Clayton, R N; Shakespear, R A; Marshall, J C
Purified bovine pituitary plasma membranes possess two specific LH-RH binding sites. The high affinity site (2.5 X 10(9) l/mol) has low capacity (9 X 10(-15) mol/mg membrane protein) while the low affinity site 6.1 X 10(5) l/mol) has a much higher capacity (1.1 X 10(-10) mol/mg). Specific LH-RH binding to plasma membranes is increased 8.5-fold during purification from homogenate whilst adenylate cyclase activity is enriched 7--8-fold. Distribution of specific LH-RH binding to sucrose density gradient interface fractions parallels that of adenylate cyclase activity. Mg2+ and Ca2+ inhibit specific [125I]LH-RH binding at micromolar concentrations. Synthetic LH-RH, up to 250 microgram/ml, failed to stimulate adenylase cyclase activity of the purified bovine membranes. Using a crude 10,800 g rat pituitary membrane preparation, LH-RH similarly failed to activate adenylate cyclase even in the presence of guanyl nucleotides. These data confirm the presence of LH-RH receptor sites on pituitary plasma membranes and suggest that LH-RH-induced gonadotrophin release may be mediated by mechanisms other than activation of adenylate cyclase.
Iwasaki, Y; Kinoshita, M; Ikeda, K; Shiojima, T
This experiment was undertaken in order to study the probable trophic effect of ceruletide and LH-RH on cultured ventral spinal cord. The ventral spinal cord from 13-14-gestational day rat embryos were explanted, following a conventional culturing method. Explants in the culture medium were fed ceruletide and LH-RH at different concentrations. An equal volume of PBS was administered to the control explants. For quantitative analysis of the trophic effect of ceruletide and LH-RH, a numerical score from 0 to 4 was determined at the 7th culture day, based on the length and extension of neurite growth estimated. The presence of ceruletide, the neuritic extension of ventral spinal cord exceeds control values 3.5-6.3 times. The growth zone of the spinal cord explants increases in the ceruletide treated culture, LH-RH treated culture, on the other hand, had no promoting effect on neurite growth. The possible mechanism of trophic effect of ceruletide on cultured ventral spinal cord was briefly discussed. These experimental observation have important implications regarding to potential therapeutic effects of ceruletide n amyotrophic lateral sclerosis.
Suwa, Seizo; And Others
Effects of luteinizing hormone-releasing hormone (LH-RH) on LH and follicle-stimulating hormone (FSH) release were studied in 26 normal children and six patients (from 1-to 14-years-old) with Turner's syndrome. (Author)
Suwa, Seizo; And Others
Effects of luteinizing hormone-releasing hormone (LH-RH) on LH and follicle-stimulating hormone (FSH) release were studied in 26 normal children and six patients (from 1-to 14-years-old) with Turner's syndrome. (Author)
Hamamoto, T; Nishimura, R; Ashitaka, Y; Tojo, S
The responses of immunoreactive free alpha-subunit of glycoprotein hormones to LH-RH administration were studied in normal men and women, and in patients with hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, trophoblastic disease and isolated ectopic alpha-subunit producing tumor. In patients with hypergonadotropic hypergonadism, basal levels of serum alpha-subunit were elevated and the responses to LH-RH were also excessive compared to those of normal men and women. Conversely, in hypogonadotropic hypogonadism, basal levels of alpha-subunit were significantly low and its response to LH-RH was barely detectable. The response of alpha-subunit to constant intravenous infusion of LH-RH (1 microgram/kg/h) was studied in 4 normal men. Both LH and alpha-subunit revealed biphasic patterns of elevation. Its releasing pattern suggests the possibility that two pools of gonadotropin are involved in the production and secretion of alpha-subunit. In patients with trophoblastic disease secreting low levels of hCG (18 mIU/ml), the responses of alpha-subunit as well as pituitary gonadotropin to LH-RH were normal. However, in cases of high concentrations of hCG (1000 mIU/ml), the responses of alpha-subunit and gonadotropin were suppressed. After the administration of LH-RH to a patient with an isolated ectopic alpha-subunit producing tumor, the serum concentration of pituitary gonadotropin increased within the normal range, although that of alpha-subunit did not show a significant change. These results suggest that the production of alpha-subunit by tumors may be autonomous in contrast with a regulatory production in the pituitary.
Taymor, M L; Thompson, I E; Berger, M J; Patton, W
A study is reported on the effects of 150 mcg. of luteinizing hormone-releasing hormone (LH-RH), administered iv to 48 women with 5 types of secondary oligoamenorrhea, on the serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) Levels. At Time 0, patients with pituitary disease showed a markedly diminished LH response and patients with polycystic ovarian disease with enlarged ovaries showed a brisk, elevated LH response. FSH levels in patients with pituitary disease and polycystic ovarian disease showed a negligible rise at Time 0. 9 of 10 patients with pituitary disease and 5 of 9 patients with dietary amenorrhea had a low LH response 30 minutes after LH-RH administration. FSH response 60 minutes after injection in patients with pituitary disease and polycystic ovarian disease seemed to be lowered though too much overlap prevented a complete diagnosis. The conclusion of this initial study is that through baseline determinations of FSH and LH, along with a LH-RH stimulation test, useful data are provided for determining whether amenorrhea is due to ovarian or pituitary failure. A 2nd study evaluated the effects of 150 mcg of LH-RH administered iv before and after the im administration of various dosages of estrogen and progesterone to anovulatory women. A vigorous response in pituitary gonadotropin, particularly LH, was observed with LH-RH administered only. The effect with estrogen and progesterone was diminished pituitary response in terms of LH production. It is concluded that estrogen and progesterone exert a negative feedback effect on gonadotropin secretion at the hypothalamic and pituitary levels.
Baumann, R; Kuhl, H; Taubert, H D; Sandow, J
A highly active LH-RH-analog (D-Ser(TBU)6-LH-RH-(1-9)-nonapeptide-ethylamide = HOE 766) was administered to normally cyclic and ovulatory women in a double-blind study. Each woman received from day 1 through day 14 of the cycle according to a randomization plan either 10 microgram HOE 766 i.m. or a placebo. Ovulation was inhibited for at least two weeks in all subjects receiving HOE 766. The initially very marked release of LH measured 4 hourse after the injection decreased within 3 days by approximately 50%, and remained at this level for the remainder of the experiment while the initially high FSH response was abolished during further treatment. In 3 out of 5 women receiving the analog, serum estradiol was severely suppressed, in the remaining 2 slightly. Within 5 days after the discontinuation of treatment, the pituitary had regained the capacity to respond normally to LH-RH. It is postulated that follicular maturation is disturbed by the unphysiologic pattern of gonadotropin secretion during administration of HOE 766.
Shterev, A D; Dokumov, S I; Matrosov, P I
FSH and LH responses to LH--RH stimulation were investigated at 0,3rd and 6th hrs in a six hours exogenous intravenous administration of 300 mg conjugated estrogens before ovarian cuneiformic resection and on the 10th day thereafter in seven patients with polycystic ovarian syndrome. Before operation exogenous pituitary LH--RH stimulation following estrogen administration increased the serum FSH concentrations and response, and decreased LH concentrations and response, while after operation a slight increase of FSH response with a concomitant excessive LH response was observed. A dual action of estrogens in modifying the pituitary gonadotrophins, as well as hypothalamic LH--RH release was supposed.
Habermeyer, Benedikt; Händel, Nadja; Lemoine, Patrick; Klarhöfer, Markus; Seifritz, Erich; Dittmann, Volker; Graf, Marc
Pedophilia is characterized by a persistent sexual attraction to prepubescent children. Treatment with anti-androgen agents, such as luteinizing hormone-releasing hormone (LH-RH) agonists, reduces testosterone levels and thereby sexual drive and arousal. We used functional magnetic resonance imaging (fMRI) to compare visual erotic stimulation pre- and on-treatment with the LH-RH agonist leuprolide acetate in the case of homosexual pedophilia. The pre-treatment contrasts of the erotic pictures against the respective neutral pictures showed an activation of the right amygdala and adjacent parahippocampal gyrus that decreased significantly under treatment with leuprolide acetate. Our single case fMRI study supports the notion that anti-androgens may modify amygdala response to visual erotic stimulation, a hypothesis that should be further examined in larger studies.
Infertility is the primary concern for boys with uni- or bilateral undescended testes. An early and seemingly successful orchiopexy does not improve fertility in a substantial number of cryptorchid males. We confirmed that LH-RH analogue (LH-RHa) treatment induces an increase in and maturation of the germ cells; however, it was uncertain if treatment would improve the chance of fertility later in life. Thirty unilateral cryptorchid boys, with an average age of 3 years at the time of surgery, were included in the study. Testicular biopsy showed that they had impaired testicular maturation and were therefore at high risk for infertility. Fifteen of the 30 unilateral cryptorchid boys were treated with 10 microg LH-RHa (Buserelin) nasal spray, administered on alternate days for a period of 6 months, following orchiopexy. The control group consisted of 15 cryptorchid boys who had been treated by Schoemakers type of orchiopexy, alone. After puberty, the ejaculates of both groups were analyzed. All males in the untreated group were severely oligospermic, with 20% being azoospermic. In contrast, 86% of the treated ex-cryptorchid males had a sperm concentration within the normal range; this was significantly different from the sperm concentration found in the untreated group (p=0.000008). For the first time, we demonstrate that infertility in cryptorchidism can be successfully corrected when suitably treated with a LH-RHa. Sperm parameters normalized following therapy in the majority of cryptorchid males who, untreated, would have remained infertile. This innovative hormonal treatment will have a profound effect on the current recommended surgical treatment of boys with undescended testes.
The aim of the study was to evaluate, the ability of a GnRH synthetic analogue [des-Gly10, D-Ala6]-LH-RH ethylamide to induce ovulation in rabbit does using intravaginal administration. A total of 138 primiparous lactating does were randomly divided into 4 groups that at the time of insemination received following treatments for ovulation induction: 1 μg of buserelin administered intramuscularly (control group); 5 μg of [des-Gly10, D-Ala6]-LH-RH ethylamide added to the semen dose (D5 group); 10 μg of [des-Gly10, D-Ala6]-LH-RH ethylamide added to the semen dose (D10 group); 15 μg of [des-Gly10, D-Ala6]-LH-RH ethylamide added to the semen dose (D15 group). Kindling rates were 68.8% in D10 and 66.7% in D15 groups and were comparable to that obtained in the control group (72.2%). The kindling rate in group D5 (29.4%) was significantly lower than those recorded in the other groups. The number of live born kits was not significantly affected by the ovulation induction treatment. The results of this study show that [des-Gly10, D-Ala6]-LH-RH ethylamide added directly into the semen dose can effectively stimulate ovulation in rabbits. The dose of 10 μg of [des-Gly10, D-Ala6]-LH-RH ethylamide per doe was sufficient to produce results comparable to those obtained by intramuscular administration of buserelin.
Lecomte-Yerna, M. J.; Hazee-Hagelstein, M. T.; Charlet-Renard, C.; Franchimont, P.
The FSH secretion-inhibiting action of inhibin in vitro under basal conditions and also in the presence of LH-RH is suppressed by the addition of MIX, a phosphodiesterase inhibitor. In the presence of LH-RH, inhibin reduces significantly the intracellular level of cAMP in isolated pituitary cells. In contrast, the simultaneous addition of MIX and inhibin raises the cAMP level, and this stimulation is comparable to the increase observed when MIX is added alone. These observations suggest that one mode of action of inhibin could be mediated by a reduction in cAMP within the pituitary gonadotropic cell.
Sato, N; Yanaihara, T; Kanazawa, M; Okinaga, S; Arai, K
The effects of the oral contraceptive on the pituitary content and plasma level of LH and the hypothalamic LH-RH level were investigated in 16 adult female rabbits. The oral contraceptive preparation, Sophia-C (Norethindrone 2mg + Mestranol 0.1 mg), as administered orally by a stomach tube each day for 7 days in 8 adult female rabbits. At the end of the treatment, the rabbits were bled from the abdominal aorta into heparinized syringes and the plasma was separated. The stalk median eminences were excised. All the materials were stored in -80 degrees C until assayed. Plasma level and the pituitary content of LH and the hypothalamic LH-RH were measured by radioimmunoassay. All the dose response curved were drawn using logitlog transformation. Radioimmunoassay procedures for LH was described in detail elsewhere. Purified rabbit LH for iodination (125-I) and strandard were prepared by T. Makino and R.O. Greep, at Research Laboratories for Human Reproduction, Harvard Medical School, Boston, U.S.A. The starting B/T was 25% at the final dilution of the antibody of 1/20,000. Minimal detectable quantity was about 40 pg/tube. The 50% intercepts were approximately 460 pg/tube. Radioimmunoassay procedures for LH-RH were performed according to the method described by Arimura et al. Antiserum against synthetic LH-RH was kindly supplied to us by Drs. A. Arimura and A.V. Schally, New Orleans, U'S.A. The synthetic LH-RH was kindly supplied to us by Dr. N. Yanaihara. The starting B/T ratio was 29% at the final dilution of the antibody of I/17,500. Minimal detectable quantity was about 40pg/tube and the 50% intercepts were 150pg/tube. It has been assumed that oral contraceptive drugs exert their action by blocking the hypothalamic LH-RH, resulting in a depression of the plasma level of LH, because plasma level of LH returned to the normal level when LH-RH was administered intravenously even while oral contraceptive steroids were given continuously. However, these findings concerning
Lee, V W; Bremner, W J; Cumming, I A; de Kretser, D M; Findlay, J K
The relationship between the pituitary gland and testis in rams was studied from birth to sexual maturity. The concentrations of LH, FSH and testosterone increased between 5 and 7 weeks of age; the rise was not correlated with any specific cytological change in the testis. An augmented pituitary response to LH-RH was demonstrated as levels of gonadotrophin increased. It is unclear whether this change in sensitivity plays a role in initiation of the pubertal process because Sertoli cell maturation, the earliest detectable change in the seminiferous epithelium, occurs between 17 and 21 weeks of age. Spermatocytes were first seen in biopsies taken at 31-36 weeks and spermatogenesis was established fully by 45 weeks. This second phase of testicular development was characterized by increases in prolactin, testosterone and LH. Leydig cells previously difficult to identify became recognizable at the time of sexual maturation. In newborn rams, castration produced significant increases in LH and FSH levels within 2-3 weeks, but higher basal FSH levels (2- to 3-fold) were observed at 5 than at 3 weeks of age. Cryptorchidism did not elevate LH or FSH significantly during the first year of life. FSH rose after this period to levels 2- to 3-fold higher than in normal rams, while LH and testosterone values remained in the normal range in spite of diminished spermatogenic activity; spermatids were absent and testis size was approximately 60% of that recorded in a normal ram. These studies demonstrate a rise in gonadotrophin and testosterone secretion in rams during the first 5-7 weeks of life, followed by a quiescent period of 8-9 months before a secondary increase occurs coincident with the establishment of sexual maturity.
Recchia, Francesco; Necozione, Stefano; Bratta, Massimo; Rosselli, Michele; Guerriero, Gabriele; Rea, Silvio
To prevent premature ovarian failure (POF), high-risk, premenopausal women with early breast cancer were given a luteinizing-hormone releasing hormone (LH-RH) analogue during adjuvant chemotherapy. After an adriamycin-based regimen, patients received radiation therapy concomitant with cyclophosphamide, methotrexate and 5-fluorouracil. An aromatase inhibitor was given to patients positive for the estrogen receptor (ER+). The median age was 43 years (range, 26-45). Among 200 consecutive patients, 46% had no axillary node, and 54% had a mean of 5.4 positive nodes (range, 1-25); 56% were ER+, 44% were estrogen receptor negative (ER-), 13% were triple negative, and 20 had tumors positive for the oncogene, c-erb-B2 (identified with fluorescent in situ hybridization). After a median follow-up of 105 months (range, 65-180), no patient under 40 years old exhibited POF, while 44% of patients over 40 years old exhibited POF. Eight pregnancies were recorded: 7 at term and 1 voluntary interruption. The 10-year disease-free survival and overall survival rates were 85 and 91%, respectively. These data showed that, in premenopausal patients with early breast cancer, the addition of an LH-RH analogue to adjuvant chemotherapy was well tolerated, prevented POF, and was associated with excellent disease-free survival and overall survival rates.
Nishimura, Reiki; Anan, Keisei; Yamamoto, Yutaka; Higaki, Kenji; Tanaka, Maki; Shibuta, Kenji; Sagara, Yasuaki; Ohno, Shinji; Tsuyuki, Shigeru; Mase, Takahiro; Teramukai, Satoshi
The aim of the present study was to assess the efficacy and tolerability of a luteinizing hormone-releasing hormone (LH-RH) analogue plus an aromatase inhibitor following failure to respond to standard LH-RH analogue plus tamoxifen (TAM) in premenopausal patients. Premenopausal women with estrogen receptor (ER)-positive and/or progesterone-receptor positive, advanced or recurrent breast cancer refractory to an LH-RH analogue plus TAM received goserelin (GOS) in conjunction with anastrozole (ANA). The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and safety. Between September 2008 and November 2010, 37 patients were enrolled. Thirty-five patients (94.6%) had ER-positive tumors, and 36 (97.3%) had human epidermal growth factor receptor (HER) 2-negative tumors. Thirty-six (97.3%) had measurable lesions and 1 (2.7%) had only bone metastasis. The ORR was 18.9% [95% confidence interval (CI), 8.0-35.2%], the CBR was 62.2% (95% CI, 44.8-77.5%) and the median PFS was 7.3 months. Eight patients had adverse drug reactions but none resulted in discontinuation of treatment. GOS plus ANA is a safe effective treatment for premenopausal women with hormone receptor-positive, recurrent or advanced breast cancer. The treatment may become viable treatment in the future, particularly when TAM is ineffective or contraindicated. Further studies and discussion are warranted.
