Suppression Of Follicle-stimulating Hormone Research Articles

Estetrol Inhibits the Prostate Cancer Tumor Stimulators FSH and IGF-1

Background: The co-treatment of androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) with the fetal estrogen estetrol (E4) may further inhibit endocrine PCa tumor stimulators. We previously reported the suppression of follicle-stimulating hormone (FSH), total and free testosterone, and prostate-specific antigen by ADT+E4. Here, we provide more detailed data on FSH suppression by E4 and present new findings on the effect of ADT+E4 on insulin-like growth factor-1 (IGF-1). Methods: A Phase II, double-blind, randomized, placebo-controlled study (the PCombi study) was conducted in advanced PCa patients treated with ADT. The study assessed the effect of E4 co-treatment with LHRH agonist ADT on tumor stimulators, including FSH and IGF-1. Patients starting ADT were randomized 2:1 to receive either 40 mg E4 (n = 41) or placebo (n = 21) for 24 weeks. Non-parametric analyses were performed on the per-protocol population (PP) and individual changes were visualized. Results: The PP included 57 patients (37 ADT+E4; 20 ADT+placebo). ADT+E4 almost completely suppressed FSH in all patients (98% versus 37%; p < 0.0001). IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo (p < 0.0001). Conclusions: The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA.

Effects of follicle-stimulating hormone on energy balance and tissue metabolic health after loss of ovarian function.

Loss of ovarian function imparts increased susceptibility to obesity and metabolic disease. These effects are largely attributed to decreased estradiol (E2), but the role of increased follicle-stimulating hormone (FSH) in modulating energy balance has not been fully investigated. Previous work that blocked FSH binding to its receptor in mice suggested this hormone may play a part in modulating body weight and energy expenditure after ovariectomy (OVX). We used an alternate approach to isolate the individual and combined contributions of FSH and E2 in mediating energy imbalance and changes in tissue-level metabolic health. Female Wistar rats were ovariectomized and given the gonadotropin releasing hormone (GnRH) antagonist degarelix to suppress FSH production. E2 and FSH were then added back individually and in combination for a period of 3 wk. Energy balance, body mass composition, and transcriptomic profiles of individual tissues were obtained. In contrast to previous studies, suppression and replacement of FSH in our paradigm had no effect on body weight, body composition, food intake, or energy expenditure. We did, however, observe organ-specific effects of FSH that produced unique transcriptomic signatures of FSH in retroperitoneal white adipose tissue. These included reductions in biological processes related to lipogenesis and carbohydrate transport. In addition, rats administered FSH had reduced liver triglyceride concentration (P < 0.001), which correlated with FSH-induced changes at the transcriptomic level. Although not appearing to modulate energy balance after loss of ovarian function in rats, FSH may still impart tissue-specific effects in the liver and white adipose tissue that might affect the metabolic health of those organs.NEW & NOTEWORTHY We find no effect of follicle-stimulating hormone (FSH) on energy balance using a novel model in which rats are ovariectomized, subjected to gonadotropin-releasing hormone antagonism, and systematically given back FSH by osmotic pump. However, tissue-specific effects of FSH on adipose tissue and liver were observed in this study. These include unique transcriptomic signatures induced by the hormone and a stark reduction in hepatic triglyceride accumulation.

Follistatin Forms a Stable Complex With Inhibin A That Does Not Interfere With Activin A Antagonism.

