and is related to invasiveness. Cyclooxygenase-2 expression increases significantly in cases of well-differentiated endometrial adenocarcinoma. Prostaglandin E2 is known to regulate aromatase gene expression and is the product of cyclooxygenase-2. The data about aromatase inhibitors are promising; in breast cancer patients, treatment with tamoxifen induces uterine abnormalities as early as 3 months after the initiation of therapy. In contrast, these abnormalities are not seen in patients who receive aromatase inhibitors and switched therapy

  1. Spontaneous conception in 40-year-old infertile woman with polycystic ovaries after complete reversal of endometrial intraepithelial neoplasia: A case report with review of literature

    PubMed Central

    Verma, Swati; Jindal, Umesh N.

    2016-01-01

    We report a case of polycystic ovary syndrome and prolonged infertility in which endometrial intraepithelial neoplasia was reversed with high dose progesterone therapy. Spontaneous conception after failure of assisted reproductive techniques highlights the role of endometrial receptivity. PMID:28216918

  2. Serum progesterone

    MedlinePlus

    ... progesterone levels start to rise midway through the menstrual cycle. It continues to rise for about 6 to ... normal ranges based upon certain phases of the menstrual cycle and pregnancy: Female (pre-ovulation): less than 1 ...

  3. Immunohistochemical detection of P-glycoprotein in endometrial adenocarcinoma.

    PubMed Central

    Axiotis, C. A.; Monteagudo, C.; Merino, M. J.; LaPorte, N.; Neumann, R. D.

    1991-01-01

    P-glycoprotein (Pgp) has emerged as the central mediator in classic multidrug resistance in model systems in vitro. High levels of Pgp also have been detected in many normal human tissues and tumors; and its role in clinical drug resistance is currently under investigation. Recently significant levels of Pgp were localized to gravid and secretory endometrium; and it was demonstrated that the combination of estrogen and progesterone is sufficient to induce high levels of both Pgp mRNA and Pgp in uterine secretory epithelium. These findings suggest that increased Pgp expression also may be present in hormone-responsive malignancies such as endometrial adenocarcinoma. To determine whether Pgp is expressed in endometrial adenocarcinoma, 36 endometrial adenocarcinomas (grade I [n = 17]; grade II [n = 6]; grade III [n = 13]) were investigated retrospectively by the avidin-biotin-complex immunohistochemical procedure using three murine monoclonal antibodies (MAb) MAb C219, MAb C494, and MAb JSB-1, which recognize spatially distinct cytoplasmic epitopes of Pgp. Seventy-two percent of the tumors showed positive immunostaining with at least one MAb; 67% showed immunostaining with MAb C219, 50% with MAb C494, and 62% with MAb JSB-1. Forty-six percent of tumors were immunoreactive to two and 29% to all three antibodies. Membranous and Golgi/paranuclear type staining patterns were observed. Overall the intensity of immunostaining varied from one sample to another for a given tumor type, and considerable heterogeneity of expression was commonly seen within a given tumor. Strong to moderate immunoreactivity was seen in diffusely infiltrating, adenosquamous, and serous papillary carcinomas. In general, immunoreactivity to MAb C494 was weaker than MAb C219 or MAb JSB-1. Adenomatous and non-neoplastic endometrium adjacent to the tumors displayed strong membranous immunostaining with MAb JSB-1. Endometrial capillaries showed weak-to-moderate immunostaining to all three antibodies. It

  4. Mig-6 Mouse Model of Endometrial Cancer.

    PubMed

    Kim, Tae Hoon; Yoo, Jung-Yoon; Jeong, Jae-Wook

    2017-01-01

    Endometrial cancer is a frequently occurring gynecological disorder. Estrogen-dependent endometrioid carcinoma is the most common type of gynecological cancer. One of the major pathologic phenomena of endometrial cancer is the loss of estrogen (E2) and progesterone (P4) control over uterine epithelial cell proliferation. P4 antagonizes the growth-promoting properties of E2 in the uterus. P4 prevents the development of endometrial cancer associated with unopposed E2 by blocking E2 actions. Mitogen inducible gene 6 (Mig-6, Errfi1, RALT, or gene 33) is an immediate early response gene that can be induced by various mitogens and common chronic stress stimuli. Mig-6 has been identified as an important component of P4-mediated inhibition of E2 signaling in the uterus. Decreased expression of MIG-6 is observed in human endometrial carcinomas. Transgenic mice with Mig-6 ablation in the uterus develop endometrial hyperplasia and E2-dependent endometrial cancer. Thus, MIG-6 has a tumor suppressor function in endometrial tumorigenesis. The following discussion summarizes our current knowledge of Mig-6 mouse models and their role in understanding the molecular mechanisms of endometrial tumorigenesis and in the development of therapeutic approaches for endometrial cancer.

  5. Endometrial spiral artery Doppler parameters in unexplained infertility patients: is endometrial perfusion an important factor in the etiopathogenesis?

    PubMed Central

    Uysal, Selda; Özbay, Elif Pelin Özün; Ekinci, Tekin; Aksüt, Hayri; Karasu, Şebnem; Işık, Ahmet Zeki; Soylu, Ferit

    2012-01-01

    Objective Uterine perfusion, particularly the endometrial blood flow, may have an important role in endometrial receptivity. In order to assess the contribution of sub endometrial blood flow in the etiopathogenesis of unexplained infertility mid luteal- peri-implantation period spiral artery transvaginal color Doppler parameters were measured and compared with fertile controls. Material and Methods Forty-two consecutive patients admitted to Izmir Katip Celebi University Ataturk Training and Research Hospital, Department of Obstetric and Gynecology with the diagnosis of unexplained infertility after standard diagnostic work up constituted the study group and they were compared with a fertile control group admitted to hospital with non specific gynecological complaints or for check-up in the same period. Mid luteal transvaginal color Doppler ultrasonography was applied to each patient by the same radiologist who was blind to the diagnosis of the particular patient and, RI (resistance index) and PI (pulsatility index) values were calculated. Results There were no significant differences between the two groups, in respect to age, body mass index, basal hormonal and mid luteal progesterone levels (p>0.05). For the fertile control group, mid luteal-peri-implantation phase endometrial spiral artery mean RI values were calculated as 0.48±0.08 SD and mean PI values as 0.65±0.18 SD. For the study group, mean RI values were calculated as 0.54±0.07 SD, PI values were calculated as 0.80±0.16 SD. The differences for RI (p=0.009) and PI (p=0.004) were statistically significant. Conclusion According to Doppler parameters, unexplained infertility patients have high impedance blood flow in spiral arteries which means that peri-implantation blood flow in these patient is lower than fertile controls. These findings suggest that endometrial perfusion may have an important contribution to etiopathogenesis of unexplained infertility. PMID:24592032

  6. Endometrial spiral artery Doppler parameters in unexplained infertility patients: is endometrial perfusion an important factor in the etiopathogenesis?

    PubMed

    Uysal, Selda; Ozbay, Elif Pelin Özün; Ekinci, Tekin; Aksüt, Hayri; Karasu, Sebnem; Işık, Ahmet Zeki; Soylu, Ferit

    2012-01-01

    Uterine perfusion, particularly the endometrial blood flow, may have an important role in endometrial receptivity. In order to assess the contribution of sub endometrial blood flow in the etiopathogenesis of unexplained infertility mid luteal- peri-implantation period spiral artery transvaginal color Doppler parameters were measured and compared with fertile controls. Forty-two consecutive patients admitted to Izmir Katip Celebi University Ataturk Training and Research Hospital, Department of Obstetric and Gynecology with the diagnosis of unexplained infertility after standard diagnostic work up constituted the study group and they were compared with a fertile control group admitted to hospital with non specific gynecological complaints or for check-up in the same period. Mid luteal transvaginal color Doppler ultrasonography was applied to each patient by the same radiologist who was blind to the diagnosis of the particular patient and, RI (resistance index) and PI (pulsatility index) values were calculated. There were no significant differences between the two groups, in respect to age, body mass index, basal hormonal and mid luteal progesterone levels (p>0.05). For the fertile control group, mid luteal-peri-implantation phase endometrial spiral artery mean RI values were calculated as 0.48±0.08 SD and mean PI values as 0.65±0.18 SD. For the study group, mean RI values were calculated as 0.54±0.07 SD, PI values were calculated as 0.80±0.16 SD. The differences for RI (p=0.009) and PI (p=0.004) were statistically significant. According to Doppler parameters, unexplained infertility patients have high impedance blood flow in spiral arteries which means that peri-implantation blood flow in these patient is lower than fertile controls. These findings suggest that endometrial perfusion may have an important contribution to etiopathogenesis of unexplained infertility.

  7. Endometriosis is associated with progesterone resistance in the baboon (Papio anubis) oviduct: evidence based on the localization of oviductal glycoprotein 1 (OVGP1).

    PubMed

    Wang, Chaohua; Mavrogianis, Patricia A; Fazleabas, Asgerally T

    2009-02-01

    Endometriosis has been associated with a reduced response to progesterone in both the eutopic and ectopic endometrium. In this study we evaluated OVGP1 and steroid receptor expression in oviducts of baboons with endometriosis during the midsecretory phase and determined whether progesterone resistance associated with endometriosis also occurs in the oviduct. Oviducts obtained during the window of uterine receptivity (Day 10 postovulation [PO]) from animals with induced and spontaneous disease were compared to control animals during the proliferative stage and in the implantation window as well as animals treated with the progesterone receptor (PGR) antagonist ZK 137.299 (ZK). OVGP1 was significantly higher in animals with endometriosis compared with Day 10 PO controls and was similar to that seen in the late proliferative phase and in ZK-treated animals. Baboons with spontaneous endometriosis also showed a similar persistence of OVGP1, which was correlated with the maintenance of estrogen receptor 1 (ESR1) in the epithelial cells of animals with endometriosis. However, epithelial cell height and the percentage of ciliation were not affected by endometriosis. These data imply that the normal antagonism of progesterone on ESR and OVGP1, which results in their downregulation during the window of implantation, is absent in animals with endometriosis. This was confirmed further when the action of PGR was antagonized in animals without disease, which also resulted in the persistence of ESR1 and OVGP1. These studies suggest that an aberrant oviductal environment may be an additive factor that contributes to endometriosis-associated infertility.

  8. Progesterone Alleviates Endometriosis via Inhibition of Uterine Cell Proliferation, Inflammation and Angiogenesis in an Immunocompetent Mouse Model.

    PubMed

    Li, Yanfen; Adur, Malavika K; Kannan, Athilakshmi; Davila, Juanmahel; Zhao, Yuechao; Nowak, Romana A; Bagchi, Milan K; Bagchi, Indrani C; Li, Quanxi

    2016-01-01

    Endometriosis, defined as growth of the endometrial cells outside the uterus, is an inflammatory disorder that is associated with chronic pelvic pain and infertility in women of childbearing age. Although the estrogen-dependence of endometriosis is well known, the role of progesterone in development of this disease remains poorly understood. In this study, we developed a disease model in which endometriosis was induced in the peritoneal cavities of immunocompetent female mice, and maintained with exogenous estrogen. The endometriosis-like lesions that were identified at a variety of ectopic locations exhibited abundant blood supply and extensive adhesions. Histological examination revealed that these lesions had a well-organized endometrial architecture and fibrotic response, resembling those recovered from clinical patients. In addition, an extensive proliferation, inflammatory response, and loss of estrogen receptor alpha (ERα) and progesterone receptor (PR) expression were also observed in these lesions. Interestingly, administration of progesterone before, but not after, lesion induction suppressed lesion expansion and maintained ERα and PR expressions. These progesterone-pretreated lesions exhibited attenuation in KI67, CD31, and pro-inflammatory cytokine expression as well as macrophage infiltration, indicating that progesterone ameliorates endometriosis progression by inhibiting cell proliferation, inflammation and neovascularization. Our studies further showed that suppression of global DNA methylation by application of DNA methyltransferase inhibitor to female mice bearing ectopic lesions restrained lesion expansion and restored ERα and PR expression in eutopic endometrium and ectopic lesions. These results indicate that epigenetic regulation of target gene expression via DNA methylation contributes, at least in part, to progesterone resistance in endometriosis.

  9. Progesterone Alleviates Endometriosis via Inhibition of Uterine Cell Proliferation, Inflammation and Angiogenesis in an Immunocompetent Mouse Model

    PubMed Central

    Kannan, Athilakshmi; Davila, Juanmahel; Zhao, Yuechao; Nowak, Romana A.; Bagchi, Milan K.; Bagchi, Indrani C.; Li, Quanxi

    2016-01-01

    Endometriosis, defined as growth of the endometrial cells outside the uterus, is an inflammatory disorder that is associated with chronic pelvic pain and infertility in women of childbearing age. Although the estrogen-dependence of endometriosis is well known, the role of progesterone in development of this disease remains poorly understood. In this study, we developed a disease model in which endometriosis was induced in the peritoneal cavities of immunocompetent female mice, and maintained with exogenous estrogen. The endometriosis-like lesions that were identified at a variety of ectopic locations exhibited abundant blood supply and extensive adhesions. Histological examination revealed that these lesions had a well-organized endometrial architecture and fibrotic response, resembling those recovered from clinical patients. In addition, an extensive proliferation, inflammatory response, and loss of estrogen receptor alpha (ERα) and progesterone receptor (PR) expression were also observed in these lesions. Interestingly, administration of progesterone before, but not after, lesion induction suppressed lesion expansion and maintained ERα and PR expressions. These progesterone-pretreated lesions exhibited attenuation in KI67, CD31, and pro-inflammatory cytokine expression as well as macrophage infiltration, indicating that progesterone ameliorates endometriosis progression by inhibiting cell proliferation, inflammation and neovascularization. Our studies further showed that suppression of global DNA methylation by application of DNA methyltransferase inhibitor to female mice bearing ectopic lesions restrained lesion expansion and restored ERα and PR expression in eutopic endometrium and ectopic lesions. These results indicate that epigenetic regulation of target gene expression via DNA methylation contributes, at least in part, to progesterone resistance in endometriosis. PMID:27776183

  10. Serum progesterone in women with lactational amenorrhoea.

    PubMed

    Joshi, U M; Joseph, R; Adatia, A R; Choudhary, V N; Joshi, J V; Mehta, S; Hazari, K T

    1980-10-01

    A cross-sectional study was conducted to detect the return of ovulation in 56 women with (LA) lactational amenorrhea ranging from 2-12 months. As serum progesterone of 5 ng/ml provides an indirect evidence of ovulation. It was estimated by radioimmunoassay in 4 blood samples collected weekly over a period of 1 month in all the women. 37 women showed persistently low values of progesterone ( 5 mg/ml) throughout the study period. The other 19 women had serum progesterone of 5 ng/ml in 1 or several samples. 13 of these women, however, continued to have LA beyond 1 month in spite of the detection of high circulating progesterone. The possibility of pregnancy was excluded in all of them. The endometrial refractoriness to the circulating steriods is proposed as a mechanism of persistent LA.

  11. Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer.

    PubMed

    Kim, Tae Hoon; Lee, Dong-Kee; Cho, Sung-Nam; Orvis, Grant D; Behringer, Richard R; Lydon, John P; Ku, Bon Jeong; McCampbell, Adrienne S; Broaddus, Russell R; Jeong, Jae-Wook

    2013-08-15

    Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure, and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal-epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6(f/f)) mice were crossed to Wnt7a-Cre mice (Wnt7a(cre+)Mig-6(f/f)). Wnt7a(cre+)Mig-6(f/f) mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in subepithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7a(cre+)Mig-6(f/f) mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7a(cre+)Mig-6(f/f) mice was prevented by progesterone treatment, whereas this treatment had no effect in PR(cre/+)Mig-6(f/f) mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer.

  12. Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer

    PubMed Central

    Kim, Tae Hoon; Lee, Dong-Kee; Cho, Sung-Nam; Orvis, Grant D.; Behringer, Richard R.; Lydon, John P.; Ku, Bon Jeong; McCampbell, Adrienne S.; Broaddus, Russell R.; Jeong, Jae-Wook

    2013-01-01

    Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal-epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6f/f) mice were crossed to Wnt7a-Cre mice (Wnt7acre+ Mig-6f/f). Wnt7acre+ Mig-6f/f mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in sub-epithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7acre+ Mig-6f/f mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7acre+ Mig-6f/f mice was prevented by progesterone treatment, whereas this treatment had no effect in PRcre/+ Mig-6f/f mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling there. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer. PMID:23811943

  13. Thalidomide in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2013-01-23

    Endometrial Adenoacanthoma; Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Recurrent Endometrial Carcinoma

  14. Endometrial cancer

    MedlinePlus

    ... therapy , and chemotherapy . Surgery to remove the uterus ( hysterectomy ) may be done in women with early stage ... uterine; Cancer - endometrial; Uterine corpus cancer Patient Instructions Hysterectomy - abdominal - discharge Hysterectomy - laparoscopic - discharge Hysterectomy - vaginal - discharge ...

  15. Endometrial polyps

    MedlinePlus

    ... cancer is higher if you are postmenopausal, on Tamoxifen, or have heavy or irregular periods. These factors may increase the risk for endometrial polyps: Obesity Tamoxifen, a treatment for breast cancer Postmenopausal hormone replacement ...

  16. The effect of a high progesterone concentration before oocyte retrieval on the peri-implantation endometrium.

    PubMed

    Liu, Liu; Sailan, Sumaia; Li, Tinchiu; Mariee, Najat; Laird, Susan; Jiang, Zhinong; Zhang, Songying

    2015-12-01

    In this single-centre, prospective cohort study, the effect of high progesterone level before oocyte retrieval on endometrial morphology and uterine natural killer cell (uKN) count in the peri-implantation period was investigated. A total of 106 women undergoing IVF treatment who did not proceed to fresh embryo transfer were included. Endometrial samples were obtained 7 days after HCG administration. Multiple regression analysis was used to identify factors affecting the results of histological staging and uNK cell count. Progesterone level on the day after HCG administration was the only significant variable associated with the results of histological staging (P = 0.004). Endometrial development in women with high progesterone level was significantly (P < 0.001) more advanced than that of women with normal progesterone; progesterone level on the day of HCG administration was the only significant variable associated with uNK cell count. The median (range) of uNK cell count of 9.6% (2.3-21.6%) in women with high progesterone was significantly (P < 0.001) higher than the median (range) of uNK cell count of 5.7% (1.4-18.7%) in women with normal progesterone. High progesterone level before oocyte retrieval was correlated with advancement in endometrial development as well as increased uNK cell count.

  17. Paragon (ANZGOG-0903): Phase 2 Study of Anastrozole in Women With Estrogen or Progesterone Receptor-Positive Platinum-Resistant or -Refractory Recurrent Ovarian Cancer.

    PubMed

    Bonaventura, Anthony; OʼConnell, Rachel L; Mapagu, Cristina; Beale, Philip J; McNally, Orla M; Mileshkin, Linda R; Grant, Peter T; Hadley, Alison M; Goh, Jeffery C H; Sjoquist, Katrin M; Martyn, Julie; DeFazio, Anna; Scurry, James; Friedlander, Michael L

    2017-06-01

    There is some evidence that a subset of patients with recurrent ovarian cancer may benefit from antiestrogen therapy. The Paragon study is a basket protocol that includes a series of phase 2 trials investigating the activity of anastrozole in patients with estrogen or progesterone receptor-positive recurrent gynecological cancers. We report the results of treatment in patients with platinum-resistant or -refractory recurrent epithelial ovarian cancer. Postmenopausal women who had estrogen and/or progesterone receptor-positive platinum-resistant or platinum-refractory recurrent ovarian cancer and disease measurable by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or GCIG (Gynecologic Cancer InterGroup) CA-125 criteria were eligible. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. The study was prospectively registered (ACTRN12610000796088). There were 49 evaluable patients, and clinical benefit was observed in 13 (27%; 95% confidence interval [CI], 16%-40%). There were no complete or partial RECIST version 1.1 responses. Clinical benefit was associated with higher global quality-of-life scores. Median progression-free survival was 2.7 months (95% CI, 2.0-2.8 months). The median duration of clinical benefit was 2.8 months (95% CI, 2.6-5.7 months). Most patients (83%) progressed within 6 months. Seven patients continued on treatment for longer than 6 months. Anastrozole was well tolerated in most patients. Subgroup analysis suggested greater clinical benefit in patients with tumors with estrogen-receptor histoscore of more than 200, but this difference was not statistically significant. A subset of patients with estrogen- or progesterone-positive platinum-resistant or platinum-refractory recurrent epithelial ovarian cancers derives clinical benefit from anastrozole, with acceptable toxicity. The challenge remains how to identify them.

  18. Megestrol Acetate or Levonorgestrel-Releasing Intrauterine System in Treating Patients With Atypical Endometrial Hyperplasia or Endometrial Cancer

    ClinicalTrials.gov

    2014-09-09

    Atypical Endometrial Hyperplasia; Endometrial Adenocarcinoma; Recurrent Endometrial Carcinoma; Stage IA Endometrial Carcinoma; Stage IB Endometrial Carcinoma; Stage II Endometrial Carcinoma; Stage IIIA Endometrial Carcinoma; Stage IIIB Endometrial Carcinoma; Stage IIIC Endometrial Carcinoma; Stage IVA Endometrial Carcinoma; Stage IVB Endometrial Carcinoma

  19. [Interest of selective progesterone receptor modulators in endometriosis].

    PubMed

    Merviel, P; Lourdel, E; Sanguin, S; Gagneur, O; Cabry, R; Nasreddine, A

    2013-09-01

    The SPRM (selective progesterone receptor modulators) are agonists and/or antagonists of progesterone receptor. They are responsible for anovulation, amenorrhea and a lower prostaglandin levels, which leads to an improvement in pain and regression of lesions in endometriosis. On the endometrium, a particular aspect, the progesterone receptor modulator-associated endometrial changes (PAEC), raises additional studies to verify its harmlessness. However, due to the lack of hypoestrogenism and metabolic effects with these drugs, it is very likely that the SPRM will in the near future an important place in the treatment of endometriosis.

  20. Mesenchymal Stem/Progenitors and Other Endometrial Cell Types From Women With Polycystic Ovary Syndrome (PCOS) Display Inflammatory and Oncogenic Potential

    PubMed Central

    Piltonen, T. T.; Chen, J.; Erikson, D. W.; Spitzer, T. L. B.; Barragan, F.; Rabban, J. T.; Huddleston, H.; Irwin, J. C.

    2013-01-01

    Context: Endometrium in polycystic ovary syndrome (PCOS) presents altered gene expression indicating progesterone resistance and predisposing to reduced endometrial receptivity and endometrial cancer. Objective: We hypothesized that an altered endocrine/metabolic environment in PCOS may result in an endometrial “disease phenotype” affecting the gene expression of different endometrial cell populations, including stem cells and their differentiated progeny. Design and Setting: This was a prospective study conducted at an academic medical center. Patients and Main Outcome Measures: Proliferative-phase endometrium was obtained from 6 overweight/obese PCOS (National Institutes of Health criteria) and 6 overweight/obese controls. Microarray analysis was performed on fluorescence-activated cell sorting-isolated endometrial epithelial cells (eEPs), endothelial cells, stromal fibroblasts (eSFs), and mesenchymal stem cells (eMSCs). Gene expression data were validated using microfluidic quantitative RT-PCR and immunohistochemistry. Results: The comparison between eEPPCOS and eEPCtrl showed dysregulation of inflammatory genes and genes with oncogenic potential (CCL2, IL-6, ORM1, TNAIFP6, SFRP4, SPARC). eSFPCOS and eSFCtrl showed up-regulation of inflammatory genes (C4A/B, CCL2, ICAM1, TNFAIP3). Similarly, in eMSCPCOS vs eMSCCtrl, the most up-regulated genes were related to inflammation and cancer (IL-8, ICAM1, SPRR3, LCN2). Immunohistochemistry scoring showed increased expression of CCL2 in eEPPCOS and eSFPCOS compared with eEPCtrl and eSFCtrl and IL-6 in eEPPCOS compared with eEPCtrl. Conclusions: Isolated endometrial cell populations in women with PCOS showed altered gene expression revealing inflammation and prooncogenic changes, independent of body mass index, especially in eEPPCOS and eMSCPCOS, compared with controls. The study reveals an endometrial disease phenotype in women with PCOS with potential negative effects on endometrial function and long-term health

  1. The levels of the sex hormones are not different between type 1 and type 2 endometrial cancer.

    PubMed

    Wan, Jiayi; Gao, Yifei; Zeng, Ke; Yin, Yongxiang; Zhao, Min; Wei, Jia; Chen, Qi

    2016-12-21

    The involvement of hormonal factors in developing endometrial cancer is well documented. In particular, excess or unopposed estrogen is a major risk factor. Endometrial cancer is divided into estrogen-dependent and estrogen-independent types. Studies suggested that the subtypes of endometrial cancer share many common risk factors. Whether the levels of sex hormones differ between types 1 and 2 endometrial cancer has not been investigated. In this study, levels of estrogen, progesterone, testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were investigated between type 1 and type 2 endometrial cancer taking into account menopausal status and parity. The sex hormones levels and estrogen and progesterone receptors were measured in 187 women with endometrial cancer. The levels of estradiol (E2), progesterone, testosterone, FSH and LH were not different between the subtypes of endometrial cancer regardless of menopausal status. In addition, the sex hormones were not different between patients of different party regardless of the menopausal status. The majority of type 1 (96%) and type 2 (82%) endometrial cancers were estrogen and progesterone receptor positive. Our data suggest that type 2 endometrial cancer is not completely estrogen independent, and type 1 and type 2 endometrial cancers may have a similar pathogenesis.

  2. The levels of the sex hormones are not different between type 1 and type 2 endometrial cancer

    PubMed Central

    Wan, Jiayi; Gao, Yifei; Zeng, Ke; Yin, Yongxiang; Zhao, Min; Wei, Jia; Chen, Qi

    2016-01-01

    The involvement of hormonal factors in developing endometrial cancer is well documented. In particular, excess or unopposed estrogen is a major risk factor. Endometrial cancer is divided into estrogen-dependent and estrogen-independent types. Studies suggested that the subtypes of endometrial cancer share many common risk factors. Whether the levels of sex hormones differ between types 1 and 2 endometrial cancer has not been investigated. In this study, levels of estrogen, progesterone, testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were investigated between type 1 and type 2 endometrial cancer taking into account menopausal status and parity. The sex hormones levels and estrogen and progesterone receptors were measured in 187 women with endometrial cancer. The levels of estradiol (E2), progesterone, testosterone, FSH and LH were not different between the subtypes of endometrial cancer regardless of menopausal status. In addition, the sex hormones were not different between patients of different party regardless of the menopausal status. The majority of type 1 (96%) and type 2 (82%) endometrial cancers were estrogen and progesterone receptor positive. Our data suggest that type 2 endometrial cancer is not completely estrogen independent, and type 1 and type 2 endometrial cancers may have a similar pathogenesis. PMID:28000774

  3. Endometrial haemostasis and menstruation.

    PubMed

    Davies, Joanna; Kadir, Rezan A

    2012-12-01

    Under normal physiological circumstances menstruation is a highly regulated, complex process that is under strict hormonal control. During normal menstruation, progesterone withdrawal initiates menstruation. The cessation of menstrual bleeding is achieved by endometrial haemostasis via platelet aggregation, fibrin deposition and thrombus formation. Local endocrine, immunological and haemostatic factors interact at a molecular level to control endometrial haemostasis. Tissue factor and thrombin play a key role locally in the cessation of menstrual bleeding through instigation of the coagulation factors. On the other hand, fibrinolysis prevents clot organisation within the uterine cavity while plasminogen activator inhibitors (PAI) and thrombin-activatable fibrinolysis inhibitors control plasminogen activators and plasmin activity. Abnormalities of uterine bleeding can result from imbalance of the haemostatic factors. The most common abnormality of uterine bleeding is heavy menstrual bleeding (HMB). Modern research has shown that an undiagnosed bleeding disorder, in particular von Willebrand disease (VWD) and platelet function disorders, can be an underlying cause of HMB. This has led to a change in the approach to the management of HMB. While full haemostatic assessment is not required for all women presenting with HMB, menstrual score and bleeding score can help to discriminate women who are more likely to have a bleeding disorder and benefit from laboratory haemostatic evaluation. Haemostatic agents (tranexamic acid and DDAVP) enhance systemic and endometrial haemostasis and are effective in reducing menstrual blood loss in women with or without bleeding disorders. Further research is required to enhance our understanding of the complex interactions of haemostatic factors in general, and specifically within the endometrium. This will lead to the development of more targeted interventions for the management of abnormal uterine bleeding in the future.

  4. Androgen Receptor Increases CD133 Expression and Progenitor-Like Population That Associate With Cisplatin Resistance in Endometrial Cancer Cell Line

    PubMed Central

    Chen, Lumin; Chang, Wei-Chun; Hung, Yao-Ching; Chang, Ying-Yi; Bao, Bo-Yin; Huang, Hsin-Ching; Chung, Wei-Min; Shyr, Chih-Rong

    2014-01-01

    Endometrial cancer (EMC) is a sex steroid hormone-related female malignancy. Androgen and androgen receptor (androgen/AR) signals have been implicated in EMC progression. Cancer stem/progenitor cells (CSPCs) are suspected to link to chemoresistance in patients with EMC. In this study, we examined the androgen/AR roles in cisplatin resistance and CSPC population. We found AR expression increased naive EMC side population, CSPC population, cell migration, and epithelial–mesenchymal transition. Meanwhile, it decreased cisplatin cytotoxic effect on EMC cells. Collaterally, endogenous AR expressions in EMC cells were upregulated in the cisplatin-resisting state. Moreover, AR expression could further enhance CD133 expression, CSPC-related markers, and drug-resistance gene messenger RNA expression in EMC cells. Finally, the AR-associated gene expression might go through indirect regulation. This is the first report revealing AR function on EMC cells’ CSPC and cisplatin resistance. PMID:23962788

  5. Differential expression of vascular endothelial growth factor angiogenic factors in different endometrial compartments in women who have an elevated progesterone level before oocyte retrieval, during in vitro fertilization-embryo transfer treatment.

    PubMed

    Chen, Xiaoyan; Jin, Xiaoying; Liu, Liu; Man, Chi Wai; Huang, Jin; Wang, Chi Chiu; Zhang, Songying; Li, Tin Chiu

    2015-10-01

    To investigate the relationship between endometrial expressions of angiogenic factors around the time of embryo implantation and P level before oocyte retrieval during IVF-ET treatment. Retrospective study. University Assisted Reproductive Unit. Forty patients were recruited, 20 women with an elevated P level, and 20 women with a normal P level, into cancelled embryo transfer (ET) cycles. Endometrial biopsy samples were obtained from women who had an elevated or normal P level 7 days after human chorionic gonadotropin administration. The protein expression levels of VEGF-A, VEGF-C, and PLGF were examined using immunohistochemistry. A semiquantitative analysis was performed using histochemical-score analysis of staining intensity in the luminal epithelium, glandular epithelium, and stroma, separately. Luminal epithelial expression of vascular endothelial growth factor (VEGF)-A, VEGF-C, and PLGF did not significantly differ in women with elevated or normal P levels before oocyte retrieval. Glandular epithelial expression of VEGF-A, VEGF-C, and PLGF was higher in women with elevated P levels, compared with those with normal P levels. A significantly higher stromal expression of VEGF-A and PLGF was found in women with elevated P levels. A high P level before oocyte retrieval was associated with expression of VEGF angiogenic factors in glandular epithelium and stromal compartment around the time of embryo implantation. Our findings suggest that the lower implantation rates observed in this group of women may relate to decreased endometrial receptivity arising from altered expression of angiogenic factors. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  6. Endometrial hyperplasia.

    PubMed

    Mills, Anne M; Longacre, Teri A

    2010-11-01

    Endometrial hyperplasia is a heterogeneous set of pathologic lesions that range from mild, reversible glandular proliferations to direct cancer precursors. These lesions comprise a continuum of morphologic appearances, with the earliest proliferation represented by crowded glands with simple tubular architecture lined by cells resembling proliferative endometrium, whereas advanced proliferations in this continuum are characterized by crowded glands with complex architecture, often containing cells with nuclear atypia resembling low-grade endometrioid adenocarcinoma. The former "early" proliferations may be isolated to an endometrial polyp, but advanced proliferations are generally more diffusely present throughout the endometrium. There are at least three major classification systems for endometrial carcinoma precursor lesions, each of which trend toward overlap at the complex end of the spectrum. Although some classifications are based on a series of molecular genetic alterations (which may or may not translate into biologically or clinically relevant risk lesions), each classification scheme ultimately uses a series of histologic features, usually a combination of architecture and cytology, to establish a diagnosis of hyperplasia. Because different pathologists may apply different histologic criteria for endometrial hyperplasia depending on the classification system used, this article will provide an overview of the classifications used in current daily practice, present the histologic criteria and relative merits of each classification system, and discuss common and not so common causes of misclassification.

  7. Progestin Intrauterine Devices and Metformin: Endometrial Hyperplasia and Early Stage Endometrial Cancer Medical Management.

    PubMed

    Nwanodi, Oroma

    2017-07-08

    Globally, endometrial cancer is the sixth leading cause of female cancer-related deaths. Non-atypical endometrial hyperplasia (EH), has a lifetime progression rate to endometrial cancer ranging from less than 5%, if simple without atypia, to 40%, if complex with atypia. Site specific, long-acting intrauterine devices (IUDs) provide fertility sparing, progestin-based EH medical management. It is unclear which IUD is most beneficial, or if progesterone sensitizing metformin offers improved outcomes. For resolution, PubMed searches for "Mirena" or "Metformin," "treatment," "endometrial hyperplasia," or "stage 1 endometrial cancer," were performed, yielding 33 articles. Of these, 19 articles were included. The 60 mg high-dose frameless IUD/20 mcg levonorgestrel has achieved sustained regression of Grade 3 endometrial intraepithelial neoplasia for 14 years. Case series on early stage endometrial cancer (EC) treatment with IUDs have 75% or greater regression rates. For simple through complex EH with atypia, the 52 mg-IUD/10-20 mcg-LNG-14t has achieved 100% complete regression in 6-months. Clearly, IUDs have an outcome advantage over oral progestins. However, studies on metformin for EH, and of progestins or metformin for early stage EC management are underpowered, with inadequate dose ranges to achieve significant differences in, or optimal outcomes for, the treatment modalities. Therefore, outcomes from the feMMe trial for the 52 mg-IUD/10-20 mcg-LNG-14t and metformin will fill a gap in the literature.

  8. The important application of thioridazine in the endometrial cancer

    PubMed Central

    Meng, Qiong; Sun, Xiao; Wang, Jing; Wang, Yudong; Wang, Lihua

    2016-01-01

    Background: Endometrial cancer (ECa) is one of the serious healthy burden for female worldwide. The treatments of ECa focus on the application of endocrine therapy and aberrant signaling proteins expression recently years. Medroxyprogesterone acrtate (MPA) plays crucial role in the endocrine therapy for ECa patients. However, the outcomes are still not ideal in the advanced stage tumor, especially in the progesterone-resistant ECa. Thioridazine (THIO) is an anti-psychotic agent, which has been reported to suppress the development of several human cancers. In this study, we aimed at to explore the clinical significant of THIO in the treatment of ECa. Methods: Two ECa cell lines (ISK and KLE) were enrolled in this study, and were grouped into fore groups based on the treatment with different agents. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to analyze the viability of ECa cell lines. The apoptosis of ECa cells was examined by using the flow cytometer. To investigate the expression of important proteins, we applied the quantitative real-time RT-PCR (qRT-PCR) method and western blot analysis. Results: The viability of ECa cells was downregulated, and the apoptosis of ECa cells was upregulated after treating with the THIO plus MPA. The expression of progesterone receptor B (PRB) and dopamine receptor D2 (DRD2) were increased, and epidermal growth factor receptor (EGFR) and p-AKT were decreased in the THIO+MPA group. All these results suggested that the THIO could promote MPA to inhibit the growth of cells in ECa, especially in the progesterone-resistant ECa. Conclusion: Taken together, all the data in the present study suggested that the THIO plus MPA might act as the suppressor of tumor growth in ECa by inhibiting the PI3K/AKT signal transduction pathway, which was mediated by PRB, DRD2 and EGFR. PMID:27398159

  9. Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert.

    PubMed

    Paulson, Richard J; Collins, Michael G; Yankov, Vladimir I

    2014-11-01

    Progesterone vaginal insert (PVI), an effervescent delivery system, dissolves rapidly, is absorbed through the vaginal epithelium, and achieves higher endometrial tissue concentrations than those achieved with progesterone in oil (PIO) given im. Our objective was to examine the pharmacokinetics and pharmacodynamics of PVI compared with PIO. Fifty-eight healthy premenopausal women were randomized to 50, 100, or 200 mg PVI once daily; 100 or 200 mg PVI twice daily; or 50 to 100 mg PIO via im injection once daily for 10 days. Serum samples were obtained after the first dose; serum and endometrial tissue were obtained after the last dose. Maximum observed serum concentration (Cmax), time to Cmax, and area under the serum-concentration time curve over the dosing interval were calculated after correcting for baseline progesterone concentrations. ANOVA and paired t test were used to compare results across and within groups. A higher Cmax was observed after PIO than PVI administration. Endometrial tissue progesterone concentrations were higher for PVI regimens. Time to Cmax was 7.3 hours after PIO and 3.3 to 5.9 hours after PVI. Steady state was achieved within 24 and 48 hours for PVI and PIO regimens, respectively. The area under the curve increased with increasing PVI dosage; however, the increase was not proportional to the increase in dosage. Downregulation of estrogen and progesterone receptors was observed in secretory biopsy specimens. The PVI system consistently allowed for rapid progesterone absorption and achieved higher endometrial tissue concentrations and lower systemic exposures than observed after im PIO.

  10. Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone

    PubMed Central

    Scholtz, Elizabeth L.; Krishnan, Shweta; Ball, Barry A.; Corbin, C. Jo; Moeller, Benjamin C.; Stanley, Scott D.; McDowell, Karen J.; Hughes, Austin L.; McDonnell, Donald P.; Conley, Alan J.

    2014-01-01

    One of the most widely accepted axioms of mammalian reproductive biology is that pregnancy requires the (sole) support of progesterone, acting in large measure through nuclear progesterone receptors (PRs) in uterine and cervical tissues, without which pregnancy cannot be established or maintained. However, mares lack detectable progesterone in the latter half of pregnancy. Instead of progesterone, several (mainly 5α-reduced) pregnanes are elevated and have long been speculated to provide progestational support in lieu of progesterone itself. To the authors' knowledge, evidence for the bioactivity of a second potent endogenously synthesized pregnane able to support pregnancy in the absence of progesterone has never before been reported. The 5α-reduced progesterone metabolite dihydroprogesterone (DHP) was shown in vivo to stimulate endometrial growth and progesterone-dependent gene expression in the horse at subphysiological concentrations and to maintain equine pregnancy in the absence of luteal progesterone in the third and fourth weeks postbreeding. Results of in vitro studies indicate that DHP is an equally potent and efficacious endogenous progestin in the horse but that the PR evolved with increased agonistic potency for DHP at the expense of potency toward progesterone based on comparisons with human PR responses. Sequence analysis and available literature indicate that the enzyme responsible for DHP synthesis, 5α-reductase type 1, also adapted primarily to metabolize progesterone and thereby to serve diverse roles in the physiology of pregnancy in mammals. Our confirmation that endogenously synthesized DHP is a biopotent progestin in the horse ends decades of speculation, explaining how equine pregnancies survive without measurable circulating progesterone in the last 4 to 5 mo of gestation. PMID:24550466

  11. Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5α-dihydroprogesterone.

    PubMed

    Scholtz, Elizabeth L; Krishnan, Shweta; Ball, Barry A; Corbin, C Jo; Moeller, Benjamin C; Stanley, Scott D; McDowell, Karen J; Hughes, Austin L; McDonnell, Donald P; Conley, Alan J

    2014-03-04

    One of the most widely accepted axioms of mammalian reproductive biology is that pregnancy requires the (sole) support of progesterone, acting in large measure through nuclear progesterone receptors (PRs) in uterine and cervical tissues, without which pregnancy cannot be established or maintained. However, mares lack detectable progesterone in the latter half of pregnancy. Instead of progesterone, several (mainly 5α-reduced) pregnanes are elevated and have long been speculated to provide progestational support in lieu of progesterone itself. To the authors' knowledge, evidence for the bioactivity of a second potent endogenously synthesized pregnane able to support pregnancy in the absence of progesterone has never before been reported. The 5α-reduced progesterone metabolite dihydroprogesterone (DHP) was shown in vivo to stimulate endometrial growth and progesterone-dependent gene expression in the horse at subphysiological concentrations and to maintain equine pregnancy in the absence of luteal progesterone in the third and fourth weeks postbreeding. Results of in vitro studies indicate that DHP is an equally potent and efficacious endogenous progestin in the horse but that the PR evolved with increased agonistic potency for DHP at the expense of potency toward progesterone based on comparisons with human PR responses. Sequence analysis and available literature indicate that the enzyme responsible for DHP synthesis, 5α-reductase type 1, also adapted primarily to metabolize progesterone and thereby to serve diverse roles in the physiology of pregnancy in mammals. Our confirmation that endogenously synthesized DHP is a biopotent progestin in the horse ends decades of speculation, explaining how equine pregnancies survive without measurable circulating progesterone in the last 4 to 5 mo of gestation.

  12. Role of nuclear progesterone receptor isoforms in uterine pathophysiology

    PubMed Central

    Patel, Bansari; Elguero, Sonia; Thakore, Suruchi; Dahoud, Wissam; Bedaiwy, Mohamed; Mesiano, Sam

    2015-01-01

    BACKGROUND Progesterone is a key hormonal regulator of the female reproductive system. It plays a major role to prepare the uterus for implantation and in the establishment and maintenance of pregnancy. Actions of progesterone on the uterine tissues (endometrium, myometrium and cervix) are mediated by the combined effects of two progesterone receptor (PR) isoforms, designated PR-A and PR-B. Both receptors function primarily as ligand-activated transcription factors. Progesterone action on the uterine tissues is qualitatively and quantitatively determined by the relative levels and transcriptional activities of PR-A and PR-B. The transcriptional activity of the PR isoforms is affected by specific transcriptional coregulators and by PR post-translational modifications that affect gene promoter targeting. In this context, appropriate temporal and cell-specific expression and function of PR-A and PR-B are critical for normal uterine function. METHODS Relevant studies describing the role of PRs in uterine physiology and pathology (endometriosis, uterine leiomyoma, endometrial cancer, cervical cancer and recurrent pregnancy loss) were comprehensively searched using PubMed, Cochrane Library, Web of Science, and Google Scholar and critically reviewed. RESULTS Progesterone, acting through PR-A and PR-B, regulates the development and function of the endometrium and induces changes in cells essential for implantation and the establishment and maintenance of pregnancy. During pregnancy, progesterone via the PRs promotes myometrial relaxation and cervical closure. Withdrawal of PR-mediated progesterone signaling triggers menstruation and parturition. PR-mediated progesterone signaling is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen on eutopic normal endometrium, and on ectopic implants in endometriosis. Similarly, ligand-activated PRs function as tumor suppressors in endometrial cancer cells through inhibition of key

  13. Effects of interferon-tau and steroids on cytochrome P450 activity in bovine endometrial epithelial cells

    USDA-ARS?s Scientific Manuscript database

    The objective of the current study was to examine cyclooxygenase (COX), cytochrome P450 1A (CYP1A) and 2C (CYP2C) activity in bovine endometrial cell cultures following exposure to oxytocin (OT), interferon-t (IFN), estradiol (E2) and/or progesterone (P4). Bovine endometrial epithelial cells were tr...

  14. Levels of oestrogen receptor, progesterone receptor and αB-crystallin in eutopic endometrium in relation to pregnancy in women with endometriosis.

    PubMed

    Moberg, Christian; Bourlev, Vladimir; Ilyasova, Natalia; Olovsson, Matts

    2015-03-01

    Endometriosis affects fertility in many women and may partly be due to decreased endometrial receptivity. Several mechanisms have been suggested, notably, progesterone resistance for which a number of candidate biomarkers have been suggested. Here we demonstrate aberrant levels of steroid hormone receptors and the small heat shock protein αB-crystallin in eutopic endometrial epithelium from 38 women with peritoneal endometriosis diagnosed during investigation for secondary infertility. Spontaneous pregnancies within 1 year after medical and surgical treatment for endometriosis were recorded and semi-quantitative immunohistochemistry data compared between women with endometriosis who did or did not become pregnant and healthy controls. Stronger immunostaining for ER-α was detected in luminal and glandular endometrial epithelium from women with endometriosis who did not become pregnant during the post-treatment observation period versus endometriosis patients who became pregnant and controls. Staining levels of PR and PR-B were lower in patients without subsequent pregnancies than in the two other groups. Endometrial levels of αB-crystallin in endometriosis patients similar to those in controls were strongly correlated with the chance of becoming pregnant, whereas higher or lower levels were not.

  15. Effects of adipocyte-secreted factors on decidualized endometrial cells: modulation of endometrial receptivity in vitro.

    PubMed

    Gamundi-Segura, Silvia; Serna, Jose; Oehninger, Sergio; Horcajadas, Jose A; Arbones-Mainar, Jose M

    2015-09-01

    Obesity is defined as an excessive accumulation of adipose tissue that may lead to health complications. Mounting evidence indicates that obesity has a negative impact on fertility. Yet, the link between adipose tissue biology and infertility remains unclear. We aimed to investigate the communication between the adipose tissue and the reproductive system and the importance of this cross talk for the development of a receptive endometrium. To that end, we generated an in vitro model with endometrial and adipocyte cell lines. Sexual hormones, progesterone and estradiol, were used to decidualize endometrial cells and sensitize adipocytes. Decidualization produced a simultaneous increase of adipokine receptors in endometrial cells paralleling changes in their receptivity status. Furthermore, sensitization of 3T3-L1 adipocytes increased mRNA levels of leptin and resistin and decreased the expression of adiponectin and chemerin levels. This was accompanied by increased isoproterenol-induced lipolysis and reduced insulin-stimulated glucose uptake. Lastly, conditioned culture medium of those sensitized adipocytes was used to feed endometrial cells. This treatment resulted in (i) upregulation of genes previously identified as positive regulators of endometrial receptivity, such as leukemia inhibitory factor and glutathione peroxidase 3, and (ii) downregulation of interleukin-15 and mucin1, both genes negatively related with endometrial receptivity. Our results indicate that the endocrine communication between adipose tissue and the reproductive system is bidirectional and stress the importance of the adipose tissue to modulate the reproductive fitness.

  16. Mig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation.

    PubMed

    Kim, Tae Hoon; Yoo, Jung-Yoon; Kim, Hong Im; Gilbert, Jenifer; Ku, Bon Jeong; Li, Jane; Mills, Gordon B; Broaddus, Russell R; Lydon, John P; Lim, Jeong Mook; Yoon, Ho-Geun; Jeong, Jae-Wook

    2014-12-15

    PTEN mutations are the most common genetic alterations in endometrial cancer. Loss of PTEN and subsequent AKT activation stimulate estrogen receptor α-dependent pathways that play an important role in endometrial tumorigenesis. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. However, the precise mechanism of PTEN/AKT signaling in endometrial cancer remains poorly understood. The progesterone signaling mediator MIG-6 suppresses estrogen signaling and it has been implicated previously as a tumor suppressor in endometrial cancer. In this study, we show that MIG-6 also acts as a tumor suppressor in endometrial cancers associated with PTEN deficiency. Transgenic mice, where Mig-6 was overexpressed in progesterone receptor-expressing cells, exhibited a relative reduction in uterine tumorigenesis caused by Pten deficiency. ERK1/2 was phosphorylated in uterine tumors and administration of an ERK1/2 inhibitor suppressed cancer progression in PR(cre/+)Pten(f/f) mice. In clinical specimens of endometrial cancer, MIG-6 expression correlated inversely with ERK1/2 phosphorylation during progression. Taken together, our findings suggest that Mig-6 regulates ERK1/2 phosphorylation and that it is crucial for progression of PTEN-mutant endometrial cancers, providing a mechanistic rationale for the evaluation of ERK1/2 inhibitors as a therapeutic treatment in human endometrial cancer. ©2014 American Association for Cancer Research.

  17. miR-200 Regulates Endometrial Development During Early Pregnancy.

    PubMed

    Jimenez, Patricia T; Mainigi, Monica A; Word, R Ann; Kraus, W Lee; Mendelson, Carole R

    2016-09-01

    For successful embryo implantation, endometrial stromal cells must undergo functional and morphological changes, referred to as decidualization. However, the molecular mechanisms that regulate implantation and decidualization are not well defined. Here we demonstrate that the estradiol- and progesterone-regulated microRNA (miR)-200 family was markedly down-regulated in mouse endometrial stromal cells prior to implantation, whereas zinc finger E-box binding homeobox-1 and -2 and other known and predicted targets were up-regulated. Conversely, miR-200 was up-regulated during in vitro decidualization of human endometrial stromal cells. Knockdown of miR-200 negatively affected decidualization and prevented the mesenchymal-epithelial transition-like changes that accompanied decidual differentiation. Notably, superovulation of mice and humans altered miR-200 expression. Our findings suggest that hormonal alterations that accompany superovulation may negatively impact endometrial development and decidualization by causing aberrant miR-200 expression.

  18. Dalantercept in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2017-05-03

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma

  19. CD82 expression alters with human endometrial cycles and affects the uterine endometrial receptivity in vitro.

    PubMed

    Wei, Xiaowei; Liu, Shuai; Wang, Xiaoqi; Yan, Qiu

    2012-03-01

    Embryo implantation is a process that requires both temporal and spatial synchronization of the uterine endometrium and the embryo, and the endometrium becomes receptive to the embryo during the window of implantation. Although the expression patterns of many implantation-related molecules change dynamically during this process, the impact of CD82 on endometrial receptivity has not been elucidated. By immunohistochemical staining, we found that CD82 levels rose from the proliferative phase to the secretory phase in human endometrium. Specifically, the highest level appeared in mid- and late-secretory phases. Consistently, RL95-2 cells, representative of high-receptive endometrial epithelium, expressed higher levels of CD82 than did HEC-1A cells, which are representative of low-receptive endometrial epithelium, as detected by reverse transcription-polymerase chain reaction, Western blot and immunofluorescence. Furthermore, progesterone up-regulated the expression of CD82 in both epithelial cell lines. Down-regulation of CD82 in RL95-2 cells by either CD82 siRNA transfection or treatment with a CD82 antibody significantly decreased the adhesion of human embryonic JAR cells to RL95-2 cell monolayers (P < 0.01) and inhibited the phosphorylation of focal adhesion kinase (FAK). In contrast, up-regulation of CD82 in HEC-1A cells by CD82 cDNA transfection promoted embryonic JAR cell adhesion to HEC-1A monolayers (P < 0.05) and activated the phosphorylation of FAK. In conclusion, the expression of CD82 increases in endometrial tissues during the window of embryo implantation, CD82 expression affects endometrial receptivity of the uterine epithelial cells in vitro, and the FAK signaling pathway may be involved in this phenomenon. The correlation between CD82 and endometrial receptivity suggests that CD82 may serve as a potential marker of endometrial function.

  20. Copanlisib in Treating Patients With Persistent or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2017-01-20

    Endometrial Endometrioid Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Metastatic Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Carcinoma

  1. Progesterone and related progestins: potential new health benefits.

    PubMed

    Sitruk-Ware, R; El-Etr, M

    2013-08-01

    Progesterone is a steroid hormone that is essential for the regulation of reproductive function. The main physiological roles of this hormone have been widely described. Progesterone and progestins have been approved for a number of indications including the treatment of irregular and anovulatory menstrual cycles and, when combined with estrogen, for contraception, and the prevention of endometrial hyperplasia in postmenopausal hormonal replacement therapy (HRT) regimens. Lack of understanding between the differences in categories of the progestins as well as with the physiological hormone has resulted in considerable controversy surrounding the use of progestins for HRT regimens. Newer evidence suggests that there are distinct differences between the molecules and there is no progestin class effect, with regard to benefits or side-effects. In addition to its role in reproduction, progesterone regulates a number of biologically distinct processes in other tissues, particularly in the nervous system and the vessels. Recently, it has been shown in animal experiments that progesterone and the progestin Nestorone(®) have positive effects on neuroregeneration and repair of brain damage, as well as myelin repair. The potential benefits of natural progesterone and its related derivatives warrant further investigation. It is hoped that a better understanding of the mechanism of action of progesterone and selected progestins will help in defining better therapies for men and women.

  2. Rethinking progesterone regulation of female reproductive cyclicity

    PubMed Central

    Kubota, Kaiyu; Cui, Wei; Dhakal, Pramod; Wolfe, Michael W.; Rumi, M. A. Karim; Vivian, Jay L.; Roby, Katherine F.; Soares, Michael J.

    2016-01-01

    The progesterone receptor (PGR) is a ligand-activated transcription factor with key roles in the regulation of female fertility. Much has been learned of the actions of PGR signaling through the use of pharmacologic inhibitors and genetic manipulation, using mouse mutagenesis. Characterization of rats with a null mutation at the Pgr locus has forced a reexamination of the role of progesterone in the regulation of the female reproductive cycle. We generated two Pgr mutant rat models, using genome editing. In both cases, deletions yielded a null mutation resulting from a nonsense frame-shift and the emergence of a stop codon. Similar to Pgr null mice, Pgr null rats were infertile because of deficits in sexual behavior, ovulation, and uterine endometrial differentiation. However, in contrast to the reported phenotype of female mice with disruptions in Pgr signaling, Pgr null female rats exhibit robust estrous cycles. Cyclic changes in vaginal cytology, uterine histology, serum hormone levels, and wheel running activity were evident in Pgr null female rats, similar to wild-type controls. Furthermore, exogenous progesterone treatment inhibited estrous cycles in wild-type female rats but not in Pgr-null female rats. As previously reported, pharmacologic antagonism supports a role for PGR signaling in the regulation of the ovulatory gonadotropin surge, a result at variance with experimentation using genetic ablation of PGR signaling. To conclude, our findings in the Pgr null rat challenge current assumptions and prompt a reevaluation of the hormonal control of reproductive cyclicity. PMID:27035990

  3. Rethinking progesterone regulation of female reproductive cyclicity.

    PubMed

    Kubota, Kaiyu; Cui, Wei; Dhakal, Pramod; Wolfe, Michael W; Rumi, M A Karim; Vivian, Jay L; Roby, Katherine F; Soares, Michael J

    2016-04-12

    The progesterone receptor (PGR) is a ligand-activated transcription factor with key roles in the regulation of female fertility. Much has been learned of the actions of PGR signaling through the use of pharmacologic inhibitors and genetic manipulation, using mouse mutagenesis. Characterization of rats with a null mutation at the Pgr locus has forced a reexamination of the role of progesterone in the regulation of the female reproductive cycle. We generated two Pgr mutant rat models, using genome editing. In both cases, deletions yielded a null mutation resulting from a nonsense frame-shift and the emergence of a stop codon. Similar to Pgr null mice, Pgr null rats were infertile because of deficits in sexual behavior, ovulation, and uterine endometrial differentiation. However, in contrast to the reported phenotype of female mice with disruptions in Pgr signaling, Pgr null female rats exhibit robust estrous cycles. Cyclic changes in vaginal cytology, uterine histology, serum hormone levels, and wheel running activity were evident in Pgr null female rats, similar to wild-type controls. Furthermore, exogenous progesterone treatment inhibited estrous cycles in wild-type female rats but not in Pgr-null female rats. As previously reported, pharmacologic antagonism supports a role for PGR signaling in the regulation of the ovulatory gonadotropin surge, a result at variance with experimentation using genetic ablation of PGR signaling. To conclude, our findings in the Pgr null rat challenge current assumptions and prompt a reevaluation of the hormonal control of reproductive cyclicity.