Hashimoto, K; Makino, S; Hirasawa, R; Takao, T; Kageyama, J; Ogasa, T; Ota, Z
We examined 8 normal subjects and 16 patients with non-functioning pituitary tumors with a combined anterior pituitary test to evaluate the clinical usefulness of the test. Diagnoses included 9 of chromophobe adenoma, 3 of craniopharyngioma, 2 of Rathke's cleft cyst, and 1 each of intrasellar cyst and tuberculum sella meningioma. All subjects received hypothalamic releasing hormones: 1 micrograms/kg corticotropin releasing hormone (CRH), 1 micrograms/kg growth hormone releasing hormone (GRH), 500 micrograms thyrotropin-releasing hormone (TRH), 100 micrograms luteinizing hormone releasing hormone (LH-RH), and a relatively small dose (5 mU/kg) of lysine vasopressin (LVP). In the normal subjects, the addition of LVP potentiated the secretion of adenocorticotropic hormone (ACTH) induced by CRH, but had no significant effect on the secretion of other anterior pituitary hormones. In the combined test with 5 releasing hormones, the plasma ACTH and cortisol responses were not impaired in the majority of the patients before pituitary surgery. Serum thyroid-stimulating hormone (TSH), prolactin (PRL) and follicle-stimulating hormone (FSH) responses were not impaired in 82%, 70% and 67% of the patients, respectively, while the serum LH and GH responses were impaired in 67% and 73% of the patients, respectively. Following pituitary surgery, responses of these hormones to combined testing were similarly impaired in more than 75% of the patients. These results indicate that plasma ACTH, cortisol and serum TSH responses are fairly good before pituitary surgery but are impaired significantly after surgery. No subjects experienced any serious adverse effects related to the testing. These results suggest that combined testing with hypothalamic hormones is a convenient and useful method for evaluating pituitary function.
NISHIMURA, REIKI; ANAN, KEISEI; YAMAMOTO, YUTAKA; HIGAKI, KENJI; TANAKA, MAKI; SHIBUTA, KENJI; SAGARA, YASUAKI; OHNO, SHINJI; TSUYUKI, SHIGERU; MASE, TAKAHIRO; TERAMUKAI, SATOSHI
The aim of the present study was to assess the efficacy and tolerability of a luteinizing hormone-releasing hormone (LH-RH) analogue plus an aromatase inhibitor following failure to respond to standard LH-RH analogue plus tamoxifen (TAM) in premenopausal patients. Premenopausal women with estrogen receptor (ER)-positive and/or progesterone-receptor positive, advanced or recurrent breast cancer refractory to an LH-RH analogue plus TAM received goserelin (GOS) in conjunction with anastrozole (ANA). The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and safety. Between September 2008 and November 2010, 37 patients were enrolled. Thirty-five patients (94.6%) had ER-positive tumors, and 36 (97.3%) had human epidermal growth factor receptor (HER) 2-negative tumors. Thirty-six (97.3%) had measurable lesions and 1 (2.7%) had only bone metastasis. The ORR was 18.9% [95% confidence interval (CI), 8.0–35.2%], the CBR was 62.2% (95% CI, 44.8–77.5%) and the median PFS was 7.3 months. Eight patients had adverse drug reactions but none resulted in discontinuation of treatment. GOS plus ANA is a safe effective treatment for premenopausal women with hormone receptor-positive, recurrent or advanced breast cancer. The treatment may become viable treatment in the future, particularly when TAM is ineffective or contraindicated. Further studies and discussion are warranted. PMID:23446822
Detection of catecholamine and luteinizing hormone-releasing hormone (LH-RH) containing nerve endings in the median eminence and the organon vasculosum laminae terminalis by fluorescence histochemistry and immunohistochemistry on the same microscopic sections.
Ibata, Y; Watanabe, K; Kinoshita, H; Kubo, S; Sano, Y; Sin, S; Hashimura, E; Imagawa, K
Distribution of catecholamine (CA) and LH-RH nerve endings in the median eminence (ME) and the organon vasculosum laminae terminalis (OVLT) of the rat was investigated by application of fluorescence histochemistry and immunohistochemistry on the same sections of the tissue. In the ME, those two kinds of endings coexisted in the lateral portion of the middle part of ME, and in the wall of tuberoinfundibular sulcus, where they might be considered to have functional correlation. In the OVLT they were also distributed in fairly near distance, but they were not so closely associated as observed in the ME.
Intercellular communications within the rat anterior pituitary. XVI: postnatal changes of distribution of S-100 protein positive cells, connexin 43 and LH-RH positive sites in the pars tuberalis of the rat pituitary gland. An immunohistochemical and electron microscopic study.
Wada, Ikuo; Sakuma, Eisuke; Shirasawa, Nobuyuki; Wakabayashi, Kenjiro; Otsuka, Takanobu; Hattori, Kazuki; Yashiro, Takashi; Herbert, Damon C; Soji, Tsuyoshi
The architecture of luteinizing hormone-releasing hormone (LH-RH) nerve ends and the S-100 protein containing folliculo-stellate cells forming gap junctions in the pars tuberalis is basically important in understanding the regulation of the hormone producing mechanism of anterior pituitary glands. In this study, intact male rats 5-60 days old were prepared for immunohistochemistry and electron microscopy. From immunostained sections, the S-100 containing cells in pars tuberalis were first detected on day 30 and increased in number to day 60; this was parallel to the immunohistochemical staining of gap junction protein, connexin 43. LH-RH positive sites were clearly observed on just behind the optic chiasm and on the root of pituitary stalk on day 30. On day 60, the width of layer increased, while follicles and gap junctions were frequently observed between agranular cells in 10 or more layers of pars tuberalis. In the present study, we investigated the sexual maturation of the anterior pituitary glands through the postnatal development of S-100 positive cells, connexin 43 and LH-RH nerves. It is suggested that the folliculo-stellate cell system including the LH-RH neurons in the pars tuberalis participates in the control of LH secretion along with the portal vein system.
Kitamura, T; Suzuki, M; Nishimatsu, H; Kurosaki, T; Enomoto, Y; Fukuhara, H; Kume, H; Takeuchi, T; Miao, L; Jiangang, H; Xiaoqiang, L
In order to assess the efficacy and toxicity of oral estramustine phosphate (EMP) administration, low-dose EMP monotherapy (study 1) and very low-dose EMP therapy with luteinizing hormone-releasing hormone (LH-RH) agonist (study 2) were conducted in previously untreated prostate cancer and long-term outcomes were compared between the 2 study groups. Studies 1 and 2 were independently performed beginning in June 1999 and November 2001, respectively. Study 1 was composed of 87 patients including 85 assessable patients. All 108 patients recruited for study 2 were assessable. Low-dose EMP monotherapy (2 capsules/day or 280 mg/day) was used in study 1 and very low-dose EMP (1 capsule/day or 140 mg/day) combined with LH-RH agonist was adopted in study 2. Overall prostate specific antigen (PSA) -response rates in studies 1 and 2 were 92.3% and 94.2%, respectively, and overall toxicity rates were 54.1% and 38.9%, respectively. EMP discontinuation due to side effects was encountered more often in study 1 (45.9%) than in study 2 (27.8%). Among the adverse side effects gastrointestinal toxicity was most prevalent in both studies. One patient died of acute pulmonary embolism in study 1, but no one died in study 2. There were 6 cancer deaths in the gastrointestinal tract in study 1 but only 2 cancer deaths in study 2. Our data indicate that the overall PSA response rate was comparable between both studies. However, rates in overall toxicity and drug discontinuation were higher in study 1 than in study 2. We consider that study 2 is more promising for the treatment of previously untreated advanced prostate cancer, although the rate of adverse side effects is still high as compared with other hormonal therapies. In order to overcome the high toxicity rate, especially the gastrointestinal toxicity, we recently elaborated a method employing tailor-made medicine using SNPs of 1A1 gene in cytochrome P-450 for decreasing the rate of gastrointestinal toxicity. Using this method of
Cavitte, J C; Lahlou, N; Mialot, J P; Mondain-Monval, M; Mialot, M; Nahoul, K; Morel, C; Roger, M; Schally, A V
The effect of long term treatment with D-Trp6-LH-RH in microcapsules (GnRH-A) on pituitary gonadal axis was studied in a adolescent and adult Fox-terrier dogs. They received intramuscularly 50 micrograms/GnRH-A/kg, on day 1 and 21 and every 4 weeks thereafter. Three adult dogs received 4 injections. cLH, cFSH and T levels were undetectable on day 7. Detectable then normal levels occurred 60 and 90 days respectively after the last injection on day 77. Testis thickness was respectively 22.1 +/- 0.8 mm and 16.3 +/- 0.8 mm on days 0 and 77; initial values were observed 90 days later. Spermatozoa disappeared from the ejaculate on day 21 in 2 dogs; reappearance and complete recovery were observed on days 161-175 and 252 respectively. Histological findings showed on day 91 atrophic lesions of testis and prostate and spermatogonia were present in all seminiferous tubules. After recovery a normal histological appearance was noticed. Three adolescent 29 weeks old dogs received 14 injections, the last one on day 357. cLH, cFSH and T levels were undetectable only from day 105. Testis thickness were respectively 15.8 +/- 0.7 mm, 18.1 +/- 0.7 mm, 12.5 +/- 0.3 mm and 21.4 +/- 0.7 mm on day 0, 21, 357 and 490. Initially, no spermatozoa were present in the ejaculates, they appeared in 2 dogs after 2 months for 20 to 40 days then disappeared until day 449. Normal semen characteristics were observed in all three dogs on day 581. Histological findings on day 371 were comparable to those observed in the adult dogs. This study demonstrates that longterm treatment with D-Trp6-LH-RH in microcapsules leads to a reversible inhibition of spermatogenesis in dogs. The delayed response in adolescent dogs might be due to a transient resistance to therapy related to.
Meakin, J.L.; Keogh, E.J.; Martin, C.E.
One hundred sixty-three patients who were given synthetic LH-RH therapeutically underwent monitoring of serum IgG anti-LH-RH antibodies. Five of the patients showed specific binding to antibodies. Development of anti-LH-RH antibodies was not limited to those patients with a congenital deficiency of LH-RH. Urticarial responses occurred in four patients, only one of whom had IgG antibodies. Patients who had IgG antibodies or an urticarial response underwent monitoring of their serum IgE anti-LH-RH antibodies, but none had a positive binding response. The refractory state which has been reported in patients in whom similar antibodies to LH-RH develop was not invariably observed among these patients.
de Quijada, M G; Redding, T W; Coy, D H; Torres-Aleman, I; Schally, A V
We investigated the effects of [D-Trp6]LH-RH [agonistic analog of luteinizing hormone-releasing hormone (LH-RH)], N-Ac-[D-p-Cl-Phe1,2,D-Trp3,D-Phe6,D-Ala10]LH-RH (antagonistic analog), and [D-5-methoxy-Trp8]somatostatin (somatostatin analog) on the growth of the prolactin and corticotropin-secreting pituitary tumor 7315a in female Buffalo rats. Chronic administration of [D-Trp6]LH-RH in a dose of 25 micrograms/day, starting 18 days after inoculation with the tumor, inhibited the growth of the pituitary tumor. Tumor weight and volume also were reduced when this agonist was administered 3 days after inoculation. The antagonistic LH-RH analog, injected in a dose of 50-100 micrograms for 14-24 days, also significantly inhibited the growth of pituitary tumor. Chronic administration of the somatostatin analog in a dose of 25 micrograms twice a day likewise decreased tumor weights in comparison with controls. The inhibition of pituitary tumor growth by LH-RH agonist, LH-RH antagonist, and somatostatin analog was accompanied by a decrease in serum prolactin levels. It was concluded that LH-RH agonist, LH-RH antagonist, and somatostatin analog can inhibit the growth of estrogen-dependent prolactin/corticotropin-secreting pituitary tumor in rats. PMID:6134284
Redding, T W; Schally, A V
Experiments were undertaken with estrogen-dependent mammary carcinomas in rats and mice to determine the antitumor activities of agonistic and antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH). Chronic administration of the agonist [D-Trp6]LH-RH or of antagonist 1 ( [NAc-D-p-Cl-Phe1,2-Phe3,D-Arg6-D-Ala10]LH-RH) at doses of 25 and 50 micrograms/day, respectively, for 21 days to mice bearing the MXT mammary carcinoma significantly decreased tumor weight and volume. The weight of the ovaries and serum progesterone levels in mice treated with [D-Trp6]LH-RH or antagonist 1 were also significantly reduced. In rats bearing the MT/W9A mammary adenocarcinoma, chronic administration of [D-Trp6]LH-RH at a dose of 25 micrograms twice a day or of antagonist 2 ( [NAc-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]LH-RH) at a dose of 50 micrograms twice a day for 28 days significantly decreased tumor weight and volume. Chronic treatment with either [D-Trp6]LH-RH or antagonist 2 markedly diminished the weight of the ovaries and serum levels of both estrogen and progesterone. Serum luteinizing hormone was significantly decreased in rats treated with antagonist 2 but not in rats treated with [D-Trp6]LH-RH. There was a significant drop in serum prolactin levels in rats treated with [D-Trp6]LH-RH but not in those receiving antagonist 2. Regression of mammary tumors in rats and mice in response to chronic administration of [D-Trp6]LH-RH and the two antagonistic analogs of LH-RH suggests that these compounds should be considered for the development of a new hormone therapy for breast cancer in women. PMID:6219395
Mason-Garcia, M; Vigh, S; Comaru-Schally, A M; Redding, T W; Somogyvari-Vigh, A; Horvath, J; Schally, A V
A sensitive and specific radioimmunoassay for [6-D-tryptophan]luteinizing hormone-releasing hormone [( D-Trp6]LH-RH) was developed and used for following the rate of liberation of [D-Trp6]LH-RH from a long-acting delivery system based on a microcapsule formulation. Rabbit antibodies were generated against [D-Trp6]LH-RH conjugated to bovine serum albumin with glutaraldehyde. Crossreactivity with LH-RH was less than 1%; there was no significant crossreactivity with other peptides. The minimal detectable dose of [D-Trp6]LH-RH was 2 pg per tube. Intra- and interassay coefficients of variation were 8% and 10%, respectively. The radioimmunoassay was suitable for direct determination of [D-Trp6]LH-RH in serum, permitting the study of blood levels of the analog after single injections into normal men and after once-a-month administration of microcapsules to rats. In men, 90 min after subcutaneous injection of 250 micrograms of the peptide, serum [D-Trp6]LH-RH rose to 6-12 ng/ml. Luteinizing hormone was increased 90 min and 24 hr after the administration of the analog. Several batches of microcapsules were tested in rats and the rate of release of [D-Trp6]LH-RH was followed. The improved batch of microcapsules of [D-Trp6]LH-RH increased serum concentrations of the analog for 30 days or longer after intramuscular injection. This was accompanied by suppression of testosterone levels for more than 30 days. This radioimmunoassay should be of value for monitoring [D-Trp6]LH-RH during long-term therapy. PMID:3156381
Ban, Y; Ban, Y; Taniyama, M; Hara, H; Abe, T; Katagiri, T
We report a patient with primary hypothyroidism associated with an aberrant ACTH response to the LH-RH test. A 40-year-old woman was admitted to our hospital displaying headache, nausea, and numbness on the left side of her face, upper limbs, and tips of her toes. Computed tomography and magnetic resonance imaging revealed a mass-like lesion in the pituitary. A high serum TSH concentration with concomitant low thyroid hormone concentrations resulted in a diagnosis of primary hypothyroidism. To exclude the possibility of a coexisting pituitary tumor including a TSH-secreting tumor, we performed dynamic TSH secretion tests. TRH testing showed an excessive, delayed TSH response, typical of primary hypothyroidism. Serum TSH decreased not only after administration of CRH, octreotide, or L-DOPA, but also after administration of LH-RH. In this case, LH-RH testing induced ACTH secretion. To determine if aberrant ACTH secretion in response to LH-RH loading is a common phenomenon in severe primary hypothyroidism, we performed the LH-RH test on 4 additional patients with pituitary enlargement due to primary hypothyroidism. Two patients demonstrated aberrant ACTH secretion in response to LH-RH loading, but the others did not. To our knowledge, this is the first report of aberrant LH-RH-stimulated ACTH secretion in primary hypothyroidism.
Kuba, Sayaka; Ishida, Mayumi; Oikawa, Masahiro; Nakamura, Yoshiaki; Yamanouchi, Kosho; Tokunaga, Eriko; Taguchi, Kenichi; Esaki, Taito; Eguchi, Susumu; Ohno, Shinji
The roles of aromatase inhibitors (AIs) and luteinizing hormone-releasing hormone (LH-RH) agonists in the management of male breast cancer remain uncertain, with no reports in Japanese men. We report four Japanese male patients with metastatic breast cancer treated with AIs with or without an LH-RH agonist, and consider the relationship between treatment effect and estradiol (E2) concentration. Three patients were initially treated with AI alone after selective estrogen receptor modulators (SERMs), and one received AIs plus an LH-RH agonist after a SERM. Two patients treated with an AI alone responded, one patient with E2 levels below the lower assay limit and the other with levels above the limit. The other treated with an AI alone experienced progression regardless of the E2 levels below the lower assay limit, however, responded after the addition of an LH-RH agonist. E2 concentrations were related to the efficacy of treatment in one patient. The patient initially treated with an AI plus an LH-RH agonist also responded. No grade 3 or 4 adverse events were observed in any of the patients treated with AIs with or without an LH-RH agonist. AIs with or without an LH-RH agonist offer an effective treatment option for hormone receptor-positive metastatic male breast cancer.