Inhibins are transforming growth factor-β family heterodimers that suppress follicle-stimulating hormone (FSH) secretion by antagonizing activin class ligands. Inhibins share a common β chain with activin ligands. Follistatin is another activin antagonist, known to bind the common β chain of both activins and inhibins. In this study, we characterized the antagonist-antagonist complex of inhibin A and follistatin to determine if their interaction impacted activin A antagonism. We isolated the inhibin A:follistatin 288 complex, showing that it forms in a 1:1 stoichiometric ratio, different from previously reported homodimeric ligand:follistatin complexes, which bind in a 1:2 ratio. Small angle X-ray scattering coupled with modeling provided a low-resolution structure of inhibin A in complex with follistatin 288. Inhibin binds follistatin via the shared activin β chain, leaving the α chain free and flexible. The inhibin A:follistatin 288 complex was also shown to bind heparin with lower affinity than follistatin 288 alone or in complex with activin A. Characterizing the inhibin A:follistatin 288 complex in an activin-responsive luciferase assay and by surface plasmon resonance indicated that the inhibitor complex readily dissociated upon binding type II receptor activin receptor type IIb, allowing both antagonists to inhibit activin signaling. Additionally, injection of the complex in ovariectomized female mice did not alter inhibin A suppression of FSH. Taken together, this study shows that while follistatin binds to inhibin A with a substochiometric ratio relative to the activin homodimer, the complex can dissociate readily, allowing both proteins to effectively antagonize activin signaling.

Follicle-stimulating hormone promotes growth of human prostate cancer cell line-derived tumor xenografts.

Chemical castration in prostate cancer can be achieved with gonadotropin-releasing hormone (GnRH) agonists or antagonists. Their effects differ by the initial flare of gonadotropin and testosterone secretion with agonists and the immediate pituitary-testicular suppression by antagonists. While both suppress luteinizing hormone (LH) and follicle-stimulating hormone (FSH) initially, a rebound in FSH levels occurs during agonist treatment. This rebound is potentially harmful, taken the expression of FSH receptors (R) in prostate cancer tissue. We herein assessed the role of FSH in promoting the growth of androgen-independent (PC-3, DU145) and androgen-dependent (VCaP) human prostate cancer cell line xenografts in nude mice. Gonadotropins were suppressed with the GnRH antagonist degarelix, and effects of add-back human recombinant FSH were assessed on tumor growth. All tumors expressed GnRHR and FSHR, and degarelix treatment suppressed their growth. FSH supplementation reversed the degarelix-evoked suppression of PC-3 tumors, both in preventive (degarelix and FSH treatment started upon cell inoculation) and therapeutic (treatments initiated 3weeks after cell inoculation) setting. A less marked, though significant FSH effect occurred in DU145, but not in VCaP xenografts. FSHR expression in the xenografts supports direct FSH stimulation of tumor growth. Testosterone supplementation, to maintain the VCaP xenografts, apparently masked the FSH effect on their growth. Treatment with the LH analogue hCG did not affect PC-3 tumor growth despite their expression of luteinizing hormone/choriongonadotropin receptor. In conclusion, FSH, but not LH, may directly stimulate the growth of androgen-independent prostate cancer, suggesting that persistent FSH suppression upon GnRH antagonist treatment offers a therapeutic advantage over agonist.

Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function

ObjectiveTo evaluate the effects of estetrol 15 mg/drospirenone 3 mg on ovarian function. Study designSingle-center, randomized, open-label, parallel study in healthy young women with proven ovulatory cycles. Participants received either estetrol 15 mg/drospirenone 3 mg (E4/DRSP) (n = 41) or ethinylestradiol 20 µg/drospirenone 3 mg (EE/DRSP) (n = 41) in a 24/4-day regimen for 3 consecutive cycles. Follicular size and endometrial thickness were measured by transvaginal ultrasound every 3 days in cycles 1 and 3. Blood was sampled for hormone analysis. Ovarian function expressed as Hoogland score was based on follicular size, serum estradiol (E2) and progesterone (P) concentrations. Ovulation was defined as a ruptured follicle-like structure >13 mm with serum E2 concentrations >100 pmol/L and serum P concentrations >5 nmol/L. We assessed return of ovulation after treatment cessation, and safety throughout the study. ResultsNone of the participants ovulated with E4/DRSP use, while one participant ovulated once and one participant ovulated twice during EE/DRSP treatment. Most participants had a Hoogland score of 1 (no ovarian activity) in cycle 1 (85.0% and 82.9% of participants on E4/DRSP and EE/DRSP, respectively) and in cycle 3 (65.8% and 83.8%, respectively). E4/DRSP suppressed follicle-stimulating hormone and luteinizing hormone to a lesser extent than EE/DRSP, whereas both treatments comparably suppressed E2 and P and endometrial thickness. Return of ovulation occurred, on average, 15.5 days after E4/DRSP treatment discontinuation. E4/DRSP was safe and well-tolerated. ConclusionsE4 15 mg/DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, comparable to a marketed combined oral contraceptive containing EE/DRSP. Implications statementTreatment with E4 15 mg/DRSP 3 mg showed complete ovulation inhibition, despite less suppression of follicle-stimulating hormone and luteinizing hormone compared to EE/DRSP. If it becomes commercially available, E4/DRSP, containing a naturally occurring estrogen, should be as effective as EE/DRSP.