  4. Endometrial receptivity: evaluation with ultrasound.

    PubMed

    Bonilla-Musoles, Fernando; Raga, Francisco; Osborne, Newton G; Castillo, Juan Carlos; Bonilla, Francisco

    2013-03-01

    An adequate endometrial receptivity is a crucial factor for embryo implantation. We describe endometrial morphology (endometrial appearance or pattern, endometrial thickness, volume, and delimitation), based on the concepts and possibilities of the new ultrasound modalities (3-dimensional/4-dimensional ultrasound, automatic volume calculation, virtual organ computer-aided analysis, tomographic ultrasound image, inverse mode, and 3-dimensional Doppler angiography) as markers of endometrial receptivity.

  5. Stem Cell-Like Differentiation Potentials of Endometrial Side Population Cells as Revealed by a Newly Developed In Vivo Endometrial Stem Cell Assay

    PubMed Central

    Miyazaki, Kaoru; Maruyama, Tetsuo; Masuda, Hirotaka; Yamasaki, Akiko; Uchida, Sayaka; Oda, Hideyuki; Uchida, Hiroshi; Yoshimura, Yasunori

    2012-01-01

    Background Endometrial stem/progenitor cells contribute to the cyclical regeneration of human endometrium throughout a woman's reproductive life. Although the candidate cell populations have been extensively studied, no consensus exists regarding which endometrial population represents the stem/progenitor cell fraction in terms of in vivo stem cell activity. We have previously reported that human endometrial side population cells (ESP), but not endometrial main population cells (EMP), exhibit stem cell-like properties, including in vivo reconstitution of endometrium-like tissues when xenotransplanted into immunodeficient mice. The reconstitution efficiency, however, was low presumably because ESP cells alone could not provide a sufficient microenvironment (niche) to support their stem cell activity. The objective of this study was to establish a novel in vivo endometrial stem cell assay employing cell tracking and tissue reconstitution systems and to examine the stem cell properties of ESP through use of this assay. Methodology/Principal Findings ESP and EMP cells isolated from whole endometrial cells were infected with lentivirus to express tandem Tomato (TdTom), a red fluorescent protein. They were mixed with unlabeled whole endometrial cells and then transplanted under the kidney capsule of ovariectomized immunodeficient mice. These mice were treated with estradiol and progesterone for eight weeks and nephrectomized. All of the grafts reconstituted endometrium-like tissues under the kidney capsules. Immunofluorescence revealed that TdTom-positive cells were significantly more abundant in the glandular, stromal, and endothelial cells of the reconstituted endometrium in mice transplanted with TdTom-labeled ESP cells than those with TdTom-labeled EMP cells. Conclusions/Significance We have established a novel in vivo endometrial stem cell assay in which multi-potential differentiation can be identified through cell tracking during in vivo endometrial tissue

  6. Does progesterone supplementation improve pregnancy rates in clomiphene citrate and intrauterine insemination treatment cycles?

    PubMed

    Elguero, Sonia; Wyman, Allison; Hurd, William W; Barker, Nichole; Patel, Bansari; Liu, James H

    2015-03-01

    To investigate the effect of empiric use of luteal phase progesterone supplementation to improve endometrial receptivity in women undergoing treatment with clomiphene citrate in combination with intrauterine insemination (CC-IUI). Retrospective cohort analysis. University fertility center. 426 CC-IUI cycles from 292 patients with unexplained infertility. Patients were treated with micronized intravaginal progesterone 100 mg twice daily beginning approximately three days after CC-IUI. Clinical pregnancy per initiated cycle as defined by presence of fetal heart rate on ultrasound. Clinical pregnancy rate was higher in patients receiving luteal phase support compared to patients not receiving luteal phase support (odds ratio: 2.04; 95% confidence interval: 1.01-4.14) after adjusting for all factors in the analysis using a multivariate logistic regression model. Age at the start of the cycle, BMI and CC dose were not shown to have an effect on clinical pregnancy rates. Patients with endometrial lining (EML) thickness 6-8 mm and >8 mm had increased clinical pregnancy rates compared to EML <6 mm independent of luteal phase progesterone use. Patients who appear to receive the greatest benefit of progesterone supplementation are in the 6-8 mm EML cohort. Luteal phase progesterone supplementation in CC-IUI cycles can improve endometrial receptivity as judged by the improved clinical pregnancy rates as the primary outcome.

  7. Progesterone and Neuroprotection

    PubMed Central

    Singh, Meharvan; Su, Chang

    2012-01-01

    Summary Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as the experimental model. And while estrogen intervention in these animals have, at least partially, restored cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for diseases such as Alzheimer’s disease during the postmenopausal period could also be contributed by this loss of progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal models and in humans. Here, we review the evidence that supports the neuroprotective effects of progesterone and discuss the various mechanisms that are thought to mediate these protective effects. We also discuss the receptor pharmacology of progesterone’s neuroprotective effects and present a conceptual model of progesterone action that supports the complementary effects of membrane-associated and classical intracellular progesterone receptors. In addition, we discuss fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin, medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined estrogen/progestin arm of the Women’s Health Initiative-Memory Study (WHIMS) and suggest that the type of progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain function. PMID:22732134

  8. Temsirolimus in Treating Patients With Metastatic or Locally Advanced Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2015-02-05

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Recurrent Endometrial Carcinoma; Stage IIIA Endometrial Carcinoma; Stage IIIB Endometrial Carcinoma; Stage IIIC Endometrial Carcinoma; Stage IVA Endometrial Carcinoma; Stage IVB Endometrial Carcinoma

  9. Trebananib in Treating Patients With Persistent or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2017-08-23

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma, Variant With Squamous Differentiation; Endometrial Serous Adenocarcinoma; Endometrioid Stromal Sarcoma; Recurrent Uterine Corpus Carcinoma

  10. Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease.

    PubMed

    Jeong, Jae-Wook; Lee, Hee Sun; Lee, Kevin Y; White, Lisa D; Broaddus, Russell R; Zhang, Yu-Wen; Vande Woude, George F; Giudice, Linda C; Young, Steven L; Lessey, Bruce A; Tsai, Sophia Y; Lydon, John P; DeMayo, Francesco J

    2009-05-26

    Normal endometrial function requires a balance of progesterone (P4) and estrogen (E2) effects. An imbalance caused by increased E2 action and/or decreased P4 action can result in abnormal endometrial proliferation and, ultimately, endometrial adenocarcinoma, the fourth most common cancer in women. We have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of progesterone receptor (PR) and steroid receptor coactivator (SRC-1) action in the uterus. Here, we demonstrate that absence of Mig-6 in mice results in the inability of P4 to inhibit E2-induced uterine weight gain and E2-responsive target genes expression. At 5 months of age, the absence of Mig-6 results in endometrial hyperplasia. Ovariectomized Mig-6(d/d) mice exhibit this hyperplastic phenotype in the presence of E2 and P4 but not without ovarian hormone. Ovariectomized Mig-6(d/d) mice treated with E2 developed invasive endometrioid-type endometrial adenocarcinoma. Importantly, the observation that endometrial carcinomas from women have a significant reduction in MIG-6 expression provides compelling support for an important growth regulatory role for Mig-6 in the uterus of both humans and mice. This demonstrates the Mig-6 is a critical regulator of the response of the endometrium to E2 in regulating tissue homeostasis. Since Mig-6 is regulated by both PR and SRC-1, this identifies a PR, SRC-1, Mig-6 regulatory pathway that is critical in the suppression of endometrial cancer.

  11. Trametinib With or Without GSK2141795 in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2017-09-11

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma

  12. Mig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation

    PubMed Central

    Kim, Tae Hoon; Yoo, Jung-Yoon; Kim, Hong Im; Gilbert, Jenifer; Ku, Bon Jeong; Li, Jane; Mills, Gordon B.; Broaddus, Russell R.; Lydon, John P.; Lim, Jeong Mook; Yoon, Ho-Geun; Jeong, Jae-Wook

    2014-01-01

    PTEN mutations are the most common genetic alterations in endometrial cancer. Loss of PTEN and subsequent AKT activation stimulate ERα-dependent pathways that play an important role in endometrial tumorigenesis. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. However, the precise mechanism of PTEN/AKT signaling in endometrial cancer remains poorly understood. The progesterone signaling mediator MIG-6 suppresses estrogen signaling and it has been implicated previously as a tumor suppressor in endometrial cancer. In this study, we show that MIG-6 also acts as a tumor suppressor in endometrial cancers associated with PTEN deficiency. Transgenic mice where Mig-6 was overexpressed in PR-expressing cells exhibited a relative reduction in uterine tumorigenesis caused by Pten deficiency. ERK1/2 was phosphorylated in uterine tumors and administration of an ERK1/2 inhibitor suppressed cancer progression in PRcre/+Ptenf/f mice. In clinical specimens of endometrial cancer, MIG-6 expression correlated inversely with ERK1/2 phosphorylation during progression. Taken together, our findings suggest that Mig-6 regulates ERK1/2 phosphorylation and that it is crucial for progression of PTEN-mutant endometrial cancers, providing a mechanistic rationale for the evaluation of ERK1/2 inhibitors as a therapeutic treatment in human endometrial cancer. PMID:25377472

  13. Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility.

    PubMed

    Charalampakis, Vasileios; Tahrani, Abd A; Helmy, Ahmed; Gupta, Janesh K; Singhal, Rishi

    2016-12-01

    One of the most effective methods to tackle obesity and its related comorbidities is bariatric surgery. Polycystic ovary syndrome (PCOS) and endometrial hyperplasia (EH), which are associated with increased risk of endometrial carcinoma, have been identified as potentially new indications for bariatric surgery. PCOS is the most common endocrine disorder in women in the reproductive age and is associated with several components of the metabolic syndrome such as obesity, insulin resistance and hypertension. EH is a pre-cancerous condition which arises in the presence of chronic exposure to estrogen unopposed by progesterone such as both in PCOS and obesity. The main bariatric procedures are Roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy and laparoscopic adjustable gastric banding. These procedures are well established and when correctly selected and performed by experienced bariatric surgeons, they can achieve significant weight loss and remission of obesity related co-morbidities. Studies have shown that bariatric surgery can play an important role in the management of patients with PCOS and improve fertility. Similarly, bariatric surgery has a positive effect on endometrial hyperplasia, making surgically induced weight loss a potentially attractive option for endometrial cancer prevention and treatment. Obesity has an adverse impact on spontaneous pregnancy, assisted reproduction methods and feto-maternal outcomes. After bariatric surgery obese women with subfertility can achieve spontaneous pregnancy. However, while bariatric surgery reduces the risk of pre-eclampsia and gestational diabetes, there is an increased risk of small for gestational age and possible increased risk of stillborn or neonatal death. In this article we will review the evidence regarding the use of bariatric surgery as a treatment modality in patients with PCOS and EH. We also provide an overview of the common bariatric procedures.

  14. Nintedanib in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2016-10-26

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Malignant Uterine Corpus Mixed Epithelial and Mesenchymal Neoplasm; Recurrent Uterine Corpus Carcinoma

  15. A murine uterine transcriptome, responsive to steroid receptor coactivator-2, reveals transcription factor 23 as essential for decidualization of human endometrial stromal cells.

    PubMed

    Kommagani, Ramakrishna; Szwarc, Maria M; Kovanci, Ertug; Creighton, Chad J; O'Malley, Bert W; Demayo, Francesco J; Lydon, John P

    2014-04-01

    Recent data from human and mouse studies strongly support an indispensable role for steroid receptor coactivator-2 (SRC-2)-a member of the p160/SRC family of coregulators-in progesterone-dependent endometrial stromal cell decidualization, an essential cellular transformation process that regulates invasion of the developing embryo into the maternal compartment. To identify the key progesterone-induced transcriptional changes that are dependent on SRC-2 and required for endometrial decidualization, we performed comparative genome-wide transcriptional profiling of endometrial tissue RNA from ovariectomized SRC-2(flox/flox) (SRC-2(f/f) [control]) and PR(cre/+)/SRC-2(flox/flox) (SRC-2(d/d) [SRC-2-depleted]) mice, acutely treated with vehicle or progesterone. Although data mining revealed that only a small subset of the total progesterone-dependent transcriptional changes is dependent on SRC-2 (∼13%), key genes previously reported to mediate progesterone-driven endometrial stromal cell decidualization are present within this subset. Along with providing a more detailed molecular portrait of the decidual transcriptional program governed by SRC-2, the degree of functional diversity of these progesterone mediators underscores the pleiotropic regulatory role of SRC-2 in this tissue. To showcase the utility of this powerful informational resource to uncover novel signaling paradigms, we stratified the total SRC-2-dependent subset of progesterone-induced transcriptional changes in terms of novel gene expression and identified transcription factor 23 (Tcf23), a basic-helix-loop-helix transcription factor, as a new progesterone-induced target gene that requires SRC-2 for full induction. Importantly, using primary human endometrial stromal cells in culture, we demonstrate that TCF23 function is essential for progesterone-dependent decidualization, providing crucial translational support for this transcription factor as a new decidual mediator of progesterone action.

  16. Dilatation and Curettage Effect on the Endometrial Thickness

    PubMed Central

    Davar, Robab; Dehghani Firouzabadi, Razieh; Chaman Ara, Kefayat

    2013-01-01

    Background Endometrial receptivity is required for successful implantation and pregnancy. Despite the remaining controversy, many studies have shown that ultrasonographic endometrial thickness can be considered as an indicator of endometrial receptivity. Objective The study objective was to investigate the effect of dilatation and curettage on the endometrial thickness. Materials and Methods Enrolled in the study were 444 patients visited in Obstetrics & Gynecology clinic of Shahid Sadoughi hospital between Jan. 2011 to Sep. 2012. Only patients whose menstrual cycle was regular were included in study. Patients with myoma, adenomyosis, endometrial polyps or other uterine anomaly, those who smoked, whose BMI was greater than 30 and who were taking medications that could affect endometrial thickness were excluded. Endometrial thickness was measured one day before evolution (n = 444) and 5-7 days after it (n = 444) using transvaginal ultrasonography. The endometrial thicknesses were correlated to the patients’ history of dilatation and curettage. Data analysis was done through SPSS software version 16 and using descriptive statistics, independent T-test and Anova. Results Endometrial thickness in patients who had 0, 1, 2, 3 and 4 D&C were 10.00 ± 0.58, 9.83 ± 0.47, 8.90 ± 0.92, 7.42 ± 0.18 and 7.40 ± 0.07, respectively one day before ovulation (spearman’s correlation coefficient = -0.33) and 10.62 ± 0.68, 9.64 ± 0.49, 8.48 ± 0.96, 6.32 ± 0.15 and 6.90 ± 0.04, respectively, 5-7 days after ovulation (spearman’s correlation coefficient = -0.66) estradiol and progesterone levels, measured in the day of 2nd ultrasonography had not statistic relation with endometrial thickness (P = 0.27 and 0.31). The relation of endometrial thickness and age was not significant (P = 0.54 and 0.06). Conclusions Dilatation and curettage has a significant effect on the endometrial thinning. PMID:24083012

  17. Elevated Progesterone Levels on the Day of Oocyte Maturation May Affect Top Quality Embryo IVF Cycles.

    PubMed

    Huang, Bo; Ren, Xinling; Wu, Li; Zhu, Lixia; Xu, Bei; Li, Yufeng; Ai, Jihui; Jin, Lei

    2016-01-01

    In contrast to the impact of elevated progesterone on endometrial receptivity, the data on whether increased progesterone levels affects the quality of embryos is still limited. This study retrospectively enrolled 4,236 fresh in vitro fertilization (IVF) cycles and sought to determine whether increased progesterone is associated with adverse outcomes with regard to top quality embryos (TQE). The results showed that the TQE rate significantly correlated with progesterone levels on the day of human chorionic gonadotropin (hCG) trigger (P = 0.009). Multivariate linear regression analysis of factors related to the TQE rate, in conventional IVF cycles, showed that the TQE rate was negatively associated with progesterone concentration on the day of hCG (OR was -1.658, 95% CI: -2.806 to -0.510, P = 0.005). When the serum progesterone level was within the interval 2.0-2.5 ng/ml, the TQE rate was significantly lower (P <0.05) than when the progesterone level was < 1.0 ng/ml; similar results were obtained for serum progesterone levels >2.5 ng/ml. Then, we choose a progesterone level at 1.5ng/ml, 2.0 ng/ml and 2.5 ng/ml as cut-off points to verify this result. We found that the TQE rate was significantly different (P <0.05) between serum progesterone levels < 2.0 ng/ml and >2.0 ng/ml. In conclusion, the results of this study clearly demonstrated a negative effect of elevated progesterone levels on the day of hCG trigger, on TQE rate, regardless of the basal FSH, the total gonadotropin, the age of the woman, or the time of ovarian stimulation. These data demonstrate that elevated progesterone levels (>2.0 ng/ml) before oocyte maturation were consistently detrimental to the oocyte.

  18. Elevated Progesterone Levels on the Day of Oocyte Maturation May Affect Top Quality Embryo IVF Cycles

    PubMed Central

    Huang, Bo; Ren, Xinling; Wu, Li; Zhu, Lixia; Xu, Bei; Li, Yufeng; Ai, Jihui; Jin, Lei

    2016-01-01

    In contrast to the impact of elevated progesterone on endometrial receptivity, the data on whether increased progesterone levels affects the quality of embryos is still limited. This study retrospectively enrolled 4,236 fresh in vitro fertilization (IVF) cycles and sought to determine whether increased progesterone is associated with adverse outcomes with regard to top quality embryos (TQE). The results showed that the TQE rate significantly correlated with progesterone levels on the day of human chorionic gonadotropin (hCG) trigger (P = 0.009). Multivariate linear regression analysis of factors related to the TQE rate, in conventional IVF cycles, showed that the TQE rate was negatively associated with progesterone concentration on the day of hCG (OR was -1.658, 95% CI: -2.806 to -0.510, P = 0.005). When the serum progesterone level was within the interval 2.0–2.5 ng/ml, the TQE rate was significantly lower (P <0.05) than when the progesterone level was < 1.0 ng/ml; similar results were obtained for serum progesterone levels >2.5 ng/ml. Then, we choose a progesterone level at 1.5ng/ml, 2.0 ng/ml and 2.5 ng/ml as cut-off points to verify this result. We found that the TQE rate was significantly different (P <0.05) between serum progesterone levels < 2.0 ng/ml and >2.0 ng/ml. In conclusion, the results of this study clearly demonstrated a negative effect of elevated progesterone levels on the day of hCG trigger, on TQE rate, regardless of the basal FSH, the total gonadotropin, the age of the woman, or the time of ovarian stimulation. These data demonstrate that elevated progesterone levels (>2.0 ng/ml) before oocyte maturation were consistently detrimental to the oocyte. PMID:26745711

  19. Integrated genomic characterization of endometrial carcinoma.

    PubMed

    Kandoth, Cyriac; Schultz, Nikolaus; Cherniack, Andrew D; Akbani, Rehan; Liu, Yuexin; Shen, Hui; Robertson, A Gordon; Pashtan, Itai; Shen, Ronglai; Benz, Christopher C; Yau, Christina; Laird, Peter W; Ding, Li; Zhang, Wei; Mills, Gordon B; Kucherlapati, Raju; Mardis, Elaine R; Levine, Douglas A

    2013-05-02

    We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

  20. Role of nuclear progesterone receptor isoforms in uterine pathophysiology.

    PubMed

    Patel, Bansari; Elguero, Sonia; Thakore, Suruchi; Dahoud, Wissam; Bedaiwy, Mohamed; Mesiano, Sam

    2015-01-01

    Progesterone is a key hormonal regulator of the female reproductive system. It plays a major role to prepare the uterus for implantation and in the establishment and maintenance of pregnancy. Actions of progesterone on the uterine tissues (endometrium, myometrium and cervix) are mediated by the combined effects of two progesterone receptor (PR) isoforms, designated PR-A and PR-B. Both receptors function primarily as ligand-activated transcription factors. Progesterone action on the uterine tissues is qualitatively and quantitatively determined by the relative levels and transcriptional activities of PR-A and PR-B. The transcriptional activity of the PR isoforms is affected by specific transcriptional coregulators and by PR post-translational modifications that affect gene promoter targeting. In this context, appropriate temporal and cell-specific expression and function of PR-A and PR-B are critical for normal uterine function. Relevant studies describing the role of PRs in uterine physiology and pathology (endometriosis, uterine leiomyoma, endometrial cancer, cervical cancer and recurrent pregnancy loss) were comprehensively searched using PubMed, Cochrane Library, Web of Science, and Google Scholar and critically reviewed. Progesterone, acting through PR-A and PR-B, regulates the development and function of the endometrium and induces changes in cells essential for implantation and the establishment and maintenance of pregnancy. During pregnancy, progesterone via the PRs promotes myometrial relaxation and cervical closure. Withdrawal of PR-mediated progesterone signaling triggers menstruation and parturition. PR-mediated progesterone signaling is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen on eutopic normal endometrium, and on ectopic implants in endometriosis. Similarly, ligand-activated PRs function as tumor suppressors in endometrial cancer cells through inhibition of key cellular signaling pathways

  1. The induction of baboon glycodelin expression by progesterone is not through Sp1.

    PubMed

    Jaffe, R C; Donnelly, K M; Fazleabas, A T

    2003-01-01

    Glycodelin is a major secretory product of the uterine glandular epithelial cells of the human and non-human primate during the late luteal phase of the menstrual cycle and early pregnancy. Since progesterone levels are elevated during these periods we sought to determine how progesterone modulates glycodelin gene expression. Co-transfection of various deletions of the baboon glycodelin promoter with the progesterone receptor (PR) into Ishikawa cells, a human endometrial cell line, revealed that full progesterone responsiveness is retained within the region -119/+48. In COS-1 cells, a kidney cell line, progesterone failed to elevate luciferase levels when various deletion constructs and the PR were co-transfected. Mutation of the Sp1 site in the -67/+48 region lowered basal expression but did not affect the ability of progesterone to increase expression of the luciferase reporter in Ishikawa cells. These findings suggest that Sp1 sites are not involved in the progesterone regulation of the baboon glycodelin gene. We propose that progesterone induces a factor that regulates glycodelin gene expression in the uterus since we failed to obtain a similar response in a non-uterine cell line.

  2. Fenretinide: A Novel Treatment for Endometrial Cancer

    PubMed Central

    Mittal, Navdha; Malpani, Saurabh; Dyson, Matthew; Ono, Masanori; Coon, John S.; Kim, Julie J.; Schink, Julian C.; Bulun, Serdar E.; Pavone, Mary Ellen

    2014-01-01

    Resistance to progestin treatment is a major hurdle in the treatment of advanced and reoccurring endometrial cancer. Fenretinide is a synthetic retinoid that has been evaluated in clinical trials as a cancer therapeutic and chemo-preventive agent. Fenretinide has been established to be cytotoxic to many kinds of cancer cells. In the present study, we demonstrate that fenretinide decreased cell viability and induced apoptosis in Ishikawa cells, which are an endometrial cancer cell line, in dose dependent manner in-vitro. This effect was found to be independent of retinoic acid nuclear receptor signaling pathway. Further, we have shown that this induction of apoptosis by fenretinide may be caused by increased retinol uptake via STRA6. Silencing of STRA6 was shown to decrease apoptosis which was inhibited by knockdown of STRA6 expression in Ishikawa cells. Results of an in-vivo study demonstrated that intraperitoneal injections of fenretinide in endometrial cancer tumors (created using Ishikawa cells) in mice inhibited tumor growth effectively. Immunohistochemistry of mice tumors showed a decrease in Ki67 expression and an increase in cleaved caspase-3 staining after fenretinide treatment when compared to vehicle treated mice. Collectively, our results are the first to establish the efficacy of fenretinide as an antitumor agent for endometrial cancer both in-vitro and in-vivo, providing a valuable rationale for initiating more preclinical studies and clinical trials using fenretinide for the treatment of endometrial cancer. PMID:25340777

  3. Fenretinide: a novel treatment for endometrial cancer.

    PubMed

    Mittal, Navdha; Malpani, Saurabh; Dyson, Matthew; Ono, Masanori; Coon, John S; Kim, Julie J; Schink, Julian C; Bulun, Serdar E; Pavone, Mary Ellen

    2014-01-01

    Resistance to progestin treatment is a major hurdle in the treatment of advanced and reoccurring endometrial cancer. Fenretinide is a synthetic retinoid that has been evaluated in clinical trials as a cancer therapeutic and chemo-preventive agent. Fenretinide has been established to be cytotoxic to many kinds of cancer cells. In the present study, we demonstrate that fenretinide decreased cell viability and induced apoptosis in Ishikawa cells, which are an endometrial cancer cell line, in dose dependent manner in-vitro. This effect was found to be independent of retinoic acid nuclear receptor signaling pathway. Further, we have shown that this induction of apoptosis by fenretinide may be caused by increased retinol uptake via STRA6. Silencing of STRA6 was shown to decrease apoptosis which was inhibited by knockdown of STRA6 expression in Ishikawa cells. Results of an in-vivo study demonstrated that intraperitoneal injections of fenretinide in endometrial cancer tumors (created using Ishikawa cells) in mice inhibited tumor growth effectively. Immunohistochemistry of mice tumors showed a decrease in Ki67 expression and an increase in cleaved caspase-3 staining after fenretinide treatment when compared to vehicle treated mice. Collectively, our results are the first to establish the efficacy of fenretinide as an antitumor agent for endometrial cancer both in-vitro and in-vivo, providing a valuable rationale for initiating more preclinical studies and clinical trials using fenretinide for the treatment of endometrial cancer.

  4. [Endometrial cancer in young patients: report of 17 cases].

    PubMed

    Dudnyikova, Anna; Horváth, Katalin; Pete, Imre

    2013-09-01

    Endometrial cancer of young (less then 40 years old) patients comprises 4-5% of all endometrial cancers in Hungary. The majority of patients did not give birth yet, so fertility sparing is very important. Fertility sparing treatment is possible if the tumor's histology is endometrial type and Grade 1 (well differentiated). The tumor localizes only to the endometrium and there is no myometrium infiltration. The authors present 17 cases of patients treated at the Department of Gynecology of National Institute of Oncology (Budapest, Hungary). In 3 cases conservative therapy (progesterone treatment) was possible, and 14 patients had to undergo surgery, because conservative treatment did fail. Of 17 patients 14 were never pregnant. The average patient's age was 32.35 ± 4.27 years. The mean body weight was 93.13 ± 30.79 kg (from 58 kg up to 147 kg); in 7 cases BMI (body mass index) was more than 30. After surgery histological examination had revealed 2 cases with normal ovaries, 1 case of simple cyst and 1 case of malignant ovarian tumor (serous adenocarcinoma, Grade 2), and 10 cases of polycystic ovaries associated with endometrial cancer. Of 3 cases that had only curettage, the endometrial cancer was Grade 1, and in 1 case radiological imaging showed simplex ovarian cyst. The authors' findings concerning young endometrial cancer patients confirm the results published in the literature. In cases suitable for fertility sparing treatment it is not sufficient to concentrate only on endometrial findings, but is very important to focus on the therapy of cystic ovaries (80% of which is PCO), obesity and diabetes mellitus as well.

  5. The role of progesterone and conceptus-derived factors in uterine biology during early pregnancy in ruminants.

    PubMed

    Spencer, Thomas E; Forde, Niamh; Lonergan, Patrick

    2016-07-01

    This review integrates established and new information on the role of progesterone, interferon tau (IFNT), and prostaglandins in uterine biology of ruminants. Establishment of pregnancy in ruminants encompasses growth of the posthatching blastocyst, elongation of the conceptus (embryo and extraembryonic membranes), and suppression of the endometrial luteolytic mechanism to maintain progesterone production by the ovary. Conceptus elongation involves exponential increases in length of the trophectoderm for pregnancy recognition signaling, implantation, and establishment of pregnancy. Pregnancy recognition signaling is accomplished by IFNT from the trophectoderm that has a paracrine antiluteolytic effect to inhibit upregulation of oxytocin receptors in the endometrial epithelia, thereby inhibiting production of luteolytic PGF2α pulses by the uterus. Survival and growth of the preimplantation blastocyst and elongating conceptus clearly requires embryotrophic factors (AA, carbohydrates, proteins, lipids, and other substances) in the uterine lumen. Individual, interactive, and coordinated actions of progesterone, IFNT, and prostaglandins regulate expression of elongation- and implantation-related genes in the endometrial epithelia that, in turn alter the uterine luminal histotroph and govern conceptus survival and growth. An increased knowledge of progesterone biology and conceptus-endometrial interactions is necessary to understand and elucidate the causes of pregnancy loss and provide a basis for new strategies to improve pregnancy outcome and reproductive efficiency in ruminants. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  6. Life-style and metformin for the prevention of endometrial pathology in postmenopausal women.

    PubMed

    Campagnoli, Carlo; Abbà, Chiara; Ambroggio, Simona; Brucato, Tiziana; Pasanisi, Patrizia

    2013-02-01

    In western women, the endometrium is frequently exposed, even after menopause, to the endogenous hormonal stimulation. Such a stimulation increases the risk of pathologic conditions such as endometrial hyperplasia and type I (endometrioid) endometrial adenocarcinoma. Metabolic syndrome, obesity, insulin resistance and type II diabetes promote the endometrial stimulation, and are recognized risk factors for endometrial cancer. Furthermore, chronic hyperinsulinemia linked both to obesity and metabolic syndrome influences endometrial proliferation through direct and indirect actions. Intentional weight loss, calorie restriction and physical activity are associated with a reduced risk of the endometrial pathology. Biological mechanisms include reduction in insulin and sex steroid hormone levels. In addition to life-style modifications, the antidiabetic metformin may be proposed as preventive agent. Metformin reduces the metabolic syndrome, lowers insulin and testosterone levels in postmenopausal women, and it is a potent inhibitor of endometrial cancer cell proliferation.

  7. Compartmentalized gene expression profiling of receptive endometrium reveals progesterone regulated ENPP3 is differentially expressed and secreted in glycosylated form

    PubMed Central

    Boggavarapu, Nageswara Rao; Lalitkumar, Sujata; Joshua, Vijay; Kasvandik, Sergo; Salumets, Andres; Lalitkumar, Parameswaran Grace; Gemzell-Danielsson, Kristina

    2016-01-01

    The complexity of endometrial receptivity at the molecular level needs to be explored in detail to improve the management of infertility. Here, differential expression of transcriptomes in receptive endometrial glands and stroma revealed Ectonucleotide Pyrophosphatase/Phosphodiesterase 3 (ENPP3) as a progesterone regulated factor and confirmed by various methods, both at mRNA and protein level. The involvement of ENPP3 in embryo attachment was tested in an in vitro model for human embryo implantation. Interestingly, there was high expression of ENPP3 mRNA in stroma but not protein. Presence of N-glycosylated ENPP3 in receptive phase uterine fluid in women confirms its regulation by progesterone and makes it possible to use in a non-invasive test of endometrial receptivity. PMID:27665743

  8. Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function.

    PubMed

    Franco, Heather L; Rubel, Cory A; Large, Michael J; Wetendorf, Margeaux; Fernandez-Valdivia, Rodrigo; Jeong, Jae-Wook; Spencer, Thomas E; Behringer, Richard R; Lydon, John P; Demayo, Francesco J

    2012-03-01

    The ovarian steroid progesterone, acting through the progesterone receptor (PR), coordinates endometrial epithelial-stromal cell communication, which is critical for its development and function. PR expression in these cellular compartments is under tight temporal and endocrine control. Although ex vivo studies demonstrated the importance of stromal PR expression, they failed to show a role for epithelial PR in uterine function. Here, the in vivo role of PR in the uterine epithelium is defined using floxed PR (PR(f/f)) mice crossed to Wnt7a-Cre mice. Progesterone was unable to stimulate the expression of its epithelial target genes, including Ihh, in the Wnt7a-Cre(+)PR(f/-) mice. Analysis was conducted on Ihh to determine whether PR directly regulates epithelial gene transcription. ChIP-on-chip analysis identified PR binding sites in the 5'-flanking region of Ihh. Cotransfection of the proximal Ihh promoter with PR demonstrated that PR directly regulates Ihh transcription. Female Wnt7a-Cre(+)PR(f/-) mice are infertile due to defects in embryo attachment, stromal cell decidualization, and the inability to cease estrogen-induced epithelial cell proliferation. Finally, progesterone was unable to inhibit neonatal endometrial glandular development in Wnt7a-Cre(+)PR(f/-) mice. Thus, epithelial PR is necessary for the regulation of progesterone epithelial target gene expression, as well as uterine function and development.

  9. Cancer-Associated Fibroblasts Promote Proliferation of Endometrial Cancer Cells

    PubMed Central

    Subramaniam, Kavita S.; Tham, Seng Tian; Mohamed, Zahurin; Woo, Yin Ling; Mat Adenan, Noor Azmi; Chung, Ivy

    2013-01-01

    Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs-conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs-mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular

  10. Endometrial adenocarcinoma in spontaneous abortion: two cases and review of the literature

    PubMed Central

    Zhou, Feng; Qian, Zhida; Li, Yinghua; Qin, Jiale; Huang, Lili

    2015-01-01

    Objectives: To report two extremely rare cases of endometrial adenocarcinoma established during the first trimester. Case presentation: A 40-year-old (gravida 0, para 0) and 33-year-old (gravida 4, para 0) woman, were diagnosed with a well-differentiated adenocarcinoma after a dilatation and curettage (D&C) for spontaneous abortions at 8 and 9 gestational weeks, respectively. Conclusions: Thirty-six cases of pregnancy-associated endometrial cancer and 20 cases of first trimester pregnancy concurrent with endometrial carcinoma have been reported as present cases in the literature. Interestingly, 15 including our two cases were detected for spontaneous abortions in first-trimester suggesting a causal correlation between endometrial adenocarcinoma and spontaneous abortions. Repeated D&C and progesterone administration may be appropriate for patients who wish to preserve fertility. PMID:26221400

  11. Defective endometrial receptivity.

    PubMed

    Revel, Ariel

    2012-05-01

    The endometrium is one of the most fascinating tissues in the human body. Its sole purpose is to enable implantation of an embryo during a relatively short window of opportunity in the menstrual cycle. It is becoming clear that overcoming the current bottleneck in improvements to assisted reproductive techniques will require a closer look at the interface between uterus and embryo. Indeed, embryo implantation requires a cross talk with a receptive endometrium. Using sonography, hysteroscopy and endometrial biopsy we can learn about anatomical and functional markers of endometrial receptivity. This article reviews the factors which might cause defective endometrial receptivity. These include uterine polyps, septa, leiomyomata and adhesions. The effect of thin endometrium, endometriosis and hydrosalpinx is also described. Finally contemporary investigation of molecular markers of endometrial receptivity is described. Improving embryo implantation by a closer look inside the uterus is the key to increasing pregnancy rates in IVF.

  12. Endometrial Cancer Screening

    MedlinePlus

    ... Transvaginal ultrasound Endometrial sampling Tests are used to screen for different types of cancer. Some screening tests ... endometrium by inserting a brush, curette , or thin, flexible tube through the cervix and into the uterus. ...

  13. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.

    PubMed

    Chwalisz, Kristof; Perez, Maria Claudia; Demanno, Deborah; Winkel, Craig; Schubert, Gerd; Elger, Walter

    2005-05-01

    Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11beta-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroids, asoprisnil suppressed both the duration and intensity of uterine bleeding in a dose-dependent manner and reduced tumor volume in the absence of estrogen deprivation. In subjects with endometriosis, asoprisnil was effective in reducing nonmenstrual pain and dysmenorrhea. Asoprisnil may, therefore, provide a novel, tissue-selective approach to control endometriosis-related pain. SPRMs have the potential to become a novel treatment of uterine fibroids and endometriosis.

  14. Vaginal progesterone in menopause: Crinone 4% in cyclical and constant combined regimens.

    PubMed

    de Ziegler, D; Ferriani, R; Moraes, L A; Bulletti, C

    2000-06-01

    Compliance with hormone replacement therapy (HRT) is notoriously low despite ample documentation of clinical efficacy. The two major reasons given by women who discontinue HRT are uterine bleeding and side-effects. The recent development of a controlled and sustained vaginal progesterone gel allowed single daily application and made prolonged use such as for menopause possible. Here we report our clinical experience with two therapeutic options for HRT using natural progesterone administered vaginally. A first group of 69 menopausal women received the sustained release vaginal progesterone gel, Crinone 4% (45 mg daily) from days 1-10 of each calendar month with oestrogens taken continuously. A second group of 67 women received Crinone 4% twice weekly in conjunction with continuous oestrogen therapy. Endometrial thickness was evaluated before and after 6 months of treatment. Histological verification was obtained in all cases of abnormal bleeding. At 6 months, 63 out of 69 (91.9%) women receiving progesterone cyclically experienced predictable withdrawal bleeding. The vast majority, 54 (80.6%) of 67 women receiving Crinone in constant combined association with oestrogen therapy, remained amenorrhoeic throughout 6 months of therapy. All cases of abnormal bleeding were biopsied and no hyperplasia was seen. Our results indicate that both regimens using the sustained release vaginal progesterone gel controlled bleeding in HRT. Combined with the lower incidence of side-effects characteristic of vaginal progesterone, both vaginal progesterone regimens have the potential of improving HRT compliance.

  15. Endometrial Ablation for Menorrhagia

    PubMed Central

    Sanders, Barry H.

    1992-01-01

    Endometrial ablation is a relatively new treatment for patients with persistent menorrhagia. The procedure can be performed by either laser photocoagulation or electrocoagulation; both have a very low risk of complication. Generally, less than 24 hours of hospitalization is required and return to normal activities, including work, is almost immediate. Endometrial ablation is likely to become a mainstay of treatment for menorrhagia as the technology and training become more readily available. PMID:21229128

  16. Progesterone antagonizes the positive influence of estrogen on Chlamydia trachomatis serovar E in an Ishikawa/SHT-290 co-culture model.

    PubMed

    Kintner, Jennifer; Schoborg, Robert V; Wyrick, Priscilla B; Hall, Jennifer V

    2015-06-01

    Studies indicate that estrogen enhances Chlamydia trachomatis serovar E infection in genital epithelial cells. Hormones have direct and indirect effects on endometrial epithelial cells. Estrogen and progesterone exposure induces endometrial stromal cells to release effectors that subsequently regulate growth and maturation of uterine epithelial cells. Estrogen enhances C. trachomatis infection by aiding entry and intracellular development in endometrial epithelial cell (Ishikawa, IK)/SHT-290 stromal cell co-culture. Enhanced chlamydial infection was mediated by direct estrogen-stimulated signaling events in epithelial cells and indirectly via estrogen-induced stromal cell effectors. The current study investigates the effects of hormones on chlamydial development using culture conditions representative of the menstrual cycle. Chlamydia trachomatis-infected IK or IK/SHT-290 cultures were exposed to 10(-8) M estrogen (E2), 10(-7) M progesterone (P4) or a combination of both hormones (10(-8) M E2 followed by 10(-9) M E2/10(-7) M P4). Chlamydial infectivity and progeny production were significantly decreased (30-66%) in cultures exposed to progesterone or estrogen/progesterone combination compared to estrogen alone. Thus, progesterone antagonized the positive effects of estrogen on chlamydial infection. These data indicate the susceptibility of endometrial epithelial cells to C. trachomatis infection during the menstrual cycle is altered by phase specific actions of sex hormones in the genital tract.

  17. Progesterone antagonizes the positive influence of estrogen on Chlamydia trachomatis serovar E in an Ishikawa/SHT-290 co-culture model

    PubMed Central

    Kintner, Jennifer; Schoborg, Robert V.; Wyrick, Priscilla B.; Hall, Jennifer V.

    2015-01-01

    Studies indicate that estrogen enhances Chlamydia trachomatis serovar E infection in genital epithelial cells. Hormones have direct and indirect effects on endometrial epithelial cells. Estrogen and progesterone exposure induces endometrial stromal cells to release effectors that subsequently regulate growth and maturation of uterine epithelial cells. Estrogen enhances C. trachomatis infection by aiding entry and intracellular development in endometrial epithelial cell (Ishikawa, IK)/SHT-290 stromal cell co-culture. Enhanced chlamydial infection was mediated by direct estrogen-stimulated signaling events in epithelial cells and indirectly via estrogen-induced stromal cell effectors. The current study investigates the effects of hormones on chlamydial development using culture conditions representative of the menstrual cycle. Chlamydia trachomatis-infected IK or IK/SHT-290 cultures were exposed to 10−8 M estrogen (E2), 10−7 M progesterone (P4) or a combination of both hormones (10−8 M E2 followed by 10−9 M E2/10−7 M P4). Chlamydial infectivity and progeny production were significantly decreased (30–66%) in cultures exposed to progesterone or estrogen/progesterone combination compared to estrogen alone. Thus, progesterone antagonized the positive effects of estrogen on chlamydial infection. These data indicate the susceptibility of endometrial epithelial cells to C. trachomatis infection during the menstrual cycle is altered by phase specific actions of sex hormones in the genital tract. PMID:25724891

  18. STAR and AKR1B10 are down-regulated in high-grade endometrial cancer.

    PubMed

    Sinreih, Maša; Štupar, Saša; Čemažar, Luka; Verdenik, Ivan; Frković Grazio, Snježana; Smrkolj, Špela; Rižner, Tea Lanišnik

    2017-02-21

    Endometrial cancer is the most frequent gynecological malignancy in the developed world. The majority of cases are estrogen dependent, and are associated with diminished protective effects of progesterone. Endometrial cancer is also related to enhanced inflammation and decreased differentiation. In our previous studies, we examined the expression of genes involved in estrogen and progesterone actions in inflammation and tumor differentiation, in tissue samples from endometrial cancer and adjacent control endometrium. The aims of the current study were to examine correlations between gene expression and several demographic characteristics, and to evaluate changes in gene expression with regard to histopathological and clinical characteristics of 51 patients. We studied correlations and differences in expression of 38 genes involved in five pathophysiological processes: (i) estrogen-stimulated proliferation; (ii) estrogen-dependent carcinogenesis; (iii) diminished biosynthesis of progesterone: (iv) enhanced formation of progesterone metabolites; and (v) increased inflammation and decreased differentiation. Spearman correlation coefficient analysis shows that expression of PAQR7 correlates with age, expression of SRD5A1, AKR1B1 and AKR1B10 correlate with body mass, while expression of SRD5A1 and AKR1B10 correlate with body mass index. When patients with endometrial cancer were stratified based on menopausal status, histological grade, myometrial invasion, lymphovascular invasion, and FIGO stage, Mann-Whitney U tests revealed significantly decreased expression of STAR (4.4-fold; adjusted p=0.009) and AKR1B10 (9-fold; adjusted p=0.003) in high grade versus low grade tumors. Lower levels of STAR might lead to decreased de-novo steroid hormone synthesis and tumor differentiation, and lower levels of AKR1B10 to diminished elimination of toxic electrophilic carbonyl compounds in high-grade endometrial cancer. These data thus reveal the potential of STAR and AKR1B10 as

  19. Intrauterine devices containing progesterone.

    PubMed

    Murad, F

    1977-05-01

    Characteristics of progesterone-releasing IUDs are reported. At present, the only progesterone-containing IUD on the market is Progestasert, a T-shaped ethylene vinyl acetate copolymer device containing 38 mg progesterone in silicone. The device releases approximately 65 mcg/day into the uterine cavity over the course of 1-year. The device does not alter pituitary function or ovulation, nor does it depend on a local mechanical effect. Rather, it may exert its effect by inhibiting sperm capacitation or survival, or it may prevent nidation by alterning the endometrium. The reported pregnancy rate for Progestasert is 1.9% in parous women and 2.5% in nulliparous women. This efficacy rate is similar to that for other IUDs and low-dose progestin-only oral contraceptives. Breakthrough bleeding is the most common side effect, and perhaps 10-15% of the acceptors will have the device removed for either bleeding, pain, or infection. The rate of spontaneous expulsion of the device is about 3-8%. It is recommended that the device be inserted during or shortly after the menstrual period.

  20. Molecular Profiling of Endometrial Malignancies

    PubMed Central

    Samarnthai, Norasate; Hall, Kevin; Yeh, I-Tien

    2010-01-01

    Molecular profiling of endometrial neoplasms reveals genetic changes in endometrial carcinomas that support the dualistic model, in which type I carcinomas are estrogen-dependent, low grade lesions and type II carcinomas are nonestrogen dependent and high grade. The molecular changes in type I endometrial carcinomas include mutations in PTEN, PIK3CA, KRAS, and β-catenin, along with microsatellite instability, whereas type II endometrial carcinomas are characterized by genetic alterations in p53, HER2/neu, p16, and E-cadherin. For endometrial neoplasms with a malignant mesenchymal component, C-MYC mutations and loss of heterozygosity are frequently seen in carcinosarcomas, and a fusion gene, JAZF1/JJAZ1, is distinctive for endometrial stromal sarcoma. In addition, p53 mutations may play an important role in tumorigenesis of undifferentiated endometrial sarcoma. These molecular changes can help in the diagnosis of endometrial neoplasms, as well as form the basis of molecular targeted therapy. PMID:20368795

  1. Brivanib Alaninate in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2016-03-16

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma

  2. Decorin induced by progesterone plays a crucial role in suppressing endometriosis.

    PubMed

    Ono, Yoshihiro Joshua; Terai, Yoshito; Tanabe, Akiko; Hayashi, Atsushi; Hayashi, Masami; Yamashita, Yoshiki; Kyo, Satoru; Ohmichi, Masahide

    2014-11-01

    Dienogest, a synthetic progestin, has been shown to be effective against endometriosis, although it is still unclear as to how it affects the ectopic endometrial cells. Decorin has been shown to be a powerful endogenous tumor repressor acting in a paracrine fashion to limit tumor growth. Our objectives were to examine the direct effects of progesterone and dienogest on the in vitro proliferation of the human ectopic endometrial epithelial and stromal cell lines, and evaluate as to how decorin contributes to this effect. We also examined DCN mRNA expression in 50 endometriosis patients. The growth of both cell lines was inhibited in a dose-dependent manner by both decorin and dienogest. Using a chromatin immunoprecipitation assay, it was noted that progesterone and dienogest directly induced the binding of the decorin promoter in the EMOsis cc/TERT cells (immortalized human ovarian epithelial cells) and CRL-4003 cells (immortalized human endometrial stromal cells). Progesterone and dienogest also led to significant induced cell cycle arrest via decorin by promoting production of p21 in both cell lines in a dose-dependent manner. Decorin also suppressed the expression of MET in both cell lines. We confirmed that DCN mRNA expression in patients treated with dienogest was higher than that in the control group. In conclusion, decorin induced by dienogest appears to play a crucial role in suppressing endometriosis by exerting anti-proliferative effects and inducing cell cycle arrest via the production of p21 human ectopic endometrial cells and eutopic endometrial stromal cells.

  3. Nuclear Receptor Co-Regulator Krüppel-like Factor 9 in Human Endometrial Stromal Cell Differentiation

    USDA-ARS?s Scientific Manuscript database

    The biological actions of ligand-bound estrogen (E) and progesterone (P) receptors are dependent on coregulator partner proteins. We have identified Krüppel-like Factor 9 (KLF9) as important for E and P actions in endometrial cells. Ablation of KLF9 in mice resulted in subfertility due partly to alt...

  4. Therapeutic options for management of endometrial hyperplasia.

    PubMed

    Chandra, Vishal; Kim, Jong Joo; Benbrook, Doris Mangiaracina; Dwivedi, Anila; Rai, Rajani

    2016-01-01

    Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH.

  5. Therapeutic options for management of endometrial hyperplasia

    PubMed Central

    2016-01-01

    Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH. PMID:26463434

  6. Management options and fertility-preserving therapy for premenopausal endometrial hyperplasia and early-stage endometrial cancer.

    PubMed

    Gressel, Gregory M; Parkash, Vinita; Pal, Lubna

    2015-12-01

    Definitive management with hysterectomy could be appropriate for some patients with endometrial cancer and its precursor lesions, but poses challenges for those desiring future fertility. To review risk factors for endometrial hyperplasia/cancer among premenopausal women and discuss management options for fertility preservation. A literature search through the PubMed, Ovid, and Cochrane databases was conducted using the terms "endometrial hyperplasia" and "endometrial cancer," cross-referenced with "fertility preservation." All articles published in English between January 1, 2000, and January 1, 2015, were considered if they were readily available online. Articles were analyzed and information was synthesized into a comprehensive review. Chronic anovulation, obesity, polycystic ovarian syndrome, metabolic syndrome, insulin resistance, and type 2 diabetes mellitus must be appreciated as risk factors for endometrial pathology. Providers must exert vigilance in identifying patients at risk and in initiating pre-emptive strategies. Risk reduction with lifestyle modification, weight loss, and glycemic control can improve regression and overall health. Fertility outcomes for these patients are promising, especially with assisted reproductive technology. Conservative management could be appropriate for carefully selected women with complex atypical endometrial hyperplasia or early-stage endometrial cancer who desire future fertility. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  7. Loss of AF-6/afadin induces cell invasion, suppresses the formation of glandular structures and might be a predictive marker of resistance to chemotherapy in endometrial cancer.

    PubMed

    Yamamoto, Takuro; Mori, Taisuke; Sawada, Morio; Matsushima, Hiroshi; Ito, Fumitake; Akiyama, Makoto; Kitawaki, Jo

    2015-04-12

    AF-6/afadin plays an important role in the formation of adherence junctions. In breast and colon cancer, loss of AF-6/afadin induces cell migration and cell invasion. We aimed to elucidate the role of AF-6/afadin in human endometrial cancer. Morphology and AF-6/afadin expression in endometrial cancer cell lines was investigated by 3-dimensional culture. We used Matrigel invasion assay to demonstrate AF-6/afadin knockdown induced invasive capability. Cell proliferation assay was performed to estimate chemoresistance to doxorubicin, paclitaxel and cisplatin induced by AF-6/afadin knockdown. The associations between AF-6/afadin expression and clinicopathological status were determined by immunohistochemical analysis in endometrial cancer tissues. Informed consent was obtained from all patients before the study. The majority of cell clumps in 3-dimensional cultures of Ishikawa cells that strongly expressed AF-6/afadin showed round gland-like structures. In contrast, the cell clumps in 3-dimensional cultures of HEC1A and AN3CA cells-both weakly expressing AF-6/afadin-showed irregular gland-like structures and disorganized colonies with no gland-like structures, respectively. AF-6/afadin knockdown resulted in reduced number of gland-like structures in 3-dimensional cultures and enhancement of cell invasion and phosphorylation of ERK1/2 and Src in the highly AF-6/afadin-expressing endometrial cancer cell line. Inhibitors of MAPK/ERK kinase (MEK) (U0126) and Src (SU6656) suppressed the AF-6/afadin knockdown-induced invasive capability. AF-6/afadin knockdown induced chemoresistance to doxorubicin, paclitaxel and cisplatin in Ishikawa cells, not in HEC1A. Immunohistochemical analysis showed that AF-6/afadin expression was significantly associated with myometrial invasion and high histological grade. AF-6/afadin regulates cell morphology and invasiveness. Invasive capability is partly regulated through the ERK and Src pathway. The inhibitors to these pathways might be

  8. Polycystic ovary syndrome and risk of endometrial cancer: a mini-review.

    PubMed

    Tokmak, Aytekin; Kokanali, Mahmut Kuntay; Guzel, Ali Irfan; Kara, Aydan; Topcu, Hasan Onur; Cavkaytar, Sabri

    2014-01-01

    The polycystic ovary syndrome is the most common endocrinological disorder of reproductive age women with a prevalence of 5 to 8 %. The most common diagnostic criteria used for polycystic ovary syndrome are oligo- or an-ovulation, clinical and/ or biochemical signs of hyperandrogenism and polycystic ovaries. Hyperandrogenism results in increased estrogen levels and lack of cyclic progesterone due to anovulation and persistent stimulation of the endometrium may lead to endometrial hyperplasia or adenocarcinoma development. In this mini review, we aimed to evaluate the possible relationship between polycystic ovary syndrome and endometrial cancer.

  9. INCIDENCE OF ENDOMETRIAL HYPERPLASIA

    PubMed Central

    REED, Susan D.; NEWTON, Katherine M.; CLINTON, Walter L.; EPPLEIN, Meira; GARCIA, Rochelle; ALLISON, Kimberly; VOIGT, Lynda F.; Weiss, Noel S.

    2009-01-01

    Objective Estimate age-specific incidence of endometrial hyperplasia: simple, complex, and atypical, in order of increasing likelihood of progression to carcinoma. Study design Women ages 18–90 years with endometrial pathology specimens (1985–2003) at a large integrated health plan were identified using automated data. Incidence rates were obtained by dividing the number of cases by the estimated number of female health plan enrollees who retained a uterus. Results Endometrial hyperplasia peak incidence was: simple-142/100,000 woman-years, complex-213/100,000 woman-years, both in the early 50s; and atypical-56/100,000 woman-years in the early 60s. Age-adjusted incidence decreased over the study period, especially for atypical hyperplasia. Conclusions Endometrial hyperplasia incidence without and with atypia peaks in the early postmenopausal years and in the early 60s, respectively. Given that some cases of endometrial hyperplasia likely go undiagnosed, the figures provided should be viewed as minimum estimates of the true incidence. PMID:19393600

  10. Progesterone for preterm birth prevention.

    PubMed

    Ransom, Carla E; Murtha, Amy P

    2012-03-01

    Preterm birth—delivery before 37 weeks of gestation—is the second leading cause of infant mortality in the United States after congenital malformations. Spontaneous preterm birth, due to either preterm labor or preterm premature membrane rupture, encompasses approximately 75% of all preterm births, almost 400,000 births per year. Since the 1960s, different formulations of progesterone have been investigated for preterm birth prevention. This article addresses the use of progesterone for the prevention of preterm birth, including selection of candidates for progesterone, pharmacokinetics, dosing, and formulations. This article aims to provide a practical guide for using progesterone in clinical practice.