Seyer, R; Aumelas, A; Caraty, A; Rivaille, P; Castro, B
The coupling reagent (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium (BOP) hexafluorophosphate was tested in the synthesis of luliberin (LH-RH) with inexpensive classically protected Boc-amino acids, in slight excess, and benzhydryl amino resin, without any other additive. The good solubility of this reagent and its by-products is of particular interest for automated peptide synthesis. [D-His2]LH-RH was also synthesized and compared with LH-RH by proton nuclear magnetic resonance spectroscopy. As shown by the biological tests and the high performance liquid chromatography study, unprotected pyroGlu and Boc-His can be used without any significant racemization but Boc-His(Boc) was found to be preferable since it gave no detectable racemization and no by-products. The difficult isolation of the minority D-derivative from the crude preparation of LH-RH was resolved by a recycling procedure in reversed phase HPLC.
Redding, T W; Schally, A V; Tice, T R; Meyers, W E
Intramuscular injection of [6-D-tryptophan]-luteinizing hormone-releasing hormone [( D-Trp6]LH-RH) in microcapsules of poly(DL-lactide-co-glycolide), designed to release a controlled dose of the peptide over a 30-day period, decreased the weights of androgen-dependent Dunning prostate tumors in rats and suppressed serum testosterone levels more effectively than daily subcutaneous administration of equivalent or double doses of unencapsulated [D-Trp6]LH-RH. The microcapsules or daily injections of [D-Trp6]LH-RH also significantly decreased tumor volumes. Microcapsules of [D-Trp6]LH-RH or related analogs that can be injected once a month should make the treatment of patients with prostate carcinoma and other neoplasms or disorders more convenient and efficacious. Images PMID:6237365
... and RH (FR54 3,600 flight cycles. through FR58). All STGR22 LH and RH 2,700 flight cycles. (FR26 through FR40). All STGR22 RH (FR58 3,000 flight cycles. through FR65). All STGR31 LH/RH (FR26 3,000 flight cycles. through FR39). MSN 0003 STGR31 LH/RH (FR54 3,600 flight cycles. through FR58). (h) For airplanes...
Kastin, Abba J.; Schally, Andrew V.; Gual, Carlos; Midgley, A. Rees; Miller, M. Clinton; Cabeza, Angela
In previous clinical studies with highly purified porcine luteinizing hormone-releasing hormone (LH-RH), administration of the somewhat arbitrarily chosen doses of 700-1500 μg resulted in increased serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The present study determined the minimum effective dose as well as the relationship of the response of serum LH and FSH to the dose of LH-RH administered. Three normal men received i.v. injections of 1.1-810 μg of LH-RH. A dose of 10 μg of LH-RH caused a statistically significant elevation in serum LH. 30 μg of LH-RH significantly increased serum FSH levels. A highly significant linear trend was observed in the log dose-response curve. The results indicate that both LH and FSH release occurs in man with doses of LH-RH much lower than previously used and that a linear log dose-response relationship can be obtained. PMID:4932985
Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V
The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells. PMID:2548207
Schally, A.V.; Paz-Bouza, J.I.; Schlosser, J.V.; Karashima, T.; Debeljuk, L.; Gandle, B.; Sampson, M.
Possible protective effects of the agonist (D-Trp/sup 6/)LH-RH and antagonist N-Ac(D-Phe(pCl)/sup 1,2/,D-Trp/sup 3/,D-Arg/sup 6/,D-Ala/sup 10/)LH-RH against testicular damage caused by x-radiation were investigated in rats. Three months after being subjected to x-irradiation of the testes with 415 or 622 rads, control rats showed marked reduction in the weights of the testes and elevated levels of LH and follicle-stimulating hormone (FSH), indicating tubular damage. Histological studies demonstrated that, in testes of rats given 415 rads, most seminiferous tubules had only Sertoli cells and no germinal cells, and, in the group give 622 rads, the depression of spermatogenesis was even more marked. Rats pretreated for 50 days with LH-RH antagonist showed a complete recovery of testicular weights and spermatogenesis 3 months after 415 rads and showed partial recovery after 622 rads, and LH and FSH levels returned to normal in both of these groups. Three experiments were also carried out in which the rats were pretreated for 1-2 months with long-acting microcapsules of the agonist (D-Trp/sup 6/)LH-RH. Some rats were then subjected to gonadal irradiation with 415 or 622 rads and allowed a recovery period of 2-4 months. On the basis of testicular weights, histology, and gonadotropin levels, it could be concluded that the agonist (D-Trp/sup 6/)LH-RH did not protect the rat testes exposed to 622 rads and, at most, only partially protected against 415 rads. These results suggest that pretreatment with LH-RH antagonists and possibly agonists, might decrease the testicular damage caused by radiation and accelerate the recovery of reproductive functions.
Yano, T; Pinski, J; Halmos, G; Szepeshazi, K; Groot, K; Schally, A V
Female athymic nude mice bearing xenografts of OV-1063 human epithelial ovarian cancer cell line were treated with potent luteinizing hormone (LH)-releasing hormone (LH-RH) antagonist SB-75 (Cetrorelix; [Ac-D-Nal(2)1, D-Phe(4 CI)2, D-Pal(3)3, D-Cit6, D-Ala10]LH-RH in which Ac-D-Nal(2) = N-acetyl-3-(2-naphthyl)-D-alanine, D-Phe(4CI) = 4-chloro-D-phenylalanine, D-Pal(3) = 3-(3-pyridyl)-D-alanine, and D-Cit = D-Citrulline) or with the agonist [D-Trp6]LH-RH. In the first experiment, SB-75 and [D-Trp6]LH-RH were administered in the form of microcapsules releasing 60 and 25 micrograms/day, respectively. In the second study, the analogs were given by daily s.c. injections in doses of 100 micrograms/day. In both experiments, tumor growth, as measured by reduction in tumor volume, percentage change in tumor volume, tumor burden, and increase in tumor doubling time, was significantly inhibited by treatment with SB-75 but not with [D-Trp6]LH-RH. Uterine and ovarian weights were reduced and serum LH levels decreased by administration of either analog. Chronic treatment with SB-75 greatly reduced the concentration of receptors for epidermal growth factor and insulin-like growth factor I in tumor cell membranes, a phenomenon that might be related to tumor growth inhibition. It is possible that the antitumoral effects of SB-75 on OV-1063 ovarian cancers are exerted not only through the suppression of the pituitary-gonadal axis, but also directly. In view of its strong inhibitory effect on the growth of OV-1063 ovarian cancers in vivo, the potent LH-RH antagonist SB-75 might be considered for possible hormonal therapy of advanced epithelial ovarian carcinoma. PMID:7518926
Schally, A V; Redding, T W
The combination of a long-acting delivery system for the agonist [D-Trp6]luteinizing hormone-releasing hormone ([D-Trp6]LH-RH) with modern somatostatin analogs was studied in the Dunning R-3327H rat prostate cancer model. Microcapsules of [D-Trp6]LH-RH releasing 25 micrograms/day were injected once a month. In the first experiment the adjunct was the somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), administered at a dose of 2.5 micrograms twice a day, and the therapy was continued for 70 days. Tumor volume was significantly decreased by [D-Trp6]LH-RH microcapsules or RC-121 given alone. The combination of microcapsules and analog RC-121 caused a greater inhibition of tumor growth than the single agents. Similar effects were seen when the percent increase in the tumor volume was examined. The inhibition of tumor growth caused by the [D-Trp6]LH-RH microcapsules was greater than that caused by RC-121. The combination of the two agents was again the most effective, resulting in the smallest increase in tumor volume. Tumor weights were much lower in the groups treated with microcapsules or RC-121 alone than in controls. The lowest tumor weights were obtained in the group that received the combination of [D-Trp6]LH-RH microcapsules and RC-121. Similar results were obtained in the second experiment, in which the animals were treated for a period of 83 days with microcapsules containing the somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) that released 5 micrograms/day and were injected twice a month alone or in combination with microcapsules of [D-Trp6]LH-RH. Microcapsules of analog RC-160 given alone significantly decreased tumor growth as measured by the final tumor volume, the percentage change from the initial tumor volume, and the reduction in tumor weight. The inhibition of tumor growth induced by [D-Trp6]LH-RH microcapsules was greater than that caused by RC-160. The most striking decrease in tumor weight and volume was
Belda, M; Coveñas, R; Narváez, J A; Aguirre, J A; Tramu, G
The distribution of luteinizing hormone-releasing hormone (LH-RH)-immunostained cell bodies and fibres was studied in the brainstem and diencephalon of the cat using an indirect immunoperoxidase technique. The brainstem and the thalamus were devoid of immunostained cell bodies, whereas in the hypothalamus immunopositive perikarya were observed in the supraoptic nucleus, the anterior hypothalamus, the preoptic region and in the arcuate nucleus. Our findings also showed that the hypothalamus is richer in immunostained fibres, and that in this region such fibres are more widely distributed than in the thalamus and upper brainstem. No immunopositive fibres were observed in the lower brainstem. Our results point to a more widespread distribution of LH-RH-immunostained perikarya in the cat hypothalamus than that previously reported in the cat; a similar distribution to that found in the rat, and a more restricted distribution than in primates. Additionally, our study shows a more widespread distribution of immunostained fibres in the cat brainstem and diencephalon than that previously described for other mammals. In this context, our results describe for the first time in the mammals central nervous system fibres containing LH-RH located in the stria medullaris of the thalamus, the supramammillary decussation, the laterodorsal and lateroposterior thalamic nuclei, the nucleus reuniens, the supraoptic nucleus, and the optic chiasm. Thus, our findings reveal that LH-RH-immunostained structures are widely distributed in the upper brainstem and in the diencephalon of the cat, suggesting that the peptide may be involved in several physiological functions.
Sakurai, Kenichi; Matsuo, Sadanori; Enomoto, Katsuhisa; Amano, Sadao; Shiono, Motomi
Little is known about the period required for menstruation recovery after long-term luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen therapy following chemotherapy. In this study we investigated the period required for menstruation recovery after the therapy. The subjects comprised 105 premenopausal breast cancer patients who had undergone surgery. All patients were administered an LH-RH agonist for 24 months and tamoxifen for 5 years following the postoperative adjuvant chemotherapy, and the status of menstruation recovery was examined. Menstruation resumed in 16 cases (15.2%) after the last LH-RH agonist treatment session. The mean period from the last LH-RH agonist treatment to the recovery of menstruation was 6.9 months. The rate of menstruation recovery was 35.5% in patients aged 40 years or younger and 8.0% in those aged 41 years or older, and it was significantly higher in those aged 40 years or younger. The period until menstruation recovery tended to be longer in older patients at the end of treatment. This study showed that menstruation resumed after treatment at higher rates in younger patients. However, because it is highly likely that ovarian function will be destroyed by the treatment even in young patients, it is considered necessary to explain the risk to patients and obtain informed consent before introducing this treatment modality.
Luteinizing hormone releasing hormone (LH RH) agonists are the major agent for androgen deprivation therapy in advanced and metastatic prostate cancer. They also have a role in endometriosis, uterine fibroids and central precocious puberty. Triptorelin embonate 22.5 mg is a new, sustained-release, 6-month formulation of an LH RH agonist. It possesses longer duration of action than the current standard 3-month preparation and appears to have similar efficacy and side effects. The use of LH RH agonists for androgen deprivation in prostate cancer has increased considerably in the last 20 years. Recent work has shown that some of this usage has constituted overtreatment and it is within these newer paradigms of therapy that the new 6-month preparation is situated. The new 6-month LH RH preparation - triptorelin embonate - will be of help in several key areas of therapy for prostate cancer, notably as an adjunct to radiation therapy and chemotherapy. It possesses a similar effect, but with fewer side effects, than those that are now commonly available.
Nishii, Masahiro; Nomura, Masashi; Sekine, Yoshitaka; Koike, Hidekazu; Matsui, Hiroshi; Shibata, Yasuhiro; Ito, Kazuto; Oyama, Tetsunari; Suzuki, Kazuhiro
Recently, adrenal androgens have been targeted as key hormones for the development of castration-resistant prostate cancer therapeutics. Although circulating adrenal androgens originate mainly from the adrenal glands, the testes also supply about 10%. Although widely used in androgen deprivation medical castration therapy, the effect of luteinizing hormone-releasing hormone (LH-RH) agonist on adrenal androgens has not been fully studied. In this study, changes in testicular and adrenal androgen levels were measured and compared to adrenocorticotropic hormone levels. To assess the possible role of LH in the adrenal glands, immunohistochemical studies of the LH receptor in normal adrenal glands were performed. Forty-seven patients with localized or locally progressive prostate cancer were treated with LH-RH agonist with radiotherapy. Six months after initiation of treatment, testosterone, dihydrotestosterone, and estradiol levels were decreased by 90%-95%, and dehydroepiandrosterone-sulfate, dehydroepiandrosterone, and androstenedione levels were significantly decreased by 26%-40%. The suppressive effect of LH-RH agonist at 12 months was maintained. Adrenocorticotropic hormone levels showed an increasing trend at 6 months and a significant increase at 12 months. LH receptors were positively stained in the cortex cells of the reticular layer of the adrenal glands. The long-term LH-RH agonist treatment reduced adrenal-originated adrenal androgens. LH receptors in the adrenal cortex cells of the reticular layer might account for the underlying mechanism of reduced adrenal androgens.
Thomas, K; Loumaye, E; Ferin, J
Around pharmacologically induced ovulation, inconstant immunoreactive plasma relaxin concentrations were observed. Increasing levels appear during HCG or LH-RH induced lutinization. These values remain high as long as the corpus luteum is sustained. These observations may suggest that relaxin has a role during early luteinization and during the non-gestational lifespan of the corpus luteum in women.
... requires a one-time inspection of the wires located between LH/RH engines Hydraulic FSOV and wing rear spar... wires located on left hand (LH) side and right-hand (RH) side of the wing rear spar, in accordance with... of the LH and RH Sides If, during the inspection required by paragraph (g) of this AD, contact(s) or...
Loffet, A; Durieux, J P
The Luteinizing hormone-releasing hormone (LH-RH), and the follicle stimulating hormone-releasing hormone (FSH-RH) have been synthesized by a new procedure involving solid phase and conventional solution coupling. The release of LH and FSH by this synthetic product has been measured in both laboratory animals and in men. Results coincide exactly with those in the published literature.
Tan, Sing-Huang; Wolff, Antonio C
Ovarian function suppression for the treatment of premenopausal breast cancer was first used in the late 19th century. Traditionally, ovarian function suppression had been accomplished irreversibly via irradiation or surgery, but analogues of the luteinizing hormone-releasing hormone (LH-RH) have emerged as reliable and reversible agents for this purpose, especially the LH-RH agonists. Luteinizing hormone-releasing hormone antagonists are in earlier stages of development in breast cancer and are not currently in clinical use. Luteinizing hormonereleasing hormone agonists act by pituitary desensitization and receptor downregulation, thereby suppressing gonadotrophin release. Limited information is available comparing the efficacies of the depot preparations of various agonists, but pharmacodynamic studies have shown comparable suppressive capabilities on estradiol and luteinizing hormone. At present, only monthly goserelin is Food and Drug Administration-approved for the treatment of estrogen receptor-positive, premenopausal metastatic breast cancer in the United States. Luteinizing hormone-releasing hormone agonists have proven to be as effective as surgical oophorectomy in premenopausal advanced breast cancer. They offer similar outcomes compared with tamoxifen, but the endocrine combination appears to be more effective than LH-RH agonists alone. In the adjuvant setting, LH-RH agonists versus no therapy reduce the annual odds of recurrence and death in women aged>50 years with estrogen receptor-positive tumors. Luteinizing hormone-releasing hormone agonists alone or in combination with tamoxifen have shown disease-free survival rates similar to chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil). Outcomes of chemotherapy with or without LH-RH agonists are comparable, though a few trials favor the combination in young premenopausal women (aged<40 years). Adjuvant LH-RH agonists with or without tamoxifen might be as efficacious as tamoxifen alone
Groves, D J; Batten, T F
Pituitaries from male and female mollies were incubated with varying amounts of mammalian LH-RH, arginine vasotocin, dopamine, or serotonin for 18 hr. Ultrastructural differences between control and experimentally treated glands were used to define the direct effects of these neurohormones and neurotransmitters on the gonadotrophic cells of the adenohypophysis. The effects varied in intensity according to the sex and reproductive state of the donor animal. LH-RH stimulated gonadotrophin secretion by the gonadotrophs, as did vasotocin, although to a much lesser extent and with noticeable differences between the sexes. Dopamine inhibited secretion by basally active gonadotrophs and probably from active cells also, although to a lesser extent. Serotonin mildly stimulated secretion at all stages in both sexes. The results of this study indicate the possible involvement of neurohypophysial octapeptides and of monoamines in the direct control of the gonadotroph of Poecilia latipinna.