The Effect of Longer-Acting vs Shorter-Acting Testosterone Therapy on Follicle Stimulating Hormone and Luteinizing Hormone.

Testosterone (T) replacement therapy causes suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that can lead to decrease in semen parameters and possible infertility. Different T formulations may have varying suppression on FSH and LH. To study whether shorter-acting T (multiple daily dosing) has less suppression on FSH and LH serum levels compared with longer-acting T (transdermal gel, injectable). A systematic literature search was conducted by following the protocol based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols. We comprehensively reviewed the literature by systematically searching manuscripts indexed in PubMed from 1995 to March 13, 2019 to identify studies reporting changes in FSH and LH in hypogonadal men treated with exogenous T which evaluated the effect of exogenous T on FSH and LH. A total of 8 studies reported the effect of T on FSH and LH in 793 hypogonadal men: 2 used long-acting injectables (enanthate or undecanoate) in a total of 16 men, 5 used intermediate-acting daily topical gels or patches in a total of 471 men, and 1 used short-acting intranasal T (125 μL/nostril, twice a day or three times a day) in 306 men. Long-acting injectables decreased FSH by 86.3%, intermediate-acting daily gels/patches decreased FSH by 60.2%, and short-acting intranasal gel decreased FSH by 37.8%. Long-acting injectables decreased LH by 71.8%, intermediate-acting daily gels/patches decreased LH by 59.2%, and short-acting intranasal gel decreased LH by 47.3%. Our findings suggest that short-acting T preparations do not decrease serum FSH or LH to the same extent as longer-acting transdermal gels and injectables. However, further clinical trial data are necessary to determine whether the effect of short-acting TRT on gonadotropins translates into similar changes in semen parameters and fertility. Masterson TA, Turner D, Vo D, etal. The Effect of Longer-Acting vs Shorter-Acting Testosterone Therapy on Follicle Stimulating Hormone and Luteinizing Hormone. Sex Med Rev 2021;9:143-148.

Estrogen Versus FSH Effects on Bone Metabolism: Evidence From Interventional Human Studies.

Provocative mouse studies and observational human data have generated considerable enthusiasm for modulating follicle-stimulating hormone (FSH) action in humans to prevent bone loss and, in addition, to treat obesity. This perspective summarizes the strengths and potential weaknesses of the mouse studies examining the skeletal phenotype of FSHβ or FSH receptor null mice, as well as more recent studies using FSH neutralizing antibodies. Although human observational studies do demonstrate correlation of serum FSH levels with postmenopausal bone loss, these studies cannot distinguish whether serum FSH is simply a better biomarker than estradiol or causally related to the bone loss. Establishing causality requires direct interventional studies either suppressing or infusing FSH in humans and to date, such studies have uniformly failed to demonstrate an effect of FSH on bone turnover independent of changes in sex steroid levels. In addition, suppression of FSH is unable to prevent increases in body fat following the induction of sex steroid deficiency, at least in men. Thus, although the preclinical mouse and human observational data are intriguing, there is currently no direct evidence from interventional studies that FSH regulates bone or fat metabolism in vivo in humans.