  11. Progesterone Deficiency and Premature Labour

    PubMed Central

    Csapo, A. I.; Pohanka, O.; Kaihola, H. L.

    1974-01-01

    Plasma oestradiol 17β and progesterone levels in 11 patients admitted to hospital for threatened premature labour of unknown aetiology were compared with those of women at similar stages of gestation whose pregnancy was normal. Oestradiol levels in the study group were slightly higher than in the normal controls but their progesterone levels were significantly lower. This progesterone deficiency increased the oestradiol/progesterone ratio in the study group patients, and it increased still more as the progesterone withdrawal continued during premature labour. Since uterine activity during pregnancy is regulated by a balanced action of several factors a deficiency in progesterone, an opponent of uterine activity, creates a regulatory imbalance which, if uncorrected, provokes premature labour. An increase in uterine volume stimulates uterine activity, and the present study reinforced our previous conclusion that the uterine-volume/plasma-progesterone ratio is a more accurate measure of the state of regulatory balance than the progesterone level alone. The cause of the progesterone deficiency in these cases remains unexplained, but we suggest that placental growth and function are contributory factors. We are investigating ways of correcting the resulting imbalance in the regulatory mechanism. PMID:4812406

  12. A critical period of progesterone withdrawal precedes menstruation in macaques

    PubMed Central

    Slayden, Ov D; Brenner, Robert M

    2006-01-01

    Macaques are menstruating nonhuman primates that provide important animal models for studies of hormonal regulation in the uterus. In women and macaques the decline of progesterone (P) at the end of the cycle triggers endometrial expression of a variety of matrix metalloproteinase (MMP) enzymes that participate in tissue breakdown and menstrual sloughing. To determine the minimal duration of P withdrawal required to induce menses, we assessed the effects of adding P back at various time points after P withdrawal on both frank bleeding patterns and endometrial MMP expression. Artificial menstrual cycles were induced by treating the animals sequentially with implants releasing estradiol (E2) and progesterone (P). To assess bleeding patterns, P implants were removed at the end of a cycle and then added back at 12, 24, 30, 36, 40, 48, 60, or 72 hours (h) after the initial P withdrawal. Observational analysis of frank bleeding patterns showed that P replacement at 12 and 24 h blocked menses, replacement at 36 h reduced menses but replacement after 36 h failed to block menses. These data indicate that in macaques, a critical period of P withdrawal exists and lasts approximately 36 h. In other similarly cycled animals, we withdrew P and then added P back either during (12–24 h) or after (48 h) the critical period, removed the uterus 24 h after P add back and evaluated endometrial MMP expression. Immunocytochemistry showed that replacement of P during the critical period suppressed MMP-1, -2 and -3 expression along with menses, but replacement of P at 48 h, which failed to suppress mense, suppressed MMP-1 and MMP-3 but did not block MMP-2. We concluded that upregulation of MMPs is essential to menses induction, but that after the critical period, menses will occur even if some MMPs are experimentally blocked. PMID:17118170

  13. A critical period of progesterone withdrawal precedes menstruation in macaques.

    PubMed

    Slayden, Ov D; Brenner, Robert M

    2006-01-01

    Macaques are menstruating nonhuman primates that provide important animal models for studies of hormonal regulation in the uterus. In women and macaques the decline of progesterone (P) at the end of the cycle triggers endometrial expression of a variety of matrix metalloproteinase (MMP) enzymes that participate in tissue breakdown and menstrual sloughing. To determine the minimal duration of P withdrawal required to induce menses, we assessed the effects of adding P back at various time points after P withdrawal on both frank bleeding patterns and endometrial MMP expression. Artificial menstrual cycles were induced by treating the animals sequentially with implants releasing estradiol (E2) and progesterone (P). To assess bleeding patterns, P implants were removed at the end of a cycle and then added back at 12, 24, 30, 36, 40, 48, 60, or 72 hours (h) after the initial P withdrawal. Observational analysis of frank bleeding patterns showed that P replacement at 12 and 24 h blocked menses, replacement at 36 h reduced menses but replacement after 36 h failed to block menses. These data indicate that in macaques, a critical period of P withdrawal exists and lasts approximately 36 h. In other similarly cycled animals, we withdrew P and then added P back either during (12-24 h) or after (48 h) the critical period, removed the uterus 24 h after P add back and evaluated endometrial MMP expression. Immunocytochemistry showed that replacement of P during the critical period suppressed MMP-1, -2 and -3 expression along with menses, but replacement of P at 48 h, which failed to suppress mense, suppressed MMP-1 and MMP-3 but did not block MMP-2. We concluded that upregulation of MMPs is essential to menses induction, but that after the critical period, menses will occur even if some MMPs are experimentally blocked.

  14. Does tamoxifen therapy affect the hormone receptor expression and cell proliferation indices of endometrial polyps? An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to tamoxifen.

    PubMed

    McGurgan, P; Taylor, L J; Duffy, S R; O'Donovan, P J

    2006-06-20

    This study set out to test the null hypothesis that tamoxifen therapy would not affect the hormone receptor expression (oestrogen and progesterone receptors-ER and PR) or markers of cell proliferation/apoptosis (Ki67 and Bcl-2) of endometrial polyps from postmenopausal women exposed and not exposed to tamoxifen. Endometrial polyps were prospectively obtained from women presenting with abnormal bleeding attending an out-patient hysteroscopy clinic who subsequently underwent endometrial polypectomy (16 from postmenopausal women not exposed to tamoxifen, 9 from women exposed to tamoxifen). Immunohistochemical staining for ER, PR, Ki67 and Bcl-2 was performed on polyps from both groups of women. Non-parametric statistical analysis was used (Mann-Whitney and Spearmans rank correlation). Endometrial polyps from tamoxifen users had significantly lower oestrogen receptor but increased progesterone receptor and Bcl-2 expression. There were no significant differences for proliferation markers (Ki67) between postmenopausal endometrial polyps exposed and not exposed to tamoxifen. Tamoxifen has a significant affect on hormone receptor expression and markers of apoptosis in endometrial polyps. The results support the hypothesis that tamoxifen promotes polyp growth by inhibiting apoptosis. The mechanism for this does not appear to be oestrogen receptor mediated.

  15. Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis.

    PubMed

    Heard, Melissa E; Velarde, Michael C; Giudice, Linda C; Simmen, Frank A; Simmen, Rosalia C M

    2015-06-01

    Krüppel-like Factor (KLF) 13 and the closely related KLF9 are members of the Sp/KLF family of transcription factors that have collectively emerged as essential regulators of tissue development, differentiation, proliferation, and programmed cell death. Steroid hormone-responsive tissues express multiple KLFs that are linked to progesterone receptor (PGR) and estrogen receptor (ESR) actions either as integrators or as coregulators. Endometriosis is a chronic disease characterized by progesterone resistance and dysregulated estradiol signaling; nevertheless, distinct KLF members' contributions to endometriosis remain largely undefined. We previously demonstrated promotion of ectopic lesion establishment by Klf9 null endometrium in a mouse model of endometriosis. Here we evaluated whether KLF13 loss of expression in endometrial cells may equally contribute to lesion formation. KLF13 transcript levels were lower in the eutopic endometria of women with versus women without endometriosis at menstrual midsecretory phase. In wild-type (WT) mouse recipients intraperitoneally administered WT or Klf13 null endometrial fragments, lesion incidence did not differ with donor genotype. No differences were noted for lesion volume, number, proliferation status, and apoptotic index as well. Klf13 null lesions displayed reduced total PGR and ESR1 (RNA and immunoreactive protein) and altered expression of several PGR and ESR1 target genes, relative to WT lesions. Unlike for Klf9 null lesions, changes in transcript levels for PGR-A, ESR1, and Notch/Hedgehog-associated pathway components were not observed for Klf13 null lesions. Results demonstrate lack of a causative relationship between endometrial KLF13 deficiency and lesion establishment in mice, and they support the broader participation of multiple signaling pathways, besides those mediated by steroid receptors, in the pathology of endometriosis.

  16. DNA Methylation Machinery in the Endometrium and Endometrial Cancer.

    PubMed

    Caplakova, Veronika; Babusikova, Eva; Blahovcova, Eva; Balharek, Tomas; Zelieskova, Maria; Hatok, Jozef

    2016-09-01

    During the normal menstrual cycle, endometrial tissue undergoes many biochemical and morphological changes which are under the control of steroid hormone levels. DNA methylation plays a key role in gene expression regulation and influences functional changes in endometrial tissue. Eliminating senescent cells from the functional layer of the endometrium is mediated by apoptotic cell death, which helps maintain cellular homeostasis. Aberrant DNA methylation changes result in deregulation of important apoptotic proteins during endometrial carcinogenesis and thus apoptosis resistance development. Evading apoptosis is still a major problem in the successful treatment of endometrial cancer patients with advanced disease. Despite intensive study of the cancer epigenome, there is missing information about disrupted apoptotic gene regulation in DNA methylation levels. Therefore, it is necessary to spread our knowledge in the field of epigenetics to help us differentiate normal and cancer tissues and detect the early stages of cancer disease. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  17. Steroids Regulate CXCL4 in the Human Endometrium During Menstruation to Enable Efficient Endometrial Repair.

    PubMed

    Maybin, Jacqueline A; Thiruchelvam, Uma; Madhra, Mayank; Saunders, Philippa T K; Critchley, Hilary O D

    2017-06-01

    Repair of the endometrial surface at menstruation must be efficient to minimize blood loss and optimize reproductive function. The mechanism and regulation of endometrial repair remain undefined. To determine the presence/regulation of CXCL4 in the human endometrium as a putative repair factor at menses. Endometrial tissue was collected throughout the menstrual cycle from healthy women attending the gynecology department. Menstrual blood loss was objectively measured in a subset, and heavy menstrual bleeding (HMB) was defined as >80 mL per cycle. Monocytes were isolated from peripheral blood. CXCL4 messenger RNA (mRNA) and protein were identified by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The function/regulation of endometrial CXCL4 was explored by in vitro cell culture. CXCL4 mRNA concentrations were significantly increased during menstruation. Intense staining for CXCL4 was detected in late secretory and menstrual tissue, localized to stromal, epithelial and endothelial cells. Colocalization identified positive staining in CD68+ macrophages. Treatment of human endometrial stromal and endothelial cells (hESCs and HEECs, respectively) with steroids revealed differential regulation of CXCL4. Progesterone withdrawal resulted in significant increases in CXCL4 mRNA and protein in hESCs, whereas cortisol significantly increased CXCL4 in HEECs. In women with HMB, CXCL4 was reduced in endothelial cells during the menstrual phase compared with women with normal menstrual bleeding. Cortisol-exposed macrophages displayed increased chemotaxis toward CXCL4 compared with macrophages incubated with estrogen or progesterone. These data implicate CXCL4 in endometrial repair after menses. Reduced cortisol at the time of menses may contribute to delayed endometrial repair and HMB, in part by mechanisms involving aberrant expression of CXCL4.

  18. Endometrial transcriptome analysis indicates superiority of natural over artificial cycles in recurrent implantation failure patients undergoing frozen embryo transfer.

    PubMed

    Altmäe, Signe; Tamm-Rosenstein, Karin; Esteban, Francisco J; Simm, Jaak; Kolberg, Liis; Peterson, Hedi; Metsis, Madis; Haldre, Kai; Horcajadas, José A; Salumets, Andres; Stavreus-Evers, Anneli

    2016-06-01

    Little consensus has been reached on the best protocol for endometrial preparation for frozen embryo transfer (FET). It is not known how, and to what extent, hormone supplementation in artificial cycles influences endometrial preparation for embryo implantation at a molecular level, especially in patients who have experienced recurrent implantation failure. Transcriptome analysis of 15 endometrial biopsy samples at the time of embryo implantation was used to compare two different endometrial preparation protocols, natural versus artificial cycles, for FET in women who have experienced recurrent implantation failure compared with fertile women. IPA and DAVID were used for functional analyses of differentially expressed genes. The TRANSFAC database was used to identify oestrogen and progesterone response elements upstream of differentially expressed genes. Cluster analysis demonstrated that natural cycles are associated with a better endometrial receptivity transcriptome than artificial cycles. Artificial cycles seemed to have a stronger negative effect on expression of genes and pathways crucial for endometrial receptivity, including ESR2, FSHR, LEP, and several interleukins and matrix metalloproteinases. Significant overrepresentation of oestrogen response elements among the genes with deteriorated expression in artificial cycles (P < 0.001) was found; progesterone response elements predominated in genes with amended expression with artificial cycles (P = 0.0052).

  19. Effects of human chorionic gonadotropin, estradiol, and progesterone on interleukin-18 expression in human decidual tissues.

    PubMed

    Wang, Fang; Zhu, Hong; Li, Bing; Liu, Mingxing; Liu, Dan; Deng, Meilian; Wang, Yanming; Xia, Xuefeng; Jiang, Qingping; Chen, Dunjin

    2017-04-01

    Interleukin (IL)-18 is a proinflammatory cytokine which mediates a myriad of inflammatory responses during pregnancy. Changes in IL-18 levels have been linked to complications during pregnancy. This study was designed to assess the effects of estradiol, human chorionic gonadotropin (hCG), and progesterone on IL-18 expression in human decidual tissues. Uterine deciduas from women with normal pregnancy, spontaneous abortion, and progesterone treated spontaneous abortion were collected, and the effects of hormones on the viability of decidual cells and IL-18 secretion were detected by MTT and ELISA assays. We found that Estradiol, hCG, and progesterone inhibited decidual cell growth independent of dosage and time.IL-18 secretion in the spontaneous abortion group was increased in the decidual cells over time, but all hormones significantly reduced its secretion (p < 0.05). Our results indicate that estradiol, hCG, and progesterone can reduce IL-18 secretion in the cultured endometrial stromal cells from patients who experienced spontaneous abortion to the levels observed following normal pregnancy. Progesterone can significantly reduce IL-18 expression and increase growth of CD56+ CD16- uNK cells, suggesting that these activities may underlie the mechanism by which progesterone improves pregnancy outcomes.

  20. Gene x environment interactions impact endometrial function and the menstrual cycle: PROGINS, life history, anthropometry, and physical activity.

    PubMed

    Rowe, Elizabeth J; Eisenstein, Toby K; Meissler, Joseph; Rockwell, L Christie

    2013-01-01

    We assessed the impact of a high frequency, functionally significant allelic variant of the progesterone receptor gene (PROGINS) on endometrial function and menstrual cycle characteristics. Further we asked whether PROGINS moderates the impact of life history characteristics, anthropometric measures, and physical activity on endometrial function. Fifty-two women were genotyped for the PROGINS variant, provided life history information, and had anthropometric measurements made. Women monitored their menstrual bleeding for three cycles, performed mid-cycle urinary ovulation tests, and recorded physical activity. A subset of women provided daily saliva samples and had mid-luteal endometrial thickness measurements taken during the third menstrual cycle. Salivary progesterone was assayed using ELISAs. The direct impact of PROGINS on endometrial and menstrual cycle characteristics was determined via independent t-tests with Bonferroni correction. Interactions between PROGINS and covariates were assessed by moderated regression. PROGINS did not directly impact any indicator of endometrial function. However, PROGINS caused an increase in menstrual cycle length with increasing mid-luteal progesterone levels; the opposite relationship was present in noncarriers (P < 0.05). Additionally, PROGINS interacted with four of six anthropometric measures (BMI, waist circumference, height, and waist-hip ratio) to impact endometrial function, however, interactions between PROGINS and life history variables, or physical activity was limited. The gene x environment interactions we report suggest that PROGINS alters endometrial sensitivity to maternal energetic condition. Thus, the possibility of genetically-based variation in sensitivity to energetic stress should be considered in future adaptive models of women's reproduction. Copyright © 2013 Wiley Periodicals, Inc.

  1. Efficacy and safety of vaginal estriol and progesterone in postmenopausal women with atrophic vaginitis.

    PubMed

    Chollet, Janet A; Carter, Gloria; Meyn, Leslie A; Mermelstein, Fred; Balk, Judith L

    2009-01-01

    The aim of this study was to assess the efficacy and safety of intravaginal estriol and progesterone on atrophic vaginitis in postmenopausal women. Under a physician-sponsored Investigational New Drug application, 19 healthy postmenopausal women with atrophic vaginitis received vaginal suppositories containing estriol (1 mg) and progesterone (30 mg). The participants were instructed to insert one suppository intravaginally once daily for 2 weeks and thrice weekly for a total of 6 months. Vaginal pH, Vaginal Maturation Index, urinalysis, self-reported vaginal dryness, menopausal quality of life, and serum estriol and progesterone levels were measured at enrollment and after 3 and 6 months of suppository use. Endometrial biopsies were obtained at enrollment and at 6 months. After 2 weeks of therapy, six participants had serum estriol and progesterone measured. The Vaginal Maturation Index, vaginal pH, and vaginal dryness rating improved significantly at 3 and 6 months compared with baseline. Menopausal quality of life scores improved significantly in all domains, with the sexual subscale showing the most improvement. There were no cases of endometrial hyperplasia after 6 months of suppository use. Serum preinsertion estriol at week 2 and months 3 and 6 were similar to baseline levels. Serum preinsertion progesterone increased but returned to baseline preinsertion levels at month 6, and preinsertion levels were significantly less at month 6 compared with month 3. Intravaginal administration of a combination estriol and progesterone agent to women with atrophic vaginitis may represent a safe and effective alternative to systemic hormone replacement, although this study was not adequate to provide proof of efficacy given that it was uncontrolled.

  2. Human Endometrial Adenocarcinoma Transplanted into Nude Mice: Growth Regulation by Estradiol

    NASA Astrophysics Data System (ADS)

    Satyaswaroop, P. G.; Zaino, R. J.; Mortel, R.

    1983-01-01

    A model for studying the growth of primary tumors of human endometrium and its regulation by 17β -estradiol has been developed in which ovariectomized nude mice are used as recipients. The receptors for sex steroids are maintained during serial transplantation of the tumor in this system. Although the rate of growth of receptor-negative endometrial tumors transplanted into ovariectomized nude mice is unaffected by the sustained presence or absence of estradiol, the growth of receptor-positive tumors is significantly increased by estradiol. Receptor-positive tumors treated with estradiol produced elevated concentrations of progesterone receptor. That the progesterone receptor is functional in this tumor is evident from the induction of estradiol 17β -dehydrogenase activity upon progestin administration. These findings are consistent with receptor-mediated regulation of growth of endometrial carcinoma.

  3. The synergistic effect of Mig-6 and Pten ablation on endometrial cancer development and progression

    PubMed Central

    Kim, Tae Hoon; Franco, Heather L.; Jung, Sung Yun; Qin, Jun; Broaddus, Russell R.; Lydon, John P.; Jeong, Jae-Wook

    2014-01-01

    Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. An additional endometrial cancer mouse model is generated by ablation of Pten (either as heterozygotes or by conditional uterine ablation). To determine the interplay between Mig-6 and the PTEN/PI3K signaling pathway during endometrial tumorigenesis, we have generated mice with Mig-6 and Pten conditionally ablated in progesterone receptor positive cells (PRcre/+Mig-6f/fPtenf/f ; Mig-6d/dPtend/d). The ablation of both Mig-6 and Pten dramatically accelerated the development of endometrial cancer compared to single ablation of either gene. The epithelium of Mig-6d/dPtend/d mice showed a significant decrease in the number of apoptotic cells compared to Ptend/d mice. The expression of the estrogen-induced apoptotic inhibitors Birc1 was significantly increased in the Mig-6d/dPtend/d mice. We identified ERK2 as a MIG-6 interacting protein by co-immunoprecipitation and demonstrated that the level of ERK2 phosphorylation was increased upon Mig-6 ablation either singly or in combination with Pten ablation. These results suggest that Mig-6 exerts a tumor suppressor function in endometrial cancer by promoting epithelial cell apoptosis through the down-regulation of the estrogen-induced apoptosis inhibitors Birc1 and the inhibition of ERK2 phosphorylation. PMID:20418913

  4. Intracrine Androgens Enhance Decidualization and Modulate Expression of Human Endometrial Receptivity Genes.

    PubMed

    Gibson, Douglas A; Simitsidellis, Ioannis; Cousins, Fiona L; Critchley, Hilary O D; Saunders, Philippa T K

    2016-01-28

    The endometrium is a complex, steroid-dependent tissue that undergoes dynamic cyclical remodelling. Transformation of stromal fibroblasts (ESC) into specialised secretory cells (decidualization) is fundamental to the establishment of a receptive endometrial microenvironment which can support and maintain pregnancy. Androgen receptors (AR) are present in ESC; in other tissues local metabolism of ovarian and adrenal-derived androgens regulate AR-dependent gene expression. We hypothesised that altered expression/activity of androgen biosynthetic enzymes would regulate tissue availability of bioactive androgens and the process of decidualization. Primary human ESC were treated in vitro for 1-8 days with progesterone and cAMP (decidualized) in the presence or absence of the AR antagonist flutamide. Time and treatment-dependent changes in genes essential for a) intra-tissue biosynthesis of androgens (5α-reductase/SRD5A1, aldo-keto reductase family 1 member C3/AKR1C3), b) establishment of endometrial decidualization (IGFBP1, prolactin) and c) endometrial receptivity (SPP1, MAOA, EDNRB) were measured. Decidualization of ESC resulted in significant time-dependent changes in expression of AKR1C3 and SRD5A1 and secretion of T/DHT. Addition of flutamide significantly reduced secretion of IGFBP1 and prolactin and altered the expression of endometrial receptivity markers. Intracrine biosynthesis of endometrial androgens during decidualization may play a key role in endometrial receptivity and offer a novel target for fertility treatment.

  5. Intracrine Androgens Enhance Decidualization and Modulate Expression of Human Endometrial Receptivity Genes

    PubMed Central

    Gibson, Douglas A.; Simitsidellis, Ioannis; Cousins, Fiona L.; Critchley, Hilary O. D.; Saunders, Philippa T. K.

    2016-01-01

    The endometrium is a complex, steroid-dependent tissue that undergoes dynamic cyclical remodelling. Transformation of stromal fibroblasts (ESC) into specialised secretory cells (decidualization) is fundamental to the establishment of a receptive endometrial microenvironment which can support and maintain pregnancy. Androgen receptors (AR) are present in ESC; in other tissues local metabolism of ovarian and adrenal-derived androgens regulate AR-dependent gene expression. We hypothesised that altered expression/activity of androgen biosynthetic enzymes would regulate tissue availability of bioactive androgens and the process of decidualization. Primary human ESC were treated in vitro for 1–8 days with progesterone and cAMP (decidualized) in the presence or absence of the AR antagonist flutamide. Time and treatment-dependent changes in genes essential for a) intra-tissue biosynthesis of androgens (5α-reductase/SRD5A1, aldo-keto reductase family 1 member C3/AKR1C3), b) establishment of endometrial decidualization (IGFBP1, prolactin) and c) endometrial receptivity (SPP1, MAOA, EDNRB) were measured. Decidualization of ESC resulted in significant time-dependent changes in expression of AKR1C3 and SRD5A1 and secretion of T/DHT. Addition of flutamide significantly reduced secretion of IGFBP1 and prolactin and altered the expression of endometrial receptivity markers. Intracrine biosynthesis of endometrial androgens during decidualization may play a key role in endometrial receptivity and offer a novel target for fertility treatment. PMID:26817618

  6. Antioxidant status and sex hormones in women with complex endometrial hyperplasia.

    PubMed

    Pejić, S; Todorović, A; Stojiljković, V; Pavlović, I; Gavrilović, L; Popović, N; Pajović, S B

    2016-09-30

    Endometrial tissue is under a strong influence of sex hormones. These hormones are considered as developmental factors of endometrial hyperplasia and endometrial cancer. We examined the influence of gonadotropins (follicle-stimulating and luteinizing hormone) and sex hormones (estradiol, progesterone) on oxidant/antioxidant parameters in blood and endometrial tissue of women with complex endometrial hyperplasia. In blood, superoxide dismutase activity was significantly higher in luteal phase and postmenopause compared to the follicular phase. A significant phase-related difference of glutathione peroxidase and glutathione reductase activity was recorded in the endometrium. Both enzymes had lower activity in luteal phase and postmenopause compared to the follicular phase. The linear regression analysis of individual hormonal variables against antioxidant parameters showed negative correlation between glutathione peroxidase activity and gonadotropin concentrations in the endometrium. The regression of hyperplastic to normal endometrium is the purpose of conservative treatment based on administration of progestogens or gonadotropin-releasing hormone analogues. Our findings indicate that gonadotropins influence the antioxidant enzymes activity in women with complex endometrial hyperplasia, which may affect disease development. Further studies are needed to clarify the molecular basis of hormone action on antioxidant system that may potentially initiate a development of treatments based on redox-dependent mechanism.

  7. Radiation Therapy With or Without Cisplatin in Treating Patients With Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2016-10-26

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma, Variant With Squamous Differentiation; Endometrial Serous Adenocarcinoma; Recurrent Uterine Corpus Carcinoma

  8. Influence of VEGFR and LHCGR on endometrial adenocarcinoma

    PubMed Central

    Kölbl, Alexandra C.; Birk, Amelie E.; Kuhn, Christina; Jeschke, Udo; Andergassen, Ulrich

    2016-01-01

    Endometrial adenocarcinoma is a common gynecological malignancy that is usually treated by surgical resection followed by radiation. However, the frequency of remote metastasis is high. The present study aimed to investigate whether patients with endometrial adenocarcinoma exhibited a positive response to treatment with a gonadotropin-releasing hormone analogue or inhibitors of neoangiogenesis, which are applied for the treatment of other malignancies. Immunohistochemical analyses were performed using 203 paraffin-embedded tissue samples of endometrial adenocarcinomas from patients who had undergone surgery at the Department of Obstetrics and Gynecology of the Ludwig Maximilians University of Munich, Germany. The tissues were incubated with antibodies against luteinizing hormone/choriogonadotropin receptor (LHCGR) and vascular endothelial growth factor receptor 2 (VEGFR2), and evaluated by bright field microscopy. The staining was categorized according to the Immune-Reactive-Score (IRS). The IRS scores were then statistically associated with various tumor traits, including tumor size, lymph node status, metastasis, grade, expression of steroid hormone receptors and patient survival. There was a significant association between VEGFR2 expression and tumor grading and estrogen receptor-α (ERα). For LHCGR, a correlation was observed with ERα and progesterone receptor (PR). No correlations were identified between VEGFR2 or LHCGR expression and the other examined tumor traits or patient survival. The associations between VEGFR2 and ERα, and between LHCGR and ERα or PR, may be explained by the interaction of these signal transduction molecules in the regulation of cellular growth and differentiation. These mechanisms also have an important role in the formation of remote metastases, which is the main cause for tumor-associated mortality. The results of the present study suggested that patients with endometrial adenocarcinoma may benefit from treatment with inhibitors

  9. Prediction of histological types of endometrial cancer by endometrial cytology.

    PubMed

    Okadome, Masao; Saito, Toshiaki; Nishiyama, Naoko; Ariyoshi, Kazuya; Shimamoto, Kumi; Shimada, Takako; Kodama, Keisuke; Imamura, Shogo; Nishiyama, Ken-ichi; Taguchi, Kenichi

    2014-07-01

    Few studies have examined the accuracy of preoperative endometrial cytology in diagnosing low- and high-risk histology in women with endometrial cancer (EC). This single-institutional retrospective study compared the accuracy of endometrial cytology and biopsy in preoperatively predicting low-risk and high-risk histology of EC. Between January 2006 and March 2013, 198 women with EC were examined by endometrial cytology, endometrial biopsy and hysterectomy specimen in National Kyushu Cancer Center. Among these women, 110 had endometrial cytology samples available to compare with endometrial biopsy, and were enrolled in our study (mean age ± standard deviation: 59.57 ± 10.32 years). Single-use plastic endometrial suction curettes were used in 12 of the 110 cases and thin metallic curettes for the rest. For type 2 EC, which includes grade 3 endometrioid adenocarcinoma and non-endometrioid histology, biopsy was 67.6% sensitive (25/37) and 84.9% specific (62/73); whereas cytology was 70.3% sensitive (26/37) and 91.8% specific (67/73). Cytology precisely diagnosed only one of 14 cases of serous carcinoma, but it diagnosed 11 of the 14 cases as type 2 EC, and its accuracy in distinguishing EC types was not inferior to endometrial biopsy (10/14). For EC, 9.1% (10/110) were unevaluable using biopsy, significantly more than the 0% (0/110) by cytology (P = 0.002). Although preoperative prediction of serous carcinoma was difficult, endometrial cytology had a higher evaluable rate for EC types. Endometrial cytology may complement endometrial biopsy in preoperative women with EC. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

  10. Combined Liquid Chromatography–Tandem Mass Spectrometry Analysis of Progesterone Metabolites

    PubMed Central

    Sinreih, Maša; Zukunft, Sven; Sosič, Izidor; Cesar, Jožko; Gobec, Stanislav; Adamski, Jerzy; Lanišnik Rižner, Tea

    2015-01-01

    Progesterone has a number of important functions throughout the human body. While the roles of progesterone are well known, the possible actions and implications of progesterone metabolites in different tissues remain to be determined. There is a growing body of evidence that these metabolites are not inactive, but can have significant biological effects, as anesthetics, anxiolytics and anticonvulsants. Furthermore, they can facilitate synthesis of myelin components in the peripheral nervous system, have effects on human pregnancy and onset of labour, and have a neuroprotective role. For a better understanding of the functions of progesterone metabolites, improved analytical methods are essential. We have developed a combined liquid chromatography—tandem mass spectrometry (LC-MS/MS) method for detection and quantification of progesterone and 16 progesterone metabolites that has femtomolar sensitivity and good reproducibility in a single chromatographic run. MS/MS analyses were performed in positive mode and under constant electrospray ionization conditions. To increase the sensitivity, all of the transitions were recorded using the Scheduled MRM algorithm. This LC-MS/MS method requires small sample volumes and minimal sample preparation, and there is no need for derivatization. Here, we show the application of this method for evaluation of progesterone metabolism in the HES endometrial cell line. In HES cells, the metabolism of progesterone proceeds mainly to (20S)-20-hydroxy-pregn-4-ene-3-one, (20S)-20-hydroxy-5α-pregnane-3-one and (20S)-5α-pregnane-3α,20-diol. The investigation of possible biological effects of these metabolites on the endometrium is currently undergoing. PMID:25680188

  11. Progesterone-associated proteins PP12 and PP14 in the human endometrium.

    PubMed

    Rutanen, E M; Koistinen, R; Seppälä, M; Julkunen, M; Suikkari, A M; Huhtala, M L

    1987-01-01

    Two proteins, designated as PP12 and PP14 were originally isolated from soluble extracts of the human placenta and its adjacent membranes. We have shown that they are synthesized by decidualized/secretory endometrium and not by placenta. Both proteins occur at high concentrations in human amniotic fluid, which is therefore an excellent source for purification. PP12 is a 34-kDa glycoprotein, which has an N-terminal amino acid sequence of Ala-Pro-Trp-Gln-Cys-Ala-Pro-Cys-Ser-Ala. This is identical with that of somatomedin-binding protein purified from the amniotic fluid. PP12 too binds somatomedin-C, or IGF-I (insulin-like growth factor-I). Human secretory endometrium synthesizes and secretes PP12, and progesterone stimulates its secretion. PP14 is a 28-kDa glycoprotein. Its N-terminal sequence shows homology to that of beta-lactoglobulins from various species. We have found PP14 in the human endometrium, serum and milk. Immunologically, PP14 is related to progestagen-associated endometrial protein (PEP), alpha-2 pregnancy-associated endometrial protein (alpha-2, PEG), endometrial protein 15 (EP15), alpha-uterine protein (AUP) and chorionic alpha-2 microglobulin (CAG-2). In ovulatory menstrual cycles, the concentration of PP14 increases in endometrial tissue as the secretory changes advance. In serum, the PP14 concentration begins to rise later than the progesterone levels, and high serum PP14 levels are maintained for the first days of the next cycle. By contrast, no elevation of serum PP14 level is seen in anovulatory cycles. Our results show that progesterone-associated proteins are synthesized by the human endometrium and appear in the peripheral circulation, where they can be quantitatively measured using immunochemical techniques.

  12. Wnt/Β-Catenin and Sex Hormone Signaling In Endometrial Homeostasis and Cancer

    PubMed Central

    Wang, Yongyi; van der Zee, Marten; Fodde, Riccardo; Blok, Leen J

    2010-01-01

    A delicate balance between estrogen and progestagen signaling underlies proper functioning of the female reproductive tract and, in particular, the monthly re- and degenerative phases characteristic of the menstrual cycle. Here, we propose that the canonical Wnt/β-catenin signaling pathway may underlie this finely tuned hormonal equilibrium in endometrial homeostasis and, upon its constitutive activation, lead to neoplastic transformation of the endometrium. During the menstrual cycle, estradiol will enhance Wnt/β-catenin signaling in the proliferative phase, while progesterone inhibits Wnt/β-catenin signaling, thus restraining estrogens' proliferative actions, during the secretory phase. In case of enhanced or unopposed estrogen signaling, constitutive activation of Wnt/β-catenin signaling will trigger endometrial hyperplasia, which may develop further into endometrial cancer. PMID:21317462

  13. 21 CFR 556.540 - Progesterone.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Progesterone. 556.540 Section 556.540 Food and... Residues of New Animal Drugs § 556.540 Progesterone. No residues of progesterone are permitted in excess of the following increments above the concentrations of progesterone naturally present in untreated...

  14. 21 CFR 556.540 - Progesterone.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Progesterone. 556.540 Section 556.540 Food and... Residues of New Animal Drugs § 556.540 Progesterone. (a) (b) Tolerances. Residues of progesterone are not permitted in excess of the following increments above the concentrations of progesterone naturally present...

  15. 21 CFR 556.540 - Progesterone.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Progesterone. 556.540 Section 556.540 Food and... Residues of New Animal Drugs § 556.540 Progesterone. (a) (b) Tolerances. Residues of progesterone are not permitted in excess of the following increments above the concentrations of progesterone naturally present...

  16. 21 CFR 556.540 - Progesterone.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Progesterone. 556.540 Section 556.540 Food and... Residues of New Animal Drugs § 556.540 Progesterone. (a) (b) Tolerances. Residues of progesterone are not permitted in excess of the following increments above the concentrations of progesterone naturally present...

  17. Assessing endometrial hyperplasia and carcinoma treated with progestin therapy.

    PubMed

    Mentrikoski, Mark J; Shah, Akeesha A; Hanley, Krisztina Z; Atkins, Kristen A

    2012-10-01

    The effects of increased amounts of progesterone on the endometrium, including such features as eosinophilic cytoplasmic metaplasia, glandular atrophy, and decidualized stroma, are well-known among surgical pathologists. These changes are typically seen as secondary effects of pregnancy or exogenous hormone therapy for birth control purposes or abnormal bleeding. Treatment with progesterone has become a viable alternative to hysterectomy in some patients with complex atypical hyperplasia (CAH) and well-differentiated endometrial carcinoma (WDC), especially those who are poor surgical candidates or those wishing to preserve fertility. To date, only 1 study has specifically examined the effects of progestin therapy on patients with a previous diagnosis of CAH or WDC. That study proposed a classification scheme for the assessment of treated CAH and WDC. The authors concluded that after 6 months of treatment, endometrial biopsy findings of persistent cytologic atypia and architectural abnormalities were associated with treatment failure. This current study aims to assess the previously proposed criteria in a cohort of 30 patients (18 with a diagnosis of CAH and 12 with a diagnosis of WDC), and determine the usefulness of these criteria in clinical practice. Our study confirms that cytologic atypia after 6 months of therapy is strongly associated with treatment failure, and should be an indication to pursue definitive surgical treatment in these patients.

  18. Role of spiral artery Doppler to screen type 2 endometrial cancer cases.

    PubMed

    Düzgüner, Soner; Ozkan, Mehmet Burak; Küçüközkan, Tuncay; Ozkaya, Enis; Kara, Fadıl; Balın, Ipek Nur; Korkmaz, Vakkas; Karslı, Mehmet Fatih; Gültekin, Burak

    2014-01-01

    The purpose of this study was to determine the value of endometrial blood flow assessment in predicting type 2 endometrial carcinoma. Sixty-five consecutive post-menopoausal women who had vaginal bleeding were enrolled in the study. All subjects were directed to transvaginal sonography to determine endometrial blood flow and underwent endometrial biopsy. Doppler findings were analysed to predict endometrial pathology. Subjects with unsatisfactory Doppler analyses were excluded from the study. Mean age of the study population was 50.1±6.9 years (42-73). Mean endometrial thickness was 10.1±2.9 mm (4-15 mm) and mean cancer antigen 125 (CA125) level was 20.1±17.4 U/mL (3-92). Histopathological evaluation revealed 14 cases of type 2 endometrial cancer and 18 cases of endometrial hyperplasia without atypia, while the other 33 cases had normal endometrial tissue. CA125 (Area under curve (AUC)=0.853, p=0.000), spiral artery resistance index (AUC=0.905, p=0.000), and spiral artery peak systolic velocity (AUC=0.822, p=0.000) were significant predictors for the type 2 endometrial cancer cases. Endometrial thickness did not significantly predict pathologic cases (p>0.05). Hyperplasia cases were not predicted by any of these diagnostic modalities (p>0.05). In patients with postmenopausal bleeding, spiral artery Doppler ultrasound, could play a role in refining the diagnosis of type 2 endometrial carcinoma; however, its predictive value should be evaluated with further studies.

  19. Recent Advances in Endometrial Cancer

    PubMed Central

    Tran, Arthur-Quan; Gehrig, Paola

    2017-01-01

    Endometrial cancer is the most common gynecologic malignancy in the United States, with yearly rates continuing to increase. Most women present with early stage disease; however, advanced disease carries a grave prognosis. As a result, novel therapies are currently under investigation for the treatment of endometrial cancer. These advances include a better understanding of the genetic basis surrounding the development of endometrial cancer, novel surgical therapies, and new molecular targets for the treatment of this disease. This review explores the literature regarding these advancements in endometrial cancer. PMID:28184290

  20. Nucleobindin 2 (NUCB2) in human endometrial carcinoma: a potent prognostic factor associated with cell proliferation and migration.

    PubMed

    Takagi, Kiyoshi; Miki, Yasuhiro; Tanaka, Sota; Hashimoto, Chiaki; Watanabe, Mika; Sasano, Hironobu; Ito, Kiyoshi; Suzuki, Takashi

    2016-01-01

    Nucleobindin 2 (NUCB2) is a multifunctional protein containing several functional domains, and associated with wide variety of biological process such as food intake and energy homeostasis. Recently, NUCB2 has been implicated in not only normal human tissues but also some kinds of human malignancies. However, its clinical and/or biological significance has largely remained unknown in endometrial carcinomas. We therefore immunolocalized NUCB2 protein in 87 endometrial carcinoma tissues and examined its clinical significance. NUCB2 immunoreactivity was detected in 19 out of 87 (22%) of endometrial carcinoma cases examined, and positively correlated with Ki67 labeling index, while there was no significant correlation between NUCB2 and stage, histological grade, and progesterone receptor status. Furthermore, NUCB2 immunoreactivity was significantly correlated with increased risk of recurrence and worse clinical outcome regardless of stage or histological grade. Subsequent multivariate analyses did reveal that NUCB2 immunoreactivity was an independent prognostic factor for both disease-free survival and endometrial cancer specific survival. In vitro experiments demonstrated that knockdown of NUCB2 using specific siRNA for NUCB2 significantly impaired cell proliferation and migration of the endometrial carcinoma cell lines, Ishikawa and Sawano cells, and that nesfatin-1 treatment significantly promoted cell proliferation and migration in Ishikawa cells. These findings possibly suggested that NUCB2 and/or nesfatin-1 had pivotal roles in the progression of endometrial carcinomas. Immunohistochemical NUCB2 status may therefore serve as a potent biomarker for endometrial carcinomas.

  1. Liquid-Based Endometrial Cytology Using SurePath™ Is Not Inferior to Suction Endometrial Tissue Biopsy in Clinical Performance for Detecting Endometrial Cancer Including Atypical Endometrial Hyperplasia.

    PubMed

    Yanaki, Fumiko; Hirai, Yasuo; Hanada, Azusa; Ishitani, Ken; Matsui, Hideo

    2017-01-01

    We evaluated the clinical performance of liquid-based endometrial cytology (SurePath™) for detecting endometrial malignancies by comparison with the performance of suction endometrial tissue biopsy. From November 2011 to May 2013, we consecutively collected 1,118 liquid-based endometrial cytology specimens and 674 suction endometrial tissue biopsy specimens. The rate of nonpositive final histology in nonpositive liquid-based endometrial cytology (98.2%) was higher than the rate of nonpositive final histology in nonpositive suction endometrial tissue biopsy (97.0%). None of the clinical performance values of liquid-based endometrial cytology for detecting the endometrial malignancies were statistically inferior to those of the suction endometrial tissue biopsy. When the positivity threshold was more than "atypical endometrial cells of undetermined significance," the rate of positive liquid-based endometrial cytology from cases with a positive final histology (84.5%) was higher than the rate of positive suction endometrial tissue biopsy from cases with a positive final histology (69.8%). However, there were still no significant differences among all the performance values. Our liquid-based endometrial cytology would be more appropriate in various clinical situations as the initial detection tool for endometrial malignancies, rather than suction endometrial tissue biopsy. In addition, it could be used in screening for endometrial malignancies on a broader scale. © 2017 S. Karger AG, Basel.

  2. Black cohosh inhibits 17β-estradiol-induced cell proliferation of endometrial adenocarcinoma cells.

    PubMed

    Park, So Yun; Kim, Hee Ja; Lee, Sa Ra; Choi, Youn-Hee; Jeong, Kyungah; Chung, Hyewon

    2016-10-01

    This study was conducted to investigate the effect of black cohosh (BC) extract on the proliferation and apoptosis of Ishikawa cells. Ishikawa human endometrial adenocarcinoma cells were treated with or without BC (1, 5, 10 and 25 μM) and cell proliferation and cytotoxicity were measured by CCK-8 assays and flow cytometry analysis. Additionally, Ishikawa cells were treated with 17β-estradiol (E2), E2 + progesterone and E2 + BC (5 and 10 μM) and the effect of BC and progesterone on E2-induced cell proliferation was analyzed. BC decreased the proliferation of Ishikawa cells at a dose-dependent rate compared with the control group (p < 0.05). The proliferation of Ishikawa cells increased in the presence of E2, whereas the subsequent addition of progesterone or BC decreased proliferation to the level of the control group (p < 0.05). The inhibitory effect of BC on E2-induced cell proliferation was greater than the inhibitory effect of progesterone. In conclusion, BC induces apoptosis in Ishikawa cells and suppresses E2-induced cell proliferation in Ishikawa cells. BC could be considered a candidate co-treatment agent of estrogen-dependent tumors, especially those involving endometrial cells.

  3. Endometrial Stromal Decidualization Responds Reversibly to Hormone Stimulation and Withdrawal

    PubMed Central

    Yu, Jie; Berga, Sarah L.; Johnston-MacAnanny, Erika B.; Sidell, Neil; Bagchi, Indrani C.; Bagchi, Milan K.

    2016-01-01

    Human endometrial stromal decidualization is required for embryo receptivity, angiogenesis, and placentation. Previous studies from our laboratories established that connexin (Cx)-43 critically regulates endometrial stromal cell (ESC) differentiation, whereas gap junction blockade prevents it. The current study evaluated the plasticity of ESC morphology and Cx43 expression, as well as other biochemical markers of cell differentiation, in response to decidualizing hormones. Primary human ESC cultures were exposed to 10 nM estradiol, 100 nM progesterone, and 0.5 mM cAMP for up to 14 days, followed by hormone withdrawal for 14 days, mimicking a biphasic ovulatory cycle. Reversible differentiation was documented by characteristic changes in cell shape. Cx43 was reversibly up- and down-regulated after the estradiol, progesterone, and cAMP treatment and withdrawal, respectively, paralleled by fluctuations in prolactin, vascular endothelial growth factor, IL-11, and glycodelin secretion. Markers of mesenchymal-epithelial transition (MET), and its counterpart epithelial-mesenchymal transition, followed reciprocal patterns corresponding to the morphological changes. Incubation in the presence of 18α-glycyrrhetinic acid, an inhibitor of gap junctions, partially reversed the expression of decidualization and MET markers. In the absence of hormones, Cx43 overexpression promoted increases in vascular endothelial growth factor and IL-11 secretion, up-regulated MET markers, and reduced N-cadherin, an epithelial-mesenchymal transition marker. The combined results support the hypothesis that Cx43-containing gap junctions and endocrine factors cooperate to regulate selected biomarkers of stromal decidualization and MET and suggest roles for both phenomena in endometrial preparation for embryonic receptivity. PMID:27035651

  4. Unusual inflammation in gynecologic pathology associated with defective endometrial receptivity.

    PubMed

    Kitaya, Kotaro; Yasuo, Tadahiro; Tada, Yoshihiro; Hayashi, Terumi; Iwaki, Yuri; Karita, Masako; Funabiki, Miyako; Taguchi, Sagiri; Spillers, Dustin; Nakamura, Yoshitaka; Yamada, Hisao

    2014-09-01

    Human cycling endometrium displays a series of periodic transitions unique to this mucosal tissue, which includes rapid proliferation, secretory transformation, physiological angiogenesis, interstitial edema, and menstrual shedding. Among these properties of the endometrium are the inflammatory changes that occur dynamically across the menstrual cycle. Immunocompetent cell composition and inflammatory gene expression pattern in the human endometrium drastically fluctuate from the proliferative phase to the secretory phase, particularly at the time of ovulation. These local immune responses are fine-tuned by the direct or indirect action of two representative ovarian steroids, estradiol and progesterone, and are essential for successful blastocyst implantation. Meanwhile, studies have been accumulating the evidence that such physiological endometrial inflammatory status is altered in the presence of certain gynecologic pathologies. Given that blastocysts are semi-allografts for maternal tissue, even subtle alterations in endometrial immunity potentially have a negative impact on implantation process. In this article, we aimed to review and discuss the physiological and pathological mucosal inflammatory conditions that can affect endometrial receptivity.

  5. Pseudo-placentational endometrial cysts in a bitch.

    PubMed

    Bartel, C; Schönkypl, S; Walter, I

    2010-02-01

    Cystic alterations of the canine endometrium compromise reproduction and fertility of the bitch and may lead to life-threatening diseases, such as pyometra. Even without clinical evidence, reduction of the uterine lumen by cysts implicates disturbances during migration, nidation and development of the embryo. Several studies point to the high variability of morphology of uterine endometrial cysts but they lack detailed analyses of alterations. In the present study, immunohistochemistry was used to investigate the expression of steroid hormone receptors (oestrogen, progesterone), proliferation activity, inflammation and infection in the cystic affected tissue regions in contrast to the normal endometrium. Oestrogen receptor expression showed a high density of receptors throughout the surface epithelial cells, crypt epithelial cells, glandular epithelial cells and stromal cells of the normal endometrium as well as the cystic affected regions. Proliferation in the cysts was verified in the middle and basal cells of the crypts. Neither in the endometrium nor in the cysts inflammatory processes or evidence of infection could be detected. Furthermore, lectin histochemistry and electron microscopic methods showed that lectin binding patterns and cell morphology of internal epithelial lining and surface epithelium of the cysts can be used to characterize and distinguish different types of cystic alterations. Analogies between epithelial cells of the glandular chambers of the canine placenta and the cystic cellular morphology, steroid hormone receptor distribution as well as lectin binding patterns of the endometrial cysts, as observed in this study, suggest to introduce the term 'pseudo-placentational endometrial cysts'.

  6. Endometrial carcinoma stage I.

    PubMed

    Baram, A; Ron, I; Kupferminc, M; Inbar, M

    1997-01-01

    Standard staging and therapeutic approach to endometrial cancer involves lymph node sampling (LNS) at the time of total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO). Lymphadenectomy prolongs time of surgery and increases the risk of morbidity; where other predictors are available, it may not contribute important supplementary information. 185/247 women with stage I endometrial carcinoma underwent the standard surgery while 62 underwent TAH+BSO. Recurrence and survival were monitored for a mean of 6.5 years and retrospectively reviewed: the rates for groups with and without known lymph node status were alike [13.5% (25/185) recurrence for the former and 12.9% (8/62) for the latter, and 5-year survival rates of 75.7% (140/185) for the former and 74.2 (46/62) for the latter]. Myometrial invasion and histological grade appeared to have been highly accurate predictors without lymph node information. Because information on histological grade is available early and is highly predictive, its use could be incorporated into a revised management algorithm for stage I endometrial cancer which would depend upon ensuring lymphadenectomy for women with low grade histopathology and omitting it for those with high grades on the grounds that no further information is necessary to act appropriately.

  7. Recurrence of endometrial polyps.

    PubMed

    Paradisi, Roberto; Rossi, Stefania; Scifo, Maria Cristina; Dall'O', Francesca; Battaglia, Cesare; Venturoli, Stefano

    2014-01-01

    To estimate the recurrence rate of patients with endometrial polyps and to evaluate whether the recurrence can be correlated with the histopathologic features of the polyp. Two hundred and eighty-two women with endometrial polyps in both pre- or postmenopausal period and suffering from abnormal uterine bleeding or not were treated by resectoscopic surgery in a tertiary university hospital and were subsequently followed to check for polyp recurrence. Polyp recurrence rate after hysteroscopic surgery and correlation between recurrence and main demographic, hysteroscopic and histopathologic characteristics were analyzed. During mean ± SD follow-up period of 26.3 ± 19.7 months, the overall recurrence rate was high (13.3%) and did not vary (p = NS) with age, parity, weight or other demographic characteristics of the patients or with the hysteroscopic appearance. On the contrary, the histopathologic features showed significant differences between patients with and without polyp recurrence. Recurrence rate was higher (p < 0.001) in women with histopathologically hyperplastic polyps without atypia and lower (p < 0.001) in women with benign polyps. The study shows that after resectoscopic polypectomy, the recurrence rate of endometrial polyps is high (13.3%). Moreover, the hyperplastic polyps without atypia recur more frequently than benign ones. © 2014 S. Karger AG, Basel.

  8. Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis.

    PubMed

    Valentijn, A J; Saretzki, G; Tempest, N; Critchley, H O D; Hapangama, D K

    2015-12-01

    How does regulation of telomerase activity (TA) in human endometrial epithelial cells (EEC) by ovarian hormones impact on telomere lengths (TL) and cell proliferation? Healthy endometrial epithelial cell proliferation is characterized by high TA and endometrial TL changes according to the ovarian hormone cycle, with shortest TL observed in the progesterone dominant mid-secretory phase, when TA is lowest, implicating progesterone in the negative regulation of TA and TL. Critical shortening of telomeres may result in permanent cell cycle arrest while the enzyme telomerase maintains telomere length (TL) and replicative capacity of cells. Telomerase expression and activity change in the human endometrium with the ovarian hormone cycle, however the effect of this on endometrial TL and cell growth is not known. A prospective observational study, which included endometrial and blood samples collected from 196 women. We studied endometrial samples from five different groups of women. Endometrial and matched blood TL and circulating steroid hormones were studied in samples collected from 85 women (Group 1). Fresh epithelial and stromal cell isolation and culture in vitro for TL and TA was done on endometrial biopsies collected from a further 74 healthy women not on hormonal therapy (Group 2) and from 5 women on medroxyprogesterone acetate (MPA) for contraception (Group 3). The epithelial TL and telomerase protein expression was examined in active, peritoneal, ectopic endometriotic and matched uterine (eutopic) endometrial samples collected from 10 women with endometriosis (Group 4); the in vivo effect of mifepristone on telomerase protein expression by immunohistochemistry (IHC) was examined in endometrium from 22 healthy women in mid-secretory phase before (n = 8), and after administering 200 mg mifepristone (n = 14) (Group 5). TA was measured by telomere repeat amplification protocol (TRAP) assay; TL by qPCR, and Q-FISH; cell proliferation was assessed by immunoblotting

  9. Wnt antagonist DKK1 is a target of Kruppel-like factor 9 (KLF9) in endometrial stromal cells: Implications for uterine receptivity

    USDA-ARS?s Scientific Manuscript database

    A significant underlying cause of pregnancy loss in mammals is the inability of the uterine epithelium to enter a "state of receptivity" for embryo implantation, due partly to the dysfunctional response of endometrial cells to progesterone (P). We previously showed that mice null for the Sp1-related...

  10. Role of progesterone in embryo development in cattle.

    PubMed

    Lonergan, Pat; Forde, Niamh; Spencer, Thomas

    2016-01-01

    Progesterone (P4) from the corpus luteum is critical for the establishment and maintenance of pregnancy and plays a major role in regulating endometrial secretions essential for stimulating and mediating changes in conceptus growth and differentiation throughout early pregnancy in ruminants. Numerous studies have demonstrated an association between elevated systemic P4 and acceleration in conceptus elongation. A combination of in vivo and in vitro experiments found that the effects of P4 on conceptus elongation are indirect and mediated through P4-induced effects in the endometrium. Despite effects on elongation, data on the effects of post-insemination supplementation with P4 on pregnancy rates are conflicting. This review highlights the effects of P4 on conceptus development and examines strategies that have been undertaken to manipulate P4 concentrations to increase fertility.

  11. Primate-specific Melanoma Antigen-A11 Regulates Isoform-specific Human Progesterone Receptor-B Transactivation*

    PubMed Central

    Su, Shifeng; Blackwelder, Amanda J.; Grossman, Gail; Minges, John T.; Yuan, Lingwen; Young, Steven L.; Wilson, Elizabeth M.