Anda, Takeo; Honda, Masaru; Ishihara, Tokuhiro; Kamei, Toshiaki
The authors describe a male patient who developed a large intracranial meningioma during the hormone therapy for pre-existing prostate cancer. A 70-year-old man received a brain check-up, and no intracranial abnormality was detected. Five months later, prostate cancer was diagnosed, and he underwent prostatectomy. Leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist, was subsequently administered to the patient once a month for 3 years. After that he presented with a large parasagittal mass, which was excised. The tumor was histologically diagnosed as meningothelial meningioma, and LH-RH receptors were verified immunohistochemically in the cytoplasm of the tumor cells. Leuprorelin acetate may accelerate the rapid growth of meningioma in this patient.
ANDA, Takeo; HONDA, Masaru; ISHIHARA, Tokuhiro; KAMEI, Toshiaki
The authors describe a male patient who developed a large intracranial meningioma during the hormone therapy for pre-existing prostate cancer. A 70-year-old man received a brain check-up, and no intracranial abnormality was detected. Five months later, prostate cancer was diagnosed, and he underwent prostatectomy. Leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist, was subsequently administered to the patient once a month for 3 years. After that he presented with a large parasagittal mass, which was excised. The tumor was histologically diagnosed as meningothelial meningioma, and LH-RH receptors were verified immunohistochemically in the cytoplasm of the tumor cells. Leuprorelin acetate may accelerate the rapid growth of meningioma in this patient. PMID:24201100
Fraser, H M; Sandow, J; Cowen, G M; Lumsden, M A; Haining, R; Smith, S K
Ten endometriosis patients received luteinizing hormone releasing hormone (LH-RH) agonist (buserelin) implant injections (6.6 mg subcutaneously) at days 0, 42, 84 and 126. Serum LH and follicle-stimulating hormone (FSH) were lowered by day 14. Luteinizing hormone remained at basal concentrations while FSH returned to values in the low-normal range of the menstrual cycle by day 35. At the end of the luteal phase during which treatment commenced, estrone and pregnanediol declined and remained at postmenopausal or early follicular phase values until days 305 to 460. Time to first ovulation ranged from 321 to 481 days after starting treatment. After the initial menstruation, only three instances of bleeding occurred during treatment. Pelvic pain was relieved or markedly reduced by day 42 and remained absent throughout the period of ovarian suppression. These results indicate the potential of a long-acting LH-RH agonist implant to form the basis for the treatment of symptomatic endometriosis.
Schally, A V; Kook, A I; Monje, E; Redding, T W; Paz-Bouza, J I
The combination of hormonal treatment based on a long-acting delivery system for the agonist [6-D-tryptophan]luteinizing hormone-releasing hormone ([D-Trp6]-LH-RH) with the chemotherapeutic agent Novantrone (mitoxantrone dihydrochloride) was studied in the Dunning R3327H rat prostate cancer model. Microcapsules of [D-Trp6]-LH-RH formulated from poly(DL-lactide-co-glycolide) and calculated to release a controlled dose of 25 micrograms/day were injected intramuscularly once a month. Novantrone (0.25 mg/kg) was injected intravenously once every 3 weeks. Three separate experiments were carried out. When the therapy was started 45 days after transplantation and continued for 70 days, tumor volume in the presence of the microcapsules (966 +/- 219 mm3) or Novantrone (3606 +/- 785 mm3) given alone was significantly decreased compared to controls (14,476 +/- 3045 mm3). However, the combination of microcapsules and Novantrone caused a greater inhibition of tumor growth (189 +/- 31 mm3) than the single agents. Similar effects were seen when the percent increase in tumor volume was examined. Tumor volume increased 10,527 +/- 1803% for the control group. The inhibition of growth caused by the [D-Trp6]LH-RH microcapsules alone (672 +/- 153% increase in volume) was again greater than that caused by Novantrone alone (2722 +/- 421% increase). The combination of the two agents was again the most effective, resulting in an increase in tumor volume of only 105 +/- 29%. Control tumors weighed 30.0 +/- 6.5 g. Tumor weights were much less in the groups treated with either microcapsules (3.28 +/- 0.69 g) or Novantrone (19.53 +/- 3.3 g) alone. The lowest tumor weights after 70 days of treatment were obtained in the group that received the combination of [D-Trp6]LH-RH microcapsules and Novantrone (1.02 +/- 0.2 g). Testes and ventral prostate weights were significantly diminished by the administration of microcapsules of [D-Trp6]LH-RH alone or in combination with Novantrone. In both of these
Murphy, G.P.; Khoury, S.; Kuss, R.; Chatelain, C.; Denis, L.
There are 65 selections in this book. Some of the titles are: Are Nuclear Shape Factors Good Predictors of the Disease Course in Patients with Carcinoma of the Prostate.; Is Cytology a Definitive Diagnostic Procedure of Prostatic Cancer; The Treatment of Prostatic Cancer by LH-RH Agonist; Progress in Pathology of Carcinoma of Prostate; and Value of Different Markers in Prostatic Carcinomas: An Immunohistological Study.
Paz-Bouza, J.I.; Redding, T.W.; Schally, A.V.
Pancreatic ductal adenocarcinoma was induced in female Syrian golden hamsters by injecting N-nitrosobis(2-oxopropyl)amine (BOP) once a week at a dose of 10 mg per kg of body weight for 18 weeks. Hamsters were then treated with somatostatin analog (RC-160) or with (6-D-tryptophan)luteinizing hormone-releasing hormone ((D-Trp/sup 6/)LH-RH) delayed delivery systems. After 18 weeks of BOP administration, the hamsters were divided into three groups of 10-20 animals each. Group I consisted of untreated controls, group II was injected with RC-160, and group III was injected with (D-Trp/sub 2/)LH-RH. A striking decrease in tumor weight and volume was obtained in animals treated with (D-Trp/sup 6/)LH-RH or with the somatostatin analog RC-160. After 45 days of treatment with either analog, the survival rate was significantly higher in groups II and III (70%), as compared with the control group (35%). The studies, done by light microscopy, high-resolution microscopy, and electron microscopy, showed a decrease in the total number of cancer cells and changes in the epithelium, connective tissue, and cellular organelles in groups II and III treated with the hypothalamic analogs as compared to controls. These results in female hamsters with induced ductal pancreatic tumors confirm and extend the authors findings, obtained in male animals with transplanted tumors, that (D-Trp/sub 6/)LH-RH and somatostatin analogs inhibit the growth of pancreatic cancers.
Okamoto, Kohei; Sekine, Yositaka; Nomura, Masashi; Koike, Hidekazu; Matsui, Hiroshi; Shibata, Yasuhiro; Ito, Kazuto; Suzuki, Kazuhiro
To assess the cognitive and sexual/hormonal functioning of prostate cancer patients treated with a luteinizing hormone-releasing hormone (LH-RH) agonist, and the relationships thereof with adrenal and residual testicular androgen levels. Previously, we reported the effect of a luteinizing hormone-releasing hormone (LH-RH) agonist on testicular and adrenal androgen production in patients with prostate cancer. A 6-month treatment with an LH-RH agonist significantly reduced testicular androgens by 90-95% and adrenal androgens by 26-40%. This study evaluated the changes in cognitive and sexual/hormonal functions in the same cohort using the Mini-Mental State Evaluation (MMSE) and Expanded Prostate Cancer Index Composite (EPIC) questionnaire, respectively. In addition, the associations of each function with the serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), dehydroepiandrosterone-sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione (A-dione), and cortisol levels were studied. Cognitive functions did not change significantly during the treatment. Sexual functions were relatively low before treatment and worsened significantly after 6 and 12 months of treatment. Interestingly, sexual bothers were improved with the treatment. The treatment significantly worsened hormonal functions and bothers. Regarding specific items in the hormonal domains, hot flashes and body weight changes were the main effects of worsened hormonal function. Low levels of T and E2 and high levels of A-dione were associated with low MMSE scores at 6 months. Regarding sexual and hormonal functions, A-dione, E2, T, cortisol, and DHEA-S were associated with poorer functioning and bother. Especially, low T levels and high E2 levels were the most significant factors associated with worse sexual and hormonal bothers. The LH-RH agonist monotherapy worsened sexual and hormonal functions and hormonal bothers, but not sexual bothers or cognitive functions. The changes in these
Sakurai, Kenichi; Enomoto, Katsuhisa; Amano, Sadao
A luteinizing hormone-releasing hormone (LH-RH) agonist and tamoxifen (TAM) are used in hormonal therapy following pre- and post-operative chemotherapy in pre-menopausal advanced breast cancer patients who are positive for hormone receptors. However, it remains to be clarified how often patients recover menstruation after long-term LH-RH agonist plus TAM therapy. In this study, the incidence of menstruation recovery after therapy was examined. The subjects included 125 pre-menopausal patients with breast cancer who were positive for hormone receptors and had undergone surgery at our institution. They were treated with four cycles of the CEF regimen and four cycles of docetaxel (Doc) before surgery as adjuvant chemotherapy. Thereafter, they were treated with an LH-RH agonist plus TAM for 24 months and followed to determine menstruation recovery. Menstruation resumed in 24 cases (19.2%) after the last LH-RH agonist treatment session. It took 7.3 ± 2.8 months for the patients to recover menstruation. The rate of menstruation recovery was 42.1% in patients aged 40 or younger and 9.2% in those aged 41 or older; the difference was significant. The period until menstruation recovery tended to be longer in older patients at the end of treatment. The menstruation recovery rate after therapy was higher in younger women. However, since ovarian function may be lost even in younger patients, the potential consequences of this therapy should be fully explained beforehand to patients who may wish to become pregnant.
Redding, T W; Schally, A V
Using animal models of acinar and ductal pancreatic cancer, we investigated the effect of analogs of hypothalamic hormones on tumor growth. In Wistar/Lewis rats bearing the acinar pancreatic tumor DNCP-322, chronic administration of [L-5-Br-Trp8]somatostatin-14 significantly decreased tumor weights and volume. Somatostatin-28 and the cyclic hexapeptide analog of somatostatin cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe) failed to influence the growth of this tumor. The agonistic analog of luteinizing hormone-releasing hormone [D-Trp6]LH-RH also significantly decreased tumor weight and volume in this model and reduced testosterone levels and the weights of the ventral prostate and tests. In Syrian hamsters bearing ductal type of pancreatic carcinoma, chronic administration of [L-5-Br-Trp8]somatostatin diminished tumor weights and volume. The percentage change in tumor volume was significantly decreased when compared to control animals. In one experiment, cyclic hexapeptide of somatostatin also inhibited growth of this tumor. [D-Trp6]LH-RH, given twice daily or injected in the form of microcapsules for constant controlled release, significantly decreased tumor weight and volume and suppressed serum testosterone levels. Hamsters castrated 4 days after transplantation of the pancreatic tumors showed a significant decrease in weight and volume of these tumors. This suggests that pancreatic cancers may, at least in part, be sex hormone sensitive. [D-Trp6]LH-RH may decrease the growth of pancreatic carcinomas by suppressing androgens. Somatostatin analogs reduce the growth of pancreatic ductal and acinar cancers, probably by inhibiting the release or stimulatory action of gastrointestinal hormones on tumor cells (or both). Inhibition of animal models of pancreatic tumors by chronic administration of somatostatin analogs and [D-Trp6]LH-RH suggests that these compounds should be considered for the development of a new hormonal therapy for cancer of the pancreas. PMID:6141560
... Inspect special Repeat at intervals For airplanes-- area-- not to exceed-- All STGR5 LH and RH 3,600 flight cycles (FR54 through FR58). All STGR22 LH and RH 2,700 flight cycles (FR26 through FR40). All STGR22 RH (FR58 3,000 flight cycles through FR65). All STGR31 LH/RH (FR26 3,000 flight cycles through...
Scherr, Douglas S; Pitts, W Reid
During the last 2 decades there has been an increase in the number of men with prostate cancer placed on luteinizing hormone releasing hormone (LH-RH) agonist therapy. In addition, the duration of individual therapy has extended from what was once only a few months to, in many cases, several years. As a result there has been an increase in the incidence of side effects, including osteoporosis, decreased cognitive abilities, vascular stiffness and fatigue. We explored the use of estrogen in the form of diethylstilbestrol (DES) as an alternative treatment for men with prostate cancer, and introduce the concept of androgen deprivation without estrogen deprivation. In doing so we hope to elucidate some of the nonhormonal nonsteroidal effects of DES. Furthermore, we hope to define the mechanisms by which DES can be useful when LH-RH agonist therapy or orchiectomy has failed. We comprehensively reviewed the literature from 1935 to the present regarding estrogen and antiandrogen therapy. Our search focused on issues pertaining to side effects, efficacy and nonsteroidal effects of antiandrogens and estrogens. It is readily apparent from the literature that androgen deprivation with DES can achieve effective prostate cancer control with demonstrable benefits compared to conventional LH-RH agonist therapy. In particular, rates of bone resorption and osteoporosis are less with the use of estrogen therapies. Estrogen has a clear beneficial effect on cognitive function. The estrogen metabolite 2-methoxyestradiol has significant antiangiogenic and pro-apoptotic effects. These effects give estrogens an added anticancer effect not otherwise seen in conventional LH-RH agonist therapy. The efficacy of 1 mg DES extends well beyond its androgen suppressive effects. Androgen deprivation without estrogen deprivation is a concept that deserves further attention in the urological community.
Recchia, Francesco; Candeloro, Giampiero; Discepoli, Stefania; Grimaldi, Marisa; Desideri, Giovambattista; Necozione, Stefano; Rea, Silvio
This multicenter prospective trial assessed the outcome in 63 patients, 40 years of age or younger, with high-risk early breast cancer (HREBC), included in an ovarian protection study. The patients were treated with a luteinizing hormone-releasing hormone (LH-RH) analogue administered for 5 years, tailored chemotherapy and an aromatase inhibitor, in estrogen receptor-positive (ER(+)) patients. T-regulatory cells (T-regs) and vascular endothelial growth factor (VEGF) were measured at baseline and yearly. The mean age of the patients was 36 years (range 26-40). Sixty-five percent had ER(+) tumors, 24% had negative axillary nodes with tumors >1 cm and high histological grade with lymphovascular invasion, while 76% had a mean of 3.6 positive axillary nodes (range 1-21). Serum estradiol was maintained at values <40 pg/ml in all of the patients. A statistically significant decrease in VEGF (P<0.0001) and T-regs (P<0.0001), with respect to baseline values, was observed after LH-RH administration. After a median follow-up of 110 months, the 10-year progression-free and overall survival rates were 86.1 and 89.7%, respectively. These data revealed that the administration of an LH-RH analogue to HREBC patients, followed by chemotherapy and hormonal therapy, decreased VEGF and T-regs and improved the expected clinical outcome.