Glucocorticoid Induced Hypothalamic-Pituitary Axis Alterations Associated with Hypogonadotropic Hypogonadism

Since the existence of cortisol in 1930 to current multiple formulations of glucocorticoids, it has been one of the most widespread medications to use for the treatment of simple to serious maladies. Glucocorticoids have gained unprecedented importance in treating autoimmune and inflammatory diseases, with one study conducted between 1998-2008 signifying that 1.2% of Americans over the age of 20 were at one point on glucocorticoid therapy, accounting for approximately 2.5 million Americans over the course of a decade. In this brief review, we focused on consequences of glucocorticoid therapy on alteration of sex steroids mainly in men with subsequent low libido, fatigue, erectile dysfunction, loss of muscle mass, increasing adipose tissue and osteoporosis. Effects of glucocorticoids appraised, based on current and available evidence at the level of the hypothalamus and pituitary, could cause alteration on the adipocyte-kisspeptin-gonadotropin-releasing hormone (GnRH)-luteinizing hormone (LH)-follicle-stimulating hormone (FSH) axis, especially with long-term use. The resultant hypogonadism occurs by suppression of GnRH-receptors, GnRH, LH, and FSH. Hypogonadism in patients with rheumatological diseases has multiple reasons, one of which is functional due to current illness and alteration in cytokines and inflammatory markers, and the other is a consequence of glucocorticoid therapy, which in either situation treatment of hypogonadism may improve quality of life and prevent complications of hypogonadism.

OR18-4 Beneficial Effect on Sperm Production of Leflutrozole in Men with Obesity-Associated Secondary Hypogonadotropic Hypogonadism: Results from a Phase II Study

Introduction: Excess aromatase activity in adipose tissue has been linked to increased conversion of testosterone (T) to estradiol, resulting in high estradiol levels and suppressing gonadotropins. In obese men, this can cause obesity-associated hypogonadotropic hypogonadism (OHH) with decreased fertility. T replacement therapies frequently result in negative feedback suppression of follicle stimulating hormone (FSH) and luteinizing hormone (LH), further impairing semen fertility. Aromatase inhibition avoids this complication, restoring T without impairing fertility parameters, by reducing inhibitory effects of excess estradiol on LH and FSH. We report the impact of a weekly (QW) oral aromatase inhibitor on hormone levels and semen parameters in patients with OHH. Methods: A 24-wk, multicenter, randomized, double-blind, placebo (PBO)-controlled phase IIb trial (NCT02730169) of 3 doses of leflutrozole QW in obese adult males (BMI 30-50 kg/m2) with morning serum T <300 ng/dL. Exclusion criteria: Type 1 or uncontrolled type 2 diabetes; clinically significant endocrinopathy; prostate disease; recently diagnosed cardiovascular conditions; treatment with confounding medications (including those affecting gonadotropin or T levels). Primary endpoint: normalization (300-1000 ng/dL) of serum T in >75% of patients by end of treatment (EOT) at Wk 24. Secondary endpoints included gonadotropin and estradiol levels; a substudy assessed change in semen parameters. Safety was monitored from 1st dose to 90 days after EOT. Results: 271 patients (means: age 50.9 (±8.7) yrs, BMI 38.1 (±5.3) kg/m2, T 231.1 (±54.6) ng/dL) were randomized to 3 doses of leflutrozole or PBO. All 3 leflutrozole-treated arms met the primary endpoint with normalized T levels by EOT in >75% of patients vs 10% for PBO (p<0.001). Dose-dependent elevations in FSH and LH (p<0.001) and dose-dependent reductions in estradiol were observed at EOT. At Wks 12 and 20, numerical increases in sperm counts were observed in all 3 leflutrozole groups vs PBO, with statistically significant improvements (LS mean difference [95% CI]) in semen volume (1.37 [0.41, 2.34] ml, p=0.006, n=24), spermatozoa (270.084 [65.007, 475.161] x106/ejaculate, p=0.011, n=23), and total motile sperm count (127.711 [12.602, 242.819] 106/ejaculate, p=0.030, n=22) in leflutrozole highest dose group vs PBO. Leflutrozole was generally well tolerated; 24.7% of patients experienced related treatment-emergent adverse events (AEs). Of these, 3.0-7.5% of patients in the 3 leflutrozole dose groups experienced serious AEs, vs 5.2% of patients receiving PBO. Conclusions: In contrast to suppression of spermatogenesis seen with exogenous T therapy, leflutrozole restores normal endogenous physiologic T levels whilst increasing FSH/LH, with positive effects on semen fertility parameters in men with OHH. A 24-wk, blinded extension study is currently ongoing.