    2012-01-01

    Progesterone acting through the progesterone receptor (PR) and its coregulators prepares the human endometrium for receptivity to embryo implantation and maintains pregnancy. The menstrual cycle-dependent expression of melanoma antigen-A11 (MAGE-11) in the mid-secretory human endometrium suggested a novel function in human PR signaling. Here we show that MAGE-11 is an isoform-specific coregulator responsible for the greater transcriptional activity of human PR-B relative to PR-A. PR was recruited to progesterone response regions of progesterone-regulated FK506-binding protein 5 (FKBP5) immunophilin and small Ras family G protein cell growth inhibitor RASD1 genes. Expression of MAGE-11 lentivirus shRNA in human endometrial Ishikawa cells expressing PR-B showed that MAGE-11 is required for isoform-specific PR-B up-regulation of FKBP5. In contrast, MAGE-11 was not required for progesterone up-regulation of RASD1 in endometrial cells expressing the PR-A/B heterodimer. Target gene specificity of PR-B depended on the synergistic actions of MAGE-11 and p300 mediated by the unique PR-B NH2-terminal 110LLXXVLXXLL119 motif that interacts with the MAGE-11 F-box region in a phosphorylation- and ubiquitinylation-dependent manner. A progesterone-dependent mechanism is proposed in which MAGE-11 and p300 increase PR-B up-regulation of the FKBP5 gene. MAGE-11 down-regulates PR-B, similar to the effects of progesterone, and interacts with FKBP5 to stabilize a complex with PR-B. We conclude that the coregulator function of MAGE-11 extends to isoform-specific regulation of PR-B during the cyclic development of the human endometrium. PMID:22891251

  12. Implantation in the baboon: endometrial responses.

    PubMed

    Fazleabas, A T; Kim, J J; Srinivasan, S; Donnelly, K M; Brudney, A; Jaffe, R C

    1999-01-01

    Blastocyst implantation in the baboon usually occurs between 8 and 10 days post ovulation. Changes that occur within this window of receptivity and immediately following implantation can be divided into three distinct phases. The first phase, regulated by estrogen and progesterone, is characterized primarily by changes in both the luminal and glandular epithelial cells in preparation for blastocyst apposition and attachment. The second phase is the further modulation of these steroid induced changes in both epithelial and stromal cells by embryonic signals. The final phase is associated with trophoblast invasion and the remodeling of the endometrial stromal compartment. During the initial phase, the actions of estrogen and progesterone are dependent on the presence of specific receptors. Estrogen up-regulates both its own receptor (ER) and the progesterone receptor (PR), while progesterone down-regulates this expression pattern. However, the pattern of progesterone-induced down-regulation of ER and PR is confined to the epithelial cells and demonstrates a gradient effect from the functionalis to the basalis. What is most intriguing is that the loss of epithelial PR is closely correlated with the establishment of uterine receptivity. Coincident with the changes in ER and PR expression, epithelial cells undergo alterations in their cytoskeletal architecture and secretory profile. These changes can be counteracted by PR antagonist treatment during the luteal phase. Although estrogen and progesterone play a critical role in establishing the initial phase of uterine receptivity, it is becoming increasingly evident that the embryo induces functional receptivity in ruminants and rodents. In our studies in the primate, we demonstrate that chorionic gonadotrophin when infused in a manner that mimics blastocyst transit, has physiological effects on the three major cell types in the uterine endometrium. The luminal epithelium undergoes endoreplication and distinct epithelial

  13. Expression patterns of progesterone receptor membrane components 1 and 2 in endometria from women with and without endometriosis.

    PubMed

    Bunch, Kristen; Tinnemore, Deborah; Huff, Seth; Hoffer, Zachary S; Burney, Richard O; Stallings, Jonathan D

    2014-02-01

    Endometriosis is a hormone-dependent inflammatory condition associated with pain and infertility. A growing body of evidence supports attenuated secretory-phase progesterone responsiveness in women with this disease. Herein, we compare the expression of progesterone receptor membrane components (PGRMC) 1 and 2 in eutopic endometrium from 11 women with laparoscopically and/or histologically proven stage III/IV endometriosis and 23 disease-free women. Menstrual cycle phase was determined using a combination of reported cycle day, serum hormone profile, and endometrial histologic dating. The PGRMC-1 (fold change -3.3; P < .05) and PGRMC-2 (fold-change -8.8; P < .05) gene expression were significantly downregulated in secretory phase, eutopic endometrium from women with endometriosis. Immunohistochemistry demonstrated decreased PGRMC-1 and PGRMC-2 protein expression in the secretory phase endometrial stroma cells of women with endometriosis. Consistent with the preclinical work of others, our results reflect downregulation of endometrial PGRMC-1 and PGRMC-2 expression in secretory phase endometrium from women with advanced stage endometriosis. Understanding the molecular mechanisms of attenuated progesterone action in endometriosis has important diagnostic and therapeutic implications.

  14. Selection of Progesterone Derivatives Specific to Membrane Progesterone Receptors.

    PubMed

    Polikarpova, A V; Maslakova, A A; Levina, I S; Kulikova, L E; Kuznetsov, Y V; Guseva, A A; Shchelkunova, T A; Zavarzin, I V; Smirnova, O V

    2017-02-01

    The search of selective agonists and antagonists of membrane progesterone receptors (mPRs) is a starting point for the study of progesterone signal transduction mechanisms mediated by mPRs, distinct from nuclear receptors. According to preliminary data, the ligand affinity for mPRs differs significantly from that for classical nuclear progesterone receptors (nPRs), which might indicate structural differences in the ligand-binding pocket of these proteins. In the present work, we analyzed the affinity of several progesterone derivatives for mPRs of human pancreatic adenocarcinoma BxPC3 cell line that is characterized by a high level of mPR mRNA expression and by the absence of expression of nPR mRNA. The values were compared with the affinity of these compounds for nPRs. All tested compounds showed almost no affinity for nPRs, whereas their selectivity towards mPRs was different. Derivatives with an additional 19-hydroxyl group and removed 3-keto group had the highest selectivity for mPRs. These results suggest these compounds as the most selective progesterone analogs for studying the mechanisms of progestin action via mPRs.

  15. Nonoperative management of atypical endometrial hyperplasia and grade 1 endometrial cancer with the levonorgestrel intrauterine device in medically ill post-menopausal women.

    PubMed

    Baker, William D; Pierce, Stuart R; Mills, Anne M; Gehrig, Paola A; Duska, Linda R

    2017-07-01

    To assess the endometrial response rates to treatment with the levonorgestrel intrauterine device in post-menopausal women with atypical hyperplasia/endometrial intraepithelial neoplasia and grade 1 endometrioid (AH/EC) endometrial carcinoma who are not surgical candidates. Chart review was undertaken of patients with AH/EC who underwent levonorgestrel intrauterine device insertion by a gynecologic oncologist within two academic health systems between 2002 and 2013. When available, tissue blocks were evaluated with immunohistochemical staining for progesterone receptor expression. A total of 41 patients received treatment for AH/EC with the levonorgestrel intrauterine device. Follow up sufficient to assess response occurred in 36 women (88%). Complete response was documented in 18 of 36 women (50%), no response in 8 patients (22%), partial response in 3 women (8%) and progression of disease in 7 patients (19%). Four of 18 patients with complete response (22%) later experienced relapse of hyperplasia or cancer. Four patients (10%) died during the study period: none had evidence of metastatic disease and 1 of the 4 woman died of perioperative complications following hysterectomy for stage I disease. Patients responding to treatment had significantly lower progesterone receptor expression on post-treatment biopsies. Intrauterine levonorgestrel is a viable treatment option for post-menopausal women with AH/EC who are poor candidates for standard surgical management. The response rate in this series is similar to published reports in premenopausal patients and includes cases of disease recurrence following conversion to benign endometrium. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Vaginal ring delivery of selective progesterone receptor modulators for contraception

    PubMed Central

    Jensen, Jeffrey T.

    2013-01-01

    Vaginal ring delivery of selective progesterone receptor modulators (SPRMs) are under development to address limitations of current hormonal methods that affect use and effectiveness. This method would be appropriate for use in women with contraindications to, or preferences to avoid, estrogens. A contraceptive vaginal ring (CVR) also eliminates the need for daily dosing, and therefore might improve the effectiveness of contraception. The principle contraceptive effect of SPRMs is the suppression of ovulation. One limiting factor of chronic SPRM administration is the development of benign endometrial thickening characterized as PRM-associated endometrial changes. Ulipristal acetate is approved for use as an emergency contraceptive pill, but no SPRM is approved for regular contraception. The Population Council is developing an ulipristal acetate CVR for regular contraception. The CVR studied is of a matrix design composed of micronized UPA mixed in a silicone rubber matrix The target product is a ring designed for continuous use over 3 months delivering near steady-state drug levels that will suppress ovulation. Results from Phase 1–2 studies demonstrate that suppression of ovulation occurs with UPA levels above 6–7 ng/mL. PMID:23040126

  17. Vaginal ring delivery of selective progesterone receptor modulators for contraception.

    PubMed

    Jensen, Jeffrey T

    2013-03-01

    Vaginal ring delivery of selective progesterone receptor modulators (SPRMs) is under development to address the limitations of current hormonal methods that affect use and effectiveness. This method would be appropriate for use in women with contraindications to, or preferences to avoid, estrogens. A contraceptive vaginal ring (CVR) also eliminates the need for daily dosing and therefore might improve the effectiveness of contraception. The principal contraceptive effect of SPRMs is the suppression of ovulation. One limiting factor of chronic SPRM administration is the development of benign endometrial thickening characterized as PRM-associated endometrial changes. Ulipristal acetate (UPA) is approved for use as an emergency contraceptive pill, but no SPRM is approved for regular contraception. The Population Council is developing an ulipristal acetate CVR for regular contraception. The CVR studied is of a matrix design composed of micronized UPA mixed in a silicone rubber matrix The target product is a ring designed for continuous use over 3 months delivering near steady-state drug levels that will suppress ovulation. Results from Phase 1 and 2 studies demonstrate that suppression of ovulation occurs with UPA levels above 6-7 ng/mL.

  18. An earlier rise in systemic progesterone and increased progesterone in the uterine vein during early pregnancy are associated with enhanced embryonic survival in the ewe.

    PubMed

    O'Connell, Anne R; Hurst, Peter R; Davis, George H; McNatty, Kenneth P; Taylor, Sarah L; Juengel, Jennifer L

    2013-08-01

    Improved livestock production efficiency through greater embryonic survival (ES) is of economic and animal welfare benefit. Physiological characterization of animals that are extreme outliers for ES provides a valuable opportunity to identify a naturally occurring mechanism by which this trait may be enhanced. The objective was to determine the likely cause for the lifetime history of enhanced or reduced ES in a line of ewes selected for high fecundity. To address this question, progesterone concentrations in peripheral plasma as well as ovarian and uterine venous plasma samples were compared between groups of ewes with a lifetime history of either enhanced or reduced ES. The ability of the uterus to synthesize progesterone de novo at Day 5 of gestation was also tested. Ewes with enhanced ES had an earlier rise in progesterone concentration after estrus, irrespective of pregnancy status. In addition, there were increased concentrations of progesterone in the uterine vein in enhanced ES compared with reduced ES ewes on Day 5 of gestation (8.3 ± 0.8 ng/mL and 3.9 ± 1.4 ng/mL, respectively, P < 0.05). However, there were no differences in ovarian venous plasma (enhanced ES, 1725 ± 166 ng/mL; reduced ES, 1665 ± 268 ng/mL) at Day 5 of gestation. Although the endometrial tissue of some ewes (3/8) at Day 5 of gestation expressed three of the key genes necessary for regulation of de novo synthesis of progesterone, expression was not present exclusively in either of the two ES groups and therefore was unlikely to explain differences in the uterine vein progesterone concentrations between the enhanced and reduced ES groups. Collectively, the earlier rise in progesterone concentrations in peripheral plasma during the first week of gestation in the enhanced ES animals was independent of the presence of an embryo. Moreover, increased progesterone concentrations were also observed in the uterine vein at Day 5 of gestation of the enhanced ES ewes. It is proposed that the

  19. The Wedelolactone Derivative Inhibits Estrogen Receptor-Mediated Breast, Endometrial, and Ovarian Cancer Cells Growth

    PubMed Central

    Xu, Defeng; Lin, Tzu-Hua; Cheng, Max A.; Chen, Lu-Min; Chang, Chawnshang; Yeh, Shuyuan

    2014-01-01

    Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 μM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers. PMID:25221777

  20. Past, present, and future of hormonal therapy in recurrent endometrial cancer

    PubMed Central

    Carlson, Matthew J; Thiel, Kristina W; Leslie, Kimberly K

    2014-01-01

    Endometrial cancer is a heterogeneous disease. Type I cancers are hormonally driven, typically present with a low grade at an early stage, and are of endometrioid histology. These cancers are often cured by surgery, and the rate of recurrence is low. Type II cancers are less differentiated, often appear at a later stage, and are of serous, clear cell, or high grade endometrioid histology. The risk of recurrence in these cancers is much higher than with type I tumors. Isolated pelvic recurrences can be treated with radiation or exenteration, but systemic disease is fatal. It is in these recurrent patients, where prolongation of progression-free survival is the goal, that hormonal therapy can have the greatest benefit. In selected patients, hormonal therapy can be as effective as cytotoxic chemotherapy, without the toxicity and at a much lower cost. Here we review the evidence for treatment of patients suffering from recurrent endometrial cancer with hormonal therapy and explore avenues for the future of hormonal treatment of endometrial cancer. Currently, progesterone is the hormonal treatment of choice in these patients. Other drugs are also used, including selective estrogen receptor modulators, aromatase inhibitors, and gonadotropin-releasing hormone antagonists. Hormonal treatment of recurrent endometrial cancer relies on expression of the hormone receptors, which act as nuclear transcription factors. Tumors that express these receptors are the most sensitive to therapy; it is for this reason that patient selection is vitally important to the successful treatment of recurrent endometrial cancer with hormonal therapy. PMID:24833920

  1. High progesterone levels in women with high ovarian response do not affect clinical outcomes: a retrospective cohort study

    PubMed Central

    2014-01-01

    Background The potentially detrimental role of progesterone during the follicular phase has been a matter of controversy for several years; however, few studies have analyzed the effects of combined raised estradiol and progesterone levels on pregnancy outcomes. The aim of the present study was to determine the influence of high progesterone levels on clinical outcomes in the context of high ovarian response. Methods We performed a retrospective cohort study that included 2850 women classified as high responders. The women were subdivided into six groups depending on their progesterone concentration on the day of human chorionic gonadotropin (hCG) administration: <0.5 ng/ml (1.81 ng/ml (>p90). Ovarian response was classified as high when > =20 oocytes were retrieved or when estradiol was > =3000 pg/ml. Clinical outcomes of each subgroup were analyzed. We also examined data from frozen-thawed embryo transfers. Results were analyzed with Student’s t- test to compare continuous variables and chi-squared test to compare proportions. A p-value of < =0.05 was considered statistically significant. Results The progesterone concentration increased with ovarian response, and elevated progesterone did not show a significant clinical impact on implantation rate and pregnancy rates. These data provide evidence that progesterone levels higher than 1.8 ng/ml do not have detrimental effect on oocyte quality or endometrial receptivity. Conclusions These data allow us to conclude that high progesterone levels correlate significantly with high estradiol levels and that in high responder women; progesterone levels do not show a significant clinical impact on results. PMID:25064138

  2. Cell cycle regulation of human endometrial stromal cells during decidualization.

    PubMed

    Logan, Philip C; Steiner, Michael; Ponnampalam, Anna P; Mitchell, Murray D

    2012-08-01

    Differentiation of endometrial stromal cells into decidual cells is crucial for optimal endometrial receptivity. Data from our previous microarray study implied that expression of many cell cycle regulators are changed during decidualization and inhibition of DNA methylation in vitro. In this study, we hypothesized that both the classic progestin treatment and DNA methylation inhibition would inhibit stromal cell proliferation and cell cycle transition. The human endometrial stromal cell line (HESC) was treated from 2 days to 18 days with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine (AZA), a mixture of estradiol/progestin/cyclic adenosine monophosphate ([cAMP]; medroxy-progesterone acetate [MPA mix]) or both. Cell growth was measured by cell counting, cell cycle transition and apoptosis were analyzed by flow cytometry, expression of cell cycle regulators were analyzed by quantitative polymerase chain reaction (qPCR) and Western blotting, and change in DNA methylation profiles were detected by methylation-specific PCR. Both AZA and MPA mix inhibited the proliferation of HESC for at least 7 days. Treatment with MPA mix resulted in an early G0/G1 inhibition followed by G2/M phase inhibition at 18 days. In contrast, AZA treatment inhibited cell cycle progression at the G2/M phase throughout. The protein levels of p21(Cip1)and 14-3-3σ were increased with both AZA and MPA mix treatments without any change in the DNA methylation profiles of the genes. Our data imply that the decidualization of HESC is associated with cell cycle arrest at G0/G1 phase initially and G2/M phase at later stages. Our results also suggest that p53 pathway members play a role in the cell cycle regulation of endometrial stromal cells.

  3. Progesterone impairs social recognition in male rats.

    PubMed

    Bychowski, Meaghan E; Auger, Catherine J

    2012-04-01

    The influence of progesterone in the brain and on the behavior of females is fairly well understood. However, less is known about the effect of progesterone in the male system. In male rats, receptors for progesterone are present in virtually all vasopressin (AVP) immunoreactive cells in the bed nucleus of the stria terminalis (BST) and the medial amygdala (MeA). This colocalization functions to regulate AVP expression, as progesterone and/or progestin receptors (PR)s suppress AVP expression in these same extrahypothalamic regions in the brain. These data suggest that progesterone may influence AVP-dependent behavior. While AVP is implicated in numerous behavioral and physiological functions in rodents, AVP appears essential for social recognition of conspecifics. Therefore, we examined the effects of progesterone on social recognition. We report that progesterone plays an important role in modulating social recognition in the male brain, as progesterone treatment leads to a significant impairment of social recognition in male rats. Moreover, progesterone appears to act on PRs to impair social recognition, as progesterone impairment of social recognition is blocked by a PR antagonist, RU-486. Social recognition is also impaired by a specific progestin agonist, R5020. Interestingly, we show that progesterone does not interfere with either general memory or olfactory processes, suggesting that progesterone seems critically important to social recognition memory. These data provide strong evidence that physiological levels of progesterone can have an important impact on social behavior in male rats. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Role of epigenomics in ovarian and endometrial cancers.

    PubMed

    Balch, Curtis; Matei, Daniela E; Huang, Tim H-M; Nephew, Kenneth P

    2010-06-01

    Ovarian cancer is the most lethal gynecologic malignancy and while constituting only 3% of all female cancers, it causes 14,600 deaths in the USA annually. Endometrial cancer, the most diagnosed and second-most fatal gynecologic cancer, afflicts over 40,000 US women annually, causing an estimated 7780 deaths in 2009. In both advanced ovarian and endometrial carcinomas, the majority of initially therapy-responsive tumors eventually evolve to a fully drug-resistant phenotype. In addition to genetic mutations, epigenetic anomalies are frequent in both gynecologic malignancies, including aberrant DNA methylation, atypical histone modifications and dysregulated expression of distinct microRNAs, resulting in altered gene-expression patterns favoring cell survival. In this article, we summarize the most recent hypotheses regarding the role of epigenetics in ovarian and endometrial cancers, including a possible role in tumor 'stemness' and also evaluate the possible therapeutic benefits of reversal of these oncogenic chromatin aberrations.

  5. Regulation of progesterone signaling during pregnancy: implications for the use of progestins for the prevention of preterm birth.

    PubMed

    Byrns, Michael C

    2014-01-01

    Preterm birth is a major cause of neonatal morbidity and mortality. Progesterone plays a critical role in suppressing the inflammatory signals that would induce parturition prior to term. Progesterone signaling is regulated in a variety of ways during pregnancy. Endocrine production of high levels of progesterone by the placenta ensures the availability of high levels of progesterone throughout pregnancy. Paracrine regulation of progesterone metabolism in target tissues, particularly the myometrium and cervix, also determines the amount of progesterone ligand available. Progesterone metabolism can also lead to the formation of metabolites that contribute to its effects. In particular, 5β-dihydroprogesterone formation by aldo-keto reductase 1D1 appears to play an important role in maintaining uterine quiescence. Progesterone signaling can also be regulated at the receptor level through changes in the relative expression of the nuclear progesterone receptor isoforms, reduced expression of membrane receptors, and changes in the expression levels of coactivators and/or corepressors, including nuclear factor κB. Progesterone and 17α-hydroxyprogesterone caproate (17OH-PC) have recently been shown to reduce preterm births in women with previous preterm birth or shortened cervix. It is important to realize that these two progestins are likely to act in significantly different ways, which will likely influence their efficacy. The structural differences and resistance to metabolism exhibited by 17OH-PC means that it will be unable to activate some of the pathways that progesterone activates, but that it also will not be subject to paracrine inactivation. The fact that progesterone therapy works for maintaining pregnancy in some women, indicates that for those women insufficient levels of progesterone ligand in target tissues is a determining factor in early parturition, despite high levels of circulating progesterone. This article is part of a Special Issue entitled

  6. Relationship between the size of the dominant follicle, vaginal electrical resistance, serum concentrations of oestradiol and progesterone and sexual receptivity during the follicular phase of the dromedary camel (Camelus dromedarius).

    PubMed

    Ghoneim, I M; Waheed, M M; Adam, Mohammed I; Al-Eknah, M M

    2015-03-01

    Thirteen dromedaries were used to study the relationship between the size of the dominant follicle, vaginal electrical resistance (VER), sexual receptivity, and serum concentrations of oestradiol-17β (E2) and progesterone (P4) throughout the follicular phase. On a daily basis, the animals experienced teasing with a vasectomised camel, trans-rectal ultrasound examination of the ovaries, and measurement of VER and blood collection for serum E2 and P4. Results revealed no significant differences between the mean VER in the animals that had a follicle of 5-10mm (group I, n=11), 11-15mm (group II, n=12) and 16-20mm (group III, n=13). The VER did not correlate with the follicular size. The E2 concentrations in the animals in groups II (60.14pg/ml) and III (66.52pg/ml) were significantly (P<0.05) higher than those of animals in group I (48.31pg/ml). E2 was positively correlated (r=0.50; P<0.05) with the overall size of the follicles. The P4 concentration was significantly (P<0.05) lower in the animals of group II than in those in groups I and III. Serum P4 concentrations were inversely correlated (r=-0.40; P<0.05) with the overall size of the follicles. Complete sexual receptivity was reported in 63.64%, 16.67% and 76.92% of the animals in groups I, II and III, respectively. In group III, significant (P<0.05) complete sexual receptivity was confirmed. However, 23.08% of the animals were incompletely receptive. In conclusion, impedometric characteristics of the vaginal mucosa were not a reliable method for predicting the dominant follicular size during the follicular phase in dromedary camels.

  7. Effects of oral and vaginal administration of levonorgestrel emergency contraception on markers of endometrial receptivity.

    PubMed

    Meng, C-X; Marions, L; Byström, B; Gemzell-Danielsson, K

    2010-04-01

    The standard regimen of the levonorgestrel-only pill (1.5 mg either in a single dose or in a dose of 0.75 mg twice, 12 h apart) administered orally for emergency contraception (EC) has been shown to have no effect on endometrial development and markers of endometrial receptivity. We aimed to explore whether repeated oral and single vaginal administration of levonorgestrel affect the endometrium and thus potentially increase the EC efficacy, compared with the standard regimen. Endometrial biopsies were taken from non-smoking, healthy women with proven fertility on cycle days LH + 6 to LH + 8 in control and levonorgestrel treatment cycles (each woman serving as her own control). Levonorgestrel was administered either orally (0.75 mg x 4, at 24 h intervals on LH + 1 to LH + 4; n = 8) or vaginally (a single dose of 1.5 mg on LH + 2; n = 7). Immunohistochemistry and real-time RT-PCR was performed to compare the levels of protein and mRNA for sex steroid receptors, interleukin-1beta, leukaemia inhibitory factor (LIF), vascular endothelial growth factor, cyclooxygenase-2, tumour necrosis factor-alpha, integrin alpha(v)beta(3) and mucin 1 in endometrial cells. Following the repeated oral treatment, the immunoreactivity of both progesterone receptor (PR)-A and PR-B declined in glandular epithelium (P = 0.03 and P = 0.02, respectively), whereas stromal immunoreactivity and mRNA expression of LIF increased compared with control (P < 0.001 and P = 0.03, respectively). However, vaginal levonorgestrel did not cause any significant endometrial changes. The two regimens of levonorgestrel caused either only minor or no alterations in markers of endometrial receptivity. New agents targeting the endometrial development should be explored in order to increase EC efficacy.

  8. Fertility-preservation in endometrial cancer: is it safe? Review of the literature

    PubMed Central

    Carneiro, Márcia Mendonça; Lamaita, Rívia Mara; Ferreira, Márcia Cristina França; Silva-Filho, Agnaldo Lopes

    2016-01-01

    Almost 5% of women with endometrial cancer are under age 40, and they often have well-differentiated endometrioid estrogen-dependent tumors. Cancer survival rates have improved over the last decades so strategies to avoid or reduce the reproductive damage caused by oncologic treatment are needed. We reviewed the published literature to find evidence to answer the following questions: How should we manage women in reproductive age with endometrial cancer? How safe is fertility preservation in endometrial cancer? Can pregnancy influence endometrial cancer recurrence? What are the fertility sparing options available? Progestins may be prescribed after careful evaluation and counseling. Suitable patients should be selected using imaging methods and endometrial sampling since surgical staging will not be performed. Conservative treatment should only be offered to patients with grade 1 well-differentiated tumors, absence of lymph vascular space invasion, no evidence of myometrial invasion, metastatic disease or suspicious adnexal masses, and expression of progesterone receptors in the endometrium. The presence of co-existing ovarian metastatic of synchronous cancer should be investigated and ruled out before the decision to preserve the ovaries. The availability of Assisted Reproductive Technology (ART) has made it possible for women with endometrial cancer to give birth to a child without compromising their prognoses. Gamete, embryo or ovarian tissue cryopreservation techniques can be employed, although the latter remains experimental. Unfortunately, fertility preservation is rarely considered. Current recommendations for conservative management are based on the overall favorable prognosis of grade 1 minimally invasive tumors. Selected patients with endometrial cancer may be candidates to a safe fertility-preserving management. PMID:28050959

  9. Progesterone Inhibits Uterine Gland Development in the Neonatal Mouse Uterus1

    PubMed Central

    Filant, Justyna; Zhou, Huaijun; Spencer, Thomas E.

    2012-01-01

    ABSTRACT Uterine glands and their secretions are required for conceptus (embryo/fetus and associated placenta) survival and development. In most mammals, uterine gland morphogenesis or adenogenesis is a uniquely postnatal event; however, little is known about the mechanisms governing the developmental event. In sheep, progestin treatment of neonatal ewes permanently ablated differentiation of the endometrial glands. Similarly, progesterone (P4) inhibits adenogenesis in neonatal mouse uterus. Thus, P4 can be used as a tool to discover mechanisms regulating endometrial adenogenesis. Female pups were treated with sesame vehicle alone as a control or P4 from Postnatal Day 2 (PD 2) to PD 10, and reproductive tracts were examined on PD 5, 10, or 20. Endometrial glands were fully developed in control mice by PD 20 but not in P4-treated mice. All other uterine cell types appeared normal. Treatment with P4 stimulated proliferation of the stroma but suppressed proliferation of the luminal epithelium. Microarray analysis revealed that expression of genes were reduced (Car2, Fgf7, Fgfr2, Foxa2, Fzd10, Met, Mmp7, Msx1, Msx2, Wnt4, Wnt7a, Wnt16) and increased (Hgf, Ihh, Wnt11) by P4 in the neonatal uterus. These results support the idea that P4 inhibits endometrial adenogenesis in the developing neonatal uterus by altering expression of morphoregulatory genes and consequently disrupting normal patterns of cell proliferation and development. PMID:22238285

  10. c-Kit proto-oncogene expression in endometrial hyperplasia and endometrial cancer.

    PubMed

    Yilmaz, Ercan; Celik, Onder; Simsek, Yavuz; Turkcuoglu, Ilgin; Celik, Ebru; Gül, Mehmet; Hascalik, Seyma; Aydin, Nasuhi Engin; Aydin, Engin

    2012-07-01

    To evaluate the expression of c-kit (CD117) in endometrial hyperplasia and endometrial cancer. Expression of c-kit in 10 normal endometrium, 18 simple endometrial hyperplasia, 16 complex endometrial hyperplasia (10 cases with atypia and 6 cases without atypia), and 6 endometrial cancer were investigated by immunohistochemistry. c-Kit expression decreased as the lesion progressed to endometrial cancer. Immunostaining was mostly focal and weak in the normal endometrium and was mostly diffuse and strong in the simple and complex endometrial hyperplasia. Simple and complex hyperplastic endometrial tissues express diffuse cytoplasmic staining for c-kit and the expression decreases with the progression of the lesion.

  11. Endometrial IL-1beta, IL-6 and TNF-alpha, mRNA expression in mares resistant or susceptible to post-breeding endometritis. Effects of estrous cycle, artificial insemination and immunomodulation.

    PubMed

    Fumuso, Elida; Giguère, Steeve; Wade, José; Rogan, Dragan; Videla-Dorna, Ignacio; Bowden, Raúl A

    2003-11-15

    Endometrial mRNA expression of the pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) was assessed in mares resistant (RM) or susceptible (SM) to persistent post-breeding endometritis (PPBE). Eight RM and eight SM, were selected based on reproductive records and functional tests out of a herd of 2,000 light cross-type mares. Three experiments were done to study transcription patterns in (i) basal conditions; (ii) after artificial insemination (AI); and (iii) after administration of an immunomodulator at time of artificial insemination. Endometrial biopsies were taken during consecutive cycles: (i) at estrus, when follicles reached 35 mm and at diestrus (7 +/- 1 days after ovulation); (ii) at 24 h post-AI, with dead semen (estrus) and in diestrus; (iii) at 24 h after treatment with a Mycobacterium phlei cell-wall extract (MCWE) preparation and AI (with dead semen), and at diestrus. mRNA expression was quantitated by real time PCR. Under basal conditions, SM had significantly higher mRNA expression of all cytokines in estrus and of IL-1beta and TNF-alpha in diestrus, compared to RM. After AI, there were no differences between RM and SM in estrus; however, mRNA expression for all three pro-inflammatory cytokines was higher than under basal conditions. In diestrus, RM showed significantly lower IL-1beta and TNF-alpha mRNA expression than SM. When MCWE was administered at time of AI, no differences between cytokine induction from RM and SM were found. Globally, mRNA expression for all three cytokines correlated well among themselves when expression was high. The present study showed that (i) in basal conditions RM had lower mRNA expression of pro-inflammatory cytokines than SM with no effect of estrous cycle; (ii) AI upregulated mRNA expression for all three cytokines in both RM and SM, with persistance in diestrus in the latter; (iii) treatment with MCWE at time of AI down-regulated mRNA expression

  12. USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment

    PubMed Central

    Mooneyham, Ashley; Mullany, Sally; Zhao, Xianda; Shahi, Maryam; Richter, James; Klein, Molly; Chen, Liqiang; Ding, Rui; Konecny, Gottfried; Kommoss, Stefan; Winterhoff, Boris; Ghebre, Rahel; Bazzaro, Martina

    2016-01-01

    Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States. Most endometrial cancer cases are diagnosed at an early stage and have good prognosis. Unfortunately a subset of patients with early stage and low grade disease experience recurrence for reasons that remain unclear. Recurrence is often accompanied by chemoresistance and high mortality. Deubiquitinating enzymes (DUBs) are key components of the ubiquitin-dependent protein degradation pathway and act as master regulators in a number of metabolic processes including cell growth, differentiation, and apoptosis. DUBs have been shown to be upregulated in a number of human cancers and their aberrant activity has been linked to cancer progression, initiation and onset of chemoresistance. Thus, selective inhibition of DUBs has been proposed as a targeted therapy for cancer treatment. This study suggests the DUB USP14 as a promising biomarker for stratifying endometrial cancer patients at diagnosis based on their risk of recurrence. Further USP14 is expressed along with the marker of proliferation Ki67 in endometrial cancer cells in situ. Lastly, pharmacological targeting of USP14 with the FDA approved small-molecule inhibitor VLX1570, decreases cell viability in chemotherapy resistant endometrial cancer cells with a mechanism consistent with cell cycle arrest and caspase-3 mediated apoptosis. PMID:27121063

  13. USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment.

    PubMed

    Vogel, Rachel Isaksson; Pulver, Tanya; Heilmann, Wiebke; Mooneyham, Ashley; Mullany, Sally; Zhao, Xianda; Shahi, Maryam; Richter, James; Klein, Molly; Chen, Liqiang; Ding, Rui; Konecny, Gottfried; Kommoss, Stefan; Winterhoff, Boris; Ghebre, Rahel; Bazzaro, Martina

    2016-05-24

    Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States. Most endometrial cancer cases are diagnosed at an early stage and have good prognosis. Unfortunately a subset of patients with early stage and low grade disease experience recurrence for reasons that remain unclear. Recurrence is often accompanied by chemoresistance and high mortality.Deubiquitinating enzymes (DUBs) are key components of the ubiquitin-dependent protein degradation pathway and act as master regulators in a number of metabolic processes including cell growth, differentiation, and apoptosis. DUBs have been shown to be upregulated in a number of human cancers and their aberrant activity has been linked to cancer progression, initiation and onset of chemoresistance. Thus, selective inhibition of DUBs has been proposed as a targeted therapy for cancer treatment.This study suggests the DUB USP14 as a promising biomarker for stratifying endometrial cancer patients at diagnosis based on their risk of recurrence. Further USP14 is expressed along with the marker of proliferation Ki67 in endometrial cancer cells in situ. Lastly, pharmacological targeting of USP14 with the FDA approved small-molecule inhibitor VLX1570, decreases cell viability in chemotherapy resistant endometrial cancer cells with a mechanism consistent with cell cycle arrest and caspase-3 mediated apoptosis.

  14. Human endometrial DNA methylome is cycle-dependent and is associated with gene expression regulation.

    PubMed

    Houshdaran, Sahar; Zelenko, Zara; Irwin, Juan C; Giudice, Linda C

    2014-07-01

    Human endometrium undergoes major gene expression changes, resulting in altered cellular functions in response to cyclic variations in circulating estradiol and progesterone, largely mediated by transcription factors and nuclear receptors. In addition to classic modulators, epigenetic mechanisms regulate gene expression during development in response to environmental factors and in some diseases and have roles in steroid hormone action. Herein, we tested the hypothesis that DNA methylation plays a role in gene expression regulation in human endometrium in different hormonal milieux. High throughput, genome-wide DNA methylation profiling of endometrial samples in proliferative, early secretory, and midsecretory phases revealed dynamic DNA methylation patterns with segregation of proliferative from secretory phase samples by unsupervised cluster analysis of differentially methylated genes. Changes involved different frequencies of gain and loss of methylation within or outside CpG islands. Comparison of changes in transcriptomes and corresponding DNA methylomes from the same samples revealed association of DNA methylation and gene expression in a number of loci, some important in endometrial biology. Human endometrial stromal fibroblasts treated in vitro with estradiol and progesterone exhibited DNA methylation changes in several genes observed in proliferative and secretory phase tissues, respectively. Taken together, the data support the observation that epigenetic mechanisms are involved in gene expression regulation in human endometrium in different hormonal milieux, adding endometrium to a small number of normal adult tissues exhibiting dynamic DNA methylation. The data also raise the possibility that the interplay between steroid hormone and methylome dynamics regulates normal endometrial functions and, if abnormal, may result in endometrial dysfunction and associated disorders.

  15. Human Endometrial DNA Methylome Is Cycle-Dependent and Is Associated With Gene Expression Regulation

    PubMed Central

    Houshdaran, Sahar; Zelenko, Zara; Irwin, Juan C.

    2014-01-01

    Human endometrium undergoes major gene expression changes, resulting in altered cellular functions in response to cyclic variations in circulating estradiol and progesterone, largely mediated by transcription factors and nuclear receptors. In addition to classic modulators, epigenetic mechanisms regulate gene expression during development in response to environmental factors and in some diseases and have roles in steroid hormone action. Herein, we tested the hypothesis that DNA methylation plays a role in gene expression regulation in human endometrium in different hormonal milieux. High throughput, genome-wide DNA methylation profiling of endometrial samples in proliferative, early secretory, and midsecretory phases revealed dynamic DNA methylation patterns with segregation of proliferative from secretory phase samples by unsupervised cluster analysis of differentially methylated genes. Changes involved different frequencies of gain and loss of methylation within or outside CpG islands. Comparison of changes in transcriptomes and corresponding DNA methylomes from the same samples revealed association of DNA methylation and gene expression in a number of loci, some important in endometrial biology. Human endometrial stromal fibroblasts treated in vitro with estradiol and progesterone exhibited DNA methylation changes in several genes observed in proliferative and secretory phase tissues, respectively. Taken together, the data support the observation that epigenetic mechanisms are involved in gene expression regulation in human endometrium in different hormonal milieux, adding endometrium to a small number of normal adult tissues exhibiting dynamic DNA methylation. The data also raise the possibility that the interplay between steroid hormone and methylome dynamics regulates normal endometrial functions and, if abnormal, may result in endometrial dysfunction and associated disorders. PMID:24877562

  16. Endometrial Intraepithelial Neoplasia (EIN) in endometrial biopsy specimens categorized by the 1994 World Health Organization classification for endometrial hyperplasia.

    PubMed

    Li, Xiao-Chao; Song, Wen-Jing

    2013-01-01

    Our study is to determine the presence of endometrial intraepithelial neoplasia (EIN) in endometrial biopsy specimens classified by the 1994 World Health Organization (WHO) criteria for endometrial hyperplasia. Endometrial biopsy specimens that were stained with hematoxylin and eosin (HE) were examined and categorized by the WHO 1994 criteria and for the presence of EIN as defined by the International Endometrial Collaborative Group. β-catenin expression was examined by immunohistochemistry. A total of 474 cases of HE stained endometrial biopsy tissues were reviewed. There were 379 cases of simple endometrial hyperplasia, 16 with simple atypical endometrial hyperplasia, 48 with complex endometrial hyperplasia, and 31 with complex atypical endometrial hyperplasia. Among the 474 endometrial hyperplasia cases, there were 46 (9.7%) that were classified as EIN. Of these 46 cases, 11(2.9%) were classified as simple endometrial hyperplasia, 1 (6.3%) as simple atypical endometrial hyperplasia, 6 (12.5%) as complex endometrial hyperplasia, and 28 (90.3%) as complex atypical endometrial hyperplasia. EIN was associated with a higher rate of β-catenin positivity than endometrium classified as benign hyperplasia (72% vs. 22.5%, respectively, P < 0.001), but a lower rate than endometrial adenocarcinoma (72% vs. 96.2%, respectively, P < 0.001). In benign endometrial hyperplasia, high β-catenin expression was noted in the cell membranes, whereas in EIN and endometrial adenocarcinoma high expression was noted in the cytoplasm. In conclusion, EIN is more accurate than the WHO classification for the diagnosis of precancerous lesions of the endometrium.

  17. Effects of Quercetin on CYP450 and Cytokines in Aroclor 1254 Injured Endometrial Cells of the Pregnant Rats

    PubMed Central

    Xu, Lina; Sun, Liyun; Lu, Liqin; Qin, Jianhua

    2014-01-01

    Polychlorinated biphenyls (PCBs) are widespread persistent residual environmental pollutants, which affect seriously the growth and reproductive alterations in humans and animals. Aroclor 1254 is a commercial mixture of PCBs. Quercetin is a flavonoid, which acts on estrogen receptors and causes the development of estrogen-related diseases. In this paper, the primary cultured endometrial cells in the pregnant rats were isolated and Aroclor 1254 was used to induce the injured endometrial cells model. The cells were treated with gradient quercetin, the viability of the endometrial cells, the expressions of CYP450, the contents of TNF-α, IL-6, estradiol (E2), and progesterone (P4) were measured. It showed that the viability of the cultured endometrial cells, the expression of CYP1A1 and CYP2B1, and the contents of TNF-α, E2, and IL-6 in the injured endometrial cells increased with the treatment of quercetin. It shows that quercetin has protective effect on the injured endometrial cells in the pregnant rats, this provide a basis on herbal medicine protection for animal reproductive diseases caused by environmental endocrine disruptors. PMID:24711995

  18. [Metabolism of retro-progesterone and 17-hydroxy-retro-progesterone].

    PubMed

    Knuppen, R; Haupt, O; Breuer, H

    1975-01-01

    In comparative studes, the metabolism of retro-progesterone (9 beta,10alpha-pregn-4-ene-3, 20-dinoe) and 17-hydrozy-retro-progesterone (17-hydroxy-9 beta, 10 alpha-prgn-4-ene-3, 20-dione) as well as of progesterone and 17-hydroxy progesterone was investigated. The microsomal fraction from rat tests served as enzmye preparation. Whereas progesterone was metablised to 17-hydroxy-progesterone, testosterone and androstendion, retno-progesterone did not yield the corresponding reaction products. 16 alpha-Hydroxy-retro progresterone was found to be the main metabolite of retro-progesterone and identified by gas-liquid chromatopgray/mass spectrometry. In contrast to 17-hydroxy-progesterone, no transformation of 17-hudroxy-retro-progesterone to C19-steriods was observed. From these experiments, it can beconcluded that C21 -retro-steriods are not attacked by the 17alpha-hydrozylase and the C17-C20-desmolase of mammalian origin.

  19. Comparison of Two Combination Chemotherapy Regimens Plus Radiation Therapy in Treating Patients With Stage III or Stage IV Endometrial Cancer

    ClinicalTrials.gov

    2015-04-30

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma, Variant With Squamous Differentiation; Endometrial Serous Adenocarcinoma; Stage III Uterine Corpus Cancer

  20. Increasing the dosage of progesterone (P) supplemention from the mid-luteal phase in women not attaining a mid-luteal homogeneous hyperechogenic (HH) pattern with sonography improves pregnancy rates (PRS) following frozen embryo transfer (ET).

    PubMed

    Check, J H; Dietterich, C; Cohen, R; Choe, J K; Amui, J; Brasile, D

    2010-01-01

    To determine if a mid-luteal phase non-homogeneous hyperechogenic (HH) endometrial echo pattern may lower pregnancy rates following frozen embryo transfer and to determine if raising the dosage of progesterone improves pregnancy outcome. Women not attaining an HH pattern at the mid-luteal phase following estrogen-progesterone replacement were randomly given (or not) an increase in progesterone dosage. Increasing the progesterone dosage in those not attaining an HH pattern significantly improved the pregnancy rate relative to controls not attaining an HH pattern and showed a trend for higher pregnancy rates than those with an HH pattern. The mid-luteal phase echo pattern should be evaluated for a non-HH pattern so that an increase in progesterone dosage could be provided possibly resulting in higher pregnancy rates.

  1. Risks of Endometrial Cancer Screening

    MedlinePlus

    ... Transvaginal ultrasound Endometrial sampling Tests are used to screen for different types of cancer. Some screening tests ... endometrium by inserting a brush, curette , or thin, flexible tube through the cervix and into the uterus. ...

  2. Drugs Approved for Endometrial Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for endometrial cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  3. Triclosan and bisphenol a affect decidualization of human endometrial stromal cells.

    PubMed

    Forte, Maurizio; Mita, Luigi; Cobellis, Luigi; Merafina, Verdiana; Specchio, Raffaella; Rossi, Sergio; Mita, Damiano Gustavo; Mosca, Lavinia; Castaldi, Maria Antonietta; De Falco, Maria; Laforgia, Vincenza; Crispi, Stefania

    2016-02-15

    In recent years, impaired fertility and endometrium related diseases are increased. Many evidences suggest that environmental pollution might be considered a risk factor for endometrial physiopathology. Among environmental pollutants, endocrine disrupting chemicals (EDCs) act on endocrine system, causing hormonal imbalance which, in turn, leads to female and male reproductive dysfunctions. In this work, we studied the effects of triclosan (TCL) and bisphenol A (BPA), two widespread EDCs, on human endometrial stromal cells (ESCs), derived from endometrial biopsies from woman not affected by endometriosis. Cell proliferation, cell cycle, migration and decidualization mechanisms were investigated. Treatments have been performed with both the EDCs separately or in presence and in absence of progesterone used as decidualization stimulus. Both TCL and BPA did not affect cell proliferation, but they arrested ESCs at G2/M phase of cell cycle enhancing cell migration. TCL and BPA also increased gene expression and protein levels of some decidualization markers, such as insulin growth factor binding protein 1 (IGFBP1) and prolactin (PRL), amplifying the effect of progesterone alone. All together, our data strongly suggest that TCL and BPA might alter human endometrium physiology so affecting fertility and pregnancy outcome.

  4. Progesterone Receptors and Proliferation of the Endometrium in Obese Women With Polycystic Ovary Syndrome-A Lifestyle Intervention Study.

    PubMed

    Paulson, Mariana; Sahlin, Lena; Hirschberg, Angelica Lindén

    2017-04-01

    Polycystic ovary syndrome (PCOS) is associated with increased risk of endometrial cancer. This is usually explained by chronic anovulation and deficient progesterone activity. However, the role of progesterone receptors (PRs) in endometrial proliferation is unclear. To evaluate PRs in relation to endometrial proliferation in women with PCOS. Cross-sectional study and lifestyle intervention. Clinical and laboratory research unit at a university hospital. Twenty obese women with PCOS and 10 age- and body mass index-matched regularly menstruating controls. Dietary management and physical exercise. Endometrial messenger RNA (mRNA) levels and immunostaining of the nuclear PRs A (PRA) and B (PRB), nongenomic progesterone receptor membrane component 1 (PGRMC1) and 2 (PGRMC2), and proliferation marker Ki67. Before lifestyle intervention, mRNA expression of PRAB was lower while PRB was higher in proliferative endometrium of obese women with PCOS compared with controls (P < 0.05). After lifestyle intervention and weight loss, mRNA expression of PRAB was still low but PRB mRNA decreased and was not different to controls in proliferative endometrium (P < 0.01). The subgroup of PCOS women who remained anovulatory displayed higher protein levels of PRB, PGRMC1, PGRMC2 and of the proliferative marker Ki67 on cycle days 21 to 23 than controls (P < 0.05). In contrast, the subgroup of PCOS women with confirmed ovulation showed immunostaining, including Ki67, in secretory endometrium that was not different to controls, except for higher PRA (P < 0.05). Lifestyle intervention improves, but not fully restores PR expression and decreases proliferation in secretory endometrium of obese PCOS women.

  5. Progesterone attenuates cocaine-induced responses.

    PubMed

    Quinones-Jenab, Vanya; Jenab, Shirzad

    2010-06-01

    In this review, we summarize literature focused on how progesterone alters cocaine-induced psychomotor, reinforcement, and physiological responses. Clinical studies suggest that progesterone attenuates the subjective effects of cocaine. Similarly, preclinical studies have demonstrated that cocaine-induced reward and psychomotor responses are attenuated after progesterone administration. In rats progesterone also reduces the reinforcement effects of cocaine attenuates acquisition, escalation, reinstatement of cocaine self-administration, and cocaine-seeking behaviors. Progesterone also counteracts the facilitatory effects of estrogen on cocaine self-administration and psychomotor activation. These findings suggest that progesterone has a potential in clinical applications as a treatment for cocaine addiction. Constantly changing progesterone serum levels in female humans and rats affect the female's reinforcement responses to cocaine and may in part contribute to the known sex differences in cocaine responses.

  6. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in adenomyosis and its rectification by a histone deacetylase inhibitor and a demethylation agent.

    PubMed

    Jichan Nie; Xishi Liu; Guo, Sun-Wei

    2010-11-01

    Adenomyosis is a fairly common gynecologic disease with unknown pathogenesis. We sought to investigate as to whether the promoter of progesterone receptor isoform B (PR-B) is hypermethylated in adenomyosis and to investigate the treatment of ectopic endometrial stromal cells with trichostatin A (TSA), a histone deacetylase inhibitor (HDI), and 5-aza-2-deoxycytidine (ADC), a demethylation agent, on PR-B gene and protein expression, and on cell viability. Ectopic endometrial tissue specimens were obtained from 9 women with adenomyosis whereas control endometrial tissue samples were obtained from 8 women with surgically diagnosed benign ovarian cysts but without any clinical history of endometriosis/adenomyosis/ myoma. Endometrial stromal cells were isolated, purified, cultured, and analyzed by methylation-specific polymerase chain reaction (PCR), real-time reverse transcriptase PCR (RT-PCR), and Western blot analysis, cell viability assays, and fluorescence-activated cell sorting. We found that none of the normal endometrial stromal cells had PR-B promoter methylation. In contrast, 2 out of 3 ectopic endometrial stromall cells had PR-B hypermethylation (P < .05). The treatment with both TSA and ADC elevated PR-B gene and protein expression in ectopic, but not in normal, endometrial stromal cells. Both TSA and ADC treatment dose-dependently reduced cell viability of ectopic endometrial stromal cells. Trichostatin A and ADC treatment also suppressed the cell cycle progression in ectopic endometrial stromal cells. Thus, this study provides the first piece of evidence that adenomyosis has epigenetic aberration and may also be an epigenetic disease amenable to rectification by pharmacological means. This perspective may shed new light onto the pathogenesis of adenomyosis and lead to novel ways to treat the disease.

  7. Disturbances in production of progesterone and their implications in plant studies.

    PubMed

    Janeczko, Anna; Oklestkova, Jana; Novak, Ondrej; Śniegowska-Świerk, Katarzyna; Snaczke, Zuzanna; Pociecha, Ewa

    2015-04-01

    Progesterone is a mammalian hormone that has also been discovered in plants but its physiological function in plants is not explained. Experiments using inhibitors of progesterone synthesis and binding would be useful in studies on the significance of this compound in plants. Until now, trilostane and mifepristone have been used in medical sciences as progesterone biosynthesis and binding inhibitors, respectively. We tested these synthetic steroids for the first time in plants and found that they reduced the content of progesterone in wheat. The aim of further experiments was to answer whether the potential disturbances in the production/binding of progesterone, influence resistance to environmental stress (drought) and the development of wheat. Inhibitors and progesterone were applied to plants via roots in a concentration of 0.25-0.5mg/l water. Both inhibitors lowered the activity of CO2 binding enzyme (Rubisco) in wheat exposed to drought stress and trilostane additionally lowered the chlorophyll content. However, trilostane-treated plants were rescued by treatment with exogenous progesterone. The inhibitors also modulated the development of winter wheat, which indicated the significance of steroid regulators and their receptors in this process. In this study, in addition to progesterone and its inhibitors, brassinosteroid (24-epibrassinolide) and an inhibitor of biosynthesis of brassinosteroids were also applied. Mifepristone inhibited the generative development of wheat (like 24-epibrassinolide), while trilostane (like progesterone and an inhibitor of biosynthesis of brassinosteroids) stimulated the development. We propose a model of steroid-induced regulation of the development of winter wheat, where brassinosteroids act as inhibitors of generative development, while progesterone or other pregnane derivatives act as stimulators.

  8. Endogenous progesterone and its cellular binding sites in wheat exposed to drought stress.

    PubMed

    Janeczko, Anna; Oklešťková, Jana; Siwek, Agata; Dziurka, Michał; Pociecha, Ewa; Kocurek, Maciej; Novák, Ondřej

    2013-11-01

    Progesterone is a basic hormone that regulates the metabolism in mammals. The presence of this compound has also been found in certain plants. It is believed that progesterone can regulate growth processes and resistance to stress, however, its precise role in plants remains unknown. The research conducted in this study was aimed at analyzing the content of endogenous progesterone and its cellular binding sites in the leaves of spring wheat exposed to drought. Changes were studied in two cultivars of wheat - a cultivar sensitive to drought (Katoda) and tolerant cultivar (Monsun). Plants had undergone periodic droughts during the seedling stage or in the phase of heading. The occurrence of free progesterone as well as its conjugated forms was observed in wheat studied. The amount of progesterone ranged from 0.2 to 5.8pmolgFW(-1) and was dependent on the cultivar, age of the plants, stage of development and fluctuated as a result of the exposure to drought. Cv. Katoda responded to a water deficit by lowering the amount of progesterone and cv. Monsun by increasing its level. Progesterone in plants grown in limited water conditions occurred primarily in a free form. While in the optimal watering conditions, some of its pool was found in the form of conjugates. In the spring wheat the occurrence of binding sites for progesterone was detected in cell membranes, cytoplasm and nuclei in the range of 10-36fmol/mg of protein. The wheat cultivars tested, Monsun and Katoda, differ in their concentration of cellular binding sites for progesterone. This number varied in the individual fractions during different stages of plant development and due to the effect of drought stress. The number of binding sites for progesterone located in the membrane fraction of seedlings and flag leaves increased significantly under drought in the cv. Katoda (35-46%), but did not change in the cv. Monsun. Whereas the number of cytoplasmic progesterone binding sites increased during the drought in

  9. Photodynamic therapy toward selective endometrial ablation

    NASA Astrophysics Data System (ADS)

    Tadir, Yona; Tromberg, Bruce J.; Krasieva, Tatiana B.; Berns, Michael W.

    1993-05-01

    Potential applications of photodynamic therapy for endometrial disease are discussed. Experimental models that may lead to diagnosis and treatment of endometriosis as well as selective endometrial ablation are summarized.

  10. Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8).

    PubMed

    Emons, Günter; Kurzeder, Christian; Schmalfeldt, Barbara; Neuser, Petra; de Gregorio, Nikolaus; Pfisterer, Jacobus; Park-Simon, Tjoung-Won; Mahner, Sven; Schröder, Willibald; Lück, Hans-Joachim; Heubner, Martin Leonhard; Hanker, Lars; Thiel, Falk; Hilpert, Felix

    2016-03-01

    To evaluate activity and toxicity of mTOR inhibitor temsirolimus in patients with platinum-refractory/resistant ovarian cancer (OC) or advanced/recurrent endometrial carcinoma (EC). Women with epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. Women with advanced/recurrent EC, no longer amenable to curative surgery and/or radiotherapy were eligible when they had no previous or only adjuvant chemotherapy. Preceding endocrine therapy for metastatic/recurrent disease was allowed. Patients received weekly IV infusions of 25mg temsirolimus. Primary endpoint was progression free survival rate after 4 months (OC) or 6 months (EC). A two stage design was applied. Forty-four patients (OC: n=22; EC: n=22) were enrolled and received temsirolimus treatment. Median age was 56 years (OC) or 63 years (EC). After eight weeks of treatment, 10 of 21 evaluable patients in the OC cohort and 8 of 20 evaluable patients in the EC cohort had progressive disease. Thus efficacy did not meet the predefined levels during the first stage of recruitment and the trial was stopped. Some patients in both cohorts had long lasting PFS (>7 months). Toxicity of temsirolimus was mild. Temsirolimus treatment was well tolerated in our patients, but did not meet the predefined efficacy criteria. In our study as in other trials on rapalogs in OC or EC, a few patients had long lasting disease stabilisations. Copyright © 2015. Published by Elsevier Inc.

  11. Intensity-Modulated Radiation Therapy, Cisplatin, and Bevacizumab Followed by Carboplatin and Paclitaxel in Treating Patients Who Have Undergone Surgery for Endometrial Cancer

    ClinicalTrials.gov

    2014-10-09

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Stage I Endometrial Carcinoma; Stage II Endometrial Carcinoma; Stage III Endometrial Carcinoma; Stage IV Endometrial Carcinoma

  12. The synergistic effect of Mig-6 and Pten ablation on endometrial cancer development and progression.

    PubMed

    Kim, T H; Franco, H L; Jung, S Y; Qin, J; Broaddus, R R; Lydon, J P; Jeong, J-W

    2010-07-01

    Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. An additional endometrial cancer mouse model is generated by the ablation of phosphatase and tensin homolog deleted from chromosome 10 (Pten) (either as heterozygotes or by conditional uterine ablation). To determine the interplay between Mig-6 and the PTEN/phosphoinositide 3-kinase signaling pathway during endometrial tumorigenesis, we generated mice with Mig-6 and Pten conditionally ablated in progesterone receptor-positive cells (PR(cre/+)Mig-6(f/f)Pten(f/f); Mig-6(d/d)Pten(d/d)). The ablation of both Mig-6 and Pten dramatically accelerated the development of endometrial cancer compared with the single ablation of either gene. The epithelium of Mig-6(d/d)Pten(d/d) mice showed a significant decrease in the number of apoptotic cells compared with Pten(d/d) mice. The expression of the estrogen-induced apoptotic inhibitors Birc1 was significantly increased in Mig-6(d/d)Pten(d/d) mice. We identified extracellular signal-regulated kinase 2 (ERK2) as an MIG-6 interacting protein by coimmunoprecipitation and demonstrated that the level of ERK2 phosphorylation was increased upon Mig-6 ablation either singly or in combination with Pten ablation. These results suggest that Mig-6 exerts a tumor-suppressor function in endometrial cancer by promoting epithelial cell apoptosis through the downregulation of the estrogen-induced apoptosis inhibitors Birc1 and the inhibition of ERK2 phosphorylation.