RECCHIA, FRANCESCO; CANDELORO, GIAMPIERO; DISCEPOLI, STEFANIA; GRIMALDI, MARISA; DESIDERI, GIOVAMBATTISTA; NECOZIONE, STEFANO; REA, SILVIO
This multicenter prospective trial assessed the outcome in 63 patients, 40 years of age or younger, with high-risk early breast cancer (HREBC), included in an ovarian protection study. The patients were treated with a luteinizing hormone-releasing hormone (LH-RH) analogue administered for 5 years, tailored chemotherapy and an aromatase inhibitor, in estrogen receptor-positive (ER+) patients. T-regulatory cells (T-regs) and vascular endothelial growth factor (VEGF) were measured at baseline and yearly. The mean age of the patients was 36 years (range 26–40). Sixty-five percent had ER+ tumors, 24% had negative axillary nodes with tumors >1 cm and high histological grade with lymphovascular invasion, while 76% had a mean of 3.6 positive axillary nodes (range 1–21). Serum estradiol was maintained at values <40 pg/ml in all of the patients. A statistically significant decrease in VEGF (P<0.0001) and T-regs (P<0.0001), with respect to baseline values, was observed after LH-RH administration. After a median follow-up of 110 months, the 10-year progression-free and overall survival rates were 86.1 and 89.7%, respectively. These data revealed that the administration of an LH-RH analogue to HREBC patients, followed by chemotherapy and hormonal therapy, decreased VEGF and T-regs and improved the expected clinical outcome. PMID:22993611
Santen, R J
A variety of studies in man and animals demonstrate that testosterone (T) is aromatized to estradiol (E) in the hypothalamus and limbic system. These observations suggested the possibility that conversion to E is an absolute requirement for the biologic activity of T on the hypothalamic-pituitary axis. Since this hypothesis implies a common mechanism of action of these two steroids, the demonstration of divergent effects of T and E on luteinizing hormone (LH) secretion would exclude this possibility. To test this hypothesis, the actions of T and E on three separate aspects of LH release (mean LH, pulsatile LH secretion, and responsiveness to LH-releasing hormone [LH-RH]) were contrasted. T and E, infused at two times their respective production rates into normal men, reduced mean LH levels similarly during 6 h of steroid infusion and for 6 h thereafter. However, these steroids exerted different effects on pulsatile secretion. E reduced the amplitude of spontaneous LH pulse from pre- and postinfusion control levels of 75+/-14 and 68+/-5.6% (SEM) to 39+/-5.7%. In contrast, T increased pulse amplited to 96+/-14% and decreased pulse frequency from basal levels of 3.4+/-0.31 to 1.8+/-0.31 pulses/6h. The site of suppressive action was determined by administering 25 microgms of LH-RH to the same men during T and E infusions and during three additional control periods without steroid administration. LH-RH produced similar 170-190% increments in serum LH during the three control periods and during T infusion. In contrast, E markedly blunted (76+/-31%, p less than 0.005) the LH response to LH-RH. Under the conditions of acute steroid infusion at doses (utilized in these experiments) producing similar inhibition of mean LH, E but not T acted directly on the pituitary to diminish LH-RH responsiveness. As further support that androgens can act without conversion to estrogens, the effects of a nonaromatizable androgen, dihydrotestosterone (DHT), on mean LH levels were studied
Schally, A V; Redding, T W
The effect of combining hormonal treatment consisting of long-acting microcapsules of the agonist [D-Trp6]LH-RH (the D-tryptophan-6 analog of luteinizing hormone-releasing hormone) with the chemotherapeutic agent cyclophosphamide was investigated in the Dunning R-3327H rat prostate cancer model. Microcapsules of [D-Trp6]LH-RH formulated from poly(DL-lactide-co-glycolide) and calculated to release a controlled dose of 25 micrograms/day were injected intramuscularly once a month. Cyclophosphamide (Cytoxan) (5 mg/kg of body weight) was injected intraperitoneally twice a week. When the therapy was started 90 days after tumor transplantation--at the time that the cancers were well developed-and was continued for 2 months, tumor volume was significantly reduced by the microcapsules or Cytoxan given alone. The combination of these two agents similarly inhibited tumor growth but did not show a synergistic effect. In another study, the treatment was started 2 months after transplantation, when the developing tumors measured 60-70 mm3. Throughout the treatment period of 100 days, the microcapsules of [D-Trp6]LH-RH reduced tumor volume more than Cytoxan did, and the combination of the two drugs appeared to completely arrest tumor growth. Tumor weights also were diminished significantly in all experimental groups, the decrease in weight being smaller in the Cytoxan-treated group than in rats that received the microcapsules. The combination of Cytoxan plus the microcapsules was 10-100 times more effective than the single agents in reducing tumor weights. In both experiments, testes and ventral prostate weights were significantly diminished, serum testosterone was suppressed to undetectable levels, and prolactin values were reduced by administration of microcapsules of [D-Trp6]LH-RH alone or in combination with Cytoxan. These results in rats suggest that combined administration of long acting microcapsules of [D-Trp6]LH-RH with a chemotherapeutic agent, started soon after the
Tyrrell, C J
For advanced prostate cancer, the main hormone treatment against which other treatments are assessed is surgical castration. It is simple, safe and effective, however it is not acceptable to all patients. Medical castration by means of luteinizing hormone-releasing hormone (LH-RH) analogues such as goserelin acetate provides an alternative to surgical castration. Diethylstilboestrol, previously the only non-surgical alternative to orchidectomy, is no longer routinely used. Castration reduces serum testosterone by around 90%, but does not affect androgen biosynthesis in the adrenal glands. Addition of an anti-androgen to medical or surgical castration blocks the effect of remaining testosterone on prostate cells and is termed combined androgen blockade (CAB). CAB has now been compared with castration alone (medical and surgical) in numerous clinical trials. Some trials show advantage of CAB over castration, whereas others report no significant difference. The author favours the view that CAB has an advantage over castration. No study has reported that CAB is less effective than castration. Of the anti-androgens which are available for use in CAB, bicalutamide may be associated with a lower incidence of side-effects compared with the other non-steroidal anti-androgens and, in common with nilutamide, has the advantage of once-daily dosing. Only one study has compared anti-androgens within CAB: bicalutamide plus LH-RH analogue and flutamide plus LH-RH analogue. At 160-week follow-up, the groups were equivalent in terms of survival and time to progression. However, bicalutamide caused significantly less diarrhoea than flutamide. Withdrawal and intermittent therapy with anti-androgens extend the range of treatment options. © 1999 Cancer Research Campaign PMID:10408706
RECCHIA, FRANCESCO; CANDELORO, GIAMPIERO; NECOZIONE, STEFANO; DESIDERI, GIOVAMBATTISTA; CESTA, ALISIA; RECCHIA, LAURA; REA, SILVIO
Estradiol (E2) plays a key role in human reproduction through the induction of vascular endothelial growth factor (VEGF) and T-regulatory cells (T-Regs), which are also important in breast cancer (BC) growth. The primary endpoint of the present study was the investigation of whether E2 suppression, chemotherapy and radiation therapy decreased the levels of VEGF and T-Regs of premenopausal patients with high-risk early BC. The secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Between April 2003 and July 2008, 100 premenopausal women with early, high-risk BC were entered into the study. The characteristics of the patients were as follows: median age, 43 years (range, 26–45); median number of positive axillary nodes, 3.3; median Ki-67, 33%. Plasma E2, VEGF and T-Reg were measured at baseline and every year. Treatment comprised luteneizing hormone-releasing hormone (LH-RH) analogue, tailored chemotherapy, radiation therapy and hormonal therapy in oestrogen receptor-positive (ER+) tumours. At 4 years, a statistically significant decrease in E2, VEGF and T-Reg levels was observed; the PFS and OS rates were 94 and 98%, respectively. Hot flushes and G1 osteopenia occurred following LH-RH analogue administration, while no unexpected toxicity was observed following chemotherapy. E2 deprivation with an LH-RH analogue, tailored chemotherapy, radiation therapy and hormonal therapy in ER+ tumours decreased plasma VEGF levels and T-Regs numbers in premenopausal high-risk ER+ and ER- BC patients. In addition, a favorable impact on PFS and OS was observed. PMID:23599749
Recchia, Francesco; Candeloro, Giampiero; Necozione, Stefano; Desideri, Giovambattista; Cesta, Alisia; Recchia, Laura; Rea, Silvio
Estradiol (E2) plays a key role in human reproduction through the induction of vascular endothelial growth factor (VEGF) and T-regulatory cells (T-Regs), which are also important in breast cancer (BC) growth. The primary endpoint of the present study was the investigation of whether E2 suppression, chemotherapy and radiation therapy decreased the levels of VEGF and T-Regs of premenopausal patients with high-risk early BC. The secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Between April 2003 and July 2008, 100 premenopausal women with early, high-risk BC were entered into the study. The characteristics of the patients were as follows: median age, 43 years (range, 26-45); median number of positive axillary nodes, 3.3; median Ki-67, 33%. Plasma E2, VEGF and T-Reg were measured at baseline and every year. Treatment comprised luteneizing hormone-releasing hormone (LH-RH) analogue, tailored chemotherapy, radiation therapy and hormonal therapy in oestrogen receptor-positive (ER(+)) tumours. At 4 years, a statistically significant decrease in E2, VEGF and T-Reg levels was observed; the PFS and OS rates were 94 and 98%, respectively. Hot flushes and G1 osteopenia occurred following LH-RH analogue administration, while no unexpected toxicity was observed following chemotherapy. E2 deprivation with an LH-RH analogue, tailored chemotherapy, radiation therapy and hormonal therapy in ER(+) tumours decreased plasma VEGF levels and T-Regs numbers in premenopausal high-risk ER(+) and ER- BC patients. In addition, a favorable impact on PFS and OS was observed.
Harvey, S; Sterling, R J; Klandorf, H
Surgical thyroidectomy increased (P less than 0.05) the basal concentrations of growth hormone (GH) and luteinizing hormone (LH) in the plasma of 10- to 12-week-old domestic fowl. The administration of thyrotrophin releasing hormone (TRH) (100 micrograms, sc) increased (P less than 0.01) the GH concentration in both intact and thyroidectomised birds. The magnitude of the TRH-induced increase in GH level was greater (P less than 0.01) in thyroidectomised birds than in intact controls. Although TRH had no effect on LH secretion in the controls, it induced a small (P less than 0.05) rise in the plasma LH level in thyroidectomised birds. In both the intact and thyroidectomised birds the LH concentration was enhanced (P less than 0.05) following the administration of LH-releasing hormone (LH-RH) (20 micrograms, sc). The increase in the LH level by LH-RH in the thyroidectomised birds was greater (P less than 0.001) than that in the intact controls. Plasma GH concentrations were unaffected by LH-RH treatment. These results suggest that thyroid hormones inhibit the secretion of LH and GH in birds. In thyroidectomised birds low levels of immunoreactive triiodothyronine (T3)-like material were measurable in the circulation, despite the absence of regenerated thyroid tissue. The administration of TRH (100 micrograms, sc) did not enhance the plasma level of this material in thyroidectomised birds, whereas plasma T3 concentrations were enhanced in intact birds following TRH treatment. These results suggest that the T3 immunoreactive substance in thyroidectomised birds is extrathyroidal in origin.
Botella Llusia, J
Of all the clinical aspects of human sterility, the anovulatory cycle is undoubtedly 1 that has produced the widest range of therapuetic successes. While in other fields progress has been very slow (male sterility or tubal obstruction), ovarian pharmacoendocrinology has shown several advances over recent years. This progress is due partly to new chemicals such as urinary menopausal gonadotropins, LH-RH, and their analogues Clomiphene and Bromocriptine. Contributing further to these good results is a greater knowledge of the etiology of anovulation and a more accurate selection of cases for treatment.
Barnea, A.; Cho, G.
The authors have shown that copper amplifies prostaglandin E/sub 2/ (PGE/sub 2/) stimulation of luteinizing hormone-releasing hormone (LH-RH) from explants of the median eminence area (MEA) and that this process is calcium-dependent. Since a Ca-cAMP pathway has been implicated in PGE/sub 2/ action on the LH-RH neuron, in this study the authors wished to ascertain if copper exerts its effect on the PGE/sub 2/ receptor or on a postreceptor component involved in PGE/sub 2/ action. MEA of adult male rats were incubated for 5 min with 200 ..mu..M Cu/histidine and then incubated for 15 min either with 10 ..mu..M PGE/sub 2/ (Cu/PGE/sub 2/), 100 ..mu..M forskolin (Cu/forskolin), or 1 mM 8-bromoadenosine 3',5'-cyclic monophosphate (Cu/cAMP). Basal release of LH-RH was 4.6 +/- 0.45 pg/15 min per MEA determined by radioimmunoassay. Net stimulated release during the 15-min exposure to PGE/sub 2/, forskolin, or 8-bromoadenosine 3',5'-cyclic monophosphate was 3.6 +/- 0.52, 3.1 +/- 0.39, and 1.6 +/- 0.42 pg/15 min per MEA, respectively. Net stimulated release after exposure to Cu/PGE/sub 2/, Cu/forskolin, or Cu/cAMP indicated that copper amplifies the action of PGE/sub 2/ and forskolin but not cAMP action. When MEA were exposed to a mixture of PGE/sub 2/ and forskolin for 15 min, the effects of these two secretagogues on LH-RH release were not additive. In contrast to PGE/sub 2/ and forskolin, copper did not amplify K/sup +/ stimulation of OH-RH release. These results are supportive of the proposition that PGE/sub 2/ stimulation of OH-RH release is mediated by the Ca-cAMP pathway and that copper amplification of PGE/sub 2/ action is a postreceptor event.
Goos, H J; Murathanoglu, O
The double antibody immunofluorescence technique was applied to serial coronal and sagittal sections of the brains of the trout, Salmo gairdneri, using an antibody against mammalian LH-RH. Immunoreactive material was found in small perikarya, situated at both sides of the ventriculus communis in the area dorsalis pars medialis of the telencephalon. The axons of these perikarya, also containing immunoreactive material, do not form a tract, but run diffusely in a caudo-ventral direction towards the pituitary stalk. The ending of these fibres has not yet been established.
Lønning, Per Eystein; Eikesdal, Hans Petter
Following their successful implementation for the treatment of metastatic breast cancer, the ‘third-generation’ aromatase inhibitors (anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancers. These drugs are characterized by potent aromatase inhibition, causing >98% inhibition of estrogen synthesis in vivo. A recent meta-analysis found no difference in anti-tumor efficacy between these three compounds. As of today, aromatase inhibitor monotherapy and sequential treatment using tamoxifen followed by an aromatase inhibitor for a total of 5 years are considered equipotent treatment options. However, current trials are addressing the potential benefit of extending treatment duration beyond 5 years. Regarding side effects, aromatase inhibitors are not found associated with enhanced risk of cardiovascular disease, and enhanced bone loss is prevented by adding bisphosphonates in concert for those at danger of developing osteoporosis. However, arthralgia and carpal tunnel syndrome preclude drug administration among a few patients. While recent findings have questioned the use of aromatase inhibitors among overweight and, in particular, obese patients, this problem seems to focus on premenopausal patients treated with an aromatase inhibitor and an LH-RH analog in concert, questioning the efficacy of LH-RH analogs rather than aromatase inhibitors among overweight patients. Finally, recent findings revealing a benefit from adding the mTOR inhibitor everolimus to endocrine treatment indicate targeted therapy against defined growth factor pathways to be a way forward, by reversing acquired resistance to endocrine therapy. PMID:23625614
Yokomizo, Yumiko; Kawahara, Takashi; Miyoshi, Yasuhide; Otani, Masako; Yamanaka, Shoji; Teranishi, Jun-Ichi; Noguchi, Kazumi; Yao, Masahiro; Uemura, Hiroji
We determined whether prostate specific antigen (PSA) would decrease with immediate antiandrogen switching from bicalutamide (BCL) to flutamide (FLT) in patients receiving combined androgen blockade for advanced prostate cancer. From 2002 to 2006, 20 patients who showed PSA failure after first-line hormonal therapy with a luteinizing hormone-release hormone (LH-RH) agonist and BCL were enrolled. All patients were immediately switched from BCL to FLT, administered with an LH-RH agonist, as second-line combined androgen blockade (CAB). We evaluated the PSA response to second-line CAB. Eight patients (40%) were responsive, showing PSA decreases of at least 50%. The median (range) duration of the PSA response was 18.4 (3-26) months. Second-line CAB using FLT was effective in 40% of patients who received first-line CAB using BCL. The lower Gleason scores at the initial prostate biopsy probably reflect the response to second-line CAB. Responders showed significantly better OS and CSS in the determination of any PSA decline and 40% PSA decline. The median OS duration in nonresponders and responders (40% PSA decline) was 1433 days versus 3617 days. It is concluded that an immediate switch from BCL to FLT is effective for some CRPC patients after first-line CAB using BCL.
Yokomizo, Yumiko; Kawahara, Takashi; Miyoshi, Yasuhide; Otani, Masako; Yamanaka, Shoji; Teranishi, Jun-ichi; Noguchi, Kazumi; Yao, Masahiro
We determined whether prostate specific antigen (PSA) would decrease with immediate antiandrogen switching from bicalutamide (BCL) to flutamide (FLT) in patients receiving combined androgen blockade for advanced prostate cancer. From 2002 to 2006, 20 patients who showed PSA failure after first-line hormonal therapy with a luteinizing hormone-release hormone (LH-RH) agonist and BCL were enrolled. All patients were immediately switched from BCL to FLT, administered with an LH-RH agonist, as second-line combined androgen blockade (CAB). We evaluated the PSA response to second-line CAB. Eight patients (40%) were responsive, showing PSA decreases of at least 50%. The median (range) duration of the PSA response was 18.4 (3–26) months. Second-line CAB using FLT was effective in 40% of patients who received first-line CAB using BCL. The lower Gleason scores at the initial prostate biopsy probably reflect the response to second-line CAB. Responders showed significantly better OS and CSS in the determination of any PSA decline and 40% PSA decline. The median OS duration in nonresponders and responders (40% PSA decline) was 1433 days versus 3617 days. It is concluded that an immediate switch from BCL to FLT is effective for some CRPC patients after first-line CAB using BCL. PMID:27493956
Pinto, F; Calarco, A; Totaro, A; Sacco, E; Volpe, A; Racioppi, M; D'Addessi, A; Bassi, P F
Androgens are involved in the development and progression of prostate cancer even if the mechanism is not well-recognized. For this reason androgen-deprivation therapy remains a milestone for the treatment of patients with advanced and metastatic disease and, in the last years, in conjunction with radiotherapy and surgery in locally advanced tumors. Alternative options, such as intermittent deprivation suppression, seem to be promising in terms of clinical benefits and toxicity profile. However, current therapies present side effects, such as testosterone surge with consequent clinical flare-up, metabolic syndrome and hormone-resistance, which develops after a variable number of years. Novel therapies such as LH-RH antagonists and prolonged depot LH-RH analogues have been developed in order to avoid clinical flare-up and testosterone microsurges. Novel androgen synthesis inhibitors, such as abiraterone acetate and MDV3100, have been recently discovered and tested as promising hormonal second-line agents in patients with castration-resistant prostate cancer. Finally, long-term side effects from androgen deprivation, such as osteoporosis, sarcopenic obesity and cardiovascular morbidity should be carefully monitored and properly treated.
Peyromaure, M; Rebillard, X; Ruffion, A; Salomon, L; Villers, A; Soulie, M
To assess the time-course of plasma testosterone in patients with prostate cancer treated by endocrine therapy. A PubMed review of the literature on plasma testosterone and the various endocrine therapies for prostate cancer was performed. The time-course of plasma testosterone varies according to the type of endocrine therapy. The effective castration level, classically considered to be 50 ng/dl, is currently tending to be replaced by 20 ng/dl. Following surgical castration, plasma testosterone reaches effective castration levels within several hours, while with LH-RH agonist therapy, plasma testosterone reaches its trough value after three to four weeks, and remains low for six months after stopping treatment. However, about 15% of patients treated with LH-RH agonists do not achieve effective castration levels. Plasma testosterone remains unchanged or even increases in response to anti-androgens. Plasma testosterone assay is of limited value in routine clinical practice in patients receiving endocrine therapy for prostate cancer, but should be performed in the case of elevation of PSA to ensure that the patient has achieved effective castration levels. The correlation between plasma testosterone and progression of prostate cancer is unclear. Other studies are therefore necessary to define the value of plasma testosterone assay in patients treated for prostate cancer.