FSH suppression and tumour control in patients with prostate cancer during androgen deprivation with a GnRH agonist or antagonist

Background: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A).Materials and methods: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman’s correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance.Results: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm.Conclusions: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control.

Comparison of pre-treatment with OCPs or estradiol valerate vs. no pre-treatment prior to GnRH antagonist used for IVF cycles: An RCT

Both oral contraceptive pills (OCPs) and estradiol valerate (E2) have been used to schedule a gonadotropin-releasing hormone antagonist in vitro fertilization (IVF) cycles. Since the suppression of follicle-stimulating hormone by OCPs can stay 5-7 days after stopping the pills, it seems that starting the gonadotropin-releasing hormone (GnRH) after 6 days of pre-treatment discontinuation may be important in IVF outcomes. The aim of the present study was to determine the number of mature oocyte and pregnancy rate of three pretreatment methods for fresh embryo transfer cycles. In this randomized controlled trial, two-hundred ten women (18-35 yr and less than 2 previous IVF attempts) undergoing IVF with the GnRH antagonist protocol were randomized to the OCP, E2, and no pretreatment arms. OCP group (n=53) received OCP (ethinyl estradiol30 μg and levonorgestrel150 μg), E2 group (n=63) received 4 mg/day oral E2 (17β-E2) for 10 days from day 20 of the previous cycle and GnRH antagonist stimulation was started 6 days after the interruption of OCP and E2. The control group (n =70) did not receive any pretreatment. No significant difference was observed in the mean number of the mature oocyte, endometrial thickness, and embryo quality. The pregnancy rate in E2 group was higher than the two other groups (42.9% vs 39.6% and 34.3% in OCP and control group, respectively), but the difference was not statistically significant (p=0.59). It seems OCP or E2 pretreatment could not improve the fresh IVF-embryo transfer outcomes.

Actions of pituitary hormones beyond traditional targets.

Studies over the past decade have challenged the long-held belief that pituitary hormones have singular functions in regulating specific target tissues, including master hormone secretion. Our discovery of the action of thyroid-stimulating hormone (TSH) on bone provided the first glimpse into the non-traditional functions of pituitary hormones. Here we discuss evolving experimental and clinical evidence that growth hormone (GH), follicle-stimulating hormone (FSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin and arginine vasopressin (AVP) regulate bone and other target tissues, such as fat. Notably, genetic and pharmacologic FSH suppression increases bone mass and reduces body fat, laying the framework for targeting the FSH axis for treating obesity and osteoporosis simultaneously with a single agent. Certain 'pituitary' hormones, such as TSH and oxytocin, are also expressed in bone cells, providing local paracrine and autocrine networks for the regulation of bone mass. Overall, the continuing identification of new roles for pituitary hormones in biology provides an entirely new layer of physiologic circuitry, while unmasking new therapeutic targets.

Male hormonal contraception: past, present, future

In certain regions of the world the enormous rate of population growth raises economic and public health concerns and widely accessible contraceptive methods would be desired. In contrast, in other countries the use of effective contraception is a question of individual preferences. Today, most of the reliable contraceptive methods are applied by women, while the options for male methods are quite limited. It is well known that significant portion of pregnancies are still unplanned and several data revealed men's willingness to take part in family planning. Based on these needs, remarkable efforts have been made to develop a suitable hormonal contraceptive agent for men. With the exogenous suppression of follicle stimulating hormone and luteinizing hormone secretion, the inhibition of the testicular testosterone production and the spermatogenesis can be achieved. In the beginning, testosterone-derivatives, or testosterone-progestin combinations were administered, later synthetic androgen agents were developed. Despite of these efforts, unfortunately, there is no safe, widely feasible male hormonal contraception to date, but in the future this goal can be achieved by solving the key hurdles. Orv Hetil. 2017; 158(46): 1819-1830.