  13. Selected Polymorphisms in Sex Hormone-Related Genes, Circulating Sex Hormones and Risk of Endometrial Cancer

    PubMed Central

    Lundin, Eva; Wirgin, Isaac; Lukanova, Annekatrin; Afanasyeva, Yelena; Krogh, Vittorio; Axelsson, Tomas; Hemminki, Kari; Clendenen, Tess V.; Arslan, Alan A.; Ohlson, Nina; Sieri, Sabina; Roy, Nirmal; Koenig, Karen L.; Idahl, Annika; Berrino, Franco; Toniolo, Paolo; Hallmans, Göran; Försti, Asta; Muti, Paola; Lenner, Per; Shore, Roy E.; Zeleniuch-Jacquotte, Anne

    2013-01-01

    Background The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. Methods We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). Results Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (ORper allele = 1.22, 95% CI = 1.01–1.47, ptrend = 0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (ORper allele = 1.20, 95% CI = 0.99 – 1.45, ptrend = 0.06). PGR rs1042838 was also marginally associated with risk (ORper allele = 1.25, 95% CI = 0.96–1.61, ptrend = 0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. Conclusion Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer. PMID:22633539

  14. Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers.

    PubMed

    Krzeslak, Anna; Wojcik-Krowiranda, Katarzyna; Forma, Ewa; Jozwiak, Paweł; Romanowicz, Hanna; Bienkiewicz, Andrzej; Brys, Magdalena

    2012-07-01

    Cancer cells have accelerated metabolism and high glucose requirements. The up-regulation of specific glucose transporters may represent a key mechanism by which malignant cells may achieve increased glucose uptake to support the high rate of glycolysis. In present study we analyzed the mRNA and protein expression of GLUT1 and GLUT3 glucose transporters by quantitative real-time polymerase chain reaction (Q-PCR) and Western blotting technique in 76 cases of endometrial carcinoma and 70 cases of breast carcinoma. SLC2A1 and SLCA2A3 mRNAs expression was found, respectively in 100% and 97.4% samples of endometrial cancers and only in 50% and 40% samples of breast cancers. In endometrial cancers GLUT1 and GLUT3 protein expression was identified in 67.1% and 30.3% of cases. Analogously, in breast cancers in 48.7% and 21% of samples, respectively. The results showed that both endometrial and breast poorly differentiated tumors (grade 2 and 3) had significantly higher GLUT1 and GLUT3 expression than well-differentiated tumors (grade 1). Statistically significant association was found between SLCA2A3 mRNA expression and estrogen and progesterone receptors status in breast cancers. GLUT1 has been reported to be involved in the uptake of glucose by endometrial and breast carcinoma cells earlier and the present study determined that GLUT3 expression is also involved. GLUT1 and GLUT3 seem to be important markers in endometrial and breast tumors differentiation.

  15. Endometrial Synovial-like Metaplasia Associated With Levonorgestrel-releasing Intrauterine System.

    PubMed

    Stewart, Colin J R; Leake, Robyn

    2015-11-01

    The levonorgestrel-releasing intrauterine system (L-IUS) is widely used in contraception and in the treatment of menorrhagia, dysmenorrhea, adenomyosis, and endometriosis. L-IUS is also increasingly considered in the management of endometrial neoplasia and its precursors. Histologic changes in the endometrium can be due to the effects of high-dose progestogen or may be caused by the local irritant or mechanical effects of an intrauterine foreign body. In the present study, we describe a novel endometrial alteration associated with L-IUS that most closely resembles synovial metaplasia reported at other extra-articular anatomic sites. Eleven cases were identified with a mean age of 49.6 yr. In most patients L-IUS was used for management of menorrhagia or endometrial hyperplasia. Endometrial synovial-like metaplasia was always a focal finding and was associated with areas of surface epithelial erosion. The synovial-like cells showed a distinctive palisaded arrangement with orientation perpendicular to the endometrial surface. Multinucleate cells were present in 2 cases, but granulomas were not identified. The synovial-like cells were vimentin immunoreactive and a variable proportion of cells expressed CD68. Only focal CD10 staining was seen and there was no expression of estrogen receptor, progesterone receptor, or cytokeratin. In summary, L-IUS may be associated with a distinctive synovial-like metaplastic alteration which most likely represents a stromal reaction to an intrauterine foreign body following endometrial surface erosion. The synovial-like cells appear to comprise histiocytes and modified fibroblasts or stromal cells similar to this process in other sites.

  16. A prospective study of dietary acrylamide intake and the risk of breast, endometrial, and ovarian cancers

    PubMed Central

    Wilson, Kathryn M.; Mucci, Lorelei A.; Rosner, Bernard A.; Willett, Walter C.

    2010-01-01

    Background Acrylamide is a probable human carcinogen formed during cooking of many common foods. Epidemiological studies of acrylamide and breast cancer risk have been null; however, positive associations with ovarian and endometrial cancers have been reported. We studied acrylamide intake and risk of breast, endometrial, and ovarian cancers in a prospective cohort study. Methods We assessed acrylamide intake among 88,672 women in the Nurses’ Health Study using food frequency questionnaires administered every four years. Between 1980 and 2006 we identified 6301 cases of invasive breast cancer, 484 cases of invasive endometrial adenocarcinoma, and 416 cases of epithelial ovarian cancer. We used Cox proportional hazards models to study the association between acrylamide and cancer risk. Results We found no association between acrylamide intake and breast cancer overall or according to estrogen and progesterone receptor status. We found an increased risk of endometrial cancer among high acrylamide consumers (adjusted relative risk [RR] for highest versus lowest quintile=1.41, 95% CI: 1.01–1.97, p-value for trend=0.03). We observed a non-significant suggestion of increased risk for ovarian cancer overall (RR 1.25, CI: 0.88–1.77, p-trend=0.12), with a significantly increased risk for serous tumors (RR 1.58, CI: 0.99–2.52, p-trend=0.04). Associations did not differ by smoking status. Conclusions We observed no association between acrylamide and breast cancer. Risk of endometrial cancer and possibly ovarian cancer was greater among high acrylamide consumers. Impact This is the second prospective study to report positive associations with endometrial and ovarian cancers. These associations should be further evaluated to inform public health policy. PMID:20693310

  17. An attempt at conservative treatment in selected cases of type I endometrial carcinoma (stage I a/G1) in young women.

    PubMed

    Stanosz, S

    2009-01-01

    The aim of the study was to evaluate an attempt of conservative treatment in selected cases of endometrial carcinoma Stage I A/type I in young women. The study comprised five young nulliparous women aged 24-38 (30.8 +/- 4.2) with well-defined type I endometrial carcinoma Stage I A/G1. Diagnostic dilatation and curettage (D&C) in these women was performed. Biochemical hormonal studies comprised the assessment of estrone, estradiol, progesterone, prolactin in basal conditions, prolactin after a metoclopramide test and total testosterone. In the treatment phase estriol was given intravaginally. Additionally progesterone was applied for 12 days in the second phase of therapeutic cycles. Moreover the women were given ergocryptine and metformin. After six months of therapy and during two years of follow-up histopathological examinations of material obtained from D&C the endometrial pattern was normal and free of cancer cells. 1) In selected cases the conservative treatment of young women diagnosed with type I endometrial carcinoma Stage I A/G1 could be indicated. 2) Conservative pharmacological treatment of young women with well-defined endometrial carcinoma Stage I A/G1 type I should be monitored with followup histopathological examinations of material obtained from D&C of the endometrium and assessment of concentrations of sex hormones in the serum. 3) This kind of therapy requires frequent and thorough gynecological and clinical follow-up.

  18. Expression of epigenetic effectors in decidualizing human endometrial stromal cells.

    PubMed

    Grimaldi, Giulia; Christian, Mark; Quenby, Siobhan; Brosens, Jan J

    2012-09-01

    Cyclic differentiation of human endometrial stromal cells (HESCs) into decidual cells is a highly coordinated process essential for embryo implantation and pregnancy. This differentiation process is closely recapitulated in culture upon exposure of purified HESCs to cyclic AMP and progesterone signaling. Mining of gene expression data revealed that HESCs express 147 genes coding for epigenetic effectors, 33 (22%) of which are significantly regulated (P < 0.05) upon decidualization. Among these are genes encoding for histone-modifying proteins and their cofactors, histone-binding proteins, histone variants, CpG-binding proteins and DNA methyltransferases (DNMTs). Interestingly, more than two-thirds of differentially expressed chromatin-modifying genes are down-regulated upon the transition from a proliferative to a differentiated HESC phenotype. Despite the strong regulation of DNMTs, colorimetric and long interspersed nuclear element 1 methylation assays did not show global changes in DNA methylation levels upon differentiation of HESCs. Taken together, the coordinated regulation of diverse effector molecules suggests that complex epigenetic modification at specific loci underpins the acquisition of a decidual endometrial phenotype.

  19. Endometrial cancer. Prevention, detection, management, and follow up.

    PubMed Central

    Elit, L.

    2000-01-01

    OBJECTIVE: To review risk factors for uterine cancer; to discuss strategies for detecting uterine cancer; to outline prognostic factors and treatment; and to review the role of follow up for patients who have completed primary therapy. QUALITY OF EVIDENCE: MEDLINE was searched from January 1996 to June 1998 using the terms endometrial neoplasms, estrogen replacement therapy, hormone replacement therapy, tamoxifen, and screening. Only English language articles were reviewed. Study types included reviews. Bibliographies of articles found were searched for further relevant titles. Causation literature is available from well conducted cohort trials. Treatment recommendations are based in part on prognostic information and a few randomized controlled trials. MAIN MESSAGE: Risk factors, both intrinsic and extrinsic, are associated with uterine cancer. Family physicians have a role in preventing disease by ensuring that all women with uteri in situ using hormone replacement therapy (HRT) have progesterone therapy as part of the HRT regimen. Detection is crucial; abnormal uterine bleeding or undiagnosed postmenopausal bleeding warrants investigation with endometrial biopsy. The goal of surgery is to remove the uterus and ovaries and identify factors that make the disease at high risk of recurrence. Although adjuvant radiation therapy does not prolong survival, it does alter the pattern of disease recurrence. The goal of follow up after primary therapy is to identify recurrent disease while it is still curable. CONCLUSIONS: Family physicians play an important role in preventing uterine cancer, initiating early diagnosis of disease, and in the future, might be more actively involved in caring for patients following primary therapy. PMID:10790821

  20. Progesterone, inflammation and preterm labor.

    PubMed

    Pařízek, Antonín; Koucký, Michal; Dušková, Michaela

    2014-01-01

    The initiation of human parturition is not fully understood to date. The data from animal experiments demonstrate that the primary impulse for the initiation of physiological labor arises from the fetal hypothalamo-pituitary-adrenal axis (HPA). HPA is responsible for the stimulation of steroid synthesis and prostaglandin production and, in turn, the cervical dilation and the beginning of myometrial contractions. Animal experiments, however, are only partly suitable for understanding the mechanism of human labor due to substantial species-specificity. In human, the changing levels of placental CRH control the production of fetal and placental steroids. The fundamental pathogenic manifestation of spontaneous preterm labor is inflammation and similar processes also underlie the full term one. While in full term labor it is not yet precisely known what starts this process, in the preterm one, several factors have been discussed like infection, uteroplacental ischemia, and hormonal abnormalities (progesterone- or CRH-related). Inflammatory processes affect both the mother and the fetus. Fetal inflammatory response (FIRS), which can be expected for children born preterm, is frequently associated with long-term complications, in particular neurological and pulmonary. Research in this field is therefore aimed at predicting preterm labor, and on predicting the fetal inflammatory response. The role of progesterone and its receptors in the pathophysiology of preterm labor are likewise intensively studied. Clinical results on the use of additive doses of progesterone in secondary prevention of preterm labor and current experimental studies point to progesterone and its receptors playing a key role in the pathophysiology of preterm labor. This article is part of a Special Issue entitled 'Pregnancy and Steroids'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Antioxidant enzymes in women with endometrial polyps: relation with sex hormones.

    PubMed

    Pejić, Snežana A; Kasapović, Jelena D; Todorović, Ana U; Stojiljković, Vesna R; Gavrilović, Ljubica V; Popović, Nataša M; Pajović, Snežana B

    2013-09-01

    To investigate whether antioxidant enzyme activities (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) and lipid hydroperoxide levels in patients with endometrial polyps are influenced by the changes in sex hormones (estradiol, progesterone, FSH, and LH) during the menstrual cycle and in postmenopause. The material consisted of blood and endometrial tissue specimens from women diagnosed with endometrial polyps. Patients were divided into groups depending on the phase of the menstrual cycle--follicular or luteal--and the postmenopause. The activities of antioxidant enzymes and the lipid hydroperoxide levels were compared among the phases and a linear regression model was used to evaluate the associations between hormones and antioxidant/oxidant variables. In the blood of examined women, a significant difference in superoxide dismutase activity and lipid hydroperoxide levels was recorded among the phases. There was also a positive correlation between the estradiol concentration and superoxide dismutase. In polyp tissue, we recorded a phase-related difference in superoxide dismutase and glutathione peroxidase activities as well as in the lipid hydroperoxide levels. A negative correlation was observed between FSH/LH and glutathione peroxidase, and between LH and superoxide dismutase. Antioxidant enzymes and lipid hydroperoxide levels in patients with endometrial polyps are influenced by the changes in sex hormones during the menstrual cycle and after the menopause, pointing to a role of the observed relationship in polyp etiology. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals

    SciTech Connect

    Fischer, L.; Deppert, W.R.; Pfeifer, D.; Stanzel, S.; Weimer, M.; Hanjalic-Beck, A.; Stein, A.; Straßer, M.; Zahradnik, H.P.; Schaefer, W.R.

    2012-05-01

    Embryo implantation is a crucial step in human reproduction and depends on the timely development of a receptive endometrium. The human endometrium is unique among adult tissues due to its dynamic alterations during each menstrual cycle. It hosts the implantation process which is governed by progesterone, whereas 17β-estradiol regulates the preceding proliferation of the endometrium. The receptors for both steroids are targets for drugs and endocrine disrupting chemicals. Chemicals with unwanted antigestagenic actions are potentially hazardous to embryo implantation since many pharmaceutical antiprogestins adversely affect endometrial receptivity. This risk can be addressed by human tissue-specific in vitro assays. As working basis we compiled data on chemicals interacting with the PR. In our experimental work, we developed a flexible in vitro model based on human endometrial Ishikawa cells. Effects of antiprogestin compounds on pre-selected target genes were characterized by sigmoidal concentration–response curves obtained by RT-qPCR. The estrogen sulfotransferase (SULT1E1) was identified as the most responsive target gene by microarray analysis. The agonistic effect of progesterone on SULT1E1 mRNA was concentration-dependently antagonized by RU486 (mifepristone) and ZK137316 and, with lower potency, by 4-nonylphenol, bisphenol A and apigenin. The negative control methyl acetoacetate showed no effect. The effects of progesterone and RU486 were confirmed on the protein level by Western blotting. We demonstrated proof of principle that our Ishikawa model is suitable to study quantitatively effects of antiprogestin-like chemicals on endometrial target genes in comparison to pharmaceutical reference compounds. This test is useful for hazard identification and may contribute to reduce animal studies. -- Highlights: ► We compare progesterone receptor-mediated endometrial effects of chemicals and drugs. ► 4-Nonylphenol, bisphenol A and apigenin exert weak

  3. JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer

    PubMed Central

    Qiu, Haifeng; Li, Jing; Clark, Leslie H.; Jackson, Amanda L.; Zhang, Lu; Guo, Hui; Kilgore, Joshua E.; Gehrig, Paola A.; Zhou, Chunxiao; Bae-Jump, Victoria L.

    2016-01-01

    Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers. PMID:27572308

  4. The use of micronised progesterone for menopausal hormone therapy, a clinical practice audit.

    PubMed

    Davis, Susan R; Dempster, Georgia; Bell, Robin J

    2016-06-01

    A clinical practice audit was undertaken to share an Australian experience of the use of micronised progesterone (mP) 100 mg daily as part of menopausal hormone therapy (MHT). Ninety-nine women attending a single practitioner were offered the option of mP as a component of MHT, under the Australian Authorised Prescriber Scheme, over 2.5 years. Each of their files was independently audited. The mean age at commencement was 55.0 (SD 6.6) years. Of the 93 postmenopausal women, 7 were lost to follow-up, 18 discontinued and treatment was ongoing for 68. The mean duration of treatment for those ongoing was 1.7 (SD 0.5) years, and for those who discontinued, 0.6 (SD 0.6) years. The most common side effect was unscheduled bleeding, which was also the most common reason for discontinuation (5/18 women). None of the 15 women who had a transvaginal ultrasound examination had an endometrial thickness >5 mm. Of the 41 women who had at least one blood progesterone measurement performed, the median value was 11.3 (range 0.7-138) nmol/L. This audit indicates that mP is well tolerated when prescribed as MHT. Although there was no evidence of endometrial hyperplasia, further research is needed to establish the safety of mP for continuous combined MHT use. © 2016 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

  5. Both slowly developing embryos and a variable pace of luteal endometrial progression may conspire to prevent normal birth in spite of a capable embryo.

    PubMed

    Franasiak, Jason M; Ruiz-Alonso, Maria; Scott, Richard T; Simón, Carlos

    2016-04-01

    Embryonic implantation requires synchrony between the endometrium and the embryo. When analyzed in isolation, competent embryos may be unsuccessful when placed on a nonreceptive endometrium or vice versa, contributing to the "black box" of implantation failure. It is when the two are assessed together that dyssynchrony becomes evident, due to premature progesterone stimulus on the endometrium, physiologic displacement of the window of implantation or late blastulation of the embryo, or all combined. From the embryonic component, detailed assessment of the timing of blastulation is essential. The molecular diagnosis of endometrial receptivity based on its transcriptomic signature could be superior to other techniques used in the past for defining the endometrial window of implantation.

  6. Good practice with endometrial ablation.

    PubMed

    Garry, R

    1995-07-01

    To provide clear guidelines for the safe and effective performance of endometrial ablation. Representatives of American, Australian, British, and Canadian hysteroscopists were brought together to produce a consensus document of good practice in endometrial ablation. The guidelines were produced after researching the literature, combining the extensive experience of the group, and debating the relevant issues. Endometrial ablation is a new procedure. Correct patient selection is essential in producing good results. Patients must be counseled carefully about the advantages, disadvantages, and potential complications of this approach to the management of menstrual disorders. The main indication for endometrial ablation is heavy menstrual loss in the absence of organic disease. Excessive uterine size, the presence of active pelvic infection, and evidence of malignant and premalignant endometrium are absolute contraindications. Ablation can be produced by electrosurgical resection, rollerball or rollerbarrel ablation and Nd-YAG laser ablation. Severe complications can occur, and techniques should be adopted to avoid uterine perforation, hemorrhage, and excessive fluid absorption. In skilled hands, endometrial ablation can be a safe and effective treatment for menorrhagia.

  7. Small non-coding RNA deregulation in endometrial carcinogenesis

    PubMed Central

    Ravo, Maria; Cordella, Angela; Rinaldi, Antonio; Bruno, Giuseppina; Alexandrova, Elena; Saggese, Pasquale; Nassa, Giovanni; Giurato, Giorgio; Tarallo, Roberta; Marchese, Giovanna; Rizzo, Francesca; Stellato, Claudia; Biancardi, Rossella; Troisi, Jacopo; Di Spiezio Sardo, Attilio; Zullo, Fulvio; Weisz, Alessandro; Guida, Maurizio

    2015-01-01

    Small non-coding RNAs (sncRNAs) represent a heterogeneous group of <200nt-long transcripts comprising microRNAs, PIWI-interacting RNAs (piRNAs) and small-nucleolar-RNAs (snoRNAs) involved in physiological and pathological processes such as carcinogenesis and tumor progression. Aberrant sncRNA expression in cancer has been associated with specific clinical phenotypes, grading, staging, metastases development and resistance to therapy. Aim of the present work is to study the role of sncRNAs in endometrial carcinogenesis. Changes in sncRNA expression were identified by high-throughput genomic analysis of paired normal, hyperplastic and cancerous endometrial tissues obtained by endometrial biopsies (n = 10). Using smallRNA sequencing and microarrays we identified significant differences in sncRNA expression pattern between normal, hyperplastic and neoplastic endometrium. This led to the definition of a sncRNA signature (129 microRNAs, 2 of which not previously described, 10 piRNAs and 3 snoRNAs) of neoplastic transformation. Functional bioinformatics analysis identified as downstream targets multiple signaling pathways potentially involved in the hyperplastic and neoplastic tissue responses, including Wnt/β-catenin, and ERK/MAPK and TGF-β-Signaling. Considering the regulatory role of sncRNAs, this newly identified sncRNA signature is likely to reflect the events leading to endometrial cancer, which can be exploited to dissect the carcinogenic process including novel biomarkers for early and non-invasive diagnosis of these tumors. PMID:25686835

  8. The Effect of Levonorgestrel on Fibrinolytic Factors in Human Endometrial Endothelial Cells.

    PubMed

    Pakrashi, Tarita; Taylor, Joelle E; Nelson, Ashley; Archer, David F; Jacot, Terry

    2016-11-01

    The levonorgestrel-releasing intrauterine system is considered a highly effective treatment of heavy menstrual bleeding (HMB). While LNG has established effects on the stromal and glandular compartments of the endometrial tissue, its effect on the endometrial endothelial cells has not been investigated. We examined whether LNG regulates fibrinolytic factors, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) secreted by human endometrial endothelial cells (HEECs) and determined the steroid receptor through which LNG exerts its effect on the endothelium. The HEECs were treated with LNG or progesterone and levels of tPA and plasminogen activator inhibitor 1 (PAI-1) measured. The HEECs were specifically examined for the presence of androgen receptors through Western blot. Levonorgestrel ± flutamide were added to HEECs and the levels of tPA and uPA were examined. An enzyme-linked immunosorbent assay performed on culture media confirmed a statistically significant decrease in tPA levels in cells treated with LNG (77.80% ± 8.0% of control; n = 5, P < .05 vs control) but not progesterone. The androgen receptor (110 kDa) was detected in HEEC lysates. The decrease in tPA was blocked by the addition of flutamide (101.3% ± 16% of control), a classic nonsteroidal androgen receptor blocker. There was no change in uPA or PAI-1 levels in cells treated with LNG. Levonorgestrel decreases tPA levels through the androgen receptor in HEECs. Thus, LNG inhibits tPA secretion by the endometrial endothelial cell. This response suggests reduction in HMB with LNG-IUS could reflect an LNG-mediated promotion of hemostasis. © The Author(s) 2016.

  9. Concentration of progesterone during the development of the ovulatory follicle: II. Ovarian and uterine responses.

    PubMed

    Cerri, R L A; Chebel, R C; Rivera, F; Narciso, C D; Oliveira, R A; Amstalden, M; Baez-Sandoval, G M; Oliveira, L J; Thatcher, W W; Santos, J E P

    2011-07-01

    Two experiments evaluated the influence of altering the concentrations of progesterone during the development of the ovulatory follicle on the composition of the follicular fluid, circulating LH and PGF(2α) metabolite (PGFM), and expression of endometrial progesterone receptor and estrogen receptor-α. In both experiments, the estrous cycles were presynchronized (GnRH and progesterone insert followed by insert removal and PGF(2α) 7 d later, and GnRH after 48 h) and cows were then enrolled in 1 of 2 treatments 7 d later (study d -16): high progesterone (HP) or low progesterone (LP). In experiment 1 (n=19), cows had their estrous cycle synchronized starting on study d -9 (GnRH and progesterone insert on d -9, and insert removal and PGF(2α) on d -2). In experiment 2 (n=25), cows were submitted to the same synchronization protocol as in experiment 1, but had ovulation induced with GnRH on study d 0. In experiment 1, plasma was sampled on d -4 and analyzed for concentrations of LH; the dominant follicle was aspirated on d 0 and the fluid analyzed for concentrations of progesterone, estradiol, and free and total IGF-1. In experiment 2, follicular development and concentrations of progesterone and estradiol in plasma were evaluated until study d 16. Uterine biopsies were collected on d 12 and 16 for progesterone receptor and estrogen receptor-α protein abundance. An estradiol/oxytocin challenge for PGFM measurements in plasma was performed on d 16. In experiments 1 and 2, LP cows had lower plasma concentrations of progesterone and greater concentrations of estradiol, and had larger ovulatory follicle diameter (20.4 vs. 17.2mm) at the end of the synchronization protocol than HP cows. Concentration of LH tended to be greater for LP than HP cows (0.98 vs. 0.84 ng/mL). The dominant follicle of LP cows had greater concentration of estradiol (387.5 vs. 330.9 ng/mL) and a lower concentration of total IGF-1 (40.9 vs. 51.7 ng/mL) than that of HP cows. In experiment 2

  10. The Impact of Serum Progesterone Levels on the Results of In Vitro Fertilization Treatments: A Literature Review.

    PubMed

    Castillo, Jaime Larach Del; Bousamra, Maroun; Fuente, Laura De La; Ruiz-Balda, Jose A; Palomo, Marissa

    2015-08-01

    The aim of this review is to analyze the relationship between preovulatory progesterone (P) rise and in vitro fertilization (IVF) pregnancy outcomes. It also investigates the sources and effects of rises in progesterone levels, including the underlying mechanisms and potential strategies in preventing its elevation during ovarian stimulation. Progesterone is produced in the early follicular phase in the adrenal gland, which shifts toward the ovaries prior to ovulation. Several factors contribute to the etiology of P level increase including the number of multiple follicles, the overdose of gonadotropins and poor ovarian response. Nowadays, the influence of the preovulatory P rise on IVF outcome remains controversial. Several authors have failed to demonstrate any negative impact, while others reported a detrimental effect associated with the rise of P. It seems that P rise (1.5 ng/ml or 4.77 nmol/l) may have deleterious effects on endometrial receptivity, namely, accelerating the endometrial maturation process that subsequently narrows the period for implantation and thus decreases pregnancy rates. Recent studies have proposed different cutoffs according to the ovarian response, which may be a little high in patients with high response in relation to those of normal response or low response. To prevent a P rise, it might be preferable to use milder stimulation protocols, earlier trigger of ovulation, cryopreservation of all embryos and transfer in the natural cycle.

  11. Regulation of numbers of macrophages in the endometrium of the sheep by systemic effects of pregnancy, local presence of the conceptus, and progesterone.

    PubMed

    Tekin, Saban; Hansen, Peter J

    2004-01-01

    Many species exhibiting hemochorial placentation experience an accumulation of macrophages in the endometrium during pregnancy. For the present study, it was tested whether macrophages also accumulate in the endometrium of the sheep, which is a species undergoing an epitheliochorial placentation. An additional objective was to determine whether regulation of endometrial macrophage number occurs via systemic or local signals and whether progesterone is one of these signals. The approach was to evaluate presence of macrophages immunohistochemically using antibodies to CD68 and CD14. Tissues examined were from cyclic ewes in the luteal phase of the estrous cycle, unilaterally-pregnant ewes at day 140 of pregnancy in which pregnancy was surgically confined to one uterine horn, ovariectomized ewes, and ovariectomized ewes treated with progesterone for 44 days. Macrophages were localized predominately to the stromal compartment of the stratum compactum region of the endometrium. In non-pregnant ewes, macrophages were not abundant regardless of physiological status. Increased numbers of endometrial macrophages were seen for both the pregnant and non-pregnant uterine horns of unilaterally pregnant ewes. Numbers of macrophages were higher in the endometrium from the pregnant uterine horn than from endometrium from the non-pregnant uterine horn. Results indicate that macrophages accumulate in the endometrium by day 140 of pregnancy in the sheep and that this induction is because of both systemic and local signals. Progesterone appears not to be an important regulator of numbers of endometrial macrophages.

  12. MiR-218 inhibits HMGB1-mediated autophagy in endometrial carcinoma cells during chemotherapy.

    PubMed

    Ran, Xiaomin; Yang, Juan; Liu, Chaoxia; Zhou, Ping; Xiao, Linzhi; Zhang, Keqiang

    2015-01-01

    Endometrial carcinoma is the most common gynecological malignancy among women worldwide. Although treatment for EC has improved with the introduction of Paclitaxel (Tax) chemotherapy, the majority of patients will develop resistance to the treatment, leading to poor prognosis. One of the causes of chemoresistance is the increased ability to undergo autophagy. In this study, we identified that miR-218 was significantly down-regulated in Tax-resistant EC cells compared to the non-drug resistant cell lines, and overexpression of miR-218 sensitized paclitaxel resistant EC cells to paclitaxel. Moreover, we demonstrated that miR-218 directly binds to the 3'-UTR of HMGB1 gene. HMGB1 was upregulated in paclitaxel resistant EC cells, it mediated autophagy and contributed to chemotherapy resistance in endometrial carcinoma in vitro. HMGB1-mediated autophagy could be suppressed by miR-218 overexpression in Tax resistant EC cells. In summary, we determined the targeting role of miR-218 to HMGB1 and the regulation of miR-218 on the HMGB1-mediated cell autophagy during chemotherapy resistance in endometrial carcinoma cells. These results reveal novel potential role of miR-218 against chemotherapy resistance during the treatment of endometrial carcinoma.

  13. Lgr4 is required for endometrial receptivity acquired through ovarian hormone signaling.

    PubMed

    Kida, Tomoyo; Oyama, Kazunori; Sone, Mizuki; Koizumi, Masae; Hidema, Shizu; Nishimori, Katsuhiko

    2014-01-01

    Previously, using the Keratin5-Cre transgenic mouse model we reported that female Lgr4-conditional KO mice (Lgr4(K5 KO)) showed subfertility with defective stromal decidualization due to abnormal development of the uterine gland. However, the impact of the LGR4 defect on luminal epithelial cells was not investigated in the previous report. Here, we focused on the receptive state of the luminal epithelium in Lgr4(K5 KO) mice that received ovarian hormone treatment. In Lgr4(K5 KO) mice, progesterone failed to inhibit the luminal epithelial cell proliferation. Immunohistochemical and qRT-PCR analyses revealed down-regulated progesterone signaling in the uterus of Lgr4(K5 KO) mice. These results demonstrated that LGR4 is essential for the acquisition of endometrial receptivity through ovarian hormone signaling.

  14. The Induction of Pro-Angiogenic Processes Within a Collagen Scaffold Via Exogenous Estradiol and Endometrial Epithelial Cells

    PubMed Central

    Pence, Jacquelyn C.; Clancy, Kathryn B. H.; Harley, Brendan A. C.

    2015-01-01

    Nutrient transport remains a major limitation in the design of biomaterials. One approach to overcome this constraint is to incorporate features to induce angiogenesis-mediated microvasculature formation. Angiogenesis requires a temporal presentation of both pro- and anti-angiogenic factors to achieve stable vasculature, leading to increasingly complex biomaterial design scheme. The endometrium, the lining of the uterus and site of embryo implantation, exemplifies a non-pathological model of rapid growth, shedding, and re-growth of dense vascular networks regulated by the dynamic actions of estradiol and progesterone. In this study, we examined the individual and combined response of endometrial epithelial cells and human umbilical vein endothelial cells to exogenous estradiol within a three-dimensional collagen scaffold. While endothelial cells did not respond to exogenous estradiol, estradiol directly stimulated endometrial epithelial cell transduction pathways and resulted in dose-dependent increases in endogenous VEGF production. Co-culture experiments using conditioned media demonstrated estradiol stimulation of endometrial epithelial cells can induce functional changes in endothelial cells within the collagen biomaterial. We also report the effect of direct endometrial epithelial and endothelial co-culture as well as covalent immobilization of estradiol within the collagen biomaterial. These efforts establish the suitability of an endometrial-inspired model for promoting pro-angiogenic events within regenerative medicine applications. These results also suggest the potential for developing biomaterial-based models of the endometrium. PMID:25944769

  15. The induction of pro-angiogenic processes within a collagen scaffold via exogenous estradiol and endometrial epithelial cells.

    PubMed

    Pence, Jacquelyn C; Clancy, Kathryn B H; Harley, Brendan A C

    2015-10-01

    Nutrient transport remains a major limitation in the design of biomaterials. One approach to overcome this constraint is to incorporate features to induce angiogenesis-mediated microvasculature formation. Angiogenesis requires a temporal presentation of both pro- and anti-angiogenic factors to achieve stable vasculature, leading to increasingly complex biomaterial design scheme. The endometrium, the lining of the uterus and site of embryo implantation, exemplifies a non-pathological model of rapid growth, shedding, and re-growth of dense vascular networks regulated by the dynamic actions of estradiol and progesterone. In this study, we examined the individual and combined response of endometrial epithelial cells and human umbilical vein endothelial cells to exogenous estradiol within a three-dimensional collagen scaffold. While endothelial cells did not respond to exogenous estradiol, estradiol directly stimulated endometrial epithelial cell transduction pathways and resulted in dose-dependent increases in endogenous VEGF production. Co-culture experiments using conditioned media demonstrated estradiol stimulation of endometrial epithelial cells can induce functional changes in endothelial cells within the collagen biomaterial. We also report the effect of direct endometrial epithelial and endothelial co-culture as well as covalent immobilization of estradiol within the collagen biomaterial. These efforts establish the suitability of an endometrial-inspired model for promoting pro-angiogenic events within regenerative medicine applications. These results also suggest the potential for developing biomaterial-based models of the endometrium. © 2015 Wiley Periodicals, Inc.

  16. Induction of mitochondrial apoptotic pathway by raloxifene and estrogen in human endometrial stromal ThESC cell line

    PubMed Central

    Andjelkovic, Marija; Zaric, Milan; Zelen, Ivanka; Canovic, Petar; Milosavljevic, Zoran; Mitrovic, Marina

    2016-01-01

    Introduction Endometrial hyperplasia is a condition that occurs as a result of hormonal imbalance between estrogen and progesterone. Morphological disturbance of endometrial cells occurs consequently leading towards endometrial cancer. In therapy of endometrial hyperplasia SERMs are used to supress effects of locally high estrogen level in uterus. There is strong evidence suggesting that estrogen could be involved in cell death – apoptosis. There are no experimental data demstrating the direct apoptotic effect of both raloxifene and estrogen on the ThESC cell line. The aim of our study wa sto investigate both cytotoxic and apototic mechanism of raloxifene and estrogen – induced death in the ThESC cell line. Material and methods In order to determine their cytotoxic and apoptotic effects, various doses of raloxifene and estrogen were applied to the ThESC cell line for 24 h. After the treatment MTT assay, FACS analysis and immunofluoroscence method were conducted. Results The results of this study for the first time demonstrated the cytotoxic and apoptotic effects of raloxifene and estrogen on human endometrial stromal cell line suggesting the involvement of the inner, mitochondrial apoptotic pathway. Conclusions Our results demonstrated apoptotic effects of investigated drugs in the ThESC cell line through increasing the Bax/Bcl-2 ratio and activation of caspase 3. PMID:28261281

  17. The effects of Arcanobacterium pyogenes on endometrial function in vitro, and on uterine and ovarian function in vivo.

    PubMed

    Miller, A N A; Williams, E J; Sibley, K; Herath, S; Lane, E A; Fishwick, J; Nash, D M; Rycroft, A N; Dobson, H; Bryant, C E; Sheldon, I M

    2007-10-15

    Uterine bacterial infection after parturition causes endometritis, perturbs ovarian function and leads to infertility in cattle. Although endometritis is caused by mixed infections, endometrial pathology is associated with the presence of Arcanobacterium pyogenes. The aims of the present study were to determine the effects of A. pyogenes on endometrial function in vitro, and on uterine and ovarian function in vivo. Heat-killed A. pyogenes did not affect the production of prostaglandin F2alpha (PGF) or prostaglandin E(2) (PGE) from endometrial explants, or purified populations of endometrial epithelial or stromal cells. However, the explants produced more PGF and PGE than controls when treated with a bacteria-free filtrate (BFF) cultured from A. pyogenes. Similarly, BFF stimulated PGF and PGE production by epithelial and stromal cells, respectively. So, BFF or control PBS was infused into the uterus of heifers (n=7 per group) for 8 days, starting the day after estrus. Emergence of the follicle wave, dominant follicle or corpus luteum diameter, and peripheral plasma FSH, LH, estradiol, progesterone, PGFM, or acute phase protein concentrations were unaffected by the BFF infusion. In the live animal it is likely that the intact uterine mucosa limits the exposure of the endometrial cells to the exotoxin of A. pyogenes, whereas the cells are readily exposed to the toxin in vitro.

  18. Expression of glucocorticoid receptor is associated with aggressive primary endometrial cancer and increases from primary to metastatic lesions.

    PubMed

    Tangen, Ingvild L; Veneris, Jennifer Taylor; Halle, Mari K; Werner, Henrica M; Trovik, Jone; Akslen, Lars A; Salvesen, Helga B; Conzen, Suzanne D; Fleming, Gini F; Krakstad, Camilla

    2017-09-16

    Glucocorticoid receptor (GR) has emerged as an important steroid nuclear receptor in hormone dependent cancers, however few data are available regarding a potential role of GR in endometrial cancer. The aim of this study was to investigate expression of GR in primary and metastatic endometrial cancer lesions, and to assess the relationship between GR expression and clinical and histopathological variables and survival. Expression of GR was investigated by IHC in 724 primary tumors and 289 metastatic lesions (from 135 patients), and correlations with clinical and histopathological data and survival were explored. Expression of GR was significantly increased in non-endometrioid tumors compared to endometrioid tumors, and was associated with markers of aggressive disease and poor survival both in univariate and multivariate analysis after correcting for age, FIGO stage and histologic grade. Within the subgroups of hormone receptor negative tumors (loss of androgen receptor, estrogen receptor or progesterone receptor) expression of GR was highly significantly associated with poor disease specific survival. There was an overall increase in GR expression from primary to metastatic lesions, and the majority of metastases expressed GR. GR expression in primary endometrial cancer is associated with aggressive disease and poor survival. The majority of metastatic endometrial cancer lesions express GR; therefore GR may represent a therapeutic target in the adjuvant therapy of poor prognosis early-stage as well as metastatic endometrial cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Progesterone in normal and pathological pregnancy.

    PubMed

    Di Renzo, Gian Carlo; Giardina, Irene; Clerici, Graziano; Brillo, Eleonora; Gerli, Sandro

    2016-07-01

    Progesterone is an essential hormone in the process of reproduction. It is involved in the menstrual cycle, implantation and is essential for pregnancy maintenance. It has been proposed and extensively used in the treatment of different gynecological pathologies as well as in assisted reproductive technologies and in the maintenance of pregnancy. Called "the pregnancy hormone", natural progesterone is essential before pregnancy and has a crucial role in its maintenance based on different mechanisms such as: modulation of maternal immune response and suppression of inflammatory response (the presence of progesterone and its interaction with progesterone receptors at the decidua level appears to play a major role in the maternal defense strategy), reduction of uterine contractility (adequate progesterone concentrations in myometrium are able to counteract prostaglandin stimulatory activity as well as oxytocin), improvement of utero-placental circulation and luteal phase support (it has been demonstrated that progesterone may promote the invasion of extravillous trophoblasts to the decidua by inhibiting apoptosis of extravillous trophoblasts). Once the therapeutic need of progesterone is established, the key factor is the decision of the best route to administer the hormone and the optimal dosage determination. Progesterone can be administered by many different routes, but the most utilized are oral, the vaginal and intramuscular administration. The main uses of progesterone are represented by: threatened miscarriage, recurrent miscarriage and preterm birth (in the prevention strategy, as a tocolytic agent and also in the maintenance of uterine quiescence).

  20. Effect of estrone treatment from day 30 to 45 of pregnancy on endometrial protein secretion and uterine capacity.

    PubMed

    Vallet, J L; Christenson, R K

    1994-12-01

    Secretion of proteins by the endometrium of pigs during pregnancy is reported to be influenced by progesterone and estrogen. The effect of estrone treatment from d 30 to 45 of pregnancy on endometrial protein secretion and uterine capacity was tested in unilaterally hysterectomized-ovariectomized (UHO) gilts. Ten intact and 16 UHO crossbred gilts were mated and assigned to the following treatments: 1) intact controls, n = 10; 2) UHO, n = 8; and 3) UHO + estrone (E; two 150-mg implants, 60-d release, implanted on d 30 of gestation), n = 8. Gilts were killed on d 45 of pregnancy. A sample of allantoic fluid was collected from each conceptus. Blood and endometrial tissue samples were collected to evaluate estrone concentrations, and placental and endometrial tissues were incubated to evaluate protein secretion. Estrone treatment increased (P < .01) plasma and endometrial tissue estrone concentrations. Unilateral hysterectomy-ovariectomy decreased (P < .01) fetal survival. No effect of estrone was detected on the number of live fetuses, protein secretion by endometrial tissue in culture, or allantoic fluid protein, acid phosphatase, retinol binding protein, or retinol. Estrone treatment decreased uterine weight (P = .05) and allantoic fluid fructose concentrations (P < .05). After correction for allantoic fluid volume, allantoic fluid protein, retinol, and acid phosphatase activity were decreased (P < .05) in UHO-treated pigs. The UHO treatment did not affect allantoic fluid fructose concentrations. These results indicate that 1) estrone treatment from d 30 to 45 of pregnancy and at the dosage used did not alter endometrial protein secretion or fetal survival, and 2) UHO decreased the amount of endometrial proteins available to conceptuses.

  1. CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial carcinoma cells.

    PubMed

    Llobet, D; Eritja, N; Encinas, M; Llecha, N; Yeramian, A; Pallares, J; Sorolla, A; Gonzalez-Tallada, F J; Matias-Guiu, X; Dolcet, X

    2008-04-17

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising antineoplastic agent because of its ability to selectively kill tumoral cells. However, some cancer cells are resistant to TRAIL-induced apoptosis. We have previously demonstrated that in endometrial carcinoma cells such resistance is caused by elevated FLICE-inhibitory protein (FLIP) levels. The present study focuses on the mechanisms by which FLIP could be modulated to sensitize endometrial carcinoma cells to TRAIL-induced apoptosis. We find that inhibition of casein kinase (CK2) sensitizes endometrial carcinoma cells to TRAIL- and Fas-induced apoptosis. CK2 inhibition correlates with a reduction of FLIP protein, suggesting that CK2 regulates resistance to TRAIL and Fas by controlling FLIP levels. FLIP downregulation correlates with a reduction of mRNA and is prevented by addition of the MG-132, suggesting that CK2 inhibition results in a proteasome-mediated degradation of FLIP. Consistently, forced expression of FLIP restores resistance to TRAIL and Fas. Moreover, knockdown of either FADD or caspase-8 abrogates apoptosis triggered by inhibition of CK2, indicating that CK2 sensitization requires formation of functional DISC. Finally, because of the possible role of both TRAIL and CK2 in cancer therapy, we demonstrate that CK2 inhibition sensitizes primary endometrial carcinoma explants to TRAIL apoptosis. In conclusion, we demonstrate that CK2 regulates endometrial carcinoma cell sensitivity to TRAIL and Fas by regulating FLIP levels.

  2. Clinical management of endometrial receptivity.

    PubMed

    Blesa, David; Ruiz-Alonso, María; Simón, Carlos

    2014-09-01

    The endometrial window of implantation (WOI), the cycle days during which normal embryo implantation can occur, has generally been assumed to begin on cycle day 19 or 20 of an idealized 28 days cycle and last for 4 to 5 days. Noyes et al took the first steps in defining the WOI by establishing a set of morphological criteria to evaluate endometrial development and receptivity, but recent studies have invalidated their use in the routine evaluation of infertility. Based on greater than 10 years of extensive research, our group has developed a molecular diagnostic tool (the endometrial receptivity array [ERA] test) based on the specific transcriptomic signature that identifies the receptive endometrium in natural and artificial (hormonal replacement therapy) cycles. The ERA test has shown that some patients have a delayed WOI, others have an advanced WOI, and others can have unusually short windows of receptivity. This identification and characterization of the WOI allows the personalization of the embryo transfer. In this review, we describe the ERA and our experience with its use in assessment of the endometrial receptivity in patients undergoing assisted reproduction.

  3. Endometrial polyps: when to resect?

    PubMed

    de Azevedo, Julia Marques da Rocha; de Azevedo, Ligia Marques da Rocha; Freitas, Fernando; Wender, Maria Celeste Osorio

    2016-03-01

    To determine the prevalence of malignant and premalignant endometrial polyps and to investigate the association of malignancy with specific factors. This is a retrospective study of women submitted to hysteroscopic resection of endometrial polyps between January 2005 and July 2013 at a university hospital in southern Brazil. Data regarding clinical characteristics and pathology findings were collected from patient charts. Of 359 patients, 87.2% had benign polyps and 9.9% had hyperplasia without atypia. Atypical hyperplasia was found in 2.6% of the sample. Endometrial adenocarcinoma was found in one woman (0.3%). A correlation was observed between malignant/premalignant polyps and patient age, menopausal status, and uterine bleeding. All patients with malignancies/premalignancies had abnormal uterine bleeding. Higher frequency of malignant polyps was observed in tamoxifen users, however, without statistical significance (p = 0.059%). Malignancy was not correlated with arterial hypertension, diabetes mellitus, obesity, hormone therapy, endometrial thickness, and polyp diameter. Malignant/premalignant findings had low prevalence and were absent in asymptomatic patients. From the data of this retrospective study, it is unclear whether routine polypectomy should be performed in asymptomatic patients. Further prospective studies including larger numbers of patients are required to guide treatment recommendations.

  4. Nucleophosmin/B23 is a negative regulator of estrogen receptor α expression via AP2γ in endometrial cancer cells

    PubMed Central

    Lee, Li-Yu; Yang, Lan-Yan; Tsai, Chia-Lung; Wang, Hsin-Shih; Lai, Chyong-Huey

    2016-01-01

    Endometrial cancers expressing estrogen and progesterone receptors respond to hormonal therapy. The disappearance of steroid hormone receptor expression is common in patients with recurrent disease, ultimately hampering the clinical utility of hormonal therapy. Here, we demonstrate for the first time that nucleophosmin (NPM1/B23) suppression can restore the expression of estrogen receptor α (ESR1/ERα) in endometrial cancer cells. Mechanistically, B23 and activator protein-2γ (TFAP2C/AP2γ) form a complex that acts as a transcriptional repressor of ERα. Our results indicate that B23 or AP2γ knockdown can restore ERα levels and activate ERα-regulated genes (e.g., cathepsin D, EBAG9, and TFF1/pS2). Moreover, AP2γ knockdown in a xenograft model sensitizes endometrial cancer cells to megesterol acetate through the upregulation of ERα expression. An increased immunohistochemical expression of AP2γ is an adverse prognostic factor in endometrial cancer. In summary, B23 and AP2γ may act in combination to suppress ERα expression in endometrial cancer cells. The inhibition of B23 or AP2γ can restore ERα expression and can serve as a potential strategy for sensitizing hormone-refractory endometrial cancers to endocrine therapy. PMID:27527851

  5. Progesterone Receptor Scaffolding Function in Breast Cancer

    DTIC Science & Technology

    2012-10-01

    Progesterone Receptors Mediates Proliferative Signaling in Breast Cancer. Funding period: 2012- 2017 17 CONCLUSION Progesterone receptors (PR) are...National Cancer Institute): R01 CA123763 (formerly R01 DK53825; NIH/National Institute of Diabetes and Digestive and Kidney Diseases). The authors have

  6. Progesterone

    MedlinePlus

    ... hormone replacement therapy in women who have passed menopause (the change of life) and have not had ... estrogen, which is used to treat symptoms of menopause and reduce the risk of developing certain diseases. ...

  7. Predictive diagnosis of endometrial hyperplasia and personalized therapeutic strategy in women of fertile age

    PubMed Central

    2013-01-01

    Introduction Endometrial hyperplasia has a high risk for malignant transformation and relapses; existing mini-invasive treatments may lead to irrevocable endometrium destruction. The aims were to analyze receptor systems in endometrial hyperplasia, to evaluate the capabilities of ultrasonography, sonoelastography for diagnosis and treatment control, and to develop treatment algorithm. Materials and methods We included 313 women (20–45 years), assessed into the following: group 1 (n = 112) with glandular cystic hyperplasia, group 2 (n = 98) endometrial polyps, and group 3 (n = 103) atypical hyperplasia; and 82 controls who have undergone hysteroscopy before in vitro fertilization in tubal origin infertility were also included. Patients underwent clinical examination, transvaginal ultrasound, immunohistochemical study, and hormonal therapy/hysteroresectoscopy. Results In patients with glandular hyperplasia, we registered increase of endometrium estrogen receptors (75.6% in the epithelium and 30.9% in the stroma; in controls, 43.3% and 29.6%, respectively); in polyps, there was a significant estrogen receptor increase in the stroma (48.2% vs 29.6% in controls), and in atypical hyperplasia, progesterone receptors significantly increased in the stroma. Ki-67 increased (40% to 50%) in the epithelium without changes in the stroma. Ultrasound has a sensitivity of 96% and a specificity of 85% for early detection of endometrial pathology and prediction outcome of intervention, and sonoelastography has a sensitivity of 91% and a specificity of 83% for polyp diagnosis. Personalized treatment was effective in 88.8%, relapse was diagnosed in 11.2% after 6 months, and conservative treatment of atypical hyperplasia was effective in 45%: in 25.8%, ablative hysteroresectoscopy was performed, while in 22.6% with comorbidities, hystero/oophorectomies were performed. Conclusions The evaluation of receptor status with ultrasound data in patients with endometrial

  8. An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations.

    PubMed

    Yang, Chieh-Hsiang; Almomen, Aliyah; Wee, Yin Shen; Jarboe, Elke A; Peterson, C Matthew; Janát-Amsbury, Margit M

    2015-07-01

    Endometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in β-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH.

  9. Progesterone Signaling Mechanisms in Brain and Behavior

    PubMed Central

    Mani, Shaila K.; Oyola, Mario G.

    2011-01-01

    Steroid hormone, progesterone, modulates neuroendocrine functions in the central nervous system resulting in alterations in physiology and behavior. These neuronal effects are mediated primarily by intracellular progestin receptors (PRs) in the steroid-sensitive neurons, resulting in transcription-dependent genomic actions (classical mechanism). In addition to progesterone, intracellular PRs can also be activated in a “ligand-independent” manner by neurotransmitters, peptide growth factors, cyclic nucleotides, and neurosteroids. Recent studies indicate that rapid, non-classical progesterone actions involving cytoplasmic kinase signaling and/or extranuclear PRs can result in both transcription-independent and transcription-dependent actions. Cross-talk between extranuclear and classical intracellular signaling pathways promotes progesterone-dependent behavior in mammals. This review focuses on the mechanisms by which progesterone-initiated signaling mechanisms converge with PRs in the brain to modulate reproductive behavior in female rodents. PMID:22649404

  10. Endometriosis Under Estradiol Stimulation Imaged Using 18F-FDG and Its Control After Estradiol Cessation and Progesterone Hormonal Replacement.

    PubMed

    Arsenault, Frédéric; Turcotte, Éric

    2016-03-01

    Endometriosis is a frequent and benign cause of disabling abdominal pain, for which a diagnosis suspicion is clinically raised, but its confirmation necessitates a surgical exploration by laparoscopy. Foci of endometriosis proliferate under estrogen stimulation, like normal endometrium. We present a patient under estradiol stimulation for a history of endometrial cancer who underwent a PET/CT scan to assess an abdominal lesion showing a high F-FDG uptake, which normalized under progesterone hormonal replacement and cessation of estradiol. Two consecutive biopsies confirmed endometriosis. F-FDG evaluation of endometriosis under estrogen stimulation could be a promising approach to refractory endometriosis assessment.

  11. Endometrial thickness predicts endometrial hyperplasia in patients with polycystic ovary syndrome.

    PubMed

    McCormick, Betsy A; Wilburn, Rochelle D; Thomas, Michael A; Williams, Daniel B; Maxwell, Rose; Aubuchon, Mira

    2011-06-30

    Body mass index is predictive of sonographic endometrial stripe thickness, which in turn is predictive of endometrial hyperplasia in patients with polycystic ovary syndrome. For every 1-mm increase in endometrial stripe, the odds ratio of hyperplasia increased by 1.48 (95% confidence interval, 1.04-2.10).

  12. Rab coupling protein (RCP): a novel target of progesterone action in primate endometrium.

    PubMed

    Patil, V S; Sachdeva, G; Modi, D N; Katkam, R R; Manjramkar, D D; Hinduja, I; Puri, C P

    2005-10-01

    Acquisition of functional receptivity by the endometrium is assumed to be effected by progesterone-dependent expression and repression of several genes during the implantation window in a menstrual cycle. In the present study, we employed differential display (DD) reverse transcription-polymerase chain reaction (RT-PCR) to identify progesterone-dependent gene/gene fragments that are differentially expressed during the peri-implantation phase in receptive and nonreceptive endometria, obtained from fertile and infertile bonnet monkeys respectively. Receptive endometria were obtained from regularly cycling (n=5) fertile female bonnet monkeys. Endometrial nonreceptivity was induced by treating bonnet monkeys with either 2.5 mg (n=5) or 5.0 mg (n=5) onapristone (ZK 98.299), an antiprogestin, on every third day for one cycle. Ovulation, levels of circulatory hormones (estradiol and progesterone) and menstrual cycle length did not change in treated animals; however, endometrial growth was retarded. DD2, one of the differentially expressed cDNA fragments, showed higher representation in nonreceptive endometria than in receptive endometria. The DD2 sequence was found to be homologous to the sequence of the carboxyl terminal region of Rab coupling protein (RCP), a recently discovered protein involved in intracellular vesicular trafficking. To confirm the identity of DD2 as RCP, RT-PCR studies were carried out with a forward primer deduced from the RCP sequence and a reverse primer from the DD2 sequence. The product (DDRCP) obtained, when sequenced, revealed 95% homology with the nucleotide number 1196-1757 of human RCP cDNA. Furthermore, the pattern of DDRCP expression at transcript level was found to be similar to that shown by DD2; that is, it was higher in nonreceptive endometrium. Northern analysis using labeled DD2 or DDRCP cDNA fragments identified two transcripts of 6.0 and 4.0 kb in human endometrium. In situ hybridization studies using digoxigenin-labeled DD2

  13. Top quality blastocyst formation rates in relation to progesterone levels on the day of oocyte maturation in GnRH antagonist IVF/ICSI cycles.