Mikata, Noriharu; Imao, Sadao; Fukasawa, Ritu
The subjects for the present study were 270 patients with prostate cancer who underwent initial treatment at our hospital over the 14 years from 1986 to 1999. They were investigated to assess the relationship between their treatment and metachronous tumors. Sixteen patients (5.9%) developed cancer of other organs after starting treatment for prostate cancer. These metachronous tumors included gastric cancer in six patients as well as lung cancer, esophageal cancer, colorectal cancer, liver cancer, renal cancer, bladder cancer, skin cancer, leukemia, and mediastinal adenocarcinoma. Treatment for prostate cancer other than surgery included radiotherapy in eight patients, administration of estramustine phosphate sodium in nine patients, and LH-RH analogues in six patients. The chi-square test showed no significant difference in the incidence of metachronous cancer in relation to the presence/absence of these three therapies. The present study therefore ruled out the possible induction of other tumors by treatment for prostate cancer.
Mondain-Monval, M; Bonnin, M; Canivenc, R; Scholler, R
A heterologous radioimmunoassay using ovine LH as the labeled hormone, canine LH as the standard, and an antiovine LH rabbit serum was validated for the measurement of fox LH. Physiological validation of the assay was evidenced by the high concentrations of LH at oestrus and following ovariectomy or the administration of LH-RH. Throughout the year, plasma LH levels demonstrate important variations, being low during and after the luteal phase (1.4 +/- 0.3 ng/ml) (mean +/- SE) and increasing during the second part of anoestrus (5.2 +/- 1.4 ng/ml). This latter increase might be correlated with that of androgens observed at the same period. Several LH rises preceded the preovulatory LH surge.
Fernández, F; Jordán, J; Carmona, M; Oliver, A; Gracia, R; González, M; Peralta, A
A case report of pseudoprecocity secondary to a unilateral ovarian tumor of granulosa cells is presented in a 13 month old female. Clinical manifestations appeared at two months of age as unilateral enlargement of the breast, development of pubic hair and vaginal discharge. Plasma estrogen levels were elevated, whereas there was no response of FSH and LH to LH-RH stimulation. The absence of a palpable abdominal mass and a normal ultrasound examination of the abdomen must be pointed out in our case. The suspected clinical and laboratory diagnosis was later confirmed by surgical abdominal examination and ovarian histopathology study. With the exception of a minimal breast enlargement which persists at two years of age, all other signs of pseudoprecocity have disappeared after the surgical removal of the neoplasm. The importance of surgical abdominal examination must be pointed out as a diagnostic method when clinical and laboratory findings suggest an ovarian tumor inspite of normal abdominal palpation, ultrasound and roentgenology.
Fadhlaoui, Anis; Ben Hassouna, Jamel; Khrouf, Mohamed; Zhioua, Fethi; Chaker, Anis
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
Hopkinson, C R; Chari, S; Sturm, G; Hirschhäuser, C
Plasma LH, FSH and testosterone were measured in testosterone-treated and untreated cryptorchid and castrated male rats. Exogenous testosterone prevented the increase in basal LH but not FSH levels seen in the untreated cryptorchids. Increases in plasma LH and FSH in response to LH-RH were greater in the cryptorchid as compared to the control group and this could not be reversed by exogenous testosterone, suggesting that spermatogenesis-related feedback factors regulate LH as well as FSH at the pituitary level in the intact rat. The results were consistent with a reduced but nevertheless significant secretion of inhibin by the cryptorchid testis. Basal plasma testosterone levels and ventral prostate weights were not significantly different from intact animals.
Ouvinha de Oliveira, R; de Santa Maria, L C; Barratt, G
In recent years, nanotechnology has been the focus of considerable attention in medicine due to the facility with which nanostructures interact with the body at the molecular scale. New therapies in cancer research using nanomedicine are being developed in order to improve the specificity and efficacy of drug delivery, thus reaching maximal effectiveness with minimal side effects. This literature review presents cases of prostate cancer in antiquity as well as the first modern reports before discussing how nanotechnology can contribute to the management of this disease. Three major nanoparticle-based platforms are described: liposomal, polymeric and metallic. Published results, including therapies in current clinical trials, are discussed. In addition, several formulations of microparticles containing LH-RH analogues approved by the authorities are listed in this document. A critical analysis of the health and environmental impact is made to highlight the need for precise control of the utilization of nanomaterials. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Goos, H J; Ligtenberg, P J; van Oordt, P G
Using antibodies against mammalian LH-RH, the double antibody-immunofluorecence technique has been applied to serial cross sections of the brains of adult Rana esculenta. Immunoreactive material was found in perikarya of an unpaired nucleus in front of the preoptic recess. The axons of these perikarya also contain fluorescing material. They form a single bundle which passes under the preoptic recess, than splits into two tracts, one on either side of the optic chiasm. The two tracts reunite just before entering the median eminence. The axons end near the capillaries in the outer zone of the median eminence. The possibility of two separate centres for the stimulation of gonadotropic activity in the brains of anurans is discussed.
Lobel, B; Cipolla, B; Labrador, J
Hormone dependence of prostate cancer is well known. In 80% of cases with metastases, hormone suppression leads to the reduction of tumour volume and related disorders. However the treatment is generally palliative because malignant process recurs after about around 16 months. Mean survival is less than 3 years in these forms. Lack of response come always together with a poor prognosis, and there is 90% mortality at 2 years. Advanced prostatic cancer should not be treated with hormones if the patient has few symptoms and his quality of life is satisfactory. Symptomatic forms require hormone manipulation. Orchidectomy or LH-RH are recommended. Total androgen ablation (combined treatment) leads rapidly to more relief of symptoms, but its drawbacks and especially high cost indicate that its use should be weighed individually. Estramustine is not a first-lune treatment. Presently, there is no criteria to predict response to treatment.
Tohei, A; Tomabechi, T; Mamada, M; Akai, M; Watanabe, G; Taya, K
Effects of ether stress on the hypothalamo-hypophysial-gonadal axis in adult male rats were examined. To clarify the role of adrenal glucocorticoids in gonadal function, the effects of adrenalectomy and Dexamethasone treatment were also investigated. Ether stress increased the plasma concentrations of ACTH and corticosterone, but decreased the plasma concentrations of LH, FSH, inhibin and testosterone. The pituitary responsiveness to LH-RH for LH release and testicular responsiveness to the endogenous LH for testosterone release were maintained in stressed rats. Adrenalectomy caused an increase in the plasma concentrations of ACTH, but decreased the plasma concentrations of LH, FSH and testosterone. Dexamethasone treatment in adrenalectomized rats recovered the levels of plasma gonadotropins to control levels. The concentration of plasma inhibin did not change in adrenalectomized rats, but it was decreased compared to control rats by Dexamethasone treatment. Treatments of Dexamethasone in intact male rats resulted in a decline in plasma levels of testosterone and inhibin without a decrease in the levels of LH and FSH, indicating the direct effect of Dexamethasone on the testes. These results indicate that increased ACTH secretion in stressed rats is probably due to hypersecretion of CRH from the hypothalamus, which suppresses gonadotropin secretion via the inhibition of LH-RH. The decreased levels of testosterone may be caused by a stress-induced decrease in plasma LH concentrations and increased secretion of corticosterone in the ether stressed rats. The low levels of plasma inhibin in stressed rats was also probably due to the direct effect of corticosterone on the Sertoli cells.
Bajaj, Sahil; Drake, Daniel; Butler, Andrew J; Dhamala, Mukesh
Coherent network oscillations (<0.1 Hz) linking distributed brain regions are commonly observed in the brain during both rest and task conditions. What oscillatory network exists and how network oscillations change in connectivity strength, frequency and direction when going from rest to explicit task are topics of recent inquiry. Here, we study network oscillations within the sensorimotor regions of able-bodied individuals using hemodynamic activity as measured by functional near-infrared spectroscopy (fNIRS). Using spectral interdependency methods, we examined how the supplementary motor area (SMA), the left premotor cortex (LPMC) and the left primary motor cortex (LM1) are bound as a network during extended resting state (RS) and between-tasks resting state (btRS), and how the activity of the network changes as participants execute left, right, and bilateral hand (LH, RH, and BH) finger movements. We found: (i) power, coherence and Granger causality (GC) spectra had significant peaks within the frequency band (0.01-0.04 Hz) during RS whereas the peaks shifted to a bit higher frequency range (0.04-0.08 Hz) during btRS and finger movement tasks, (ii) there was significant bidirectional connectivity between all the nodes during RS and unidirectional connectivity from the LM1 to SMA and LM1 to LPMC during btRS, and (iii) the connections from SMA to LM1 and from LPMC to LM1 were significantly modulated in LH, RH, and BH finger movements relative to btRS. The unidirectional connectivity from SMA to LM1 just before the actual task changed to the bidirectional connectivity during LH and BH finger movement. The uni-directionality could be associated with movement suppression and the bi-directionality with preparation, sensorimotor update and controlled execution. These results underscore that fNIRS is an effective tool for monitoring spectral signatures of brain activity, which may serve as an important precursor before monitoring the recovery progress following brain
Recchia, Francesco; Candeloro, Giampiero; Rosselli, Michele; Bratta, Massimo; Pasta, Vittorio; D'Orazi, Valerio; Fumagalli, Luca A; Rea, Silvio
Premenopausal patients with breast cancer and more than 10 positive axillary nodes (BC>10) have a poor prognosis: In these patients the best adjuvant therapy (CT) has not yet been established. Forty-two BC>10 received, in sequence, the following adjuvant treatments: luteinizing hormone releasing hormone (LH-RH) analog for 5 years; anthracycline-based induction chemotherapy; radiation therapy; platinum-based high-dose CT, with autologous bone marrow transplantation; immunotherapy with interleukin 2 (IL2) and 13-cis retinoic acid (RA); anastrazole given 5 years to estrogen receptor-positive patients. Primary endpoints of the study were disease-free survival (DFS) and overall (OS) survival. A secondary endpoint was toxicity. The median age of patients was 41 years, and the mean number of positive axillary nodes was 14. Estrogen and progesterone receptors were positive in 57% and 29% of patients respectively, while 14% of patients had triple-negative disease. With a median follow-up of 120 months for patients remaining alive at the end of study, median DFS and OS, had not yet been reached. The 20-year DFS and OS rates were 63.8%, and 81.6%, respectively. One to two years after the end of the therapy, three patients had had four full-term pregnancies. Treatment with LH-RH analog, high-dose CT, peripheral blood progenitor cells and IL2 with RA for patients with BC>10 is feasible, has moderate toxicity, while preserving ovarian function, seems to improve the expected DFS and OS for these high-risk patients. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
Immunoreactive gonadotropin-releasing hormone-like material in the brain and the pituitary gland during the periovulatory period in the brown trout (Salmo trutta L.): relationships with the plasma and pituitary gonadotropin.
Breton, B; Motin, A; Billard, R; Kah, O; Geoffre, S; Precigoux, G
In fish there are few data on the gonadotropin-releasing hormone (Gn-RH) neurosecretory activity, which could explain long- and short-term variations of the gonadotropin secretion. There is no biological species specificity between mammal and fish Gn-RH; although there is a structural difference, they are, on the contrary, characterized by a high immunological specificity which does not allow measurement of fish Gn-RH using radioimmunoassay for LH-RH. We have synthesized salmon Gn-RH according to the formula recently proposed by Sherwood (N. Sherwood, L. Eiden, M. Brownstein, J. Spies, J. Rivier, and W. Vale, 1983. Proc. Natl. Acad. Sci. USA 80, 2794-2798). Its activity has been tested by its ability to stimulate the gonadotropin hormone (GtH) secretion in vivo in testosterone-implanted juvenile rainbow trout, and for the recognition of synthesized Gn-RH (s-Gn-RH) perykaria by a specific antibody raised against the s-Gn-RH in regions of the brain described as containing LH-RH immunoreactive-like material. A radioimmunoassay has been developed for the salmon Gn-RH, and its specificity to measure trout Gn-RH has been tested. Using this assay, the brain and pituitary Gn-RH contents have been measured throughout the final phases of maturation and ovulation. Brain Gn-RH increases from the end of vitellogenesis (8.9 +/- 0.76 ng/brain) to ovulation (more than 15 ng/brain). Pituitary Gn-RH is lower (1.58 +/- 0.69 ng/pituitary) at the end of vitellogenesis and follows a similar profile as in the brain, except for a significant decrease just prior the beginning of oocyte maturation. The correlations between Gn-RH levels and GtH pituitary and plasma levels show that total brain Gn-RH is never correlated to the GtH, suggesting that the increase in the brain Gn-RH content is related to a Gn-RH system closely related to maturation and ovulation, which remains to be investigated. On the contrary, pituitary Gn-RH levels are well correlated with pituitary and plasma GtH levels
Scattoni, Vincenzo; Lazzaro, Carlo; Rigatti, Patrizio
The aim of the paper is to report on the economics of managing patients with prostate cancer (PC). After a thorough research on MEDLINE, 15 recent articles (1994-2000) concerning the economics of PC have been selected. Costs taken from articles were supplemented with accounting data provided by Research and Teaching Hospital San Raffaele, Milan. Only medical costs have been considered. In Western countries, PC is becoming one of the most frequent neoplasms among males, with a 20% life-time probability of occurrence. In the near future, the global burden of illness related to PC is expected to grow consistently with the increasing number of 50-aged men. The average survival of PC patients is generally increased, probably due to the improvement of diagnostic tests, instruments and programmes. When targeted to selected classes of men, screening for early diagnosis of PC seems to be cost-effective when compared to "watchful waiting", since cost per Quality-Adjusted Life Year (QALY) gained ranges between US$ 12,502 and US$ 27,025. Healthcare programmes are deemed cost-effective if cost per life year (or per QALY) gained is lower than US$ 50,000. In USA, the total cost for treating PC patients has reached US$ 1,720 billion per year; cost for radical prostatectomy approaches US$ 19,000. The average Italian cost for prostatectomy (Euro 4,000) is hardly covered by Regional DRG reimbursement (Euro 3,600 in Lombardy). When brachytherapy is considered, the gap between cost (Euro 4,806) and DRG tariff (Euro 3,500 in Lombardy) becomes even wider; this difference is mainly due to the high cost of I-125 needles (Euro 55,77 each). In 1997, USA drug expenditure for PC has approached 761 million US$: LH-RH analogues and antiandrogens account for a relevant share of this amount. However, LH-RH analogues can be the only treatment option for a metastatic PC patient who refuses orchiectomy. In managing PC, urologists are increasingly faced with healthcare budget constraints. Cost for
Yoshida, K; Utsunomiya, T; Kadota, T; Yamaguchi, S
It has been established that the pathogenesis of a complete form of testicular feminization syndrome (TFM) is due to end-organ unresponsiveness to androgens. In the present study, two sibling cases with TFM have been reported with special reference to the effect of danazol (a derivative of 17 alpha-ethynyltestosterone) on gonadal estradiol-17 beta (E2) secretion in vivo and in vitro. Both patients showed hypergonadotropic-hypergonadism with good response to LH-RH. In one case, peripheral blood E2 levels seemed to fall independently of gonadotropins during danazol administration in vivo. Administrations of danazol to the culture media also inhibited E2 secretion from the cultured monolayered cells of the testes. These results suggest a direct inhibitory effect of danazol on gonadal E2 secretion. However, the feedback mechanisms of hypothalamic-pituitary units to E2 were preserved in both cases. Spermatogeneses were almost undetectable as in immature embryonal testes when using either light or electron microscopies, though spermatogonia were differentiated from Sertoli cells by these techniques. Finally, plasma T and E2 levels in both patients were considerably lower after gonadectomy.
Edwards, Ashley; Jones, Susan M
The hypothalamic-pituitary-gonadal axis plays a central role in the regulation of gamete maturation, sex steroid production and the stimulation of reproductive behaviours in vertebrates. In seasonal breeders, the timely activation and deactivation of this control system is important to ensure successful reproduction: this process is not well understood in species which breed irregularly. Males of the viviparous blotched blue-tongued lizard, Tiliqua nigrolutea, breed annually, while females display a multiennial cycle. We investigated seasonal variation in hypothalamic-pituitary-gonadal axis responsiveness in both sexes of T. nigrolutea. We measured changes in plasma concentrations of testosterone and estrogen in response to a single intraperitoneal injection of a GnRH agonist, chicken-II LH-RH, at three reproductively distinct times of year. Plasma testosterone concentrations in males were significantly increased during gonadal quiescence, but not initial or final spermatogenesis. There was no estrogen response in males at any time of year. Conversely, in females, there was an increase in plasma testosterone, but not estrogen, concentration, in reproductively quiescent females several months in advance of a successful pregnancy. These results indicate clear variation in HPG axis activity with sex, season and reproductive condition in this seasonally breeding viviparous lizard. This study opens the way for further investigation into the mechanisms by which internal (body condition) and external seasonal cues (temperature and photoperiod) are coordinated to regulate reproduction in irregularly-breeding reptiles.