How to personalize ovarian stimulation in clinical practice.

Controlled ovarian stimulation (COS) in in vitro fertilization (IVF) cycles is the starting point from which couple’s prognosis depends. Individualization in follicle-stimulating hormone (FSH) starting dose and protocol used is based on ovarian response prediction, which depends on ovarian reserve. Anti-Müllerian hormone levels and the antral follicle count are considered the most accurate and reliable markers of ovarian reserve. A literature search was performed for studies that addressed the ability of ovarian reserve markers to predict poor and high ovarian response in assisted reproductive technology cycles. According to the predicted response to ovarian stimulation (poor- normal- or high- response), it is possible to counsel couples before treatment about the prognosis, and also to individualize ovarian stimulation protocols, choosing among GnRH-agonists or antagonists for endogenous FSH suppression, and the FSH starting dose in order to decrease the risk of cycle cancellation and ovarian hyperstimulation syndrome. In this review we discuss how to choose the best COS therapy, based on ovarian reserve markers, in order to enhance chances in IVF.

Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women

Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women. We evaluated the pharmacokinetics and pharmacodynamics of elagolix. This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days. Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events. Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women.

Adult granulosa cell tumors of the ovary: a retrospective study of 30 cases with respect to the expression of steroid synthesis enzymes.

ObjectiveSome, but not all, granulosa cell tumors are characterized by estrogen production. This study was designed to determine whether there are clinical or pathological variations in granulosa cell tumors in relation to the expression of sex steroid synthesis enzymes.MethodsClinical symptoms, serum hormonal values, and histology of 30 granulosa cell tumor patients who underwent surgery between 2002 and 2014 were retrospectively reviewed.ResultsMost patients presented with abnormal genital bleeding including abnormal menstrual cycles. Eight of 16 patients older than 50 years had endometrial hyperplasia and one had endometrial cancer. Serum 17β-estradiol (E2) levels tended to be higher in patients over 50 years of age (p=0.081). Serum follicle-stimulating hormone (FSH) levels were low in all patients irrespective of serum E2 levels. Magnetic resonance imaging revealed a thicker endometrium in older as compared to younger patients (p<0.05). Tumor cells in the majority of cases were positive for inhibin α and P450 aromatase, irrespective of age and serum E2 levels. P450 17α-hydroxylase (P450c17) expression varied among cases. P450c17 was strongly positive in luteinized tumor cells and weakly positive in theca cells and fibroblasts. High E2 levels were associated with P450c17-positive cells in the tumor (p<0.05).ConclusionThe expression of hormone-synthesizing enzymes divides granulosa cell tumors into 2 distinct types; tumors with P450c17-positive cells show elevated serum E2 and related clinical symptoms, while tumors without these cells show symptoms related to FSH suppression by inhibin.

Agoraphobia and Follicle-Stimulating Hormone Levels between Tamoxifen and Goserelin versus Tamoxifen Alone in Premenopausal Hormone Receptor-Positive Breast Cancer: A 12-Month Prospective Randomized Study.

ObjectiveTamoxifen is an estrogen receptor antagonist used to prevent recurrence of breast cancer, which may provoke depression and anxiety and increase follicle-stimulating hormone (FSH) to patients. We compared anxiety and depression symptoms and FSH levels who received conventional tamoxifen alone and combination treatment of goserelin, a gonadotropin-releasing hormone (GnRH) analogue, with tamoxifen.MethodsSixty-four premenopausal women with hormone receptor-positive early-stage breast cancer were included and were assigned randomly to receive either tamoxifen and goserelin combination or tamoxifen alone for 12 months. The participants were evaluated blindly using the Hamilton Depression and Anxiety Rating Scale, the Beck Depression Rating Scale, and the Albany Panic and Phobia Questionnaire (APPQ). Blood FSH levels were assessed at baseline, 6 and 12 months.ResultsA significant time×group difference was detected in the agoraphobia trends subscale of the APPQ and in FSH levels. The combination group showed significantly less increases in agoraphobia subscale of APPQ and greater decreases in FSH level than those in the tamoxifen-alone group from baseline to 12 months of treatment. No significant differences for age, tumor grade, body mass index, or family history were found at baseline between the two groups.ConclusionOur results suggest that the combination treatment of tamoxifen and goserelin resulted in less agoraphobia than tamoxifen alone in premenopausal women with breast cancer, which may associated with FSH suppression of goserelin.