    PubMed

    Vanni, V S; Somigliana, E; Reschini, M; Pagliardini, L; Marotta, E; Faulisi, S; Paffoni, A; Vigano', P; Vegetti, W; Candiani, M; Papaleo, E

    2017-01-01

    Cycles with progesterone elevation during controlled ovarian stimulation (COS) for IVF/ICSI are commonly managed with a "freeze-all" strategy, due to a well-recognized detrimental effect of high progesterone levels on endometrial receptivity. However, also a detrimental effect of elevated progesterone on day-3 embryo quality has recently been found with regards to top quality embryo formation rate. Because blastocyst culture and cryopreservation are largely adopted, we deemed relevant to determine whether this detrimental effect is also seen on blastocyst quality on day 5-6. This issue was investigated through a large two-center retrospective study including 986 GnRH antagonist IVF/ICSI cycles and using top quality blastocyst formation rate as the main outcome. Results showed that on multivariate analysis sperm motility (p<0.01) and progesterone levels at ovulation triggering (p = 0.01) were the only two variables that significantly predicted top quality blastocyst formation rate after adjusting for relevant factors including female age, BMI, basal AMH and total dose of FSH used for COS. More specifically, progesterone levels at induction showed an inverse relation with top quality blastocyst formation (correlation coefficient B = -1.08, 95% CI -1.9 to -0.02) and ROC curve analysis identified P level >1.49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts (AUC 0.55, p<0.01). Our study is the first to investigate the top quality blastocyst formation rate in relation to progesterone levels in IVF/ICSI cycles, showing that increasing progesterone is associated with lower rates of top quality blastocyst. Hence, the advantages of prolonging COS to maximize the number of collected oocytes might eventually be hindered by a decrease in top quality blastocysts available for transfer, if increasing progesterone levels are observed. This observation extends the results of two recent studies focused on day-3 embryos and

  14. Endometrial echo complex thickness in postmenopausal endometrial cancer.

    PubMed

    Chandavarkar, Uma; Kuperman, Julie M; Muderspach, Laila I; Opper, Neisha; Felix, Juan C; Roman, Lynda

    2013-10-01

    To determine the preoperative pelvic ultrasonographic characteristics of postmenopausal women diagnosed with endometrial cancer (EC) at our institution. Postmenopausal women with EC who underwent preoperative transvaginal pelvic ultrasound from 1999-2009 were identified from our institutional database. The histologic diagnosis was based on pathologic findings in the hysterectomy specimen. Endometrial echo complex (EEC) thickness was abstracted from ultrasound reports. In all instances, ultrasound preceded the biopsy by a maximum of 3 months. Means with standard deviations were calculated for all categorical data. Differences between type 1 and type 2 ECs were determined using Mann-Whitney U tests and Chi squared/Fisher's exact tests, as appropriate. A p-value of <0.05 was considered statistically significant. Among 250 patients with postmenopausal EC, 156 had type 1 EC while 94 had type 2 EC. Thirty-six percent of the cohort had an EEC ≤ 4 mm, including 37% of patients with type 1 EC and 34% of patients with type 2 EC (p=0.63). There were no significant differences between type 1 and type 2 ECs in any demographic characteristic, other than likelihood of postmenopausal bleeding. Current expert opinion recommends no further diagnostic procedure in a woman with postmenopausal bleeding and an EEC ≤ 4 mm. These results indicate that a sizable proportion of women with EC have EECs ≤ 4 mm during their initial evaluation. An EEC ≤ 4 mm does not completely rule out endometrial cancer and cannot supplant histologic evaluation. © 2013.

  15. Endometrial aspiration cytology in gynecological disorders

    PubMed Central

    Jadhav, Meenal V.; Phatke, Anjali S.; Kadgi, Nalini Vinayak; Rane, Sharda R.; Kulkarni, Kalpana K.

    2016-01-01

    Context: Endometrial aspiration is not a popular modality for the study of the endometrium despite its simplicity and potential utility. Aim: The present study was aimed at evaluating the utility of endometrial aspiration in various gynecological disorders. Materials and Methods: In this diagnostic accuracy study, 55 prospectively registered women with various gynecological disorders were evaluated clinically and subjected to endometrial aspiration cytology and study of endometrial histology. Endometrial aspiration was performed by infant feeding tube in 10 cases and intra cath cannula in 45 cases. The slides were stained with rapid Papanicolaou (PAP) stain and Leishman stain. Results: Endometrial aspiration cytology showed 90% and 94.6% sampling adequacy with infant feeding tube and intra cath cannula, respectively. Intra cath cannula was very convenient to handle and superior to infant feeding tube in aspirating the endometrium. Of the two stains used, rapid PAP stain was less time-consuming and superior to Leishman stain in studying the nuclear details. Leishman stain was helpful in detecting cytoplasmic vacuoles of secretory endometrium. Overall diagnostic accuracy of endometrial cytology was 90.4% while that for morphological hormonal evaluation was 97.6%. It enjoyed a sensitivity of 91.66%, a specificity of 88.23%, positive predictive value of 94.28%, and negative predictive value of 83.33%. Conclusion: Intra cath cannula emerged as an inexpensive, effective, and convenient device for endometrial aspiration. Endometrial aspiration proved to be a fairly effective, simple, and informative diagnostic modality. PMID:27011435

  16. Hypertriglyceridemia is Frequent in Endometrial Cancer Survivors

    PubMed Central

    Hirasawa, Akira; Makita, Kazuya; Akahane, Tomoko; Yokota, Megumi; Yamagami, Wataru; Banno, Kouji; Susumu, Nobuyuki; Aoki, Daisuke

    2013-01-01

    Objective Previous studies have reported an association between endometrial cancer and the risk of metabolic syndrome; however, the pattern of endometrial cancer-associated dyslipidemia is not well understood. The standard therapy for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Premenopausal bilateral salpingo-oophorectomy may cause adverse events, including dyslipidemia. Gynecologists have to care dyslipidemia in endometrial cancer survivors at cancer follow-up clinic. Methods This study included 693 patients who had undergone bilateral salpingo-oophorectomy, and included 412 women with incident endometrial cancer and 281 controls. We divided the patients into two categories according to whether they had a premenopausal or postmenopausal bilateral oophorectomy. Serum lipid levels were measured and statistically analyzed. Results Hypertriglyceridemia was statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy both before and after menopause than in the corresponding non-endometrial cancer controls. High levels of low-density lipoprotein cholesterol and a high low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio were statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy before menopause than in non-endometrial cancer controls. Conclusions Our report highlights the importance of the relationship between endometrial cancer and lipid metabolism, which may aid in preventing cerebrovascular or cardiovascular diseases due to dyslipidemia and improving the quality of life in endometrial cancer survivors. PMID:23999769

  17. A proposed model for endometrial serous carcinogenesis.

    PubMed

    Zheng, Wenxin; Xiang, Li; Fadare, Oluwole; Kong, Beihua

    2011-01-01

    Endometrial serous carcinomas constitute no more than 10% of endometrial adenocarcinomas, but frequently present at an advanced stage and have a significantly worse prognosis than the more common low-grade and intermediate-grade endometrioid adenocarcinomas. The neoplasm's potential for rapid tumor progression and the high mortality that is associated with advanced-stage disease underscore the importance of understanding endometrial serous carcinogenesis so that its precancers can be diagnosed and an effective therapeutic intervention can be administered. In this study, the authors summarize the current state of knowledge on endometrial serous carcinogenesis and propose a model for its development based on recent work from our group and published data from other researchers. In this model, endometrial serous carcinoma arises predominantly in the resting endometrium, manifesting first as p53 immunoreactive, morphologically normal endometrial cells (p53 signatures), evolving to endometrial glandular dysplasia (which is the first morphologically identifiable precursor lesion), then to serous endometrial intraepithelial carcinoma (a carcinoma with a noninvasive growth pattern in the uterus but which is not infrequently associated with extrauterine disease), and finally into fully developed serous carcinoma. Endometrial glandular dysplasia is a lesion, which can be diagnosed by routine microscopic evaluation, whose ablation or removal may potentially offer the opportunity to prevent the development of the associated malignancy. The diagnostic criteria, practical applicability, and evidentiary basis for the delineation of this lesion are studied.

  18. 21 CFR 884.1060 - Endometrial aspirator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... and pipette, or catheter. This device is used to study endometrial cytology (cells). (b... endometrium, and (ii) Contraindications: Pregnancy, history of uterine perforation, or a recent cesarean...

  19. 21 CFR 884.1060 - Endometrial aspirator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... and pipette, or catheter. This device is used to study endometrial cytology (cells). (b... endometrium, and (ii) Contraindications: Pregnancy, history of uterine perforation, or a recent cesarean...

  20. Endometrial tuberculosis compounding polycystic ovary syndrome in a subfertile woman: a case report.

    PubMed

    Mariara, Charles; Koech, Angela; Waweru, Peter; Murage, Alfred

    2016-06-07

    Asymptomatic female genital tuberculosis can impair tubal and endometrial function and later present as subfertility. A majority of the patients with genital tuberculosis in endemic regions present with subfertility and the delay in presentation, coupled with the potential the disease has in mimicking other gynecological conditions, renders it elusive. In addition to the challenge of diagnosing genital tuberculosis, fertility outcomes after treatment are not impressive. This is particularly so in the background of another confounding subfertility factor to which interventional efforts may initially be directed, at the expense of undiagnosed genital tuberculosis. We therefore present a case of subfertility due to endometrial tuberculosis, but confounded by other subfertility factors notably polycystic ovary syndrome. To the best of our knowledge this case report is the first of its kind in the literature. This is a case report of a 42-year-old woman of African descent who presented to our fertility clinic with a 10-year history of primary subfertility and amenorrhea of 6 years duration. She was a nurse in a medical ward and had no prior history of tuberculosis. She had undergone a diagnostic laparoscopy 8 years prior which demonstrated dense pelvic adhesions and an impression of tubal factor subfertility was made. At presentation, her gonadal hormone profile and pelvic ultrasound were consistent with polycystic ovary syndrome. A negative response to a progesterone challenge test prompted a hysteroscopic evaluation which revealed endometrial atrophy. Endometrial biopsies confirmed histological features consistent with tuberculosis. Normal endometrial function was not restored despite adequate treatment and her options were limited to surrogacy or adoption. Genital tuberculosis is elusive in presentation and clinicians should consider it in patients with amenorrhea and/or tubal disease from tuberculosis-endemic regions. Due to the attendant high cost of fertility

  1. Preovulatory, postovulatory, and postmaternal recognition effects of concentrations of progesterone on embryonic survival in the cow.

    PubMed

    Inskeep, E K

    2004-01-01

    Although fertilization rate usually is very high when male fertility is normal, pregnancy rates are below expectations when defined by the birth of live offspring in response to first service. Factors that affect establishment and retention of pregnancy include 1) preovulatory influences on the follicle and oocyte, 2) early postovulatory uterine and luteal function, 3) concentrations of hormones associated with trophoblastic and endometrial function during maternal recognition of pregnancy, and 4) less-well understood factors during the peri-attachment period. For example, decreased progesterone during preovulatory follicular development leads to a persistent follicle, premature resumption of meiosis, and a high incidence of embryonic death between the 2- and 16-cell stages. Elevated PGF(2alpha) during d 4 to 9 of the estrous cycle not only caused luteolysis but also had a direct embryotoxic effect during the morula-to-blastocyst transition. Ideal conditions during placentation and attachment are not clearly defined. Late embryonic mortality might be increased after ovulation of persistent or immature follicles. Nominal increases in secretion of PGF(2alpha) between d 30 and 35 might be important for attachment and placentation. Lower survival of embryos from wk 5 to wk 7 to 9 of gestation in the cow was associated with lower circulating concentrations of progesterone on wk 5. To maximize embryonic survival in the cow, management must provide high progesterone before estrus, quality detection of estrus, and timely insemination. Luteolytic influences of estradiol-17beta or PGF(2alpha) must be minimized early after mating and during maternal recognition of pregnancy, and high progesterone is needed during the late embryonic/early fetal period.

  2. Overview of progesterone profiles in dairy cows.

    PubMed

    Blavy, P; Derks, M; Martin, O; Höglund, J K; Friggens, N C

    2016-09-01

    The aim of this study was to gain a better understanding of the variability in shape and features of all progesterone profiles during estrus cycles in cows and to create templates for cycle shapes and features as a base for further research. Milk progesterone data from 1418 estrus cycles, coming from 1009 lactations, was obtained from the Danish Cattle Research Centre in Foulum, Denmark. Milk samples were analyzed daily using a Ridgeway ELISA-kit. Estrus cycles with less than 10 data points or shorter than 4 days were discarded, after which 1006 cycles remained in the analysis. A median kernel of three data points was used to smooth the progesterone time series. The time between start of progesterone rise and end of progesterone decline was identified by fitting a simple model consisting of base length and a quadratic curve to progesterone data, and this luteal-like phase (LLP) was used for further analysis. The data set of 1006 LLP's was divided into five quantiles based on length. Within quantiles, a cluster analysis was performed on the basis of shape distance. Height, upward and downward slope, and progesterone level on Day 5 were compared between quantiles. Also, the ratio of typical versus atypical shapes was described, using a reference curve on the basis of data in Q1-Q4. The main results of this article were that (1) most of the progesterone profiles showed a typical profile, including the ones that exceeded the optimum cycle length of 24 days; (2) cycles in Q2 and Q3 had steeper slopes and higher peak progesterone levels than cycles in Q1 and Q4 but, when normalized, had a similar shape. Results were used to define differences between quantiles that can be used as templates. Compared to Q1, LLP's in Q2 had a shape that is 1.068 times steeper and 1.048 times higher. Luteal-like phases in Q3 were 1.053 times steeper and 1.018 times higher. Luteal-like phases in Q4 were 0.977 times steeper and 0.973 times higher than LLP's in Q1. This article adds to our

  3. Endometrial Ablation: a Review Article.

    PubMed

    Famuyide, Abimbola

    2017-09-06

    The destruction of the endometrium in women with heavy menstrual bleeding has been employed for well over a century and the various techniques of delivering forms of thermal energy have been modified over the years to assure a safe and effective treatment approach. Today, six non-resectoscopic devices are approved for use in the United States in addition to resectoscopic techniques that rely on skillful use of the operative hysteroscope. Regardless of the technique employed, endometrial ablation uniformly reduces menstrual blood loss, improves general and menstrual related quality of life and prevents hysterectomy in four out of five women who undergo the procedure. When patients are appropriately selected, outcomes are optimized and risks of serious complications are minimized. This article reviews the literature with singular reference to non-resectoscopic endometrial ablation procedures including historical background, appropriate patient selection, clinical outcomes data, complication and special or unique considerations. Copyright © 2017. Published by Elsevier Inc.

  4. 21 CFR 529.1940 - Progesterone intravaginal inserts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Progesterone intravaginal inserts. 529.1940... Progesterone intravaginal inserts. (a) Specifications. Each insert contains: (1) 1.38 grams (g) progesterone in molded silicone over a nylon spine. (2) 0.3 g progesterone in molded silicone over a flexible nylon spine...

  5. 21 CFR 529.1940 - Progesterone intravaginal inserts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Progesterone intravaginal inserts. 529.1940... Progesterone intravaginal inserts. (a) Specifications. Each insert contains: (1) 1.38 grams (g) progesterone in molded silicone over a nylon spine. (2) 0.3 g progesterone in molded silicone over a flexible nylon spine...

  6. 21 CFR 862.1620 - Progesterone test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Progesterone test system. 862.1620 Section 862....1620 Progesterone test system. (a) Identification. A progesterone test system is a device intended to measure progesterone (a female hormone) in serum and plasma. Measurements obtained by this device are used...

  7. 21 CFR 862.1620 - Progesterone test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Progesterone test system. 862.1620 Section 862....1620 Progesterone test system. (a) Identification. A progesterone test system is a device intended to measure progesterone (a female hormone) in serum and plasma. Measurements obtained by this device are used...

  8. 21 CFR 862.1620 - Progesterone test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Progesterone test system. 862.1620 Section 862....1620 Progesterone test system. (a) Identification. A progesterone test system is a device intended to measure progesterone (a female hormone) in serum and plasma. Measurements obtained by this device are used...

  9. 21 CFR 862.1620 - Progesterone test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Progesterone test system. 862.1620 Section 862....1620 Progesterone test system. (a) Identification. A progesterone test system is a device intended to measure progesterone (a female hormone) in serum and plasma. Measurements obtained by this device are used...

  10. 21 CFR 529.1940 - Progesterone intravaginal inserts.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Progesterone intravaginal inserts. 529.1940... Progesterone intravaginal inserts. (a) Specifications. Each insert contains: (1) 1.38 grams (g) progesterone in molded silicone over a nylon spine. (2) 0.3 g progesterone in molded silicone over a flexible nylon spine...

  11. 21 CFR 529.1940 - Progesterone intravaginal inserts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Progesterone intravaginal inserts. 529.1940... Progesterone intravaginal inserts. (a) Specifications. Each insert contains: (1) 1.38 grams (g) progesterone in molded silicone over a nylon spine. (2) 0.3 g progesterone in molded silicone over a flexible nylon spine...

  12. 21 CFR 529.1940 - Progesterone intravaginal inserts.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Progesterone intravaginal inserts. 529.1940... Progesterone intravaginal inserts. (a) Specifications. Each insert contains: (1) 1.38 grams (g) progesterone in molded silicone over a nylon spine. (2) 0.3 g progesterone in molded silicone over a flexible nylon spine...

  13. 21 CFR 862.1620 - Progesterone test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Progesterone test system. 862.1620 Section 862....1620 Progesterone test system. (a) Identification. A progesterone test system is a device intended to measure progesterone (a female hormone) in serum and plasma. Measurements obtained by this device are...

  14. Progesterone Inhibition of Neuronal Calcium Signaling Underlies Aspects of Progesterone-Mediated Neuroprotection

    PubMed Central

    Luoma, Jessie I; Stern, Christopher M; Mermelstein, Paul G.

    2011-01-01

    Progesterone is being utilized as a therapeutic means to ameliorate neuron loss and cognitive dysfunction following traumatic brain injury Although there have been numerous attempts to determine the means by which progesterone exerts neuroprotective effects, studies describing the underlying molecular mechanisms are lacking What has become clear, however, is the notion that progesterone can thwart several physiological processes that are detrimental to neuron function and survival, including inflammation, edema, demyelination and excitotoxicity One clue regarding the means by which progesterone has restorative value comes from the notion that these aforementioned biological processes all share the common theme of eliciting pronounced increases in intracellular calcium. Thus, we propose the hypothesis that progesterone regulation of calcium signaling underlies its ability to mitigate these cellular insults, ultimately leading to neuroprotection. Further, we describe recent findings that indicate neuroprotection is achieved via progesterone block of voltage-gated calcium channels, although additional outcomes may arise from blockade of various other ion channels and neurotransmitter receptors. PMID:22101209

  15. Endometrial prostaglandin synthases, ovarian steroids, and oxytocin receptors in mares with oxytocin-induced luteal maintenance.

    PubMed

    Rebordão, Maria R; Galvão, António; Pinto-Bravo, Pedro; Pinheiro, Joana; Gamboa, Sandra; Silva, Elisabete; Mateus, Luísa; Ferreira-Dias, Graça

    2017-01-01

    Oxytocin (OXT) has been used to prolong the luteal phase in mares, but its mechanism of action is unknown. The aim of this study was to evaluate the effect of chronic exogenous OXT administration to mid-luteal phase mares on luteal maintenance. Also, endometrial expression of prostaglandin endoperoxide synthase 2 (PTGS2), prostaglandin F2α, E2 and I2 synthases (AKR1C3, PTGES, and PTGIS), oxytocin receptor (OXTR), progesterone receptor (PGR), and estrogen receptors 1 (ESR1) and 2 (ESR2) were assessed in mares experiencing luteal maintenance 2 weeks after chronic exogenous OXT administration. Control mares (n = 5; C group) received 6 mL of saline im, whereas OXT (60 units/mare) was administered im (n = 6; OXT group), every 12 hours, on days 7 to 14 postovulation. After endometrial biopsy in groups C (Day 10) and OXT (Day 24), luteolysis occurred within 3 or 6 days, respectively. Luteal maintenance took place in 4 of 6 (67%) of OXT-treated mares. Progesterone in C group was the highest on biopsy day (P < 0.05). In OXT mares, PTGS2, ESR1 (P < 0.05), PTGES, PTGIS, PGR, and ESR2 (P < 0.01) gene transcription decreased, whereas OXTR increased (P < 0.05) in comparison with the C group. In OXT-treated mares, endometrial ESR2 protein expression decreased (P < 0.05), but OXTR increased (P < 0.05) compared with control animals. In both experimental groups, PTGS2 was mainly immunolocalized in surface epithelium, whereas AKR1C3, PTGES, PTGIS, and PGR were in surface and glandular epithelia. ESR1 and ESR2 were found in glandular epithelium and OXTR in stromal cells. High immunolabeling for PTGES, PTGIS, PGR, and OXTR and low for ESR2 was detected in endometrium of OXT-group mares with extended diestrus. Prolonged luteal function associated with chronic OXT treatment may be related to different spatial expression of OXTR and PGR in the endometrium. The observed reduction of endometrial ESR2 may be responsible for the maintenance of PGR in luminal and glandular

  16. Cyclic remodeling of the nonhuman primate endometrium: a model for understanding endometrial receptivity.

    PubMed

    Slayden, Ov Daniel

    2014-09-01

    Old World monkeys display physiological responses to steroid hormones that are similar to those of women. In this review, we describe cyclic morphological changes that take place within the uterus of Old World primates during the menstrual cycle. In primates, estrogen stimulates endometrial growth in the follicular phase of the menstrual cycle. Progesterone secreted in the luteal phase acts to induce secretory differentiation, which is required for successful embryo implantation. During the differentiation process, endometrial estrogen receptor-1 (ESR-1) is suppressed, and reduced staining for ESR-1 is a definitive marker of the onset of uterine receptivity. Downregulation of ESR-1 is topographically limited to the functionalis (upper) zones of the endometrium, the zones in which embryo implantation occurs, indicating that zone-specific factors play a role in the differentiation process. Future genomic and proteomic studies are expected to reveal additional markers for diagnosing endometrial receptivity. Due to the distinct zonal response of the endometrium to ovarian steroids, accurate histological characterization will remain necessary to interpret novel targets in the assessment of fertility.

  17. Endometrial Cancer: What Is New in Adjuvant and Molecularly Targeted Therapy?

    PubMed Central

    Zagouri, Flora; Bozas, George; Kafantari, Eftichia; Tsiatas, Marinos; Nikitas, Nikitas; Dimopoulos, Meletios-A.; Papadimitriou, Christos A.

    2010-01-01

    Endometrial cancer is the most common gynaecological cancer in western countries. Radiotherapy remains the mainstay of postoperative management, but accumulating data show that adjuvant chemotherapy may display promising results after staging surgery. The prognosis of patients with metastatic disease remains disappointing with only one-year survival. Progestins represent an effective option, especially for those patients with low-grade estrogen and/or progesterone receptor positive disease. Chemotherapy using the combination of paclitaxel, doxorubicin, and cisplatin is beneficial for patients with advanced or metastatic disease after staging surgery and potentially for patients with early-stage disease and high-risk factors. Toxicity is a point in question; however, the combination of paclitaxel with carboplatin may diminish these concerns. In women with multiple medical comorbidities, single-agent chemotherapy may be better tolerated with acceptable results. Our increased knowledge of the molecular aspects of endometrial cancer biology has paved the way for clinical research to develop novel targeted antineoplastic agents (everolimus, temsirolimus, gefitinib, erlotinib, cetuximab, trastuzumab, bevacizumab, sorafenib) as more effective and less toxic options. Continued investigation into the molecular pathways of endometrial cancer development and progression will increase our knowledge of this disease leading to the discovery of novel, superior agents. PMID:20148071

  18. Expression of Endometrial Receptivity Genes Increase After Myomectomy of Intramural Leiomyomas not Distorting the Endometrial Cavity.

    PubMed

    Unlu, Cihat; Celik, Onder; Celik, Nilufer; Otlu, Baris

    2016-01-01

    This study was designed to investigate whether endometrial receptivity genes are altered in infertile patients with intramural leiomyomas (IM) not distorting the endometrial cavity undergoing myomectomy. We measured endometrial HOXA-10, HOXA-11, LIF, ITGB3, and ITGAV messenger RNA (mRNA) expressions levels before and after myomectomy/metroplasty during mid-luteal phase in participants with IM, submucosal leiomyomas (SM), and septate uterus and fertile participants without fibroids. Initial endometrial sampling was obtained at the time of surgery, and second sampling was obtained 3 months after myomectomy/metroplasty. Expressions of each gene were evaluated using real-time reverse transcriptase polymerase chain reaction (RT-PCR). A trend toward decreased endometrial HOXA-10, HOXA-11, and ITGAV mRNA expression was detected in both SM and IM groups before myomectomy when compared to both fertile group and septate uterus. However, the differences failed to show statistical significance. After myomectomy of IM, we have detected 12.8-fold increase in endometrial HOXA-10 mRNA expression and 9.0-fold increase in endometrial HOXA-11 mRNA expression. This increase in endometrial HOXA-10 and 11 mRNA expression was significant. Accordingly, 2 patients having intramural fibroids greater than 5 cm were able to remain pregnant after myomectomy. Conversely, submucosal myomectomy did not cause any significant effect on endometrial receptivity markers. Likewise, all markers of endometrial receptivity remained unchanged after metroplasty. Myomectomy of IM have favorable effect on endometrial HOXA-10 and 11 mRNA expression.

  19. Progesterone Modulates a Neuronal Nicotinic Acetylcholine Receptor

    NASA Astrophysics Data System (ADS)

    Valera, S.; Ballivet, M.; Bertrand, D.

    1992-10-01

    The major brain nicotinic acetylcholine receptor is assembled from two subunits termed α 4 and nα 1. When expressed in Xenopus oocytes, these subunits reconstitute a functional acetylcholine receptor that is inhibited by progesterone levels similar to those found in serum. In this report, we show that the steroid interacts with a site located on the extracellular part of the protein, thus confirming that inhibition by progesterone is not due to a nonspecific perturbation of the membrane bilayer or to the activation of second messengers. Because inhibition by progesterone does not require the presence of agonist, is voltage-independent, and does not alter receptor desensitization, we conclude that the steroid is not an open channel blocker. In addition, we show that progesterone is not a competitive inhibitor but may interact with the acetylcholine binding site and that its effect is independent of the ionic permeability of the receptor.

  20. Does male sexual behavior require progesterone?

    PubMed

    Andersen, Monica Levy; Tufik, Sergio

    2006-06-01

    In this article, we provide a concise review of the past and current literature on the neglected influence of progesterone on male sexual behavior. Although there has been increased interest in all aspects of male sexual function, and the importance of androgens in the regulation of male copulatory behavior has long been well documented, knowledge of the role of progesterone on male sexual behavior is still patchy. Very little human data exist on this theme, and most of the literature concerns animal research, in particular reptiles and rodents. This review attempts to outline specific progesterone mechanisms involved in male sexual behavior, showing that this hormone plays a more relevant role in the control of male sexual behavior than commonly assumed. Exploring the neuroendocrine mechanisms of progesterone in the sexual behavior of males may provide insights into the regulation of sexuality in this gender.

  1. Progesterone metabolism in cultured amniotic fluid cells.

    PubMed

    Beling, C G; Cederqvist, L L

    1978-01-01

    Amniotic fluid cells obtained by amnicentesis at 16-20 weeks' gestation were grown in culture until a confluent monolayer of cell had been formed. Radiolabeled pregnenolone, progesterone and 20 alpha-dihydroprogesterone were added to the cell cultures; steroid metabolites which formed after 24 and 48 hours of incubation were identified. Incubation of the cell cultures with pregnenolone-3H resulted in the formation of progesterone, 17alpha-progesterone and 20 alpha-dihydroprogesterone. A significant amount of progesterone was identified after incubating the cell cultures with 20 alpha-dihydroprogesterone. The results indicate that 3 beta-ol-dehydrogenase, 17 alpha-hydroxylase and 20 alpha-hydroxysteroid dehydrogenase enzymes are present in cultured amniotic fluid cells obtained at 16-20 weeks' gestation.

  2. Detection of progesterone in whole blood samples.

    PubMed

    Ehrentreich-Förster, Eva; Scheller, Frieder W; Bier, Frank F

    2003-04-01

    The progesterone concentration in blood samples can be utilised as a marker for the diagnosis of early pregnancy, endocrinopathy and virilism. Here, we describe a method for progesterone detection and measurement in whole blood samples by a surface sensitive biosensor used in conjunction with an integrated optical grating coupler. This device determines refractive index changes near the biosensor's surface. Hence, biological species bound to a surface layer can be measured in real-time without any label. For the measurements, we have modified the indirect competitive immunoassay principle. The concentration of the progesterone antibody was kept at 1 microg/ml. Progesterone concentration was determined in buffer solution and whole blood in a range between 0.005 and 10 ng/ml. The detection limit was determined to be 3 pM. The relative standard deviation was calculated to be 3.5%.

  3. Naproxen sodium decreases prostaglandins secretion from cultured human endometrial stromal cells modulating metabolizing enzymes mRNA expression.

    PubMed

    Carrarelli, Patrizia; Funghi, Lucia; Bruni, Simone; Luisi, Stefano; Arcuri, Felice; Petraglia, Felice

    2016-01-01

    Dysmenorrhea, defined as painful cramps occurring immediately before or during the menstrual period, is a common symptom of different gynecological diseases. An acute uterine inflammatory response driven by prostaglandins (PGs) is responsible for painful symptoms. Progesterone withdrawal is responsible for activation of cyclooxygenase (COX-2) enzyme and decrease of hydroxyprostaglandin dehydrogenase (HPDG) with consequent increased secretion of PGs secretion, inducing uterine contractility and pain. The most widely used drugs for the treatment of pelvic pain associated with menstrual cycle are non steroidal anti-inflammatory drugs (NSAIDs). The uterine site of action of these drugs is still not defined and the present study evaluated the effect of naproxen sodium in cultured human endometrial stromal cells (HESC) collected from healthy women. PGE2 release was measured by ELISA; COX-2 and HPDG mRNA expression were assessed by qRT-PCR. Naproxen sodium did not affect HESC vitality. Naproxen sodium significantly decreased PGE2 secretion (p < 0.01) and COX-2 mRNA expression (p < 0.01). TNF-α induced PGE2 release was reduced in presence of naproxen sodium (p < 0.05), in association with decreased COX-2 and increased HPDG mRNAs expression. Naproxen sodium decreases endometrial PGE2 release induced by inflammatory stimulus acting on endometrial COX-2 and HPDG expression, suggesting endometrial synthesis of prostaglandins as a possible target for reduction of uterine inflammatory mechanism in dysmenorrhea.

  4. Endometrial cancer arising from atypical complex hyperplasia: The significance in an endometrial biopsy and a diagnostic challenge

    PubMed Central

    Byun, Jung Mi; Jeong, Dae Hoon; Kim, Young Nam; Cho, En Bee; Cha, Ju Eun; Sung, Moon Su; Lee, Kyung Bok

    2015-01-01

    Objective We investigated the features of endometrial hyperplasia with concurrent endometrial cancer that had been diagnosed by endometrial sampling. Further, we attempted to identify an accurate differential diagnostic method. Methods We retrospectively studied 125 patients who underwent a diagnostic endometrial biopsy or were diagnosed after the surgical treatment of other gynecological lesions, such as leiomyoma or polyps. Patients were diagnosed between January 2005 and December 2013 at Busan Paik Hospital. Clinical and histopathological characteristics were compared in patients who had atypical endometrial hyperplasia with and without concurrent endometrial cancer. Results The patients were grouped based on the final pathology reports. One hundred seventeen patients were diagnosed with endometrial hyperplasia and eight patients were diagnosed with endometrioid adenocarcinoma arising from atypical hyperplasia. Of the 26 patients who had been diagnosed with atypical endometrial hyperplasia by office-based endometrial biopsy, eight (30.8%) were subsequently diagnosed with endometrial cancer after they had undergone hysterectomy. The patients with endometrial cancer arising from endometrial hyperplasia were younger (39.1 vs. 47.2 years, P=0.0104) and more obese (body mass index 26.1±9.6 vs. 23.8±2.8 kg/m2, P=0.3560) than the patients with endometrial hyperplasia. The correlation rate between the pathology of the endometrial samples and the final diagnosis of endometrial hyperplasia was 67.3%. Conclusion In patients with atypical endometrial hyperplasia, the detection of endometrial cancer before hysterectomy can decrease the risk of suboptimal treatment. The accuracy of endometrial sampling for the diagnosis of concurrent endometrial carcinoma was much lower than that for atypical endometrial hyperplasia. Therefore, concurrent endometrial carcinoma should be suspected and surgical intervention should be considered in young or obese patients who present with

  5. HER-2/neu (c-erbB-2) oncoprotein in hyperplastic endometrial polyps detected in two cats.

    PubMed

    Misirlioglu, Deniz; Nak, Deniz; Ozyigit, Musa Ozgur; Nak, Yavuz; Akkoc, Ahmet

    2009-10-01

    The presence of HER-2/neu (c-erbB-2) oncoprotein, oestrogen-alpha receptor (ER), and progesterone receptor (PR) in hyperplastic endometrial polyps (EPs) of two cats with cystic endometrial hyperplasia-pyometra (CEH-P) complex was investigated. Immunohistochemistry assay for ER, PR and c-erbB-2 oncoprotein in the glandular and stromal tissue of the EPs was performed. ER and c-erbB-2 immunoreactivity was observed in the glandular epithelium of the EPs whereas PR immunoreactivity was detected only in the stromal fibroblasts. The c-erbB-2 oncoprotein may play a role with the ER in the pathogenesis of the hyperplastic EPs, although the role of this oncoprotein in the pathogenesis of EPs has yet to be determined.

  6. Endometrial polyps in 2 African pygmy hedgehogs.

    PubMed

    Phillips, Irene D; Taylor, Jacqueline J; Allen, Andrew L

    2005-06-01

    Reports of spontaneously occurring endometrial polyps in animals are rare and have only involved a few species. This report is intended to advise veterinarians that older African pygmy hedgehogs may develop endometrial polyps and that these lesions can be a cause of bloody vaginal discharge, sometimes interpreted as hematuria.

  7. Diagnosis and Management of Endometrial Cancer.

    PubMed

    Braun, Michael M; Overbeek-Wager, Erika A; Grumbo, Robert J

    2016-03-15

    Endometrial cancer is the most common gynecologic malignancy. It is the fourth most common cancer in women in the United States after breast, lung, and colorectal cancers. Risk factors are related to excessive unopposed exposure of the endometrium to estrogen, including unopposed estrogen therapy, early menarche, late menopause, tamoxifen therapy, nulliparity, infertility or failure to ovulate, and polycystic ovary syndrome. Additional risk factors are increasing age, obesity, hypertension, diabetes mellitus, and hereditary nonpolyposis colorectal cancer. The most common presentation for endometrial cancer is postmenopausal bleeding. The American Cancer Society recommends that all women older than 65 years be informed of the risks and symptoms of endometrial cancer and advised to seek evaluation if symptoms occur. There is no evidence to support endometrial cancer screening in asymptomatic women. Evaluation of a patient with suspected disease should include a pregnancy test in women of childbearing age, complete blood count, and prothrombin time and partial thromboplastin time if bleeding is heavy. Most guidelines recommend either transvaginal ultrasonography or endometrial biopsy as the initial study. The mainstay of treatment for endometrial cancer is total hysterectomy with bilateral salpingo-oophorectomy. Radiation and chemotherapy can also play a role in treatment. Low- to medium-risk endometrial hyperplasia can be treated with nonsurgical options. Survival is generally defined by the stage of the disease and histology, with most patients at stage I and II having a favorable prognosis. Controlling risk factors such as obesity, diabetes, and hypertension could play a role in the prevention of endometrial cancer.

  8. Endometrial polyps in 2 African pygmy hedgehogs

    PubMed Central

    2005-01-01

    Abstract Reports of spontaneously occurring endometrial polyps in animals are rare and have only involved a few species. This report is intended to advise veterinarians that older African pygmy hedgehogs may develop endometrial polyps and that these lesions can be a cause of bloody vaginal discharge, sometimes interpreted as hematuria. PMID:16048013

  9. Sunitinib Malate in Treating Patients With Recurrent or Metastatic Endometrial Cancer

    ClinicalTrials.gov

    2017-01-31

    Endometrial Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma; Endometrial Serous Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma; Uterine Corpus Carcinosarcoma

  10. Determining the Optimal Duration of Progesterone Supplementation prior to Transfer of Cryopreserved Embryos and Its Impact on Implantation and Pregnancy Rates: A Pilot Study

    PubMed Central

    Majumdar, Abha

    2016-01-01

    Objective. To determine the optimal duration of progesterone supplementation prior to transfer of cryopreserved embryos and its impact on implantation and pregnancy rates. Study Design. Prospective randomised study. Materials and Methods. In an IVF unit of a tertiary centre, sixty-six patients undergoing cryopreserved embryo transfer cycles were included. Endometrial preparation was done with estradiol valerate. Once it reached a minimum of 7 mm, patients were allocated randomly into group I (n = 39) and group II (n = 27). Injectable progesterone 100 mg daily was then started for 3 and 4 days, respectively. This was followed by transfer of at least one thawed cleavage stage day 2 embryo of good quality. Groups I and II were compared in terms of clinical pregnancy and implantation rates. Results. In group I (3-day progesterone) and group II (4-day progesterone) the pregnancy rates were 41.02% (16/39) and 18.51% (5/27), respectively. On the other hand, the implantation rates were 16.82% (18/107) and 7.69% (6/78), respectively. The difference was statistically significant (p values 0.0172 and 0.0386, resp.). Conclusion. Progesterone supplementation for three days before the transfer of cleavage stage (day 2) cryopreserved embryos has significantly higher pregnancy and implantation rates, as compared to four-day supplementation. PMID:27752538

  11. Chemomertical analysis of endometrial tissue fluorescence spectra

    NASA Astrophysics Data System (ADS)

    Vaitkuviene, Aurelija; Auksorius, E.; Fuchs, D.; Gavriushin, V.

    2002-10-01

    An effort has been made to detect neopterin spectrum in fluorescence of premalignant endometrial tissue and to estimate the number of fluorophores naturally existing in the tissue with fluorescence present above the noise level. Endometrial Tissue fluorescence was measured in vitro by excitation with the third harmonic of Nd YAG laser. Multivariate curve resolution was used for testing neopterin presence in endometrial tissue. Fluorescence spectra ofneopterin was measured and used as a target spectrum for testing. Seven factors -fluorescence ofnatural fluorophores ofendometrial tissue were found to be present above the noise level in the overall autofluorescence. Neopterin concentration may be too low in endometrial tissue to make its fluorescence above the noise level because neopterin spectrum was not found to be among the spectra resolved by multivariate curve resolution. An intensity increase in the neopterin spectrum spectral region in hyperplastic endometrial samples might be associated with neopterin concentration increase.

  12. Evaluation of endometrial cancer epidemiology in Romania.

    PubMed

    Bohîlțea, R E; Furtunescu, F; Dosius, M; Cîrstoiu, M; Radoi, V; Baroș, A; Bohîlțea, L C

    2015-01-01

    Endometrial cancer represents the most frequent gynecological malignant affection in the developed countries, in which the incidence of cervical cancer has significantly decreased due to the rigorous application of screening methods and prophylaxis. According to its frequency, endometrial cancer is situated on the fourth place in the category of women's genital-mammary malignant diseases, after breast, cervical and ovarian cancer in Romania. The incidence and mortality rates due to endometrial cancer have registered an increasing trend worldwide and also in Romania, a significant decrease of the age of appearance for the entire endometrial pathology sphere being noticed. At the national level, the maximum incidence is situated between 60 and 64 years old, the mortality rate of the women under 65 years old being high in Romania. The study evaluates endometrial cancer, from an epidemiologic point of view, at the national level compared to the international statistic data.

  13. Risk Factors for Endometrial Cancer among Women with a BRCA1 or BRCA2 Mutation: A Case Control Study

    PubMed Central

    Segev, Yakir; Rosen, Barry; Lubinski, Jan; Gronwald, Jacek; Lynch, Henry T.; Moller, Pal; Kim-Sing, Charmaine; Ghadirian, Parviz; Karlan, Beth; Eng, Charis; Gilchrist, Dawna; Neuhausen, Susan L.; Eisen, Andrea; Friedman, Eitan; Euhus, David; Ping, Sun; Narod, Steven A.

    2016-01-01

    Purpose BRCA mutation carriers may use tamoxifen for breast cancer prevention or treatment. Hormone replacement therapy is often prescribed after surgical menopause and oral contraceptives are recommended for ovarian cancer prevention. The objective of this study was to assess the impact of these medications and other risk factors on endometrial cancer risk in BRCA carriers. Methods Women with a BRCA1 or BRCA2 mutation were identified from a registry of mutation carriers. Cases were 83 women who had a diagnosis of endometrial cancer. Controls were 1027 matched women who did not develop endometrial cancer and who had an intact uterus. All women completed a baseline questionnaire, which included questions about ages at menarche and menopause, oral contraceptive use, hormone replacement therapy use, hysterectomy, oophorectomy, breast cancer history and tamoxifen use. We estimated the odds ratio associated with each risk factor in a multivariate analysis. Results No differences were found between cases and controls in terms of age at menarche, BMI, smoking, or oral contraceptive use. In a multivariate analysis, for women taking estrogen-only hormone replacement therapy, the odds ratio was 0.23 (95% CI 0.03–1.78, p = 0.16), and for women taking progesterone-only hormone replacement therapy the odds ratio was 6.91 (95% CI 0.99–98.1, p = 0.05). The adjusted odds ratio for endometrial cancer associated with a history of tamoxifen use was 3.50 (95% CI 1.51 to 8.10; p = 0.003). Conclusions The observed increased risk of associated with progesterone-only therapy merits further study. PMID:25838159

  14. Effect of progesterone and its synthetic analogues on the activity of mitochondrial permeability transition pore in isolated rat liver mitochondria.

    PubMed

    Fedotcheva, Nadezhda I; Teplova, Vera V; Fedotcheva, Tatiana A; Rzheznikov, Vladimir M; Shimanovskii, Nikolai L

    2009-10-15

    The influence of progesterone and its synthetic analogues on the induction of the Ca(2+)-dependent mitochondrial permeability transition pore (MPTP) has been studied. The novel synthetic analogue of progesterone 17a-acetoxy-3b-butanoyloxy-6-methyl-pregna-4,6-diene-20-on (buterol) was compared with progesterone and medroxyprogesterone acetate (MPA). It was found that progesterone and buterol have opposite effects on the induction of MPTP opening by calcium ions. By contrast to progesterone, which decreased the calcium ion concentration necessary for pore opening, and MPA, which also, although at a lesser extent, activated the pore induction, buterol at a concentration of 20-100 microM blocked the pore opening and increased the calcium retention capacity of mitochondria more than twofold. The action of buterol is specific to the pore since it did not affect the respiration, whereas progesterone completely inhibited NAD-dependent respiration. MPA acted similar to progesterone but less effectively. The inhibitory effect of buterol was eliminated in the presence of carboxyatractyloside, which selectively binds the thiol groups of adenylate translocase and prevents the adenine nucleotide binding. These data indicate that buterol interacts with thiol groups, which explains its inhibitory effect not only on the mitochondrial pore but also on the transport system of xenobiotics in tumor cells in which buterol reduces the multidrug resistance.

  15. Luteotropic and luteolytic factors regulate mRNA and protein expression of progesterone receptor isoforms A and B in the bovine endometrium.

    PubMed

    Rekawiecki, Robert; Kowalik, Magdalena Karolina; Kotwica, Jan

    2014-12-17

    The aim of the present study was to examine the effects of luteotropic and luteolytic factors on the mRNA and protein levels of progesterone receptor isoforms A (PGRA) and B (PGRB) in the bovine endometrium. Endometrial slices from Days 6-10 and 17-20 of the oestrous cycle were treated with LH (100ngmL-1), oestradiol (E2; 1×10-8M), prostaglandin (PG) E2 (1×10-6M) and PGF2? (1×10-6M) and the nitric oxide donor NONOate (1×10-4M); these treatments lasted for 6h for mRNA expression analysis and 24h for protein expression analysis. On Days 6-10 of the oestrous cycle PGRAB (PGRAB; the entire PGRA mRNA sequence is common to the PGRB mRNA sequence) mRNA expression in endometrial slices was enhanced by E2 treatment (PPGRB mRNA expression was increased by LH (PPPPGRAB mRNA expression increased after E2 (P2 (PPGRB mRNA expression was increased by PGE2 (P2? (PPPPPP2? (P2 (P2? (P<0.001). These data suggest that luteotropic and luteolytic factors affect PGRA and PGRB mRNA and protein levels, and this may regulate the effects of progesterone on endometrial cells.

  16. Expression of focal adhesion kinase in endometrial stromal cells of women with endometriosis was adjusted by ovarian steroid hormones.

    PubMed

    Mu, Lin; Ma, Yan-Yan

    2015-01-01

    The aim of our study is to investigate the effects of ovarian steroid hormones on focal adhesion kinase (FAK) expression in ESCs and whether there is alteration in women with endometriosis. FAK expression was assessed by western blotting analysis. Elevated expression of FAK was seen in the cultured ESCs treated with estrogen (P < 0.05). Expression of FAK protein was not changed in ESCs after treated by progesterone or treated by estrogen and progesterone. The level of up-regulation by estrogen in endometriosis is significantly higher than that from women without endometriosis (P < 0.05). FAK expression in endometrial stromal cells from endometriosis was more sensitive to estrogen, which might contribute to the pathogenesis and progress of endometriosis.

  17. Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

    PubMed Central

    Holst, Frederik; Hoivik, Erling A.; Gibson, William J.; Taylor-Weiner, Amaro; Schumacher, Steven E.; Asmann, Yan W.; Grossmann, Patrick; Trovik, Jone; Necela, Brian M.; Thompson, E. Aubrey; Meyerson, Matthew; Beroukhim, Rameen; Salvesen, Helga B.; Cherniack, Andrew D.

    2016-01-01

    The estrogen receptor alpha (ERα) is highly expressed in both endometrial and breast cancers, and represents the most prevalent therapeutic target in breast cancer. However, anti-estrogen therapy has not been shown to be effective in endometrial cancer. Recently it has been shown that hormone-binding domain alterations of ERα in breast cancer contribute to acquired resistance to anti-estrogen therapy. In analyses of genomic data from The Cancer Genome Atlas (TCGA), we observe that endometrial carcinomas manifest recurrent ESR1 gene amplifications that truncate the hormone-binding domain encoding region of ESR1 and are associated with reduced mRNA expression of exons encoding the hormone-binding domain. These findings support a role for hormone-binding alterations of ERα in primary endometrial cancer, with potentially important therapeutic implications. PMID:27160768

  18. The utility of endometrial thickness measurement in asymptomatic postmenopausal women with endometrial fluid.

    PubMed

    Seckin, B; Ozgu-Erdinc, A S; Dogan, M; Turker, M; Cicek, M N

    2016-01-01

    The aim of this study was to assess the clinical usefulness of sonographic endometrium thickness measurement in asymptomatic postmenopausal women with endometrial fluid collection. Fifty-two asymptomatic postmenopausal women with endometrial fluid, who underwent endometrial sampling were evaluated. Histopathological findings revealed that 25 (48.1%) women had insufficient tissue, 20 (38.4%) had atrophic endometrium and 7 (13.5%) had endometrial polyps. No case of malignancy was found. There was no statistically significant difference between the various histopathological categories (insufficient tissue, atrophic endometrium and polyp) with regard to the mean single-layer endometrial thickness (1.54 ± 0.87, 2.04 ± 1.76 and 1.79 ± 0.69 mm, respectively, p = 0.436). Out of 44 patients with endometrial thickness of less than 3 mm, 38 (86.4%) had atrophic changes or insufficient tissue and 6 (13.6%) had endometrial polyps. In conclusion, if the endometrial thickness is 3 mm or less, endometrial sampling is not necessary in asymptomatic postmenopausal women with endometrial fluid.

  19. Ovarian steroids, mitogen-activated protein kinases, and/or aspartic proteinases cooperate to control endometrial remodeling by regulating gene expression in the stroma and glands.

    PubMed

    Gaide Chevronnay, Héloïse P; Lemoine, Pascale; Courtoy, Pierre J; Marbaix, Etienne; Henriet, Patrick

    2010-09-01

    Explants from nonmenstrual endometria cultured in the absence of ovarian hormones undergo tissue breakdown. Addition of estradiol and progesterone (EP) prevents proteolysis. Explants include stromal and epithelial compartments which play different but complementary roles in endometrial physiology, including tissue remodeling and hormonal response. In order to characterize the cell type-specific contribution to regulation of tissue breakdown, we characterized the transcriptomes of microdissected stromal and glandular areas from endometrial explants cultured with or without EP. The datasets were also compared to other published endometrial transcriptomes. Finally, the contribution of proteolysis, hypoxia, and MAPKs to the regulation of selected genes was further investigated in explant culture. This analysis identified distinct gene expression profiles in stroma and glands, with differential response to EP, but functional clustering underlined convergence in biological processes, further indicating that endometrial remodeling requires cooperation between the two compartments through expression of cell type-specific genes. Only partial overlaps were observed between lists of genes involved in different occurrences of endometrial breakdown, pointing to a limited number of potentially crucial regulators but also to the requirement for additional mechanisms controlling tissue remodeling. We identified a group of genes differentially regulated by EP in stroma and glands among which some were sensitive to MAPKs and/or aspartic proteinases and were not induced by hypoxia. In conclusion, MAPKs and/or aspartic proteinases likely act in concert with EP to locally and specifically control differential expression of genes between degrading and preserved areas of the human endometrium.

  20. Progesterone modulates the LPS-induced nitric oxide production by a progesterone-receptor independent mechanism.

    PubMed

    Wolfson, Manuel Luis; Schander, Julieta Aylen; Bariani, María Victoria; Correa, Fernando; Franchi, Ana María

    2015-12-15

    Genital tract infections caused by Gram-negative bacteria induce miscarriage and are one of the most common complications of human pregnancy. LPS administration to 7-day pregnant mice induces embryo resorption after 24h, with nitric oxide playing a fundamental role in this process. We have previously shown that progesterone exerts protective effects on the embryo by modulating the inflammatory reaction triggered by LPS. Here we sought to investigate whether the in vivo administration of progesterone modulated the LPS-induced nitric oxide production from peripheral blood mononuclear cells from pregnant and non-pregnant mice. We found that progesterone downregulated LPS-induced nitric oxide production by a progesterone receptor-independent mechanism. Moreover, our results suggest a possible participation of glucocorticoid receptors in at least some of the anti-inflammatory effects of progesterone.

  1. The effect of progesterone on coronary blood flow in anaesthesized pigs.

    PubMed

    Molinari, C; Battaglia, A; Grossini, E; Mary, D A; Stoker, J B; Surico, N; Vacca, G

    2001-01-01

    The present study was designed to investigate the effect of progesterone on the coronary circulation and to determine the mechanisms involved. In pigs anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary blood flow caused by intravenous infusion of progesterone at constant heart rate and arterial blood pressure were assessed using an electromagnetic flowmeter. In 14 pigs, infusion of 1 mg h(-1) of progesterone caused an increase in coronary blood flow without affecting left ventricular dP/dtmax (rate of change of left ventricular systolic pressure) and filling pressures of the heart. In a further four pigs, this vasodilatory coronary effect was enhanced by graded increases in the dose of the hormone of between 1, 2 and 3 mg h(-1). The mechanisms of the above response were studied in the 14 pigs by repeating the experiment after haemodynamic variables had returned to the control values observed before infusion. In six pigs, blockade of muscarinic cholinoceptors and adrenoceptors with atropine, propranolol and phentolamine did not affect the coronary vasodilatation caused by progesterone. In the remaining eight pigs, this response was abolished by intracoronary injection of N(omega)-nitro-L-arginine methyl ester (L-NAME) even when performed after reversing the increase in arterial blood pressure and coronary vascular resistance caused by L-NAME with continuous intravenous infusion of papaverine. The present study showed that intravenous infusion of progesterone primarily caused coronary vasodilatation. The mechanism of this response was shown to involve the endothelial release of nitric oxide.

  2. Endometrial transcriptional profiling of a bovine fertility model by Next-Generation Sequencing

    PubMed Central

    Mesquita, F.S.; Ramos, R.S.; Pugliesi, G.; Andrade, S.C.S.; Van Hoeck, V.; Langbeen, A.; Oliveira, M.L.; Gonella-Diaza, A.M.; Gasparin, G.; Fukumasu, H.; Pulz, L.H.; Membrive, C.M.; Coutinho, L.L.; Binelli, M.

    2015-01-01

    Studying the multitude of molecular networks and pathways that are potentially involved in a complex trait such as fertility requires an equally complex and broad strategy. Here, we used Next-Generation Sequencing for the characterization of the transcriptional signature of the bovine endometrial tissue. Periovulatory endocrine environments were manipulated to generate two distinctly different fertility phenotypes. Cycling, non-lactating, multiparous Nelore cows were manipulated to ovulate larger (> 13 mm; LF group; high fertility phenotype) or smaller (< 12 mm; SF group) follicles. As a result, greater proestrus estrogen concentrations, corpora lutea and early diestrus progesterone concentrations were also observed in LF group in comparison to SF group. Endometrial cell proliferation was estimated by the protein marker MKI67 on tissues collected 4 (D4) and 7 (D7) days after induction of ovulation. Total RNA extracts from D7 were sequenced and compared according to the transcriptional profile of each experimental group (LF versus SF). Functional enrichment analysis revealed that LF and SF endometria were asynchronous in regards to their phenotype manifestation. Major findings indicated an LF endometrium that was switching phenotypes earlier than the SF one. More specifically, a proliferating SF endometrium was observed on D7, whereas the LF tissue, which expressed a proliferative phenotype earlier at D4, seemed to have already shifted towards a biosynthetically and metabolically active endometrium on D7. Data on MKI67 support the transcriptomic results. RNA-Seq-derived transcriptional profile of the endometrial tissue indicated a temporal effect of the periovulatory endocrine environment, suggesting that the moment of the endometrial exposure to the ovarian steroids, E2 and P4, regulates the timing of phenotype manifestation. Gene expression profiling revealed molecules that may be targeted to elucidate ovarian steroid-dependent mechanisms that regulate

  3. Assessment of bioavailability of oral micronized progesterone using a salivary progesterone enzymeimmunoassay.

    PubMed

    Bolaji, I I; Tallon, D F; O'Dwyer, E; Fottrell, P F

    1993-06-01

    Salivary progesterone was measured sequentially by enzymeimmunoassay following 1 month and 6 months of oral therapy with 100 mg of micronized progesterone (MOP) in 40 healthy estrogenized postmenopausal women (aged 40-68 years). MOP was administered for 23 days every month. There were striking differences in the absorption of MOP between various subjects. Significant increases occurred in salivary progesterone concentrations over baseline and pretreatment levels and persisted for at least 10 h. Levels of salivary progesterone remained higher than pretreatment levels for at least 24 h after administration of MOP. Maximum mean concentrations of salivary progesterone of 827.2 and 888 pmol/l in the 1st and 6th months of therapy, respectively, were achieved within 2 h of administration and were above the 95th percentile of a control corridor which corresponds to the range found in the luteal phase. The areas under the salivary progesterone curve (AUC0-24 h, pmol/l) were 7177.75 and 7388.20 respectively, in the 1st and 6th months of therapy but the difference was not statistically significant. Serum and salivary progesterone peaked simultaneously and there was a significant correlation between the concentrations measured concurrently (y = 233.08 + 35.575x; r = 0.89, p < 0.001) thus supporting the current concept of a relatively rapid diffusion of steroids from plasma to saliva. Results of this study confirm those of previous investigations which monitored the bioavailability of MOP with the use of serum progesterone measurements and showed that luteal phase progesterone concentrations can be attained easily. The use of non-invasive salivary sampling and a cost-effective, direct enzymeimmunoassay showed a considerable advantage in the present study, compared with previous ones. We conclude that 100 mg MOP should be given at least twice-daily to maintain a stable physiological luteal phase level of progesterone during clinical hormone replacement therapy.