Brzozowska, Anna; Mazurkiewicz, Maria; Starosławska, Elzbieta; Stasiewicz, Dominika; Mocarska, Agnieszka; Burdan, Franciszek
The prostate cancer is one of the most often cancers amongst males. Its frequency is increasing with age. Thanks to widespread of screening denomination of specific prostate specific antigen (PSA), ultrasonography including the one in transrectal (TRUS), computed tomography, magnetic resonance and especially the awareness of society, the number of patients with low local advance of illness is increasing. The basic method of treatment in such cases is still the surgical removal of prostate with seminal bladder or radiotherapy. To this purpose tele-(IMRT, VMAT) or brachytherapy (J125, Ir192, Pa103) is used. In patients with higher risk of progression the radiotherapy may be associated with hormonotherapy (total androgen blockage-LH-RH analog and androgen). Despite numerous clinical researches conducted there is still no selection of optimal sequence of particular methods. Moreover, no explicit effectiveness was determined. The general rule of treatment in patients suffering from prostate cancer still remains individual selection of therapeutic treatment depending on the age of a patient, general condition and especially patient's general preferences. In case of elderly patients and patients with low risk of progression, recommendation of direct observation including systematical PSA denomination, clinical transrectal examination, TRUS, MR of smaller pelvis or scintigraphy of the whole skeleton may be considered.
[A phase II pharmacological study of leuprolide acetate 6-month depot, TAP-144-SR (6M), in treatment-Nazve patients with prostatic cancer who received a single subcutaneous or intramuscular injection].
Komura, Emiko; Fujimoto, Tsukasa; Takabayashi, Nobuyoshi; Okamoto, Hiroyuki; Akaza, Hideyuki
The aim of this phase II study was to evaluate the pharmacokinetics, pharmacodynamics, efficacy, and safety of a 6- month depot formulation of a luteinizing hormone-releasing hormone (LH-RH) agonist, TAP-144-SR (6M), in Japanese treatment-naÏve patients with prostatic cancer. Each subject received a single subcutaneous or intramuscular injection of TAP- 144-SR (6M) and was monitored for 24 weeks. The primary endpoint was the change in serum testosterone levels. The serum testosterone level in six subjects who received 22.5 mg of TAP-144 (SR) subcutaneously decreased below the castrate level after 4 weeks and remained suppressed during the 24 weeks of follow-up. With regard to safety, TAP-144-SR (6M)was not associated with any additional concerns compared to those reported for the approved 1-month and 3-month depot formulations of TAP-144-SR. In addition, 30 mg of TAP-144-SR (6M) was administered subcutaneously to six subjects, and, on the basis of the results, the optimal clinical dosage of TAP-144-SR (6M) in Japan was considered to be 22.5 mg. Outcomes with 22.5mg TAP-144-SR (6M) administered intramuscularly were similar to those with TAP-144-SR (6M) administered subcutaneously.
Ueno, Soichiro; Nakakuma, Takashi; Murata, Osamu; Sengoku, Norihiko; Karikomi, Kazuhiro; Honma, Megumi
Of the 210 patients who underwent breast-conserving surgery for breast cancer and received radiation therapy for 3 years from April 2012 to March 2015 at the Department of Therapeutic Radiology of our hospital, 6 were diagnosed with cryptogenic organizing pneumonia(COP)-like pneumonia and treated as reported. The mean age of the patients was 51years(40- 65 years), and the pathological subtypes were the luminal type(5 cases)and HER2 type(1case ), all of which were treated with radiation therapy for breast conservation. Postoperative systemic therapy included hormonal therapy with anastrozole in 2 cases, tamoxifen plus LH-RH agonist in 3 cases, and chemotherapy in 1case. The mean onset time of COP was 4.2 months after the completion of irradiation therapy, and all of the 5 patients who received endocrine therapy received it concurrently with radiation therapy. The major symptoms were fever(4 cases)and cough(6 cases). Chest radiography showed an infiltrative shadow consistent with pneumonia. Steroid therapy was effective in all cases while antibiotics were not. It was inferred that COP should be regarded as one of the complications of radiation therapy after breast-conserving surgery.
Nakai, Yasushi; Tanaka, Nobumichi; Anai, Satoshi; Miyake, Makito; Tatsumi, Yoshihiro; Fujimoto, Kiyohide
The study aims to compare serial changes in prostate-specific antigen (PSA), testosterone, dehydroepiandrosterone (DHEA), and androstenedione in patients treated with either of the antiandrogen agents, bicalutamide or flutamide, using a randomized controlled study. Patients had to meet the following inclusion criteria: (1) presence of histopathologically confirmed prostate cancer, (2) prostate cancer treatment naive, (3) no current treatment with luteinizing hormone-releasing hormone (LH-RH) agonist for sexual interest and physical capacity, (4) clinical stage T1-cT3N0M0, (5) Gleason score ≤ 7, and (6) Cooperative Oncology Group performance status 0-1. Patients were randomly allocated to two groups: flutamide and bicalutamide monotherapy group 1:1. PSA levels were significantly decreased in both groups at 4 weeks. PSA levels were significantly lower in the bicalutamide group compared with the flutamide group at 4 and 8 weeks. Testosterone levels in the bicalutamide group were significantly higher than the baseline levels between 4 and 24 weeks of treatment. Testosterone levels in the flutamide group were significantly increased at 4 and 12 weeks and returned to baseline levels at 16 and 24 weeks. DHEA levels in the bicalutamide group were unchanged from baseline at 4 and 24 weeks. However, DHEA levels in the flutamide group were decreased at 24 weeks. Androstenedione levels increased slightly in both groups, but the increase did not reach statistical significance. PSA, testosterone, and DHEA levels significantly differed between bicalutamide and flutamide monotherapy.
Pasqualini, T; Diez, B; Domene, H; Escobar, M E; Gruñeiro, L; Heinrich, J J; Martinez, A; Iorcansky, S; Sackmann-Muriel, F; Rivarola, M
Thirteen children with medulloblastoma, were studied after 2 to 62 months off radiotherapy and chemotherapy with methotrexate and BCNU. Ages at time of study ranged from 2.3 to 15.7 years. Eleven patients, followed for a mean of 22 months, showed a significant decrease of height score, whereas nine patients had deficient growth hormone (GH) response to provocative tests. Clinical pubertal progression was normal in all patients, and three of five girls with advanced pubertal development had menarche. No evidences of gonadotropin disturbances were found in five patients whereas seven had raised basal follicle-stimulating hormone (FSH) level or FSH response to luteinizing hormone-releasing hormone (LH-RH). Abnormalities in thyrotrophin (TSH) secretion were found in 9 of 13 patients. This study shows that poor growth and GH deficiency were frequent in our patients. The high frequency of thyroid disturbances observed point out the need of evaluating thyroid function for adequate replacement therapy. Perhaps modification of adjuvant chemotherapy in the future can diminish drug-induced gonadal damage.
Pałubska, Sylwia; Adamiak-Godlewska, Aneta; Winkler, Izabela; Rechberger, Tomasz; Gogacz, Marek
Hyperprolactinaemia especially affects women in reproductive age (90/100,000) but also often is diagnosed in menopause age and leads to disturbances in functioning of LH-RH neurons and, as a consequence, to a decrease of FSH and LH, which causes inhibition of oestradiol production. Prolactin is a peptide hormone, phylogenetically one of the oldest, stimulating cells of various organs, which is produced and secreted mainly by lactotrophic acidophilic cells of the anterior lobe of the pituitary. It influences the increase in the mass of the mammary glands, and stimulation and maintenance of lactation after delivery. There are a number of factors apart of pregnancy, delivery, and lactation than can influence secretion of the hormone in other physiological and pathological circumstances, like high-protein diet, stress, REM sleep, or neoplastic tumours, inflammatory diseases, chronic systematic diseases, thyroid hormonal changes, and drug intake. The purpose of this review is to summarise the current knowledge regarding the proper diagnosis and possible influence of hyperprolactinaemia on fertility and menopause symptoms and current treatment methods PMID:28546800
Alberto, Chloé; Konstantinou, Maria Polina; Martinage, Catherine; Casassa, Eline; Tournier, Emilie; Bagheri, Haleh; Sibaud, Vincent; Mourey, Loïc; Mazereeuw-Hautier, Juliette; Meyer, Nicolas; Paul, Carle; Bulai Livideanu, Cristina
Enzalutamide (Xtandi®) is a new potent inhibitor of the signaling pathway for the androgen receptor with a half-life of 5.8 days. It has been on the market for the treatment of metastatic castration-resistant prostate cancer since November 2013. We report the first case of acute generalized exanthematous pustulosis (AGEP) induced by enzalutamide. A 62-year-old male patient with no significant medical history, was diagnosed in April 2014 with metastatic prostatic adenocarcinoma. In April 2015 the patient received a second line oral therapy with enzalutamide, 160 mg/day, coupled with a subcutaneous implant of 10.8 mg of goserelin, an agonist analog of natural luteinising hormone releasing hormone (LH-RH). Ten days after starting enzalutamide treatment and four days after introduction of first goserelin subcutaneous implant, the patient experienced an acute skin reaction. It is about of the plaques covered with widespread millimetric non-follicular pustules. Complete resolution of skin lesions occurred within four weeks. According to the AGEP validation score of the European Study of Severe Cutaneous Adverse Reactions, the total score in the current case was 7, interpreted as probable AGEP. According to criteria that assess adverse drug reactions, it was concluded that enzalutamide was responsible for this case of AGEP (suggestive imputation). Dermatologist can be confronted with adverse skin drug reactions attributable to new therapeutic molecules. The slow resolution of symptoms seems be due to the long half-life of enzalutamide.
Raju, K; Vijayan, E
Circulating plasma cholesterol levels were measured in conscious ovariectomized rats, bearing an indwelling silastic catheter in the external jugular vein, after intravenous (i.v.) pulse injection of 100 microliter 0.9% NaCl containing varying doses of neurotensin and/or substance P. Control injections of saline or decapeptide LH-RH or phosphate buffer did not modify plasma cholesterol levels. 10 or 20 micrograms doses of neurotensin produced a significant and dose-related increase in plasma cholesterol levels while similar doses of substance P had an opposite effect and induced a significant decline in plasma cholesterol levels in ovariectomized rats. 4-APP, a drug which selectively inhibits hepatic secretion of lipoproteins, significantly lowers plasma cholesterol to levels comparable to those produced by substance P. 4-APP and substance P induced hypocholesterolemia was readily reversed by a single dose of neurotensin. These findings indicate that neurotensin acts to increase circulating cholesterol levels and substance P antagonizes this hypercholesterolemic effect of neurotensin presumably by acting at some step in cholesterol transport. Reversal of the inhibitory effects of 4-APP and substance P on blood cholesterol by neurotensin may be through its action on hepatic secretion of lipoproteins, since 4-APP is known to lower circulating cholesterol by its specific action on hepatic secretion of lipoproteins.
Gross-Goupil, Marine; Roca, Sophie; Pasticier, Gilles; Ravaud, Alain
If androgen deprivation, chemical with LH-RH analogs or surgical with bilateral orchiectomy, still remains the stone edge of treatment of prostate cancer, in the metastatic setting, this hormonosensitivity, most of the time long, finally move on in hormonal-failure. If rare changes in the therapeutic strategy have been achieved in this setting since 2004 and the arrival of docetaxel, it is the global perception of the disease that has been modified and the definition of one specific entity: the castrate-resistant prostate cancer. This new definition and the changes of design and end-points of clinical trials testing new agents with strong recruitment during the past years have conducted to a real revolution in the management of castrate-refractory prostate cancer. The place of secondary hormonal manipulations, such as withdrawal of the anti-androgen, oestrogen or ketoconazole, still exists for a selected group of patients. In case of aggressive disease and symptoms, chemotherapy should be selected, docetaxel, in a three weeks schedule, and may be combined with Estracyt. It is time to consider the revolution of the post-chemotherapy setting with the arrival of two new drugs ; a cytotoxic one, the cabazitaxel and hormonal for the second one, the abiraterone acetate. The place of the immunotherapy with the sipuleucel-T may be more difficult to precise, especially in Europe, even if it has been finally indicated in the United States in the metastatic setting. Concerning bone metastasis, zoledronic acid was during a long time the only bone-targeted agent, effective in reducing the incidence of skeletal related events, and was recently exceeded by the denosumab, an anti-RANK ligand. Finally, let us hope that other changes will be achieved in the near future, with the cabazitaxel-docetaxel confrontation in the first-line setting, and the introduction of the abiraterone acetate before chemotherapy with docetaxel, already tested in ongoing trials.
Salas, Christian E; Gross, James J; Turnbull, Oliver H
In the past decade, there has been growing interest in the neuroanatomical and neuropsychological bases of reappraisal. Findings suggest that reappraisal activates a set of areas in the left hemisphere (LH), which are commonly associated with language abilities and verbally mediated cognitive control. The main goal of this study was to investigate whether individuals with focal damage to the LH (n = 8) were more markedly impaired on a reappraisal generation task than individuals with right hemisphere lesions (RH, n = 8), and healthy controls (HC, n = 14). The reappraisal generation task consisted of a set of ten pictures from the IAPS, depicting negative events of different sorts. Participants were asked to quickly generate as many positive reinterpretations as possible for each picture. Two scores were derived from this task, namely difficulty and productivity. A second goal of this study was to explore which cognitive control processes were associated with performance on the reappraisal task. For this purpose, participants were assessed on several measures of cognitive control. Findings indicated that reappraisal difficulty - defined as the time taken to generate a first reappraisal - did not differ between LH and RH groups. However, differences were found between patients with brain injury (LH + RH) and HC, suggesting that brain damage in either hemisphere influences reappraisal difficulty. No differences in reappraisal productivity were found across groups, suggesting that neurological groups and HC are equally productive when time constraints are not considered. Finally, only two cognitive control processes inhibition and verbal fluency- were inversely associated with reappraisal difficulty. Implications for the neuroanatomical and neuropsychological bases of reappraisal generation are discussed, and implications for neuro-rehabilitation are considered.
Salas, Christian E.; Gross, James J.; Turnbull, Oliver H.
In the past decade, there has been growing interest in the neuroanatomical and neuropsychological bases of reappraisal. Findings suggest that reappraisal activates a set of areas in the left hemisphere (LH), which are commonly associated with language abilities and verbally mediated cognitive control. The main goal of this study was to investigate whether individuals with focal damage to the LH (n = 8) were more markedly impaired on a reappraisal generation task than individuals with right hemisphere lesions (RH, n = 8), and healthy controls (HC, n = 14). The reappraisal generation task consisted of a set of ten pictures from the IAPS, depicting negative events of different sorts. Participants were asked to quickly generate as many positive reinterpretations as possible for each picture. Two scores were derived from this task, namely difficulty and productivity. A second goal of this study was to explore which cognitive control processes were associated with performance on the reappraisal task. For this purpose, participants were assessed on several measures of cognitive control. Findings indicated that reappraisal difficulty – defined as the time taken to generate a first reappraisal – did not differ between LH and RH groups. However, differences were found between patients with brain injury (LH + RH) and HC, suggesting that brain damage in either hemisphere influences reappraisal difficulty. No differences in reappraisal productivity were found across groups, suggesting that neurological groups and HC are equally productive when time constraints are not considered. Finally, only two cognitive control processes inhibition and verbal fluency- were inversely associated with reappraisal difficulty. Implications for the neuroanatomical and neuropsychological bases of reappraisal generation are discussed, and implications for neuro-rehabilitation are considered. PMID:24711799
Massil, H Y; O'Brien, P M
Comprehensive management of premenstrual syndrome (PMS) is reviewed, including assessment, counseling, diet, relaxation techniques, exercise, social adaptation, hormonal and medical treatment. Studies of PMS are remarkable for high (40-95%) placebo response, and good results with any treatment, especially in the 1st cycle in uncontrolled studies, but poor performance of therapies in random, double-blind, placebo-controlled studies. Heterogeneous groups of subjects, small numbers and too few cycles may contribute to these findings. The 1st step in treating PMS is thorough assessment and counseling, with at least a hour of listening to the patient. A healthy, varied diet should be suggested, limiting refined sugars, salt, red meat, diary products, chocolate, caffeine products, tobacco, alcohol, and increasing complex carbohydrates and PUFAs, in several small meals. PMS patients rarely have abnormal glucose tolerance tests, but they often exhibit related symptoms. Relaxation and exercise should be prescribed so as to raise endorphins, lower stress, increase control and provide enjoyment. Starting with non-hormonal medications, 100 mg vitamin B6 daily and 1.5 g evening primrose oil bid are suggested to regulate dopamine, serotonin and prostaglandin metabolism. Depending on symptoms, spironolactone diuretics, non-steroidal antiinflammatory drugs or anxiolytics may be prescribed. Hormone treatment ranges from progesterone per rectum or vagina, or oral progestins (usually didrogesterone), estradiol sc, implants, orally or transdermally, oral contraceptives, to hormonal antagonists such as bromocriptine, danazol or LH-RH analogues. The theoretical case for hormone treatments is not established, although some women obtain relief from certain treatments.