Suppression of Sertoli cell tumour development during the first wave of spermatogenesis in inhibin α-deficient mice.

A dynamic partnership between follicle-stimulating hormone (FSH) and activin is required for normal Sertoli cell development and fertility. Disruptions to this partnership trigger Sertoli cells to deviate from their normal developmental pathway, as observed in inhibin α-knockout (Inha-KO) mice, which feature Sertoli cell tumours in adulthood. Here, we identified the developmental windows by which adult Sertoli cell tumourigenesis is most FSH sensitive. FSH was suppressed for 7 days in Inha-KO mice and wild-type littermates during the 1st, 2nd or 4th week after birth and culled in the 5th week to assess the effect on adult Sertoli cell development. Tumour growth was profoundly reduced in adult Inha-KO mice in response to FSH suppression during Weeks 1 and 2, but not Week 4. Proliferative Sertoli cells were markedly reduced in adult Inha-KO mice following FSH suppression during Weeks 1, 2 or 4, resulting in levels similar to those in wild-type mice, with greatest effect observed at the 2 week time point. Apoptotic Sertoli cells increased in adult Inha-KO mice after FSH suppression during Week 4. In conclusion, acute FSH suppression during the 1st or 2nd week after birth in Inha-KO mice profoundly suppresses Sertoli cell tumour progression, probably by inhibiting proliferation in the adult, with early postnatal Sertoli cells being most sensitive to FSH action.

DOSE AND DURATIONAL EFFECTS OF THE GONADOTROPIN-RELEASING HORMONE AGONIST, DESLORELIN: THE MALE RAT (RATTUS NORVEGICUS) AS A MODEL

Gonadotropin-releasing hormone (GnRH) agonists are routinely used to suppress the reproductive axis of many mammals, especially in zoos. Current treatments are reversible. There is a need to develop nonreversible agents, and this study investigates the effects of high-dose and long-duration exposure to the GnRH agonist, deslorelin, in the rat model. Studies indicate that the follicle-stimulating hormone (FSH) gonadotropin is predominantly affected, and following high-dose exposure to deslorelin for a long duration, the ability of gonadotropes to synthesize FSH may be compromised, perhaps permanently. Understanding the mechanisms by which such persistent suppression of FSH occurs may facilitate the development of novel next-generation contraceptives. It is hypothesized that direct testicular effects of GnRH agonists may play a critical role in the efficacy of GnRH agonists in male contraception.

Antifertility effect of chronically administered Tabernaemontana divaricata leaf extract on female albino mice

ObjectiveTo study the antifertility activity of Tabernaemontana divaricata leaf extract on female albino mice. MethodsAnimals were divided into three groups consisting of five animals in each group. One group served as control and received vehicle orally for 21 days. The other two groups received dried ethanolic extract of leaves orally at a dose of 250 and 450 mg/kg animal body weight per day. After 21 days of treatment, extract was withdrawn from the mice and estrous cycle was studied for another 21 days. ResultsThe results of this study revealed that treatment of mice with extract of 250 and 450 mg/kg body weight for 21 days caused a prolonged eastrous cycle with significant increase in the duration of diestrus phase and elongation of estrus stage in treatment with higher dose (450 mg/kg body weight) and simultaneously decrease in the luteinizing hormone (LH) in both the treated groups and follicle stimulating hormone (FSH) in higher dose of treatment compared to the control animals may indicate the disturbance of estrous cycle and ovulation through suppression of FSH. ConclusionsIt concludes that disturbance on the estradiol secretion with significant decrease during estrous stage of the cycle observed with the extract treatment may be due to impairment of LH and FSH.