  4. Vascular endothelial growth factor in primate endometrium is regulated by oestrogen-receptor and progesterone-receptor ligands in vivo.

    PubMed

    Greb, R R; Heikinheimo, O; Williams, R F; Hodgen, G D; Goodman, A L

    1997-06-01

    We investigated hormonal regulation of endometrial angiogenesis in menstruating primates. This study was designed to demonstrate: (i) that cell-specific vascular endothelial growth factor (VEGF) production and expression in monkey endometrium are regulated by steroid receptor ligands; and (ii) mifepristone (RU 486) alters VEGF production even in the absence of a progestin agonist. Endometrial VEGF production was compared by computer-assisted immunohistochemical analysis during induced hypoestrogenism and after oestradiol, progestin, or antiprogestin (mifepristone) treatment. VEGF gene expression was estimated by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in endometrial samples from castrate cynomolgus monkeys, from intact monkeys in the luteal phase, and from monkeys treated for 20 days with levonorgestrel (LNG) or mifepristone. VEGF staining intensities in glandular epithelium and VEGF mRNA expression were highest in hypoestrogenic monkeys. Progestin treatment induced intense VEGF staining in the stroma. Gene expression of VEGF-189, but not other isoforms, was higher in progesterone- and progestin (LNG)-exposed endometria compared to mifepristone-exposed endometria or endometria from anovulatory cycles (P < 0.04). Mifepristone abolished VEGF staining in glandular epithelium almost completely. We conclude that VEGF protein and VEGF mRNA expression levels in primate endometrium depend on the steroidal milieu. Anti-angiogenic effects of mifepristone via suppression of VEGF production might represent a mechanism for its quelling effects on endometrium.

  5. Crosstalk between estrogen receptor and mitogen-activated protein kinase signaling in the development and progression of endometrial cancer.

    PubMed

    Zhou, Long; Cai, Bin; Bao, Wei; He, Yin-Yan; Chen, Xiao-Yue; Yang, Yi-Xia; Liu, Xue-Lian; Wan, Xiao-Ping

    2011-11-01

    The objectives of the study were to evaluate the role of mitogen-activated protein kinase (MAPK) signaling in normal, hyperplastic, and neoplastic endometrium in relation to estrogen receptor (ER) status and to investigate whether 17β-estradiol (E2) and tamoxifen (TAM) mediate the proliferation and apoptosis of endometrial cancer cells through the MAPK pathway. The expressions of phosphorylated and total extracellular signal-regulated kinases 1/2 (phosphorylated extracellular signal-regulated kinase 1/2 [p-ERK1/2] and total ERK1/2 [t-ERK1/2]) were analyzed with immunohistochemistry in normal, hyperplastic, and neoplastic endometrium. The expression levels of p-ERK1/2 and t-ERK1/2 in RL95-2 and KLE after stimulation by E2, progesterone (P), and TAM were detected by Western blotting. The effects of E2 and TAM in combination with MAPK pathway inhibitors on the growth and apoptosis of endometrial cancer cells were examined by the MTS assay and flow cytometry analysis. The expression level of p-ERK1/2 was significantly associated with the International Federation of Gynecology and Obstetrics stage (P = 0.0072). The ratio of phosphorylated/total ERK1/2 was higher in ER-positive endometrial cancer tissues and cells (P < 0.05). 17β-Estradiol increased ERK1/2 phosphorylation, and TAM decreased ERK1/2 phosphorylation in endometrial cancer cell lines within 30 minutes (P < 0.05). The MEK1/2 inhibitor, U0126, and the stress-activated protein kinase/c-Jun NH2-terminal kinase inhibitor, SP600125, significantly suppressed the proliferation of human endometrial cancer cell lines RL95-2 and KLE induced by E2 (P < 0.05). The level of TAM-induced apoptosis was greater in KLE than in RL95-2 cells, and the p38 cascade was involved in the TAM-induced apoptosis of both cell lines (P < 0.05). The cross-talk between MAPK signaling and ER status might exert a key role in progression of endometrial cancer. Furthermore, the effects of E2 or TAM on the proliferation or apoptosis of ER

  6. Dietary fat intake and endometrial cancer risk

    PubMed Central

    Zhao, Jing; Lyu, Chen; Gao, Jian; Du, Li; Shan, Boer; Zhang, Hong; Wang, Hua-Ying; Gao, Ying

    2016-01-01

    Abstract Since body fatness is a convincing risk factor for endometrial cancer, dietary fat intake was speculated to be associated with endometrial cancer risk. However, epidemiological studies are inconclusive. We aimed to conduct a meta-analysis to assess the associations between dietary fat intake and endometrial cancer risk. We searched the PubMed, Embase, and Web of science databases updated to September 2015. In total, 7 cohort and 14 case–control studies were included. Pooled analysis of case–control studies suggested that endometrial cancer risk was significantly increased by 5% per 10% kilocalories from total fat intake (P=0.02) and by 17% per 10 g/1000 kcal of saturated fat intake (P < 0.001). Summary of 3 cohort studies showed significant inverse association between monounsaturated fatty acids and endometrial cancer risk (odds ratio = 0.84, 95% confidence interval = 0.73–0.98) with a total of 524583 participants and 3503 incident cases. No significant associations were found for polyunsaturated fatty acids and linoleic acid. In conclusion, positive associations with endometrial cancer risk were observed for total fat and saturated fat intake in the case–control studies. Results from the cohort studies suggested higher monounsaturated fatty acids intake was significantly associated with lower endometrial cancer risk. PMID:27399120

  7. The Emerging Genomic Landscape of Endometrial Cancer

    PubMed Central

    Le Gallo, Matthieu; Bell, Daphne W.

    2014-01-01

    BACKGROUND Endometrial cancer is responsible for ~74,000 deaths amongst women worldwide each year. It is a heterogeneous disease that consists of multiple different histological subtypes. In the United States, the majority of deaths from endometrial carcinoma are attributed to the serous and endometrioid subtypes. An understanding of the fundamental genomic alterations that drive serous and endometrioid endometrial carcinomas lays the foundation for the identification of molecular markers that could improve the clinical management of patients presenting with these tumors. CONTENT Herein we review the current state of knowledge of the somatic genomic alterations that are present in serous and endometrioid endometrial tumors. We present this knowledge in a historical context – reviewing the genomic alterations that have been identified over the past two decades or more, from studies of individual genes and proteins, followed by a review of very recent studies that have conducted comprehensive, systematic surveys of genomic, exomic, transcriptomic, epigenomic, and proteomic alterations in serous and endometrioid endometrial carcinomas. SUMMARY The recent mapping of the genomic landscape of serous and endometrioid endometrial carcinomas has resulted in the first comprehensive molecular classification of these tumors and has distinguished four molecular subgroups: a POLE ultramutated subgroup, a hypermutated/microsatellite unstable subgroup, a copy number low/microsatellite stable subgroup, and a copy number high subgroup. This molecular classification may ultimately serve to refine the diagnosis and treatment of women with endometrioid and serous endometrial tumors. PMID:24170611

  8. Molecular classification of human endometrial cycle stages by transcriptional profiling.

    PubMed

    Ponnampalam, Anna P; Weston, Gareth C; Trajstman, Albert C; Susil, Beatrice; Rogers, Peter A W

    2004-12-01

    Endometrium is a dynamic tissue that undergoes cyclic changes each month, under the overall control of estrogen and progesterone. The aims of this study were to investigate the changing global gene expression profile of human endometrium during the menstrual cycle using microarray technology and to determine the correlation between histopathological evaluation and molecular profile of the samples. Standard two-colour cDNA microarrays were performed on the 43 samples against a common reference, using a 10.5 K cDNA glass slide microarray. The results were validated using real-time PCR. Analysis of expression data was carried out using parametric analysis of variance with Benjamini-Hochberg correction. Hierarchical clustering reveals a strong relationship between histopathology and transcriptional profile of the samples. The study identified 1452 genes that showed significant changes in expression (P< or =0.05) across the menstrual cycle, with 425 genes having changes that are at least 2-fold. The data were also independently analysed by a CSIRO algorithm called GeneRaVE that identified a small subset of genes whose expression profiles could be used to classify nearly all the biopsies into their correct cycle stage. We also identified and validated three genes [(natural cytotoxicity triggering receptor (NCR)3, fucosyl transferase (FUT)4 and Fyn-binding protein (FYB)] that had not been shown to have significant cyclic changes in the human endometrium, previously. We have shown for the first time that endometrial cycle stage prediction is possible based on global gene expression profile.

  9. Cabozantinib-S-Malate in Treating Patients With Recurrent or Metastatic Endometrial Cancer

    ClinicalTrials.gov

    2017-03-20

    Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Metastatic Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IV Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  10. CRISPLD2 is a target of progesterone receptor and its expression is decreased in women with endometriosis.

    PubMed

    Yoo, Jung-Yoon; Shin, Heesung; Kim, Tae Hoon; Choi, Won-Seok; Ferguson, Susan D; Fazleabas, Asgerally T; Young, Steven L; Lessey, Bruce A; Ha, Un-Hwan; Jeong, Jae-Wook

    2014-01-01

    Endometriosis, defined as the presence of endometrial cells outside of the uterine cavity, is a major cause of infertility and pelvic pain, afflicting more than 10% of reproductive age women. Endometriosis is a chronic inflammatory disease and lipopolysaccharide promotes the proliferation and invasion of endometriotic stromal cells. Cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) has high affinity for lipopolysaccharide and plays a critical role in defense against endotoxin shock. However, the function of CRISPLD2 has not been studied in endometriosis and uterine biology. Herein, we examined the expression of CRISPLD2 in endometrium from patients with and without endometriosis using immunohistochemistry. The expression of CRISPLD2 was higher in the secretory phase in human menstrual cycle compared to proliferative phase. The expression of CRISPLD2 was significantly decreased in the endometrium of women with endometriosis in the early secretory phase compared to women without endometriosis. The increase of CRISPLD2 expression at the early secretory and dysregulation of its expression in endometriosis suggest progesterone (P4) regulation of CRISPLD2. To investigate whether CRISPLD2 is regulated by P4, we examined the expression of the CRISPLD2 in the uteri of wild-type and progesterone receptor knock out (PRKO) mice. The expression of CRISPLD2 was significantly increased after P4 treatment in the wild-type mice. However, CRISPLD2 expression was significantly decreased in the (PRKO) mice treated with P4. During early pregnancy, the expression of CRISPLD2 was increased in decidua of implantation and post-implantation stages. CRISPLD2 levels were also increased in cultured human endometrial stromal cells during in vitro decidualization. These results suggest that the CRISPLD2 is a target of the progesterone receptor and may play an important role in pathogenesis of endometriosis.

  11. Endometrial receptivity array: Clinical application.

    PubMed

    Mahajan, Nalini

    2015-01-01

    Human implantation is a complex process requiring synchrony between a healthy embryo and a functionally competent or receptive endometrium. Diagnosis of endometrial receptivity (ER) has posed a challenge and so far most available tests have been subjective and lack accuracy and a predictive value. Microarray technology has allowed identification of the transcriptomic signature of the window of receptivity window of implantation (WOI). This technology has led to the development of a molecular diagnostic tool, the ER array (ERA) for diagnosis of ER. Use of this test in patients with recurrent implantation failure (RIF) has shown that the WOI is displaced in a quarter of these patients and use of a personalized embryo transfer (pET) on the day designated by ERA improves reproductive performance. Our results in the Indian population revealed an endometrial factor in 27.5% RIF patients, which was significantly greater than the non-RIF group 15% (P = 0.04). After pET, the overall ongoing pregnancy rate was 42.4% and implantation rate was 33%, which was at par with our in-vitro fertilization results over 1-year. We also performed ERA in patients with persistently thin endometrium, and it was reassuring to find that the endometrium in 75% of these patients was receptive despite being 6 mm or less. A pregnancy rate of 66.7% was achieved in this group. Though larger studies are required to validate these results ERA has become a useful tool in our diagnostic armamentarium for ER.

  12. Endometrial receptivity array: Clinical application

    PubMed Central

    Mahajan, Nalini

    2015-01-01

    Human implantation is a complex process requiring synchrony between a healthy embryo and a functionally competent or receptive endometrium. Diagnosis of endometrial receptivity (ER) has posed a challenge and so far most available tests have been subjective and lack accuracy and a predictive value. Microarray technology has allowed identification of the transcriptomic signature of the window of receptivity window of implantation (WOI). This technology has led to the development of a molecular diagnostic tool, the ER array (ERA) for diagnosis of ER. Use of this test in patients with recurrent implantation failure (RIF) has shown that the WOI is displaced in a quarter of these patients and use of a personalized embryo transfer (pET) on the day designated by ERA improves reproductive performance. Our results in the Indian population revealed an endometrial factor in 27.5% RIF patients, which was significantly greater than the non-RIF group 15% (P = 0.04). After pET, the overall ongoing pregnancy rate was 42.4% and implantation rate was 33%, which was at par with our in-vitro fertilization results over 1-year. We also performed ERA in patients with persistently thin endometrium, and it was reassuring to find that the endometrium in 75% of these patients was receptive despite being 6 mm or less. A pregnancy rate of 66.7% was achieved in this group. Though larger studies are required to validate these results ERA has become a useful tool in our diagnostic armamentarium for ER. PMID:26538853

  13. Isolated Abdominal Wall Metastasis of Endometrial Carcinoma

    PubMed Central

    Simões, Jorge; Gonçalves, Matilde; Matos, Isabel

    2014-01-01

    A woman in her mid-60s presented with a bulky mass on the anterior abdominal wall. She had a previous incidental diagnosis of endometrial adenocarcinoma FIGO stage IB following a vaginal hysterectomy. Physical exam and imaging revealed a well circumscribed bulging tumour at the umbilical region, measuring 10 × 9 × 9 cm, with overlying intact skin and subcutaneous tissue. Surgical resection was undertaken, and histological examination showed features of endometrial carcinoma. She began chemotherapy and is alive with no signs of recurrent disease one year after surgery. This case brings up to light an atypical location of a solitary metastasis of endometrial carcinoma. PMID:25349753

  14. Prevalence of Co-existing Endometrial Carcinoma in Patients with Preoperative Diagnosis of Endometrial Hyperplasia

    PubMed Central

    Kadirogullari, Pinar; Atalay, Cemal Resat; Sari, Mustafa Erkan

    2015-01-01

    Introduction Endometrial hyperplasia has been associated with the presence of concomitant endometrial carcinoma. In this study, patients who were diagnosed with endometrial hyperplasia and had hysterectomy, determination of the incidence of endometrial cancer accompanying postoperatively and clinical parameters associated with cancer are aimed. Materials and Methods Endometrial biopsies were taken from patients for various reasons and among them 158 patients diagnosed with endometrial hyperplasia from pathologic examination results were retrospectively evaluated. All of the patient’s age, parity, weight, transvaginal ultrasound measured by endometrial thickness, concomitant systemic disease (diabetes, hypertension, hypothyroidism), tamoxifen use, hormone use and whether in reproductive age or menopause were all questioned. Patients who applied with endometrial cancer, their cervical stromal involvement, lymph node involvement, cytology positivity and omental metastases were examined. Patients were classified according to their stage and grade. Patients who had intraoperative frozen were re-evaluated. Results Fifteen cases with preoperative endometrial hyperplasia diagnosed with endometrial cancer postoperatively, 2 cases had complex hyperplasia without atypia and 13 cases had complex atypical hyperplasia. The rate of preoperative hyperplasia with postoperative endometrial cancer was found to be 10.8% where by 15 cases of patients diagnosed with endometrial cancer postoperatively 11 cases were in postmenopausal period. In patients diagnosed with endometrial cancer according to their histologic types 14 cases had endometrioid adenocarcinoma while one patient with preoperative complex hyperplasia without atypia was diagnosed with serous papillary carcinoma postoperatively. Evaluation of stages in patients diagnosed with cancer, 7 cases of patients had stage IA, 7 cases of patients had stage IB, and 7 cases cases of patients with serous papillary carcinoma were

  15. Breast cancer susceptibility polymorphisms and endometrial cancer risk: a Collaborative Endometrial Cancer Study.

    PubMed

    Healey, Catherine S; Ahmed, Shahana; O'Mara, Tracy A; Ferguson, Kaltin; Lambrechts, Diether; Garcia-Dios, Diego A; Vergote, Ignace; Amant, Frederic; Howarth, Kimberley; Gorman, Maggie; Hodgson, Shirley; Tomlinson, Ian; Yang, Hannah P; Lissowska, Jolanta; Brinton, Louise A; Chanock, Stephen; Garcia-Closas, Montserrat; Hall, Per; Liu, Jianjun; Shah, Mitul; Pharoah, Paul D P; Thompson, Deborah J; Rebbeck, Timothy R; Strom, Brian L; Dunning, Alison M; Easton, Douglas F; Spurdle, Amanda B

    2011-12-01

    Recent large--scale association studies, both of genome-wide and candidate gene design, have revealed several single-nucleotide polymorphisms (SNPs) which are significantly associated with risk of developing breast cancer. As both breast and endometrial cancers are considered to be hormonally driven and share multiple risk factors, we investigated whether breast cancer risk alleles are also associated with endometrial cancer risk. We genotyped nine breast cancer risk SNPs in up to 4188 endometrial cases and 11,928 controls, from between three and seven Caucasian populations. None of the tested SNPs showed significant evidence of association with risk of endometrial cancer.

  16. Breast cancer susceptibility polymorphisms and endometrial cancer risk: a Collaborative Endometrial Cancer Study

    PubMed Central

    Ahmed, Shahana; O’Mara, Tracy A.; Ferguson, Kaltin; Lambrechts, Diether; Garcia-Dios, Diego A.; Vergote, Ignace; Amant, Frederic; Howarth, Kimberley; Gorman, Maggie; Hodgson, Shirley; Tomlinson, Ian; Yang, Hannah P.; Lissowska, Jolanta; Brinton, Louise A.; Chanock, Stephen; Garcia-Closas, Montserrat; Hall, Per; Liu, Jianjun; Shah, Mitul; Pharoah, Paul D.P.; Thompson, Deborah J.; Rebbeck, Timothy R.; Strom, Brian L.; Dunning, Alison M.; Easton, Douglas F.; Spurdle, Amanda B.

    2011-01-01

    Recent large--scale association studies, both of genome-wide and candidate gene design, have revealed several single-nucleotide polymorphisms (SNPs) which are significantly associated with risk of developing breast cancer. As both breast and endometrial cancers are considered to be hormonally driven and share multiple risk factors, we investigated whether breast cancer risk alleles are also associated with endometrial cancer risk. We genotyped nine breast cancer risk SNPs in up to 4188 endometrial cases and 11 928 controls, from between three and seven Caucasian populations. None of the tested SNPs showed significant evidence of association with risk of endometrial cancer. PMID:21965274

  17. Therapeutic effects of progesterone in animal models of neurological disorders.

    PubMed

    De Nicola, Alejandro F; Coronel, Florencia; Garay, Laura I; Gargiulo-Monachelli, Gisella; Gonzalez Deniselle, Maria Claudia; Gonzalez, Susana L; Labombarda, Florencia; Meyer, Maria; Guennoun, Rachida; Schumacher, Michael

    2013-12-01

    Substantial evidence supports that progesterone exerts many functions in the central and peripheral nervous system unrelated to its classical role in reproduction. In this review we first discussed progesterone effects following binding to the classical intracellular progesterone receptors A and B and several forms of membrane progesterone receptors, the modulation of intracellular signalling cascades and the interaction of progesterone reduced metabolites with neurotransmitter receptors. We next described our results involving animal models of human neuropathologies to elucidate the protective roles of progesterone. We described: (a) the protective and promyelinating effects of progesterone in experimental spinal cord injury; (b) the progesterone protective effects exerted upon motoneurons in the degenerating spinal cord of Wobbler mouse model of amyotropic lateral sclerosis; (c) the protective and anti-inflammatory effects of progesterone in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis and after lysolecithin demyelination; (d) the progesterone prevention of nociception and neuropathic pain which follow spinal cord injury; and (e) the protective effect of progesterone in experimental ischemic stroke. Whenever available, the molecular mechanisms involved in these progesterone effects were examined. The multiplicity of progesterone beneficial effects has opened new venues of research for neurological disorders. In this way, results obtained in animal models could provide the basis for novel therapeutic strategies and pre-clinical studies.

  18. Androgen receptors are acquired by healthy postmenopausal endometrial epithelium and their subsequent loss in endometrial cancer is associated with poor survival

    PubMed Central

    Kamal, A M; Bulmer, J N; DeCruze, S B; Stringfellow, H F; Martin-Hirsch, P; Hapangama, D K

    2016-01-01

    Background: Endometrial cancer (EC) is a hormone-driven disease, and androgen receptor (AR) expression in high-grade EC (HGEC) and metastatic EC has not yet been described. Methods: The expression pattern and prognostic value of AR in relation to oestrogen (ERα and ERβ) and progesterone (PR) receptors, and the proliferation marker Ki67 in all EC subtypes (n=85) were compared with that of healthy and hyperplastic endometrium, using immunohistochemisty and qPCR. Results: Compared with proliferative endometrium, postmenopausal endometrtial epithelium showed significantly higher expression of AR (P<0.001) and ERα (P=0.035), which persisted in hyperplastic epithelium and in low-grade EC (LGEC). High-grade EC showed a significant loss of AR (P<0.0001), PR (P<0.0001) and ERβ (P<0.035) compared with LGEC, whilst maintaining weak to moderate ERα. Unlike PR, AR expression in metastatic lesions was significantly (P=0.039) higher than that in primary tumours. Androgen receptor expression correlated with favourable clinicopathological features and a lower proliferation index. Loss of AR, with/without the loss of PR was associated with a significantly lower disease-free survival (P<0.0001, P<0.0001, respectively). Conclusions: Postmenopausal endometrial epithelium acquires AR whilst preserving other steroid hormone receptors. Loss of AR, PR with retention of ERα and ERβ may promote the unrestrained growth of HGEC. Androgen receptor may therefore be a clinically relevant prognostic indicator and a potential therapeutic target in EC. PMID:26930451

  19. Osteopontin and Integrin αvβ3 Expression during the Implantation Window in IVF Patients with Elevated Serum Progesterone and Oestradiol Level

    PubMed Central

    He, Z.; Ma, Y.; Li, L.; Liu, J.; Yang, H.; Chen, C.; Lin, N.; Bai, Y.; Ma, R.; Li, R.; Wu, Z.; Qiao, J.

    2016-01-01

    Background: To explore whether endometrial receptivity is determined by osteopontin (OPN) and integrin αvβ3 expression in women with elevated serum progesterone (P) and/or oestradiol (E2) who are undergoing in vitro fertilisation (IVF). Methods: According to serum hormone levels on the day of HCG administration, 33 infertile women were divided into 3 groups: the high E2, high P, and high E2 and P groups. The control group included 11 fertile, healthy women. Endometrial biopsy was performed on ovulation day + 7 to + 8 for all study participants, and the mRNA and protein expression levels of OPN and integrin αvβ3 were analyzed. Result: No statistically significant differences regarding OPN and integrin αvβ3 expression were found between infertile patients in the high P, high E2, high E2 and P and control groups. There was no significant correlation between OPN and integrin αvβ3 staining intensity during the implantation window biopsy in any of the groups studied. Conclusion: Endometrial OPN and integrant αvβ3 expression/co-expression is not impaired during the window of implantation in patients with high P, high E2, or high E2 and P levels. The clinical value of assessing endometrial receptivity with OPN and integrin αvβ3 seems to be uncertain. PMID:27365542

  20. The effects of intrauterine infusion of peanut oil on endometrial health, salivary cortisol and interovulatory period in mares.

    PubMed

    Campbell, Madeleine L H; Hampshire, Daniel; Hamstead, Lauren E; Rose, Belinda V; Smith, Ken C; de Mestre, Amanda M

    2017-10-15

    Intrauterine infusion of peanut oil at Day 10 post-ovulation has been reported to prolong dioestrus in mares. However, the effects of peanut oil treatment on the endometrium and whether the technique is painful have not been assessed. The objectives of this study were, (i) to determine the effect of intrauterine infusion of peanut oil on endometrial health, (ii) to determine whether use of intrauterine peanut oil is painful and (iii) to confirm that peanut oil causes prolonged dioestrus. Six mares aged 3-12 years old were used in a cross-over design with each mare administered both 1 ml of intrauterine peanut oil and a sham treatment on different oestrous cycles. The effect of intrauterine infusion of 1 ml peanut oil or sham treatment were measured using interovulatory period, uterine fluid accumulation as determined by transrectal ultrasonography, serum progesterone levels, endometrial Kenney biopsy scores and histological features, endometrial eosinophil numbers and salivary cortisol measurements. The individual mare response to intrauterine infusion of peanut oil was variable. Peanut oil infusion did not statistically prolong the luteal phase, nor elevate salivary cortisol levels but did cause superficial erosion of the endometrial surface epithelium in all mares and significantly increased eosinophil numbers in the endometrium (P = 0.0068). The Kenney grade for biopsies from 2/6 mares worsened transiently following infusion. In conclusion, intra-uterine peanut oil does not statistically increase the duration of the luteal phase but results in an inflammatory response and increase in endometrial eosinophil numbers suggesting treatment may be associated with a hypersensitivity-type reaction. Those contemplating using peanut oil to suppress oestrus should also be aware of the legislative and regulatory implications. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Endometrial cytology and computerized morphometric analysis of epithelial nuclei: a useful tool for reproductive diagnosis in the bitch.

    PubMed

    Groppetti, D; Pecile, A; Arrighi, S; Di Giancamillo, A; Cremonesi, F

    2010-04-15

    New diagnostic approaches are required to recognize early canine hypofertility or infertility. We suggest that the identification of different cytologic types, cellular aspects, and nuclear features of the endometrial epithelial cells may be suitable for this purpose. This study was performed on the bitch (Canis familiaris) during the physiologic reproductive cycle and in uterine diseases. We also applied computerized cytomorphometry to evaluate nuclear area, perimeter, diameter, density, aspect, and roundness of endometrial epithelial cells in healthy dogs (N=35) at different stages of the reproductive cycle (before puberty, during proestrus, estrus, diestrus, and anestrus) and in bitches affected by uterine disorders (N=10). The stage of the estrous cycle was determined by vaginal cytology and progesterone evaluation and also confirmed by clinical and histologic observations. Samples for endometrial cytology were collected in vivo by uterine flushing with transcervical uterine cannulation. After uterine sampling, each dog underwent OHE or uterine stump revision. Cytologic analyses were compared with histologic examinations to verify the uterine condition. The uterine cellular population was represented by endometrial epithelial cells, erythrocytes, neutrophils, lymphocytes, eosinophils, macrophages, plasma cells, and cervical or incidental vaginal cells. Bacteria and amorphous material were observed. The proportion of different cells and nuclear features in the cytologic samples varied throughout the stages of the reproductive cycle and between normal and pathologic uterine conditions. The computer-assisted nuclear morphometry, performed in cytologic specimens by means of the six nuclear parameters chosen to evaluate the endometrial epithelial cell population, proved to be useful for determining the stage of the reproductive cycle. Furthermore, this system was demonstrated to be a valid support to diagnose and distinguish uterine disorders.

  2. Delayed uterine fluid clearance and reduced uterine perfusion in bitches with endometrial hyperplasia and clinical management with postmating antibiotic.

    PubMed

    England, G C W; Moxon, R; Freeman, S L

    2012-10-15

    In many species a transient uterine inflammatory response follows mating and is proposed to remove excess spermatozoa, bacteria, and other contaminants from the uterus. Similar events have been documented in the bitch involving increased uterine contractions, polymorphonuclear neutrophil influx and uterine artery vasodilation. Some healthy bitches with endometrial hyperplasia have increased numbers of uterine luminal polymorphonuclear neutrophils after mating and reduced fertility; it is purported that this represents a presumed postmating endometritis. This study used B-mode and Doppler ultrasonography at the time of mating to measure uterine contractions, clearance of ejaculated fluid, and uterine artery velocity in normal bitches and those with endometrial hyperplasia. Mating resulted in an increase in the number of uterine contractions, although fewer mating-induced contractions were noted in bitches with endometrial hyperplasia. Interestingly, uterine fluid cleared significantly more slowly after mating from the bitches with endometrial hyperplasia than the normal bitches (P = 0.01). In a further study, Doppler ultrasonography showed that in normal bitches there was a significant increase in uterine artery blood velocity (P = 0.04) and a decrease in the resistance index after mating (P = 0.04), indicating vasodilation. In bitches with endometrial hyperplasia the baseline resistance index was significantly higher than normal bitches (P = 0.05), and furthermore, although there was a significant decrease in resistance index after mating, in the bitches with endometrial hyperplasia this was of a smaller magnitude that in normal bitches. These findings indicate lower baseline uterine perfusion, and a blunted vasodilation response to mating in bitches with endometrial hyperplasia. Short-duration postmating administration of systemic antibiotic increased pregnancy rates in bitches with endometrial hyperplasia (P < 0.01). Litter sizes in bitches with endometrial

  3. Systematic review of progesterone use by midlife and menopausal women.

    PubMed

    Spark, M Joy; Willis, Jon

    2012-07-01

    Progesterone treatment for menopausal symptoms is still controversial. Progesterone levels fall during menopause transition, therefore some menopausal women may benefit from progesterone therapy. A systematic review was conducted of studies published from 2001 reporting on progesterone use to treat symptoms associated with menopause or postmenopausal women. Fourteen data bases were searched using the search terms progesterone, menopause, aged, female and human; exclusions were breast cancer, animal and contraception. Thirteen studies were selected for inclusion (11 clinical trials, 1 cohort study and 1 qualitative study), evaluating progesterone effects on menopausal symptoms, bone, sleep, skin, cognition, plasma lipids and plaque progression. Most studies were of low methodological quality (GRADE low or very low). Progesterone improved vasomotor symptoms and sleep quality, with minimal risk. Large studies designed to identify confounders, such as hormone levels, menopausal status and metabolism are required to understand the place of progesterone in clinical practice.

  4. Intraperitoneal Paclitaxel, Doxorubicin Hydrochloride, and Cisplatin in Treating Patients With Stage III-IV Endometrial Cancer

    ClinicalTrials.gov

    2017-08-23

    Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  5. Dasatinib, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2015-12-22

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

  6. Coculturing human endometrial epithelial cells and stromal fibroblasts alters cell-specific gene expression and cytokine production

    PubMed Central

    Chen, Joseph C.; Erikson, David W.; Piltonen, Terhi T.; Meyer, Michelle R.; Barragan, Fatima; McIntire, Ramsey H.; Tamaresis, John S.; Vo, Kim Chi; Giudice, Linda C.; Irwin, Juan C.

    2013-01-01

    Objective To determine the effects of coculturing endometrial epithelial cells (eEC) with paired endometrial stromal fibroblasts (eSF) on cell-specific gene expression and cytokine secretion patterns. Design In vitro study. Setting University research laboratory. Patient(s) Endometrial biopsies were obtained from premenopausal women. Intervention(s) Polarized eEC and subject-paired eSF were cultured for 12.5 hours alone (monoculture) or combined in a two-chamber coculture system without cell-cell contact. Cells and conditioned media were analyzed for global gene expression and cytokine secretion, respectively. Purified, endometrial tissue-derived eEC and eSF isolated by fluorescent activated cell sorting (FACS) were used as noncultured controls. Main Outcome Measure(s) Cell-specific global gene expression profiling and analysis of secreted cytokines in eEC/eSF cocultures and respective monocultures. Result(s) Transepithelial resistance, diffusible tracer exclusion, expression of tight junction proteins, and apical/basolateral vectorial secretion confirmed eEC structural and functional polarization. Distinct transcriptomes of eEC and eSF were consistent with their respective lineages and their endometrial origin. Coculture of eEC with eSF resulted in altered cell-specific gene expression and cytokine secretion. Conclusion(s) This coculture model provides evidence that interactions between endometrial functionally polarized epithelium and stromal fibroblasts affect cell-specific gene expression and cytokine secretion underscoring their relevance when modeling endometrium in vitro. PMID:23849844

  7. 21 CFR 884.1185 - Endometrial washer.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... with negative pressure. This device is used to study endometrial cytology (cells). (b) Classification... a recent cesarean section, and (iii) Warning: Do not attach to a wall or any external suction, and...

  8. 21 CFR 884.1185 - Endometrial washer.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... with negative pressure. This device is used to study endometrial cytology (cells). (b) Classification... a recent cesarean section, and (iii) Warning: Do not attach to a wall or any external suction, and...

  9. 21 CFR 884.1185 - Endometrial washer.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... with negative pressure. This device is used to study endometrial cytology (cells). (b) Classification... a recent cesarean section, and (iii) Warning: Do not attach to a wall or any external suction, and...

  10. The epidemic of endometrial cancer: a commentary.

    PubMed Central

    Jick, H; Walker, A M; Rothman, K J

    1980-01-01

    Vital statistics show that a rise in incidence of endometrial cancer began in the mid-1960s on the West Coast of the United States. This rise was continuous and reached a peak in 1975. Elsewhere, incidence rates for endometrial cancer rose during the 1970s. It now seems evident that much of the rise in all areas of the country was due to replacement estrogen treatment. We estimated from data obtained from the Commission on Professional and Hospital Activities-Professional Activity Study of Ann Arbor, Michigan, that over 15,000 cases of endometrial cancer were caused by replacement estrogens during the five-year period 1971--1975 alone. This represents one of the largest epidemics of serious iatrogenic disease that has ever occurred in this country. With the substantial fall in estrogen sales starting in January 1976, there has been an associated decline in the incidence rates of endometrial cancer nationwide. PMID:7356090

  11. 21 CFR 884.1100 - Endometrial brush.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... endometrial cytology (cells). (b) Classification. Class II. The special controls for this device are: (1) FDA...) Indication: Only to evaluate the endometrium, and (ii) Contraindications: Pregnancy, history of uterine...

  12. 21 CFR 884.1100 - Endometrial brush.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... endometrial cytology (cells). (b) Classification. Class II. The special controls for this device are: (1) FDA...) Indication: Only to evaluate the endometrium, and (ii) Contraindications: Pregnancy, history of uterine...

  13. 21 CFR 884.1100 - Endometrial brush.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... endometrial cytology (cells). (b) Classification. Class II. The special controls for this device are: (1) FDA...) Indication: Only to evaluate the endometrium, and (ii) Contraindications: Pregnancy, history of uterine...

  14. 21 CFR 884.1100 - Endometrial brush.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... endometrial cytology (cells). (b) Classification. Class II. The special controls for this device are: (1) FDA...) Indication: Only to evaluate the endometrium, and (ii) Contraindications: Pregnancy, history of uterine...

  15. 21 CFR 884.1060 - Endometrial aspirator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... and pipette, or catheter. This device is used to study endometrial cytology (cells). (b) Classification. Class II. The special controls for this device are: (1) FDA's: (i) “Use of International...

  16. 21 CFR 884.1060 - Endometrial aspirator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... and pipette, or catheter. This device is used to study endometrial cytology (cells). (b) Classification. Class II. The special controls for this device are: (1) FDA's: (i) “Use of International...

  17. Revised FIGO staging system for endometrial cancer.

    PubMed

    Lewin, Sharyn N

    2011-06-01

    In 1988 the International Federation of Gynecologists and Obstetricians (FIGO) developed a surgical staging system for endometrial cancer. The FIGO staging system was recently revised in 2009 to reflect our growing understanding of the natural history of endometrial cancer. In this review, we describe the revised 2009 FIGO staging system for tumors of the uterine corpus and examine the effect of the new changes in the staging criteria.

  18. [Endometrial vasculature in women with hydrosalpinx].

    PubMed

    Kirichenko, A K; Khorzhevskiĭ, V A

    2014-01-01

    To study the endometrial vasculature in women with hydrosalpinx and to determine a possible correlation between its state and the morphometric parameters of other structural components of the uterine mucosa. The endometrium was studied in 20 patients with primary tubal infertility in hydrosalpinx. A control group included 20 women with established fertility and a regular menstrual cycle with a good obstetric and gynecological history. The spectrum of morphometric parameters included the relative volumes occupied by the endometrial glands and glandular epithelium; the height of the integumentary epithelium; and the number of stromal cells per mm2. Stereometric (glandular-stromal, epithelial-stromal) indices and epithelium/glandular lumen ratio were calculated. The endometrial vasculature was estimated by immunohistochemical assay of CD31- and CD34-expressing cells. There was a decrease in the specific volume occupied by positively stained vascular endotheliocytes and a predominance of the stromal component of the endometrium over its epithelial one. Correlations were found between the degree of development of the endometrial vasculature and endometrial glands, which reflects their normal relationships in the proliferation phase. In the study group, the correlation between the height of the integumentary epithelium and the development of the endometrial vasculature was moderately positive, which was absent in the control group where this correlation was strong and positive. The findings are evidence in favor of the negative impact of hydrosalpinx on the uterine mucosa. The found changes in the main endometrial structural components (vessels, glands, and stromal cells) reflect impaired mucosal maturation processes during the proliferation phase. The substantial negative impact of hydrosalpinx has an effect on the height of the integumentary epithelium of the endometrium. The given data suggest that there are significant and complex endometrial changes in hydrosalpinx

  19. 21 CFR 522.1940 - Progesterone and estradiol benzoate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...: (1) Suckling beef calves—(i) Amount—(A) 100 milligrams (mg) progesterone and 10 mg estradiol benzoate (one implant consisting of 4 pellets, each pellet containing 25 mg progesterone and 2.5 mg estradiol benzoate) per implant dose. (B) 100 mg progesterone and 10 mg estradiol benzoate (one implant consisting...

  20. The progesterone receptor antagonist, onapristone has differential effects on the timing and control of the luteolytic mechanism depending on timing of administration in sheep.

    PubMed

    Mann, G E; Wathes, D C; Robinson, R S

    2013-08-25

    Cyclic ewes were treated with control vehicle or progesterone receptor antagonist (onapristone; 100mg i.m. twice daily) during either early (day 3-5) or late (day 12-14) luteal phase and plasma samples collected for hormone analysis and to determine endogenous and oxytocin induced PGF2α release. On day 14 and 17, ewes were euthanised and reproductive tracts collected for ovarian morphology and endometrium for oxytoxin and steroid hormone receptor analysis. Early treatment increased LH, but not progesterone or oestradiol, while late treatment elevated all three hormones. Early treatment delayed the up-regulation of endometrial oxytocin receptors and responsiveness to oxytocin challenge, delaying luteolysis. Late treatment advanced development of oxytocin receptors and responsiveness to oxytocin though not timing of luteolysis. Patterns of hormone receptor mRNA were differentially disrupted by treatments. Results provide mechanistic insight into hormonal control of the oestrous cycle and identify the ability of the luteolytic mechanism to dissociate from functional luteolysis.

  1. Progesterone for Symptomatic Perimenopause Treatment – Progesterone politics, physiology and potential for perimenopause

    PubMed Central

    Prior, J.C.

    2011-01-01

    Perimenopause, women’s normal midlife reproductive transition, is highly symptomatic for about 20% of women who are currently inaccurately counseled and inappropriately treated with oral contraceptives, menopausal hormone therapy or hysterectomy. About 80% of perimenopausal women experience vasomotor symptoms (VMS), 25% have menorrhagia, and about 10% experience mastalgia. The majority of women describe varying intensities of sleep, coping or mood difficulties. Women are more symptomatic because common knowledge inaccurately says that estradiol (E2) levels are dropping/deficient. Evidence shows that with disturbed brain-ovary feedbacks, E2 levels average 26% higher and soar erratically – some women describe feeling pregnant! Also, ovulation and progesterone (P4) levels become insufficient or absent. The most symptomatic women have higher E2 and lower P4 levels. Because P4 and E2 complement/counterbalance each other’s tissue effects, oral micronized P4 (OMP4 300 mg at bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and premenstrual mastalgia. Menorrhagia is treated with ibuprofen 200mg/6h plus OMP4 cycle d 4-28. For insulin resistance, metformin plus cyclic or daily OMP4 decreases insulin resistance and weight gain. Non-responsive migraines need daily OMP4 plus usual therapies. VMS and insomnia in late perimenopause respond to daily OMP4. In summary, OMP4 is a physiology-based therapy that improves sleep, treats VMS, does not increase breast proliferation or cancer risk, increases bone formation and has beneficial cardiovascular effects. A controlled trial is testing OMP4 for perimenopausal VMS – more evidence-based data are needed. PMID:24753856

  2. Circulating Adiponectin and Risk of Endometrial Cancer

    PubMed Central

    Zheng, Qiaoli; Wu, Haijian; Cao, Jiang

    2015-01-01

    Background Adiponectin is an insulin-sensitizing hormone produced by adipocytes. It has been suggested to be involved in endometrial tumorigenesis. Published data have shown inconsistent results for the association between circulating adiponectin levels and endometrial cancer. In this study, we conducted a meta-analysis to evaluate the predictive value of circulating adiponectin levels on the development of endometrial cancer. Methods PubMed, Embase, ISI web of knowledge, and Cochrane databases were searched for all eligible studies, and the summary relative risk (SRR) was calculated. Additionally, we performed dose-response analysis with eight eligible studies. Results A total of 1,955 cases and 3,458 controls from 12 studies were included. The SRR for the ‘highest’ vs ‘lowest’ adiponectin levels indicated high adiponectin level reduced the risk of endometrial cancer [SRR = 0.40, 95% confidence interval (CI), 0.33–0.66]. Results from the subgroup analyses were consistent with the overall analysis. The SRR for each 1 µg/ml increase of adiponectin indicated a 3% reduction in endometrial cancer risk (95% CI: 2%–4%), and a 14% reduction for each increase of 5 µg/ml (95% CI: 9%–19%). No evidence of publication bias was found. Conclusions This meta-analysis demonstrates that low level of circulating adiponectin is a risk factor for endometrial cancer. PMID:26030130

  3. Pregnancy history and risk of endometrial cancer.

    PubMed

    Pocobelli, Gaia; Doherty, Jennifer A; Voigt, Lynda F; Beresford, Shirley A; Hill, Deirdre A; Chen, Chu; Rossing, Mary Anne; Holmes, Rebecca S; Noor, Zorawar S; Weiss, Noel S

    2011-09-01

    Epidemiologic studies are consistent in finding that women who have had at least one birth are less likely to develop endometrial cancer. Less clear is whether timing of pregnancies during reproductive life influences risk, and the degree to which incomplete pregnancies are associated with a reduced risk. We evaluated pregnancy history in relation to endometrial cancer risk using data from a series of 4 population-based endometrial cancer case-control studies of women 45-74 years of age (1712 cases and 2134 controls) during 1985-2005 in western Washington State. Pregnancy history and information on other potential risk factors were collected by in-person interviews. Older age at first birth was associated with a reduced risk of endometrial cancer after adjustment for number of births and age at last birth (test for trend P = 0.004). The odds ratio comparing women at least 35 years of age at their first birth with those younger than 20 years was 0.34 (95% confidence interval = 0.14-0.84). Age at last birth was not associated with risk after adjustment for number of births and age at first birth (test for trend P = 0.830). Overall, a history of incomplete pregnancies was not associated with endometrial cancer risk to any appreciable degree. In this study, older age at first birth was more strongly associated with endometrial cancer risk than was older age at last birth. To date, there remains some uncertainty in the literature on this issue.

  4. Molecular Pathogenesis of Endometrial and Ovarian Cancer

    PubMed Central

    Merritt, Melissa A.; Cramer, Daniel W.

    2013-01-01

    Pregnancy, breastfeeding, and oral contraceptive pill use interrupt menstrual cycles and reduce endometrial and ovarian cancer risk. This suggests the importance of turnover within Mullerian tissues, where the accumulation of mutations in p53 and PTEN has been correlated with number of cycles. The most common type of endometrial cancer (Type I) is endometrioid and molecular abnormalities include mutations in PTEN, KRAS and β-catenin. The Type I precursor is Endometrial lntraepithelial Neoplasia which displays PTEN defects. Type II endometrial cancer (whose precursors are less clear) includes serous and clear cell tumors and the most common alteration is p53 mutation. For ovarian cancer, histopathologic types parallel endometrial cancer and include serous, mucinous, endometrioid, and clear cell; some molecular features are also shared. The most frequent type of ovarian cancer is high grade serous that often displays p53 mutation and its precursor lesions may originate from normal-appearing fallopian tube epithelium that contains a p53 “signature”. Mutations in KRAS, BRAF and PTEN are described in mucinous, endometrioid and low grade serous cancers and these may originate from ovarian cortical inclusion cysts. A consideration of molecular and other pathogenetic features, like epidemiology and histopathology, may provide a bener understanding of endometrial and ovarian cancer. PMID:22112481

  5. Controversies in the Management of Endometrial Carcinoma

    PubMed Central

    Zhang, Ying; Wang, Jian

    2010-01-01

    Endometrial carcinoma is the most common type of female genital tract malignancy. Although endometrial carcinoma is a low grade curable malignancy, the condition of the disease can range from excellent prognosis with high curability to aggressive disease with poor outcome. During the last 10 years many researches have provided some new valuable data of optimal treatments for endometrial carcinoma. Progression in diagnostic imaging, radiation delivery systems, and systemic therapies potentially can improve outcomes while minimizing morbidity. Firstly, total hysterectomy and bilateral salphingo-oophorectomy is the primary operative procedure. Pelvic lymhadenectomy is performed in most centers on therapeutic and prognostic grounds and to individualize adjuvant treatment. Women with endometrial carcinoma can be readily segregated intraoperatively into “low-risk” and “high-risk” groups to better identify those women who will most likely benefit from thorough lymphadenectomy. Secondly, adjuvant therapies have been proposed for women with endometrial carcinoma postoperatively. Postoperative irradiation is used to reduce pelvic and vaginal recurrences in high risk cases. Chemotherapy is emerging as an important treatment modality in advanced endometrial carcinoma. Meanwhile the availability of new hormonal and biological agents presents new opportunities for therapy. PMID:20613958

  6. Laparoscopic pelvic surgery for endometrial cancer.

    PubMed

    Tay, Eng-Hseon

    2009-02-01

    The traditional approach for the treatment of endometrial cancer by laparotomy is increasingly being replaced by laparoscopic surgery. The advantages of laparoscopy have been well-documented. Laparoscopy avoids the morbidity of a laparotomy, overcomes the limitations of vaginal hysterectomy, provides adequate pathological information for an accurate surgical staging and expedites the postoperative recovery of patients. This paper reports the outcome of a series of 50 consecutive cases of laparoscopic hysterectomy and pelvic lymphadenectomy for endometrial cancers that were performed by the author. The objective is to review the perioperative, postoperative experience and survival outcomes of patients with endometrial cancer managed by laparoscopic surgery performed by a single surgeon. The records of 50 consecutive patients with endometrial cancers from October 1995 to October 2007 treated by laparoscopic pelvic lymphadenectomy and laparoscopic hysterectomy (total and assisted) were retrospectively reviewed. Data on patients' attributes, endometrial cancers, surgical procedures, surgical complications and morbidity, perioperative experience, length of hospital stays and clinical outcome were analysed. Laparoscopic surgery was successful in all 50 patients and is clearly an option for the treatment of early endometrial cancer. Careful patient selection and surgical competency are instrumental in ensuring successful treatment.

  7. Evidence for estrogen-dependent uterine serpin (SERPINA14) expression during estrus in the bovine endometrial glandular epithelium and lumen.

    PubMed

    Ulbrich, Susanne E; Frohlich, Thomas; Schulke, Katy; Englberger, Eva; Waldschmitt, Nadine; Arnold, Georg J; Reichenbach, Horst-Dieter; Reichenbach, Myriam; Wolf, Eckhard; Meyer, Heinrich H D; Bauersachs, Stefan

    2009-10-01

    Uterine secretions have a dominant impact on the environment in which embryo development takes place. The uterine serpins (SERPINA14, previously known as UTMP) are found most abundantly during pregnancy in the uterus of ruminants. Although progesterone is currently assumed to be the major regulator of SERPINA14 expression, our recent study of transcriptome changes in bovine endometrium during the estrous cycle unexpectedly detected a marked upregulation of SERPINA14 mRNA levels at estrus. The present study describes the full-length mRNA sequence, genomic organization, and putative promoter elements of the SERPINA14 gene. The SERPINA14 mRNA abundance was quantified by real-time RT-PCR in intercaruncular endometrium at several time points during the estrous cycle and early pregnancy. Highest levels were found at estrus, followed by a dramatic decrease and a moderate expression during the luteal phase. Transcript levels were higher in pregnant endometrium compared with controls at Day 18. At estrus, immunoreactive protein was localized in deep glandular epithelium, and Western blotting concomitantly showed the 52-kDa form in uterine flushings. SERPINA14 mRNA was significantly upregulated in glandular endometrial cells in vitro after stimulation with estradiol-17beta and progesterone, but not after interferon-tau treatment. Our results clearly demonstrate that SERPINA14 appears distinctly in bovine endometrium during the estrus phase. A supporting role toward providing a well-prepared endometrial environment for passing gametes, especially sperm, is assumed.

  8. Expression and regulation of c-Jun N-terminal kinase (JNK) in endometrial cells in vivo and in vitro.

    PubMed

    Kizilay, Gulnur; Cakmak, Hakan; Yen, Chih-Feng; Atabekoglu, Cem; Arici, Aydin; Kayisli, Umit Ali

    2008-10-01

    JNK(c-Jun N-terminal kinase) is one of the main types of mitogen-activated protein kinases. JNK modulates inflammation and apoptosis in response to stress. Our hypothesis is that temporal and spatial changes in JNK activity regulate inflammation in human endometrium and that fluctuation in estrogen and progesterone levels may play a role in JNK activation. Therefore, we aimed to determine total-(t-) and active-(phosphorylated, p-) JNK expression in endometrial tissues in vivo by immunohistochemistry, and in vitro by immunocytochemistry and Western blot analysis. Immunohistochemistry revealed moderate cytoplasmic and nuclear t-JNK immunoreactivity, and mostly nuclear p-JNK immunoreactivity throughout the menstrual cycle and early pregnancy. The highest p- and t-JNK immunoreactivity was detected in late secretory phase (P < 0.05). We observed that endometrial stromal cell (ESC)s showed a significant increase in p-JNK expression following 48 h of estrogen combined with progesterone (E(2) + P(4)) withdrawal from the culture conditions, compared to control and non-withdrawal groups (P < 0.05). Upon treatment with JNK inhibitor SP600125, we observed a significantly decreased interleukin (IL)-8 level (P < 0.05) in the presence and absence of E(2). These results demonstrate that JNK expression increases during the late secretory phase when the inflammatory response is highest. Inhibition of IL-8 expression by SP600125 suggests that JNK is involved in regulation of proinflammatory mediators of endometrium.