Nonomura, K; Koyama, T; Toyota, K; Asano, Y; Gotoh, T; Togashi, M; Koyanagi, T; Adachi, Y; Fujieda, K
In order to clarify the clinical aspects of sex chromosomal mosaicism, we evaluated the karyotypes, the anatomy of external genitalia and internal ductal system, the pituitary-gonadal function, and the histopathology of the gonads by immuno-staining for glutathion S-transferase (GST) in 5 patients who had been all raised as female. Three patients have the 45, X/46, XYq- karyotype in the initial lymphocyte culture or the subsequent culture of skin fibroblasts. Another two karyotypes were 45, X/46, XYq-/47, XYq-, Yq- and 45, X/46, XdicY. Thus, Y chromosome of all patients retained short arms in which the testis determining factor is encoded. Three prepubertal patients were referred to us for their ambigious external genitalia and two postpubertal patients were for the short statures. Although the vaginal orifice was separated from the urethral meatus in all of them, the phallic enlargement was noted in 4 patients and the posterior labial fusion in 2 patients. The oldest patient had a normal female appearance of external genitalia except the vaginal septum. Serum gonadotrophin (GnH) levels were basically high in the postopubertal patients and the responses of GnH to LH-RH were significantly increased in the prepubertal patients. Serum testosterone levels to hCG stimulation ranged from no response to low normal response. All patients underwent the exploratory laparotomy together with the feminizing genitoplasty. The gonads in 3 patients, diagnosed as mixed gonadal dysgenesis (MGD), consisted of a unilateral testis and a contralateral streak gonad. Two patients had variants, including one with bilateral dysgenetic testis and another with bilateral streak gonads.(ABSTRACT TRUNCATED AT 250 WORDS)
Cellini, N; Luzi, S; Morganti, A G; Smaniotto, D; Niespolo, R M; Valentini, V
The combination of concomitant external beam radiotherapy (ERT) and neoadjuvant hormonotherapy was shown to be able to significantly improve local control and disease-free survival in locally advanced prostatic carcinoma. (RTOG study 8610). Aim of this analysis was to assess the clinical results observed in a population of patients undergoing this combined treatment and, more particularly, to examine the prognostic impact of local control. 84 patients (T2: 47%, T3: 49.4%, T4: 3.6%) underwent concomitant ERT (dose to pelvic volume: 45 Gy; mean dose to prostatic volume: 65 Gy) and neoadjuvant hormonotherapy (flutamide: 250 mg three times/daily for 30 days; LH-RH analogue: 1 oral dose every 28 days starting 2 months prior to radiotherapy and for its whole duration). With a median follow-up of 36 months, 3.6% of patients were deceased; hematogenous metastases and local disease progression were recorded in 16.7% and 4.8% of patients, respectively. Local disease progression was shown to be significantly correlated with the incidence of metastases. In fact, the actuarial incidence of metastases at 5 years was 100% and 27% in patients with and without local recurrence (p = 0.0043) respectively. Overall, metastases-free local and biochemical recurrence-free survival was 89.2%, 66.5%, 85.0% and 41.9% respectively. At univariate analysis (logrank) the clinical stage (T) was shown to be significantly correlated with the incidence of metastases (p = .0004) and local progression (p < .0001). In conclusion, this study has confirmed the low rate of local progression with the combination of hormonotherapy and radiotherapy and the significant correlation of local control with the incidence of hematogenous metastases.
Maeda, Masaki; Tanaka, Sachiko; Ishizawa, Hitomi; Nakamura, Yurie; Onda, Kenji; Hirano, Toshihiko
Certain kinds of peptide antibiotics are suggested to have immunomodulatory effects; however, few studies have been carried out systemically to evaluate the antiproliferative effects of peptide antibiotics in human lymphoid cells. The suppressive efficacies of nine peptide antibiotics and seven non-antibiotic peptides against proliferation of human peripheral-blood mononuclear cells (PBMCs) stimulated with T cell mitogen were examined in vitro. Nigericin (CAS 28643-80-3), valinomycin (CAS 2001-95-8), gramicidin D (CAS 1405-97-6), and tyrothricin (CAS 1404-88-2) strongly inhibited the proliferation of concanavalin A-stimulated PBMCs with IC50 values of 0.15-11.2 ng/ml, while these antibiotics did not show cytotoxicity at 10 000 ng/ml. The IC50 value of the immunosuppressant cyclosporine (CAS 59865-13-3) was 5.2 ng/ml. Virginiamycin (CAS 11006-76-1) and gramicidin S (CAS 113-73-5) moderately inhibited PBMC-proliferation with IC50 values of 1000 and 1900 ng/ml, respectively. On the other hand, bacitracin (CAS 1405-87-4), capreomycin (CAS 11003-38-6), polymyxin B (1404-26-8), angiotensin II antipeptide (CAS 121379-63-3), angiotensin III antipeptide (CAS 133605-55-7), fibrinogen binding inhibitor peptide (CAS 89105-94-2), LH-RH (CAS 71447-49-9), pepstatin A (CAS 26305-03-3), oxytocin (CAS 50-56-6), and vasopressin (CAS 16679-58-6) showed little or no suppressive effect on PBMC-proliferation. Nigericin and valinomycin decreased the concentrations of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, and IL-17 in the culture medium with IC50 values less than 0.01 ng/ml. Nigericin also decreased the concentrations of IL-4 and IL-6 with IC50 values of less than 1 ng/ml. The results show that peptide antibiotics such as nigericin and valinomycin efficiently suppress the production of several cytokines and proliferation in mitogen-stimulated human PBMCs.
Kim, Hyun-Chul; Yoo, Seung-Schik; Lee, Jong-Hwan
Electroencephalography (EEG) data simultaneously acquired with functional magnetic resonance imaging (fMRI) data are preprocessed to remove gradient artifacts (GAs) and ballistocardiographic artifacts (BCAs). Nonetheless, these data, especially in the gamma frequency range, can be contaminated by residual artifacts produced by mechanical vibrations in the MRI system, in particular the cryogenic pump that compresses and transports the helium that chills the magnet (the helium-pump). However, few options are available for the removal of helium-pump artifacts. In this study, we propose a recursive approach of EEG-segment-based principal component analysis (rsPCA) that enables the removal of these helium-pump artifacts. Using the rsPCA method, feature vectors representing helium-pump artifacts were successfully extracted as eigenvectors, and the reconstructed signals of the feature vectors were subsequently removed. A test using simultaneous EEG-fMRI data acquired from left-hand (LH) and right-hand (RH) clenching tasks performed by volunteers found that the proposed rsPCA method substantially reduced helium-pump artifacts in the EEG data and significantly enhanced task-related gamma band activity levels (p=0.0038 and 0.0363 for LH and RH tasks, respectively) in EEG data that have had GAs and BCAs removed. The spatial patterns of the fMRI data were estimated using a hemodynamic response function (HRF) modeled from the estimated gamma band activity in a general linear model (GLM) framework. Active voxel clusters were identified in the post-/pre-central gyri of motor area, only from the rsPCA method (uncorrected p<0.001 for both LH/RH tasks). In addition, the superior temporal pole areas were consistently observed (uncorrected p<0.001 for the LH task and uncorrected p<0.05 for the RH task) in the spatial patterns of the HRF model for gamma band activity when the task paradigm and movement were also included in the GLM. Copyright © 2014 Elsevier Inc. All rights reserved.
Ito, T; Mamiya, Y; Aizawa, T; Akiyama, A; Yamamoto, S; Tsuzuki, M; Yoshimasa, O; Miki, M; Furusato, M
Combined androgen blockade (CAB) uning LH-RH agonist and flutamide has been performed as neoadjuvant therapy for T 2, 3 prostate cancers (CaP). The histological effects of neoadjuvant CAB therapy and influential factors were investigated. Materials were 20 CaP cases which were underwent radical prostatectomy (RP) after neoadjuvant CAB therapy. All cases were diagnosed by echo-guided sextant needle biopsies. RP was performed after serum PSA was decreased to undetectable level. Histological effect was evaluated by general rule for clinical and pathological studies on prostate cancer (Japanese Urological Association). All cases were divided 2 groups by histological effects as follows: Group A (poor effect group): G 0 and G 1, Group B (good effect group): G 2 and G 3. Immunostaining of p 53 (mutant type), bcl-2 and Chromogranin A (ChA) were performed for both pretreatment needle biopsy and RP specimen. In addition, pretreatment serum PSA and Gleason grade were also investigated. Down grading were found in 30%. Down staging were found in 35% (7 cases). All 7 cases were negative surgical margins and 5 of 7 were clinical T 3. Negative bcl-2 of biopsy specimen was correlation with down grading (p = 0.008). In the histopathological evaluation, G 0 was 1, G 1 were 10, G 2 were 6 and G 3 were 3 cases. Gleason 4 or 5 elements of biopsy were found in 9/11 cases in Group A but only 3/9 cases in Group B (p = 0.027). The bcl-2 positive cells of biopsy were found in 8/11 cases in Group A but only 1/9 cases in Group B (p = 0.006). The p 53 and/or bcl-2 positive cells of biopsy were found in 10/11 cases in Group A but only 3/9 cases in Group B (p = 0.007). Serum PSA and ChA were not correlation with histological effect of neoadjuvant CAB therapy. But, in 3 cases, ChA positive cell appeared after neoadjuvant therapy. We could not expect more than 50% cases to show the down grading and down staging. But, in T 3 case, surgical failure could be decrease. We could expect prostate cancer
Hoshi, Senji; Hayashi, Natsuho; Yagi, Mayu; Ookubo, Teppei; Muto, Akinori; Sugano, Osamu; Numahata, Kenji; Bilim, Vladimir; Hoshi, Kiyotugu; Sasagawa, Isoji
The efficacy and safety of degarelix, a luteinizing hormone-releasing hormone(LH-RH)antagonist, in patients with prostate cancer(PCa)were evaluated in a phase II, open-label, multicenter clinical trial. In this trial, a total of 13 patients were accrued at the Yamagata Prefectural Central Hospital from 2007 to 2008. The median age was 80 years(range, 65-85 years), and clinical stages were T1c, T2, T3, and T4 in 1, 4, 6, and 2 patients, respectively. Nodal(N)status was N0 in 9 patients and N1 in 4 patients. Distant metastases were absent(M0)in 12 patients and present(M1b)in 1 patient. The median prostate- specific antigen(PSA)level was 29.1 ng/mL(range, 6.3-427 ng/mL). All but one patient, who died of an unrelated cause, received a monthly dose(80 or 160mg)of degarelix for 12 months and were followed-up for 3 years. The PSA level declined in all patients. One patient died of an unrelated cause during the phase II trial. After completion of the phase II trial, 5 patients were treated with combined and rogen blockade(CAB)(leuprolide plus anti-androgen therapy), 2 patients were treated with single-agent leuprolide, 2 patients received single-agent bicalutamide, and 1 patient was followed-up without additional treatment. Radical prostatectomy was performed in 2 patients. Among the 5 patients treated with CAB, 2 died of metastatic cancer. CAB was effective in suppressing PSA levels in 3 patients. In 1 patient with T3aN1M1b PCa, colon cancer with lung metastases was detected during the follow-up period. Treatment with chemotherapy for colon cancer was effective in suppressing PSA levels for 12 months. In 1 patient with cT3aN1M0 PCa, the PSA level declined to <0.02 ng/mL, and a reduction in size of the prostate gland and metastatic lymph nodes was observed. This effect persisted for 3.5 years after the completion of the 12-month degarelix regimen, and no additional treatment was required.
Cellini, Numa; Luzi, Stefano; Morganti, Alessio Giuseppe; Mantini, Giovanna; Valentini, Vincenzo; Racioppi, Marco; Leone, Mariavittoria; Mattiucci, Gian Carlo; Di Gesù, Cinzia; Giustacchini, Mario; Destito, Antonio; Smaniotto, Daniela; Alcini, Eugenio
The aim of this study was to evaluate the prognostic role of several clinical variables in a patient population undergoing neoadjuvant hormonotherapy (NHT) with external beam radiotherapy (ERT) to identify subsets of patients with an unfavorable prognosis who require intensified therapy. Eighty-four patients (mean age, 68.2 +/- 6.1 years; range, 52-81 years) underwent ERT (45 Gy to pelvic volume; 65 Gy mean dose to prostate volume) and NHT (oral flutamide: 250 mg three times daily for 30 days; LH-RH analogue: one vial every 28 days starting two months before radiotherapy and for its entire duration). The distribution according to clinical stage was T2: 46.4%, T3: 50.0%, T4: 3.6%. The distribution according to the Gleason score was grade 2-4: 17.9%; grade 5-7: 53.6%; grade 8-10: 28.5%. The distribution according to pretreatment PSA levels (in ng/mL) was 0-4: 5.9%; 4-10: 26.2%; 10-20:16.7%; > or = 20: 51.2%. With a median follow-up of 36 months, 3.6% of patients died; hematogenous metastases and local disease progression were found in 16.7% and 6% of patients, respectively. Overall, the incidence of disease progression was 17.9%. 32.9% of patients showed biochemical failure during followup. Overall, metastasis-free, local progression-free and biochemical failure-free actuarial survival at five years was 89.2%, 66.5%, 85.0% and 41.9%, respectively. At univariate analysis (log-rank) clinical stage (cT) was shown to be significantly correlated with the incidence of metastasis (P = 0.0004), local progression (P < 0.0001) and disease-free survival (P = 0.0005). At multivariate analysis (Cox) the correlations between clinical stage and metastasis (P = 0.0175), local progression (P = 0.0200) and disease-free survival (P = 0.0175) were confirmed. Gleason score and pretreatment PSA levels did not show any significant correlation with these endpoints. These results confirm the indications of the recent literature, which, in prostate carcinoma at higher clinical stages, suggest
Brüssow, Klaus-Peter; Schneider, Falk; Kanitz, Ellen; Otten, Winfried; Tuchscherer, Margret
Prenatal stress has been seen as a reason for reproductive failures in pig offspring mostly originated or mediated by changed maternal functions. Experiments were conducted in pregnant gilts (n=32) to characterize effects of elevated maternal glucocorticoids on the secretion of reproductive hormones (LH, progesterone) during the 1st (EXP 1), 2nd (EXP 2) and 3rd (EXP 3) trimester of pregnancy (TP). Transiently elevated cortisol release was repeatedly achieved by application of 100 IU adenocorticotropic hormone (ACTH) (Synacthen Depot) six times every second day beginning either on day 28 (EXP 1), day 49 (EXP 2) or day 75 of pregnancy (EXP 3). Glucocorticoid concentrations were examined in umbilical blood vessels of fetuses which mothers were subjected to ACTH at 2nd and 3rd TP (EXP 4). Furthermore, the pituitary function of newborn piglets of EXP 2 was checked by a LH-RH challenge test. In sows, LH concentrations were at low basal level (0.1-0.2 ng/ml) but with pulsatory release pattern during each TP. The number of LH pulses/6 h (LSM +/- SE) of saline treated Controls increased with ongoing pregnancy and decreased to the 3rd TP (1.3 +/- 0.2 in EXP 1 vs. 2.0 +/- 0.1 in EXP 2 vs. 1.4 +/- 0.1 in EXP 3, p<0.05). After ACTH treatment the number of LH pulses left unchanged in Experiments 1 and 2 (1.3 +/- 0.2 and 1.5 +/- 0.1) and decreased in EXP 3 (0.8 +/- 0.2, p<0.05). Differences (p<0.05) were obtained comparing the LH pulse number of ACTH and saline treated sows at the 2nd and 3rd TP. Moreover, areas under the curve (AUC) of each LH pulse and of LH over baseline were significantly reduced by treatment. Levels of progesterone increased (p<0.05) for 150 to 170 min after each ACTH application both in EXP 1 and EXP 2, but not in EXP 3. The mean progesterone concentration was different between trimesters, and ACTH and Controls (1st TP: 30.0 +/- 0.9 and 24.4 +/- 0.7 ng/ml; 2nd TP: 35.5 +/- 0.9 and 29.1 +/- 1.0 ng/ml; 3rd TP: 13.6 +/- 0.2 and 13.1 +/- 0.1 ng/ml; p<0.05). In
Zhu, Naiqiang; Wang, Huan; Jin, Guoxin; Zhang, Lei
To study the relationship between cervical pedicle and compressed spinal cord. One hundred and five patients (53 male,52 female,age from 29 to 80 years) with cervical spondylotic myelopathy who needed surgery were included from December 2011 to January 2013 in Shengjing Hospital. Plain MRI scan was used for cross section of C4 - C7 vertebral bodies parallel to the axis of bilateral pedicle, and the images were sent to the workstation. PACS system was applied to measure the anatomical parameters related to the security of cervical pedicle screw, including the shortest distance from medial left/right cervical pedicle to the cervical spinal cord (LH/RH), and the smallest angle between the longitudinal axis of left/right cervical pedicle and the screw which was assumed to just touch the cervical spinal cord (LSA/RSA). All these data in each segment were classified according to compression or not:with compression and without compression. Twelve cases were selected and measured by MRI and 3D cervical CT for spinal canal width D, namely the straight-line distance between the medial margins of cervical pedicle. And the results of two methods were compared to see whether there were statistical differences. At C4, LH was (7.2±1.3) mm, RH was (6.7±1.4) mm, and the average was (6.9±1.4) mm; at C5, LH was (7.7±1.4) mm, RH was (6.7±1.4) mm, and the average was (7.2±1.5) mm; at C6, LH was (8.2±1.5) mm, RH was (6.9±1.3) mm, and the average was (7.5±1.5) mm; at C7, LH was (8.2±1.4) mm, RH was (7.3±2.1) mm, and the average was (7.7±1.8) mm. At C4, LSA was 34.4°±4.2°, RSA was 34.4°±5.2° and the average angle was 34.4°±4.7°; at C5, LSA was 35.9°±5.2°, RSA was 34.6°±5.4° and the average angle was 35.3°±5.3°; at C6, LSA was 37.4°±4.8°, RSA was 34.8°±4.8° and the average angle was 36.1°±5.0°; at C7, LSA was 39.2°±5.8°, RSA was 37.1°±5.2° and the average angle was 38.1°±5.6°; There were no statistically significant differences between