  9. Progesterone Receptor Expression Declines in the Guinea Pig Uterus during Functional Progesterone Withdrawal and in Response to Prostaglandins

    PubMed Central

    Welsh, Toni N.; Hirst, Jonathan J.; Palliser, Hannah; Zakar, Tamas

    2014-01-01

    Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone withdrawal, promote

  10. Coffee drinking and risk of endometrial cancer – a population-based cohort study

    PubMed Central

    Friberg, Emilie; Orsini, Nicola; Mantzoros, Christos S.; Wolk, Alicja

    2009-01-01

    Coffee drinking has been reported to have beneficial effects on insulin resistance which has been directly associated with endometrial cancer. Although a relationship between coffee consumption and endometrial cancer risk is biologically plausible, this hypothesis has been previously explored in only two prospective studies, with a small number of cases. We used data from the Swedish Mammography Cohort, a population-based prospective cohort study of 60 634 women. During 17.6 years of follow-up, 677 participants were diagnosed with incident endometrial cancer (adenocarcinoma). We examined the association between self-reported coffee consumption (at baseline 1987–90 and in 1997) and endometrial cancer risk using Cox proportional hazards models. Each additional cup (200g) of coffee per day was associated with a RR of 0.90 (95% CI 0.83–0.97). In women drinking four or more cups of coffee a day the risk reduction of endometrial cancer was RR 0.75 (95% CI 0.58–0.97) as compared to those who drank one cup or less. The association seemed largely confined to overweight and obese women, who showed a respective risk reduction of 12% (95% CI 0–23%) and 20% (95% CI 7–31%) for every cup of coffee, but was not observed among normal weight women. There was a statistically significant interaction between coffee consumption and body mass index (pinteraction <0.001). These data indicate that coffee consumption may be associated with decreased risk of endometrial cancer, especially among women with excessive body weight. If confirmed by other prospective studies, these results are of major public health significance. PMID:19585497

  11. Progesterone to prevent spontaneous preterm birth

    PubMed Central

    Romero, Roberto; Yeo, Lami; Chaemsaithong, Piya; Chaiworapongsa, Tinnakorn; Hassan, Sonia

    2014-01-01

    Summary Preterm birth is the leading cause of perinatal morbidity and mortality worldwide, and its prevention is an important healthcare priority. Preterm parturition is one of the ‘great obstetrical syndromes’ and is caused by multiple etiologies. One of the mechanisms of disease is the untimely decline in progesterone action, which can be manifested by a sonographic short cervix in the midtrimester. The detection of a short cervix in the midtrimester is a powerful risk factor for preterm delivery. Vaginal progesterone can reduce the rate of preterm delivery by 45%, and the rate of neonatal morbidity (admission to neonatal intensive care unit, respiratory distress syndrome, need for mechanical ventilation, etc.). To prevent one case of spontaneous preterm birth <33 weeks of gestation, 12 patients with a short cervix would need to be treated. Vaginal progesterone reduces the rate of spontaneous preterm birth in women with a short cervix both with and without a prior history of preterm birth. In patients with a prior history of preterm birth, vaginal progesterone is as effective as cervical cerclage to prevent preterm delivery. 17α-Hydroxyprogesterone caproate has not been shown to be effective in reducing the rate of spontaneous preterm birth in women with a short cervix. PMID:24315687

  12. Progesterone biotransformation by plant cell suspension cultures.

    PubMed Central

    Yagen, B; Gallili, G E; Mateles, R I

    1978-01-01

    Progesterone was converted to 5alpha-pregnane-3alpha-ol-20-one, delta4-pregnene-20alpha-ol-3-one, delta4-pregnene-14alpha-ol-3,20-dione, delta4-pregnene-7beta,14alpha-diol-3,20-dione, and delta4-pregnene-6beta,11alpha-diol-3,20-dione by cell cultures of Lycopersicon esculentum. Cell cultures of Capsicum frutescens (green) metabolized progesterone to delta4-pregnene-20alpha-ol-3-one in very high yield, and Vinca rosea yielded delta4-pregnene-20beta-ol-3-one and delta4-pregnene-14alpha-ol-3,20-dione. A stereospecific reduction of the keto groups and a double bond and stereospecific introduction of hydroxyl groups at the 6, 11, and 14 positions have been observed. The mono- and dihydroxylated progesterones have not previously been reported as metabolic products of progesterone by plant cell systems and represent de novo hydroxylation of a nonglycosylated steroid. PMID:697360

  13. Progesterone for acute traumatic brain injury.

    PubMed

    Ma, Junpeng; Huang, Siqing; Qin, Shu; You, Chao; Zeng, Yunhui

    2016-12-22

    Traumatic brain injury (TBI) is a leading cause of death and disability, and the identification of effective, inexpensive and widely practicable treatments for brain injury is of great public health importance worldwide. Progesterone is a naturally produced hormone that has well-defined pharmacokinetics, is widely available, inexpensive, and has steroidal, neuroactive and neurosteroidal actions in the central nervous system. It is, therefore, a potential candidate for treating TBI patients. However, uncertainty exists regarding the efficacy of this treatment. This is an update of our previous review of the same title, published in 2012. To assess the effects of progesterone on neurologic outcome, mortality and disability in patients with acute TBI. To assess the safety of progesterone in patients with acute TBI. We updated our searches of the following databases: the Cochrane Injuries Group's Specialised Register (30 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2016), MEDLINE (Ovid; 1950 to 30 September 2016), Embase (Ovid; 1980 to 30 September 2016), Web of Science Core Collection: Conference Proceedings Citation Index-Science (CPCI-S; 1990 to 30 September 2016); and trials registries: Clinicaltrials.gov (30 September 2016) and the World Health Organization (WHO) International Clinical Trials Registry Platform (30 September 2016). We included randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI. Two review authors screened search results independently to identify potentially relevant studies for inclusion. Independently, two review authors selected trials that met the inclusion criteria from the results of the screened searches, with no disagreement. We included five RCTs in the review, with a total of 2392 participants. We assessed one trial to be at low risk of bias; two at unclear risk of bias (in one multicentred trial the possibility of

  14. 3D models of lamprey progesterone receptor complexed with progesterone, 7α-hydroxy-progesterone and 15α-hydroxy-progesterone.

    PubMed

    Baker, Michael E; Asnaashari, Paiyuam; Chang, David J; McDonnell, Sunsanee

    2011-01-01

    Sea lamprey, a basal vertebrate, contains a progesterone receptor [PR]. An unusual property of lamprey is that gonadotropin-releasing hormone induces synthesis of 15α-hydroxy-progesterone [15α-OH-P] instead of progesterone. There also is indirect evidence for 7α-OH-P in lamprey serum. To determine if there is a structural basis for the binding of 7α-OH-P and 15α-OH-P to lamprey PR, we constructed 3D models of the lamprey PR complexed with progesterone, 7α-OH-P and 15α-OH-P. These 3D models reveal that Met-277 in lamprey PR has a specific interaction with the 15α-hydroxyl on 15α-OH-P and with Met-192, which also contacts the 15α-hydroxyl group. We also find that 7α-OH-P has favorable contacts with side-chains in lamprey PR. BLAST searches reveal that Met-277 on lamprey PR is unique among vertebrate PRs. This unique site on lamprey PR could be a target for compounds to control reproduction in sea lamprey, an environmental pest in Lake Michigan. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. 17β-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review.

    PubMed

    Mirkin, Sebastian; Amadio, Julia M; Bernick, Brian A; Pickar, James H; Archer, David F

    2015-05-01

    Several formulations combining estrogens and progestins for hormone therapy (HT) have been approved worldwide for the treatment of menopausal symptoms, yet recent data indicate a decline in their use and an increase in compounded bioidentical HT. Up to now, no single product combining natural 17β-estradiol and progesterone has been approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A phase 3 trial (REPLENISH) is underway to study a novel oral formulation of solubilized 17β-estradiol and natural progesterone combined in a single gelatin capsule (TX-001HR; TherapeuticsMD, Inc, Boca Raton, FL) for treating vasomotor symptoms (VMS) in postmenopausal women. The REPLENISH trial evaluates the efficacy and safety of TX-001HR (4 doses) versus placebo for the reduction of moderate to severe VMS frequency and severity at 4 and 12 weeks and evaluates the endometrial safety of the combinations at 1 year. TX-001HR contains hormones that are molecularly identical to endogenous estradiol and progesterone and is intended as an option for women who prefer bioidentical hormones; further, it does not contain peanut oil, a common allergen. The constituents of TX-001HR, in a pharmacokinetic report, showed similar bioavailability and safety compared with reference estradiol tablets and micronized progesterone capsules administered together. Published data suggest a safer profile of estradiol and natural progesterone compared with HT containing conjugated equine estrogens and progestins. This report summarizes the methodology of the REPLENISH trial and reviews the evidence suggesting clinical differences between HT containing progesterone or progestins, and estradiol or conjugated equine estrogens.

  16. Selective progesterone receptor modulators (SPRMs) for uterine fibroids.

    PubMed

    Murji, Ally; Whitaker, Lucy; Chow, Tiffany L; Sobel, Mara L

    2017-04-26

    Uterine fibroids are smooth muscle tumours arising from the uterus. These tumours, although benign, are commonly associated with abnormal uterine bleeding, bulk symptoms and reproductive dysfunction. The importance of progesterone in fibroid pathogenesis supports selective progesterone receptor modulators (SPRMs) as effective treatment. Both biochemical and clinical evidence suggests that SPRMs may reduce fibroid growth and ameliorate symptoms. SPRMs can cause unique histological changes to the endometrium that are not related to cancer, are not precancerous and have been found to be benign and reversible. This review summarises randomised trials conducted to evaluate the effectiveness of SPRMs as a class of medication for treatment of individuals with fibroids. To evaluate the effectiveness and safety of SPRMs for treatment of premenopausal women with uterine fibroids. We searched the Specialised Register of the Cochrane Gynaecology and Fertility Group, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinical trials registries from database inception to May 2016. We handsearched the reference lists of relevant articles and contacted experts in the field to request additional data. Included studies were randomised controlled trials (RCTs) of premenopausal women with fibroids who were treated for at least three months with a SPRM. Two review authors independently reviewed all eligible studies identified by the search. We extracted data and assessed risk of bias independently using standard forms. We analysed data using mean differences (MDs) or standardised mean differences (SMDs) for continuous data and odds ratios (ORs) for dichotomous data. We performed meta-analyses using the random-effects model. Our primary outcome was change in fibroid-related symptoms. We included in the review 14 RCTs with a total of 1215 study participants. We could not

  17. Differences in the binding mechanism of RU486 and progesterone to the progesterone receptor

    SciTech Connect

    Skafar, D.F. )

    1991-11-12

    The binding mechanism of the antagonist RU486 to the progesterone receptor was compared with that of the agonists progesterone and R5020. Both progesterone and RU486 bound to the receptor with a Hill coefficient of 1.2, indicating the binding of each ligand is positive cooperative. However, when each ligand was used to compete with ({sup 3}H)progesterone for binding to the receptor at receptor concentrations near 8 nM, at which the receptor is likely a dimer, the competition curve for RU486 was significantly steeper than the curves for progesterone and R5020. This indicated that a difference in the binding mechanism of RU486 and progesterone can be detected when both ligands are present. In contrast, at receptor concentrations near 1 nM, at which the receptor is likely a monomer, the competition curves for all three ligands were indistinguishable. These results indicate that RU486 and agonists have different binding mechanisms for the receptor and further suggest that this difference may be related to site-site interactions within the receptor.

  18. Inhibition of Progesterone Metabolism Mimics the Effect of Progesterone Withdrawal on Forced Swim Test Immobility

    PubMed Central

    Finn, Deborah A.

    2007-01-01

    Withdrawal from high levels of progesterone in rodents has been proposed as a model for premenstrual syndrome or postpartum depression. Forced swim test (FST) immobility, used to model depression, was assessed in intact female DBA/2J mice following progesterone withdrawal (PWD) or treatment with the 5α-reductase inhibitor finasteride. Following 5 daily progesterone injections (5 mg/kg IP) FST immobility increased only in mice withdrawn for 3 days (p < .05). In another experiment, 3 days of PWD significantly decreased levels of progesterone compared to 0 days of withdrawal, but progesterone levels at 3 days of PWD did not differ from vehicle-treated controls. In a final study, mice received daily injections of progesterone (5 mg/kg IP) for 8 days, with 0 mg/kg, 50 mg/kg, or 100 mg/kg finasteride co-administered for the last three days. Mice that received 100 mg/kg finasteride, but not 50 mg/kg finasteride, displayed increased FST immobility. PWD and finasteride treatment, both of which reduce allopregnanolone levels, were associated with increased FST immobility in female DBA/2J mice. These findings suggest that decreased levels of the GABAergic neurosteroid allopregnanolone contributes to symptoms of PWD. Future studies of PWD may provide information about human conditions that are associated with hormone changes such as premenstrual syndrome or postpartum depression. PMID:17597197

  19. Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility.

    PubMed

    Beckley, Ethan H; Finn, Deborah A

    2007-10-01

    Withdrawal from high levels of progesterone in rodents has been proposed as a model for premenstrual syndrome or postpartum depression. Forced swim test (FST) immobility, used to model depression, was assessed in intact female DBA/2J mice following progesterone withdrawal (PWD) or treatment with the 5alpha-reductase inhibitor finasteride. Following 5 daily progesterone injections (5 mg/kg IP) FST immobility increased only in mice withdrawn for 3 days (p<.05). In another experiment, 3 days of PWD significantly decreased levels of progesterone compared to 0 days of withdrawal, but progesterone levels at 3 days of PWD did not differ from vehicle-treated controls. In a final study, mice received daily injections of progesterone (5 mg/kg IP) for 8 days, with 0 mg/kg, 50 mg/kg, or 100 mg/kg finasteride co-administered for the last three days. Mice that received 100 mg/kg finasteride, but not 50 mg/kg finasteride, displayed increased FST immobility. PWD and finasteride treatment, both of which reduce allopregnanolone levels, were associated with increased FST immobility in female DBA/2J mice. These findings suggest that decreased levels of the GABAergic neurosteroid allopregnanolone contribute to symptoms of PWD. Future studies of PWD may provide information about human conditions that are associated with hormone changes such as premenstrual syndrome or postpartum depression.

  20. Study establishes basis for genomic classification of endometrial cancers

    Cancer.gov

    A comprehensive genomic analysis of nearly 400 endometrial tumors suggests that certain molecular characteristics – such as the frequency of mutations – could complement current pathology methods and help distinguish between principal types of endometrial

  1. Endometrial Cancer Treatment (PDQ®)—Health Professional Version

    Cancer.gov

    Endometrial cancer is usually diagnosed at an early stage and can be treated with surgery. Learn about the symptoms, diagnosis, prognosis, staging, and treatment for early- and advanced-stage endometrial cancer in this expert-reviewed summary.

  2. Gonadectomy and progesterone treatment induce protection in murine cysticercosis.

    PubMed

    Vargas-Villavicencio, J A; Larralde, C; Morales-Montor, J

    2006-12-01

    The effects of progesterone on castrated mice of both sexes infected with Taenia crassiceps cysticerci were studied. Gonadectomy and treatment with progesterone before infection decreased parasite loads by 100% compared with intact uninfected mice. mRNA levels of IFN-gamma and IL-2 (typically associated to Th1-like profiles) were markedly decreased in infected gonadectomized (Gx) mice, whereas progesterone treatment of infected Gx mice did not affected its expression. mRNA levels of IL-4, and IL-10 (typically associated with Th2-like profiles) were reduced by gonadectomy, whereas restitution with progesterone did not affected this pattern in infected Gx progesterone-treated mice. Infection markedly induced expression of progesterone receptor isoform A in splenocytes of Gx mice (5-fold), whereas isoform B had no changes. Progesterone metabolism to dehydroepiandrosterone (DHEA) in Gx animals was increased 3-fold only in infected progesterone-treated uninfecteds of both sexes, but was not detectable in infected Gx progesterone-treated mice. Conversely, DHEA levels increased 100-fold in infected Gx progesterone-treated mice. However, androgen receptor expression in splenocytes of male mice showed a reduction by gonadectomy, and by infection, whereas in females AR expression showed no changes in the different mouse groups. These results suggest that progesterone, through its metabolism to DHEA, negatively affects the establishment, growth, and reproduction of Taenia crassiceps, by a mechanism that does not implicate a classic genomic pathway involving a nuclear androgen receptor.

  3. The hyperventilation of cirrhosis: progesterone and estradiol effects.

    PubMed

    Lustik, S J; Chhibber, A K; Kolano, J W; Hilmi, I A; Henson, L C; Morris, M C; Bronsther, O

    1997-01-01

    Progesterone and estradiol are metabolized in the liver and are elevated in patients with cirrhosis. Progesterone stimulates ventilation by activating progesterone receptors in the central nervous system; estradiol may facilitate progesterone's actions by increasing progesterone receptors. This study evaluated whether progesterone and estradiol contribute to the respiratory alkalosis common in cirrhotic patients. Arterial blood gases and progesterone and estradiol levels were obtained in 50 patients with cirrhosis. Multiple linear regression revealed a statistically significant correlation between PaCO2 and progesterone and estradiol (r = .54, P < .05). Patients with severe hyperventilation (PaCO2 < or = 30 mm Hg) had statistically higher levels of progesterone and estradiol than did patients with mild hyperventilation (30 < PaCO2 < or = 35) or normal ventilation (PaCO2 > 35) (P < .05). Although the progesterone levels were two orders of magnitude lower than those associated with hyperventilation in pregnant patients, the increased ventilatory effect may be because of the altered blood-brain barrier (BBB) present in cirrhotic patients. Progesterone and estradiol appear to contribute to the hyperventilation in cirrhotic patients.

  4. Steroid hormones acutely regulate expression of a Nudix protein-encoding gene in the endometrial epithelium of sheep.

    PubMed

    Ing, Nancy H; Wolfskill, Rebecca L; Clark, Shauna; DeGraauw, Jennifer A; Gill, Clare A

    2006-08-01

    Steroid hormones regulate endometrial gene expression to meet the needs of developing embryos. Our hypothesis is that steroid hormones transiently induce expression of genes in the endometrial epithelium to make the uterine environment different between the earliest days of pregnancy. We identified one such gene product using differential display-polymerase chain reactions. The gene product that was strongly induced in ewes between day 3 and 6 of the estrous cycle was cloned and sequenced to identify it as encoding a member of the Nudix family of hydrolase enzymes. Northern blot analyses indicated that NUDT16 mRNA concentrations were elevated 10-fold in the endometrium of sheep from day 5 to 9 of the estrous cycle and returned to basal levels by day 11. In assays of RNA samples from 15 different tissues from an adult ewe, the concentrations of NUDT16 mRNA were greatest in endometrium. In situ hybridization localized NUDT16 mRNA exclusively to the endometrial epithelial cells of the glands and uterine lumen. In ovariectomized ewes, NUDT16 mRNA was induced by a regimen of alternating estrogen and progesterone therapy designed to mimic the hormonal experiences of a ewe at day 6 of the estrous cycle. The final estrogen treatment in the regimen was critical to the expression of NUDT16 as well as progesterone receptor and estrogen receptor-beta genes. Characterization of the NUDT16 gene identified putative steroid hormone response elements, which can now be investigated to understand its unique pattern of regulation in the earliest days of pregnancy.

  5. Levonorgestrel intrauterine system in adjuvant tamoxifen treatment: balance of breast risks and endometrial benefits--systematic review of literature.

    PubMed

    Gizzo, Salvatore; Di Gangi, Stefania; Bertocco, Anna; Noventa, Marco; Fagherazzi, Simone; Ancona, Emanuele; Saccardi, Carlo; Patrelli, Tito Silvio; D'Antona, Donato; Nardelli, Giovanni Battista

    2014-04-01

    Levonorgestrel intrauterine system (LNG-IUS) is used in patients with breast patients taking tamoxifen (TAM) to prevent endometrial proliferation. The benefits (on endometrium), the side effects (on breast), and the patients suitable for this treatment are not still clear. Aim of this systematic review is to define the breast risks and endometrial benefits in TAM-treated women using Mirena and to define which patients could benefit from LNG-IUS use. In all, 3 studies on LNG-IUS effects on endometrium in TAM-treated women and 4 studies on breast cancer recurrence were selected for the study. All studies described a reduction in benign endometrial pathologies among Mirena users, but controversial data showed malignant disease and breast cancer recurrence. So it is mandatory to define hormonal status before TAM treatment. In selected patients Mirena was proven to protect endometrium. Perspective clinical trials on Mirena pharmacological features are necessary to establish whether systemic levels of progesterone could increase breast cancer recurrence in such patients.

  6. Sleep duration and endometrial cancer risk.

    PubMed

    Sturgeon, Susan R; Luisi, Nicole; Balasubramanian, Raji; Reeves, Katherine W

    2012-04-01

    Recent data indicate that night shift work is associated with increased endometrial cancer risk, perhaps through a pathway involving lower melatonin production. Melatonin is an antiestrogenic hormone, with production in a circadian pattern that is dependent on presence of dark at night. Sleep duration is positively associated with melatonin production and may be an indicator of melatonin levels in epidemiologic studies. We evaluated associations between self-reported sleep duration and endometrial cancer risk using publicly available prospective data on 48,725 participants in the Women's Health Initiative Observational Study, among whom 452 adjudicated incident cases of endometrial cancer were diagnosed over approximately 7.5 years of follow-up. Sleep duration was self-reported at baseline. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for endometrial cancer risk with adjustment for potential confounders. Most women reported sleeping ≤ 6 (33.3%) or 7 (38.5%) h each night; fewer reported sleeping 8 (23.4%) or ≥ 9 (4.8%) h each night. In adjusted analyses, there was an indication of reduced risk associated with longer sleep duration, though no statistically significant association was observed. Women who slept ≥ 9 h had a nonsignificant reduced risk of endometrial cancer compared with women who slept ≤ 6 h (HR = 0.87; 95% CI = 0.51-1.46). We found weak evidence of an association between sleep duration and endometrial cancer risk. Self-reported sleep duration may not adequately represent melatonin levels, thus further studies utilizing urinary melatonin levels are necessary to establish the mechanism by which night shift work increases endometrial cancer risk.

  7. Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma.

    PubMed Central

    Bui, T. D.; Zhang, L.; Rees, M. C.; Bicknell, R.; Harris, A. L.

    1997-01-01

    Wnt genes are transforming to mouse breast epithelium and are hormonally regulated in vivo. To assess their role in another endocrine-responsive human cancer, the expression of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a, 7b and 10b) in normal human endometrium and endometrial cells, and endometrial carcinoma tissues and cell lines was investigated by ribonuclease protection analysis. Wnt2, 3, 4 and 5a mRNAs but not Wnt7a, 7b or 10b mRNAs were expressed in primary culture of normal endometrial epithelial (NEE) and stromal (NES) cells. In contrast, in four endometrial carcinoma cell lines (RL95-2, HEC-1-A, AN3 CA and Ishikawa), Wnt2 and Wnt3 mRNAs were absent. Wnt4 was expressed in only one out of four cell lines (RL95-2), and Wnt5a was much lower. Wnt7a and Wnt7b mRNAs were expressed in three out of four cell lines (RL95-2, HEC-1-A and Ishikawa). Wnt10b mRNA was expressed in RL95-2 and AN3 CA. In fresh tissues, all Wnt genes apart from Wnt10b were expressed in normal endometrium and endometrial carcinoma. Similar to the cell lines, the level of Wnt4 mRNA expression was significantly higher in the normal endometrium than endometrial carcinoma. Wnt2, 3 and 5a mRNAs were also lower in endometrial carcinoma compared with normal endometrium. There was no difference in the level of Wnt2, 3, 4 and 5a mRNA expression between proliferative phase and secretory phase of the menstrual cycle, or between either menstrual phase and the first trimester of pregnancy. In vitro, progesterone and/or 17beta-oestradiol had no effect on Wnt2, 3, 4, 5a and 7b mRNA expression in NES and all endometrial carcinoma cell lines. The data indicate that all Wnt genes were expressed in vitro, six out of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a and 7b) were expressed endogenously in the human endometrium, their mRNA expression was hormonally independent and Wnt4 gene down-regulation as well as down-regulation of Wnt 2, 3 and 5a may be associated with endometrial carcinoma. Images Figure 1 Figure 3 Figure 4

  8. mRNA-binding protein TIA-1 reduces cytokine expression in human endometrial stromal cells and is down-regulated in ectopic endometrium.

    PubMed

    Karalok, Hakan Mete; Aydin, Ebru; Saglam, Ozlen; Torun, Aysenur; Guzeloglu-Kayisli, Ozlem; Lalioti, Maria D; Kristiansson, Helena; Duke, Cindy M P; Choe, Gina; Flannery, Clare; Kallen, Caleb B; Seli, Emre

    2014-12-01

    Cytokines and growth factors play important roles in endometrial function and the pathogenesis of endometriosis. mRNAs encoding cytokines and growth factors undergo rapid turnover; primarily mediated by adenosine- and uridine-rich elements (AREs) located in their 3'-untranslated regions. T-cell intracellular antigen (TIA-1), an mRNA-binding protein, binds to AREs in target transcripts, leading to decreased gene expression. The purpose of this article was to determine whether TIA-1 plays a role in the regulation of endometrial cytokine and growth factor expression during the normal menstrual cycle and whether TIA-1 expression is altered in women with endometriosis. Eutopic endometrial tissue obtained from women without endometriosis (n = 30) and eutopic and ectopic endometrial tissues from women with endometriosis (n = 17) were immunostained for TIA-1. Staining intensities were evaluated by histological scores (HSCOREs). The regulation of endometrial TIA-1 expression by immune factors and steroid hormones was studied by treating primary cultured human endometrial stromal cells (HESCs) with vehicle, lipopolysaccharide, TNF-α, IL-6, estradiol, or progesterone, followed by protein blot analyses. HESCs were engineered to over- or underexpress TIA-1 to test whether TIA-1 regulates IL-6 or TNF-α expression in these cells. We found that TIA-1 is expressed in endometrial stromal and glandular cells throughout the menstrual cycle and that this expression is significantly higher in the perimenstrual phase. In women with endometriosis, TIA-1 expression in eutopic and ectopic endometrium was reduced compared with TIA-1 expression in eutopic endometrium of unaffected control women. Lipopolysaccharide and TNF-α increased TIA-1 expression in HESCs in vitro, whereas IL-6 or steroid hormones had no effect. In HESCs, down-regulation of TIA-1 resulted in elevated IL-6 and TNF-α expression, whereas TIA-1 overexpression resulted in decreased IL-6 and TNF-α expression. Endometrial

  9. mRNA-Binding Protein TIA-1 Reduces Cytokine Expression in Human Endometrial Stromal Cells and Is Down-Regulated in Ectopic Endometrium

    PubMed Central

    Karalok, Hakan Mete; Aydin, Ebru; Saglam, Ozlen; Torun, Aysenur; Guzeloglu-Kayisli, Ozlem; Lalioti, Maria D.; Kristiansson, Helena; Duke, Cindy M. P.; Choe, Gina; Flannery, Clare; Kallen, Caleb B.

    2014-01-01

    Background: Cytokines and growth factors play important roles in endometrial function and the pathogenesis of endometriosis. mRNAs encoding cytokines and growth factors undergo rapid turnover; primarily mediated by adenosine- and uridine-rich elements (AREs) located in their 3′-untranslated regions. T-cell intracellular antigen (TIA-1), an mRNA-binding protein, binds to AREs in target transcripts, leading to decreased gene expression. Objective: The purpose of this article was to determine whether TIA-1 plays a role in the regulation of endometrial cytokine and growth factor expression during the normal menstrual cycle and whether TIA-1 expression is altered in women with endometriosis. Methods: Eutopic endometrial tissue obtained from women without endometriosis (n = 30) and eutopic and ectopic endometrial tissues from women with endometriosis (n = 17) were immunostained for TIA-1. Staining intensities were evaluated by histological scores (HSCOREs). The regulation of endometrial TIA-1 expression by immune factors and steroid hormones was studied by treating primary cultured human endometrial stromal cells (HESCs) with vehicle, lipopolysaccharide, TNF-α, IL-6, estradiol, or progesterone, followed by protein blot analyses. HESCs were engineered to over- or underexpress TIA-1 to test whether TIA-1 regulates IL-6 or TNF-α expression in these cells. Results: We found that TIA-1 is expressed in endometrial stromal and glandular cells throughout the menstrual cycle and that this expression is significantly higher in the perimenstrual phase. In women with endometriosis, TIA-1 expression in eutopic and ectopic endometrium was reduced compared with TIA-1 expression in eutopic endometrium of unaffected control women. Lipopolysaccharide and TNF-α increased TIA-1 expression in HESCs in vitro, whereas IL-6 or steroid hormones had no effect. In HESCs, down-regulation of TIA-1 resulted in elevated IL-6 and TNF-α expression, whereas TIA-1 overexpression resulted in

  10. Progesterone receptor is not required for progesterone action in the rat corpus luteum of pregnancy.

    PubMed

    Telleria, C M; Stocco, C O; Stati, A O; Deis, R P

    1999-11-01

    In this study, we investigated whether progesterone exerts a local action regulating the function of the corpus luteum of pregnancy in rats. The luteal activities of the enzymes 3beta-hydroxysteroid dehydrogenase (3beta-HSD), involved in progesterone biosynthesis, and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), that catabolizes progesterone and reduces progesterone secretion by the corpus luteum, were evaluated after intrabursal ovarian administration of progesterone in pregnant rats that had received a luteolytic dose of prostaglandin F2alpha (PGF2alpha). Luteal 3beta-HSD activity decreased and 20alpha-HSD activity increased after PGF2alpha treatment (100 microg x 2 intraperitoneally on Day 19 of pregnancy at 12:00 p.m. and 4:00 p.m.) when compared with controls sacrificed at 8:00 p.m. on Day 20 of pregnancy. This effect of PGF2alpha on the luteal 3beta-HSD and 20alpha-HSD activities was abolished in animals that also received an intraovarian dose of progesterone (3 microg/ovary on Day 19 of pregnancy at 8:00-9:00 a.m.). In a second functional study, luteal cells obtained from 19-day pregnant rats responded to the synthetic progestin promegestone (R5020) in a dose-dependent manner, with an increase in the progesterone output. In addition, the glucocorticoid agent hydrocortisone did not affect progesterone accumulation in the same luteal cell culture. We also examined by immunocytochemistry the expression of progesterone receptors (PR) in the corpora lutea during pregnancy and demonstrated the absence of PR in this endocrine gland in all the days of pregnancy studied. In the same pregnant rats, positive staining for PR was observed in cells within the uteroplacental unit, such as cells of the decidua basalis and trophoblast giant cells of the junctional zone. In addition, positive PR staining was observed in the ovarian granulosa and theca cells of growing follicles, but not in corpora lutea of ovaries obtained from cycling rats at proestrus. In summary

  11. Assessment of endometrial receptivity for gestation in patients undergoing in vitro fertilization, using endometrial thickness and the endometrium-myometrium relative echogenicity coefficient.

    PubMed

    Leibovitz, Z; Grinin, V; Rabia, R; Degani, S; Shapiro, I; Tal, J; Eibschitz, I; Harari, O; Paltieli, Y; Aharoni, A; Zeevi, J; Ohel, G

    1999-09-01

    To evaluate the outcome of in vitro fertilization (IVF) treatment in relation to the sonographic parameters of the endometrium. Seventy-five patients with no uterine pathology (age 31.1 +/- 5.4 years) treated in our IVF clinic for various indications were assessed during 75 cycles in which good-quality (grades 1 and 2) embryos were transferred. Controlled ovarian stimulation was achieved by the long protocol (gonadotropin releasing hormone agonist and gonadotropins). The bilayered endometrial thickness (BET), estradiol, luteinizing hormone and progesterone serum levels were measured in 272 tests. A special computer program was used to measure endometrial echogenicity relative to myometrial echogenicity. The gray-level data were analyzed on the basis of the midsagittal sonographic uterine image. Endometrium-myometrium relative echogenicity coefficient (E/M REC) values were computed and displayed graphically along the anteroposterior axis of the endometrial layers in the upper part of the uterine cavity. The area under the E/M REC curve within the BET limits was defined as the relative echogenicity area (REA) and was used as a measure of endometrial echogenicity. Each cycle was sampled in six time segments representing desensitization, follicular and luteal phases. Assigning the day of ovum pick-up as day 0, the time segments of each cycle were: first, day -20 to day -11; second, day -10 to day -6; third, day -5 to day -2; fourth, day 0; fifth, day +7 to day +14; sixth, day +15 to day +21. A total of 276 embryos were transferred (3.68 +/- 1.01 per cycle), of which 223 were of good quality (2.97 +/- 1.51 per cycle). An intrauterine pregnancy was diagnosed in 29 patients. All patients in this study had a BET of > 5 mm in the third and the fourth time segments. There was no significant difference in BET and REA between pregnant and non-pregnant patients tested in the first to the fifth time segments of the IVF cycles. Both BET and REA measured in the sixth time segment

  12. Human Endometrial Stromal Cells Are Highly Permissive To Productive Infection by Zika Virus.

    PubMed

    Pagani, Isabel; Ghezzi, Silvia; Ulisse, Adele; Rubio, Alicia; Turrini, Filippo; Garavaglia, Elisabetta; Candiani, Massimo; Castilletti, Concetta; Ippolito, Giuseppe; Poli, Guido; Broccoli, Vania; Panina-Bordignon, Paola; Vicenzi, Elisa

    2017-03-10

    Zika virus (ZIKV) is a recently re-emerged flavivirus transmitted to humans by mosquito bites but also from mother to fetus and by sexual intercourse. We here show that primary human endometrial stromal cells (HESC) are highly permissive to ZIKV infection and support its in vitro replication. ZIKV envelope expression was detected in the endoplasmic reticulum whereas double-stranded viral RNA colocalized with vimentin filaments to the perinuclear region. ZIKV productive infection also occurred in the human T-HESC cell line together with the induction of interferon-β (IFN-β) and of IFN-stimulated genes. Notably, in vitro decidualization of T-HESC with cyclic AMP and progesterone upregulated the cell surface expression of the ZIKV entry co-receptor AXL and boosted ZIKV replication by ca. 100-fold. Thus, endometrial stromal cells, particularly if decidualized, likely represent a crucial cell target of ZIKV reaching them, either via the uterine vasculature in the viremic phase of the infection or by sexual viral transmission, and a potential source of virus spreading to placental trophoblasts during pregnancy.

  13. Uterine superficial serous carcinomas and extensive serous endometrial intraepithelial carcinomas: clinicopathological analysis of 6 patients.

    PubMed

    Ono, Kyoko; Hayashi, Hiroyuki; Tateno, Masatoshi; Tanaka, Reiko; Suzuki, Rie; Maruyama, Yasuyo; Miyagi, Yohei; Furuya, Mitsuko

    2014-01-01

    Uterine superficial serous carcinoma (SSC) and serous endometrial intraepithelial carcinoma (SEIC) are unique malignancies found primarily in postmenopausal women. SSC and SEIC lesions measuring 1 cm or less are categorized as minimal uterine serous carcinoma (MUSC). Less well understood, however, the clinical behavior of SSC and SEIC lesions measuring more than 1 cm. We investigated 6 postmenopausal patients, aged 69-83 years, with SSC or SEIC and without hyperestrogenism. All but 1 patient had tumors originating from the surface of polyps, including 3 patients who each had an enormous polyp occupying the entire uterine cavity. Two patients had extensive SEICs measuring more than 1 cm; the others had SSCs, including 1 MUSC. The mesenchymal cells of the cancer-bearing polyps lacked the morphologic characteristics of endometrial stroma, and the cancer glands often immunostained negatively for estrogen receptors and progesterone receptors. Diffuse immunostaining for human epidermal growth factor receptor 2 was detected in 3 patients, and p53 was detected in all. Cyclin E, a downstream molecule of the F-box and WD repeat domain-containing 7 (FBXW7), was detected in all patients. Microdissected cancer glands showed p53 mutations in 2 patients and a FBXW7 mutation in 1 patient. These findings suggest that mutations of FBXW7 and p53 may contribute to the carcinogenesis of less invasive tumor subtypes. Pathologists and physicians should carefully evaluate SSC and SEIC lesions involving large polyps but lacking myometrial invasion.

  14. Androgens induce prolactin production by human endometrial stromal cells in vitro.

    PubMed

    Narukawa, S; Kanzaki, H; Inoue, T; Imai, K; Higuchi, T; Hatayama, H; Kariya, M; Mori, T

    1994-01-01

    Although there is a significant quantity of androgens in the endometrium, the function of these hormones has not been clarified, except for being estrogen precursors. Human endometrial stromal cells (ESC) were cultured in the presence of testosterone (T) and 5 alpha-dihydrotestosterone. Following culture, prolactin (PRL), a biochemical marker of stromal cell differentiation (decidualization) which is produced by ESC, was examined. T induced PRL production in a time- and dose-dependent manner, as reported previously for progesterone (P) stimulation. In addition, 5 alpha-dihydrotestosterone, which cannot be converted to estrogens, similarly induced PRL production. T in combination with P enhanced PRL production in cultured ESC significantly more than either P or T stimulation alone. A specific androgen receptor blocker, flutamide, when added to cultures containing T, inhibited PRL production in a dose-dependent manner, but did not affect the production of PRL induced by P. These results indicate that in vitro PRL production by human ESC is induced not only by P, but also by androgens through specific receptors and further suggest that androgens play an important role in human endometrial differentiation.

  15. Human Endometrial Stromal Cells Are Highly Permissive To Productive Infection by Zika Virus

    PubMed Central

    Pagani, Isabel; Ghezzi, Silvia; Ulisse, Adele; Rubio, Alicia; Turrini, Filippo; Garavaglia, Elisabetta; Candiani, Massimo; Castilletti, Concetta; Ippolito, Giuseppe; Poli, Guido; Broccoli, Vania; Panina-Bordignon, Paola; Vicenzi, Elisa

    2017-01-01

    Zika virus (ZIKV) is a recently re-emerged flavivirus transmitted to humans by mosquito bites but also from mother to fetus and by sexual intercourse. We here show that primary human endometrial stromal cells (HESC) are highly permissive to ZIKV infection and support its in vitro replication. ZIKV envelope expression was detected in the endoplasmic reticulum whereas double-stranded viral RNA colocalized with vimentin filaments to the perinuclear region. ZIKV productive infection also occurred in the human T-HESC cell line together with the induction of interferon-β (IFN-β) and of IFN-stimulated genes. Notably, in vitro decidualization of T-HESC with cyclic AMP and progesterone upregulated the cell surface expression of the ZIKV entry co-receptor AXL and boosted ZIKV replication by ca. 100-fold. Thus, endometrial stromal cells, particularly if decidualized, likely represent a crucial cell target of ZIKV reaching them, either via the uterine vasculature in the viremic phase of the infection or by sexual viral transmission, and a potential source of virus spreading to placental trophoblasts during pregnancy. PMID:28281680

  16. Interleukins affect equine endometrial cell function: modulatory action of ovarian steroids.

    PubMed

    Szóstek, Anna Z; Galvão, Antonio M; Hojo, Takuo; Okuda, Kiyoshi; Skarzynski, Dariusz J

    2014-01-01

    The aim of the present study was to investigate the interaction between ovarian steroids, interleukins and prostaglandins (PG) in equine epithelial and stromal cells in vitro. In Experiment 1, cells were exposed to IL-1α (10 ng/mL), IL-1β (10 ng/mL) or IL-6 (10 ng/mL) for 24 h and cell proliferation was determined using MTT. In Experiment 2, cells were exposed to progesterone (P4; 10(-7) M); 17-β estradiol (E2; 10(-9) M) or P4+E2 for 24 h and later medium was replaced with a fresh one treated with IL-1α, IL-1β or IL-6 (10 ng/mL, each) for 24 h. The oxytocin (OT; 10(-7) M) was used as a positive control. In Experiment 3, cells were exposed to P4 (10(-7) M), E2 (10(-9) M) or P4+E2 for 24 h and the IL receptor mRNAs transcription was determined using Real-time PCR. Prostaglandins concentration was determined using the direct enzyme immunoassay (EIA) method. Our findings reveal a functional linking between ovarian steroids and IL-stimulated PG secretion by equine endometrial cells. This interaction could be one of the mechanisms responsible for endometrial local orchestrating events during the estrous cycle and early pregnancy.

  17. Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats.

    PubMed

    Taketa, Yoshikazu; Inoue, Kaoru; Takahashi, Miwa; Sakamoto, Yohei; Watanabe, Gen; Taya, Kazuyoshi; Yoshida, Midori

    2016-06-01

    Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten-week-old female Donryu rats were treated once with N-ethyl-N'-nitro-N-nitrosoguanidine (20 mg kg(-1) ), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride-treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol-17β, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol-17β to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  18. MORPHOLOGICAL PATTERN OF ENDOMETRIAL BIOPSIES IN SOUTHWESTERN NIGERIA.

    PubMed

    Abdullahi, Y M; Ajani, M A; Iyapo, O; Aramide, K O; Okolo, C A; Akang, Eeu

    2016-12-01

    Endometrium remains the most sensitive indicator of ovarian function and endometrial biopsy is one of the diagnostic procedures in endometrial pathology. The current study was carried out to examine the morphological pattern of endometrial biopsies in Ibadan, South-western Nigeria and compare the results with similar studies. A retrospective study was undertaken to review all cases of endometrial biopsies received in the Department of Pathology, University College Hospital, Ibadan between January 1999 and December 2008. The patients' data were retrieved from the surgical pathology daybooks and Histology Request forms. The neoplastic lesions were classified according to 2003 World Health Organization classification for endometrial neoplasms. A total of 2,444 cases of endometrial biopsies were received during the 10-year study period. The functional endometrial changes were the most common histopathological diagnostic category, accounting for 53.8% (1035) of cases. Other pathological diagnoses included endometritis (7.8%), simple endometrial hyperplasia (5.8%), partial hydatidiform mole (2.3%), complete hydatidiform mole (2.1%) and malignant neoplastic lesions (3.9%). Infertility was the most common (57%) indication for endometrial biopsies followed by uterine bleeding (33%) while the least common clinical indication were the menstrual disorders (10%). The functional endometrial changes account for the highest morphological patterns while malignant lesions account for the least pattern of the endometrial biopsies evaluated for etiological basis of infertility, uterine bleeding and menstrual disorders in Ibadan. Infertility was the commonest indication for endometrial biopsies while the least common clinical indication was menstrual disorders.

  19. Effects of Simvastatin Pretreatment on Clomiphene Response in Clomiphene – Resistant Women with Polycystic Ovary Syndrome

    PubMed Central

    Ghorbani, Raheb; Faraji, Zahra

    2013-01-01

    Objective The aim of this study is to determine if simvastatin pretreatment would change clomiphene response in clomiphene citrate-resistant (CC-R)women with (PCOS). Materials and methods This quasi experimental study included twenty five clomiphene resistant women with PCOS. All patients received cyclic oral contraceptives pills (OCP) (30µg of ethinyl estradiol and 150µg of desogestrol) from the 5th day of their spontaneous or progesterone (P) induced menstrual cycle; in addition, they received simvastatin (20mg/day) from the first day of cycle for two consecutive months. Then, patients were given 100 mg clomiphene citrate (CC) (Iran Hormone, Iran) for five days starting from day three of their menstrual cycles. The primary outcome measures were ovulation and pregnancy rates. The change in body mass index (BMI), the mean number of follicles ≥ 18 mm, the mean of follicular size and endometrial thickness on the day of human chorionic gonadotropin (HCG) administration were secondary outcome measures. Results Ovulation occurred in 5 out of 25 (20%) patients, but none of the patients conceived in this study. No important change in BMI was observed after using simvastatin (0.28 + 1.13; p = 0.228). In all patients with ovulation, the number of follicles ≥ 18mm was one. The mean follicular size and endometrial thickness on the day of HCG administration were 19.67 ± 2.04 and 7.00 ± 1.34, respectively. Conclusion In this study, we did not observe the favorable effect on ovulation and pregnancy rates with CC following of simvastatin pretreatment in CC-resistant PCOS women. So, further studies with a larger number of patients, higher doses of CC and more cycles are necessary to make this obvious. PMID:24971120

  20. Correlation of endometrial glycodelin expression and pregnancy outcome in cases with polycystic ovary syndrome treated with clomiphene citrate plus metformin: a controlled study.

    PubMed

    Uysal, Selda; Zeki Isik, Ahmet; Eris, Serenat; Yigit, Seyran; Yalcin, Yakup; Ozun Ozbay, Pelin

    2015-01-01

    Objective. The purpose of this study was to evaluate the relationship between clomiphene citrate (CC) plus metformin treatment and endometrial glycodelin expression and to then correlate this relationship with pregnancy outcomes. Material and Methods. A total of 30 patients diagnosed with polycystic ovary syndrome (PCOS) according to the Rotterdam criteria constituted our study group. All had been admitted to the gynecology outpatient clinic between June 1, 2011, and January 1, 2012, for infertility treatment. Our control group consisted of 20 patients admitted for routine Pap smear control. They had no history of infertility and were not using contraceptives and they were actively attempting pregnancy. Midluteal progesterone measurement and pipelle endometrial biopsies were performed with both groups. For PCOS patients, metformin treatment was initiated right after the biopsy and CC was added in the second menstrual cycle. Pipelle endometrial biopsies were repeated. Histological dating and immunohistochemistry for glycodelin were performed by a single pathologist who was blinded to the patients' clinical data. Result(s). The posttreatment ovulation rate in the study group was 93.3%. No pregnancies were achieved in either group when glycodelin expression was not present, even in the presence of ovulation. When glycodelin expression was high in PCOS group, the pregnancy rate was 60% and all pregnancies ended in live births. In weak expression group, however, three out of four pregnancies ended as early pregnancy losses. Conclusion(s). Endometrial glycodelin expression is an important predictor of pregnancy outcomes in both PCOS and fertile groups.

  1. Altrenogest and progesterone therapy during pregnancy in bottlenose dolphins (Tursiops truncatus) with progesterone insufficiency.

    PubMed

    Robeck, Todd R; Gill, Claudia; Doescher, Bethany M; Sweeney, Jay; De Laender, Piet; Van Elk, Cornelis E; O'Brien, Justine K

    2012-06-01

    Progesterone production is essential for growth and development of the conceptus during pregnancy. Abnormal development of the corpus luteum (CL) after conception can result in early embryonic loss or fetal abortion. Routine monitoring of bottlenose dolphin (Tursiops truncatus) pregnancy after artificial insemination or natural conception with ultrasonography and serum progesterone determination has allowed for the establishment of expected fetal growth rates and hormone concentrations. Using these monitoring techniques, we revealed four pregnant dolphins (12-24 yr old) with abnormally low progesterone production indicative of luteal insufficiency. Once diagnosed, animals were placed on altrenogest (0.044-0.088 mg/kg once daily) alone or with oral progesterone (50-200 mg twice daily). Doses of hormone were increased or decreased in each animal based on how fetal skull biparietal and thoracic growth rates compared with published normal values. Hormones were withdrawn starting from day 358 of gestation in animals 1 and 2, with labor occurring 6 and 7 days after withdrawal and at 376 and 373 days of gestation, respectively. Both deliveries were dystocic, with each calf requiring manual extraction and fetotomy for calf 1. The fetuses in animals 3 and 4 died at 348 and 390 days of gestation, respectively. Induction of labor was attempted in both animals, after fetal death, by using a combination of rapid progesterone withdrawal and steroid and prostaglandin F2alpha administration. The calf of animal 4 had to be removed with manual cervical dilation and fetotomy All adult females survived the procedures. These data provide the first in vivo evidence that the CL is the primary source of progesterone throughout pregnancy in the bottlenose dolphin. Until further characterization of hormones required during pregnancy and at parturition has been accomplished, the exogenous progestagen supplementation protocol described here cannot be recommended for treatment of progesterone

  2. Dynamic remodeling of endometrial extracellular matrix regulates embryo receptivity in cattle.

    PubMed

    Scolari, Saara Carollina; Pugliesi, Guilherme; Strefezzi, Ricardo de Francisco; Andrade, Sónia Cristina; Coutinho, Luiz Lehmann; Binelli, Mario

    2016-10-17

    We aimed to evaluate in the bovine endometrium whether (1) key genes involved in endometrial extracellular matrix (ECM) remodeling are regulated by the endocrine peri-ovulatory milieu; and (2) specific endometrial ECM-related transcriptome can be linked to pregnancy outcome. In Experiment 1, pre-ovulatory follicle growth of cows was manipulated to obtain two groups with specific endocrine peri-ovulatory profiles: the Large Follicle-Large CL group (LF-LCL) served as a paradigm for greater receptivity and fertility and showed greater plasma pre-ovulatory estradiol and post-ovulatory progesterone concentrations when compared to the Small Follicle-Small CL group (SF-SCL). Endometrium was collected on days 4 and 7 of the estrous cycle. Histology revealed a greater abundance of total collagen content in SF-SCL on day 4 endometrium. In Experiment 2, cows were artificially inseminated and, six days later, endometrial biopsies were collected. Cows were retrospectively divided into pregnant and non-pregnant (P vs. NP) groups after diagnosis on day 30. In both experiments, expression of genes related to ECM remodeling in the endometrium was studied by RNAseq and qPCR. Gene ontology analysis showed an inhibition in the expression of ECM-related genes in the high receptivity groups (LF-LCL and P). Specifically, there was down-regulation of TGFB2, ADAMTS2, 5 and 14, TIMP3 and COL1A2, COL3A1, COL7A1 and COL3A3 in the LF-LCL and P groups. In summary, the overlapping set of genes differently expressed in both fertility models: (1) suggests that disregulation of ECM remodeling can impair receptivity and (2) can be used as markers to predict pregnancy outcome in cattle.

  3. Visfatin concentrations in patients with endometrial cancer.

    PubMed

    Nergiz Avcioglu, Sümeyra; Altinkaya, Sunduz Ozlem; Küçük, Mert; Yüksel, Hasan; Ömürlü, Imran Kurt; Yanik, Serdar

    2015-03-01

    Visfatin is one of the most recent proteins shown to be highly expressed in adipose tissue. The purpose of this study was to determine visfatin levels in patients with endometrial cancer (EC). A total of 90 patients (46 EC patients and 44 healthy controls) were included in the study. Fasting venous blood samples were collected from all patients. Serum visfatin levels were measured by an enzyme-linked immunosorbent assay (ELISA). The correlation between serum visfatin levels and clinicopathologic variables were determined. Serum visfatin levels were found to be higher in patients with EC (p < 0.001). Visfatin concentrations were positively correlated with age (p = 0.002, r = 0.323), body mass index (BMI) (p = 0.001, r = 0.354), fasting insulin (p = 0.002, r = 0.326), total cholesterol (TC) (p = 0.006, r = 0.285), triglyceride (TG) (p < 0.001, r = 0.364) levels and homeostasis model-resistance index (HOMA-IR) (p = 0.007, r = 0.281) of patients. By using classification and regression trees (C&RT) method, we found that visfatin predicted patients with EC 100% and controls 81.8%. Visfatin was the most important risk factor for occurrence of EC other than, age, BMI, Diabetes Mellitus and other biochemical factors like HDL, LDL, TG, TC. Clearly, there are largely unknown aspects of visfatin pathophysiology in EC and require further study.

  4. Expression of leptin receptor in endometrial biopsies of endometrial and ovarian cancer patients

    PubMed Central

    MÉNDEZ-LÓPEZ, LUIS FERNANDO; DÁVILA-RODRÍGUEZ, MARTHA IMELDA; ZAVALA-POMPA, ANGEL; TORRES-LÓPEZ, ERNESTO; GONZÁLEZ-MARTÍNEZ, BLANCA EDELIA; LÓPEZ-CABANILLAS-LOMELÍ, MANUEL

    2013-01-01

    The adipokine leptin plays a critical role in the regulation of reproductive function and there has been growing interest in its potential role in the development of cancers in which obesity is an established risk factor. Serum leptin levels were found to be higher in patients diagnosed with endometrial and ovarian cancer compared to those observed in healthy individuals. This study was conducted to determine the expression of the leptin receptor (Ob-R) in endometrial biopsies of patients diagnosed with endometrial and ovarian cancer. In this preliminary study, immunohistochemistry (IHC) and the color deconvolution method were used to assess the expression levels of the Ob-R protein in three groups of endometrial tissue: one from patients diagnosed with endometrioid endometrial carcinoma, one from patients diagnosed with ovarian cancer and one from individuals without any diagnosed gynecologic disease (control group). Our results demonstrated that the highest expression of Ob-R protein in endometrial biopsies was detected in the ovarian cancer group (P=0.000). This finding suggests that changes in Ob-R expression may be assessed through the measurement of the optical density of endometrial biopsies and may become a useful tool in preventive screening, particularly for ovarian cancer. PMID:24649005

  5. Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α.

    PubMed

    Pang, Yefei; Dong, Jing; Thomas, Peter

    2015-05-15

    Progesterone exerts beneficial effects on the human cardiovascular system by inducing rapid increases in nitric oxide (NO) production in vascular endothelial cells, but the receptors mediating these nongenomic progesterone actions remain unclear. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that progesterone binds to plasma membranes of HUVECs with the characteristics of membrane progesterone receptors (mPRs). The selective mPR agonist Org OD 02-0 had high binding affinity for the progesterone receptor on HUVEC membranes, whereas nuclear PR (nPR) agonists R5020 and medroxyprogesterone acetate displayed low binding affinities. Immunocytochemical and Western blot analyses confirmed that mPRs are expressed in HUVECs and are localized on their plasma membranes. NO levels increased rapidly after treatment with 20 nM progesterone, Org OD 02-0, and a progesterone-BSA conjugate but not with R5020, suggesting that this progesterone action is at the cell surface and initiated through mPRs. Progesterone and Org OD 02-0 (20 nM) also significantly increased endothelial nitric oxide synthase (eNOS) activity and eNOS phosphorylation. Knockdown of mPRα expression by treatment with small-interfering RNA (siRNA) blocked the stimulatory effects of 20 nM progesterone on NO production and eNOS phosphorylation, whereas knockdown of nPR was ineffective. Treatment with PI3K/Akt and MAP kinase inhibitors blocked the stimulatory effects of progesterone, Org OD 02-0, and progesterone-BSA on NO production and eNOS phosphorylation and also prevented progesterone- and Org OD 02-0-induced increases in Akt and ERK phosphorylation. The results suggest that progesterone stimulation of NO production in HUVECs is mediated by mPRα and involves signaling through PI3K/Akt and MAP kinase pathways.

  6. Chemoresistance and targeted therapies in ovarian and endometrial cancers

    PubMed Central

    Brasseur, Kevin; Gévry, Nicolas; Asselin, Eric

    2017-01-01

    Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers. PMID:28008141

  7. Pregnancy effects on distribution of progesterone receptors, oestrogen receptor alpha, glucocorticoid receptors, Ki-67 antigen and apoptosis in the bovine interplacentomal uterine wall and foetal membranes.

    PubMed

    Boos, A; Kohtes, J; Janssen, V; Mülling, C; Stelljes, A; Zerbe, H; Hässig, M; Thole, H H

    2006-01-01

    Until recently, studies dealing with the uterus of the pregnant cow focus primarily on the placentome or on early and late pregnancy. Thus, there is a paucity of information about many aspects of the interplacentomal uterine wall including adherent foetal membranes. Corresponding tissue specimens were collected at the slaughterhouse and in animals undergoing premature caesarean section. Two specimens per month of pregnancy were assessed immunohistochemically for progesterone receptors, oestrogen receptor alpha and glucocorticoid receptors, Ki-67 protein and TUNEL procedure was performed. The latter two methods were employed in three animals each per months 1 and 2, 3 and 4, 7 and 8 and in six animals undergoing caesarean section at days 274 and 275 post insemination or during spontaneous labour. Results indicate that proliferation and apoptosis are of minor importance for tissue homeostasis since both can histochemically be detected only sporadically. Thus, at the sites investigated here, cellular hypertrophy plays an important role for tissue growth during pregnancy. Progesterone receptors, oestrogen receptor alpha and glucocorticoid receptors, however, exhibit cell type and pregnancy stage specific distribution patterns within the tissues assessed. Progesterone receptor immunoreactive scores remained fairly unchanged during pregnancy. Oestrogen receptor alpha scores, however, generally decreased and glucocorticoid receptors increased with ongoing gestation. Progesterone receptors and oestrogen receptor alpha were present in endometrial stroma and in myometrial smooth muscle cells during whole pregnancy. Oestrogen receptor alpha was detectable during whole pregnancy also in uterine glands. Progesterone receptors were, however, present at a very low level at the latter site only during months 1-3 and 6-9. Oestrogen receptor alpha and glucocorticoid receptors may also mediate uterine blood flow since they were present in the tunica media of uterine blood vessels

  8. Hydroxylation of progesterone by some Trichoderma species.

    PubMed

    El-Kadi, I A; Mostafa, M Eman

    2004-01-01

    Thirty-three isolates belonging to six species of the genus Trichoderma were tested for the ability to hydroxylate progesterone to 11alpha-, 11beta-, 11alpha,17alpha- and 6beta, 17alpha-derivatives, and epicortisol. T. aureoviride, T. harzianum, T. polysporum and T. pseudokoningii produced 11alpha-hydroxyprogesterone. T. harzianum and T. hamatum can form only the 11beta-isomer. T. koningii and T. hamatum produced 11alpha-, 11beta-, 11alpha,17alpha- and 6beta,11alpha-hydroxy derivative