Gonadotropin Secretion In Women Research Articles

Vitamin D Status Determines the Impact of Metformin on Gonadotropin Levels in Postmenopausal Women.

Metformin was found to decrease elevated levels of anterior pituitary hormones. Its impact on lactotrope secretory function was absent in women with vitamin D insufficiency. This study investigated whether vitamin D status determines metformin action on overactive gonadotropes. We compared the effect of six-month metformin treatment on the plasma levels of gonadotropins, TSH, prolactin, ACTH, estradiol, free thyroid hormones, IGF-1, and 25-hydroxyvitamin D, as well as on glucose homeostasis markers between three matched groups of postmenopausal women at high risk for diabetes: untreated subjects with vitamin D insufficiency (group A), untreated women with normal vitamin D status (group B), and individuals receiving vitamin D supplementation with normal 25-hydroxyvitamin D levels (group C). Only in groups B and C did metformin reduce FSH levels and tend to decrease LH levels, and these effects correlated with baseline gonadotropin levels, baseline 25-hydroxyvitamin D levels, and the improvement in insulin sensitivity. Follow-up gonadotropin levels were higher in group A than in the other two groups. The drug did not affect circulating levels of TSH, prolactin, ACTH, estradiol, free thyroid hormones, IGF-1, or 25-hydroxyvitamin D. The obtained results suggest that the impact of metformin on gonadotropin secretion in women after menopause is determined by vitamin D status.

Kisspeptin and neurokinin B interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome.

STUDY QUESTIONWhat is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)?SUMMARY ANSWERAdministration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to kisspeptin-10 was maintained.WHAT IS KNOWN ALREADYPCOS is characterized by abnormal GnRH/LH secretion. NKB and kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear.STUDY DESIGN, SIZE, DURATIONThe NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle.PARTICIPANTS/MATERIALS, SETTING, METHODSSubjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion.MAIN RESULTS AND THE ROLE OF CHANCENK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment.LIMITATIONS, REASONS FOR CAUTIONThe study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects.WIDER IMPLICATIONS OF THE FINDINGSThese data demonstrate the interactive regulation of GnRH/LH secretion by NKB and kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback.STUDY FUNDING/COMPETING INTEREST(S)Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose.TRIAL REGISTRATION NUMBERN/A.

Discovery of new receptors regulating luteinizing hormone and follicle-stimulating hormone secretion by bovine gonadotrophs to explore a new paradigm for mechanisms regulating reproduction

Previous studies in the 1960s and 1970s have reported that both gonadotropin-releasing hormone (GnRH) and estradiol-activated nuclear estrogen receptors regulate gonadotropin secretion in women. However, I had previously reported that gonadotroph function is regulated by complex crosstalk between several membrane receptors. RNA-seq had previously revealed 259 different receptor genes expressed in the anterior pituitary of heifers. However, the biological roles of most of these receptors remain unknown. I identified four new receptors of interest: G protein-coupled receptor 30 (GPR30), anti-Mullerian hormone (AMH) receptor type 2 (AMHR2), and G protein-coupled receptors 61 and 153 (GPR61 and GPR153). GPR30 rapidly (within a few minutes) mediates picomolar, but not nanomolar, levels of estradiol to suppress GnRH-induced luteinizing hormone (LH) secretion from bovine gonadotrophs, without decreasing mRNA expressions of the LHα, LHβ, or follicle-stimulating hormone (FSH) β subunits. GPR30 is activated by other endogenous estrogens, estrone and estriol. Moreover, GPR30 activation by zearalenone, a nonsteroidal mycoestrogen, suppresses LH secretion. AMHR2, activated by AMH, stimulates LH and FSH secretion, thus regulating gonadotrophs, where other TGF-β family members, including inhibin and activin, potentially affect FSH secretion. I also show that GPR61, activated by its ligand (recently discovered) significantly alters LH and FSH secretion. GPR61, GPR153, and AMHR2 co-localize with the GnRH receptor in unevenly dispersed areas of the bovine gonadotroph cell surface, probably lipid rafts. The findings summarized in this review reveal a new paradigm regarding the mechanisms regulating reproduction via novel receptors expressed on bovine gonadotrophs.

Hypothalamic-Pituitary-Ovarian Axis Reactivation by Kisspeptin-10 in Hyperprolactinemic Women With Chronic Amenorrhea.

Context:Hyperprolactinemia-induced hypogonadotropic amenorrhea (hPRL-HA) is a major cause of hypothalamic gonadotrophin-releasing hormone (GnRH) deficiency in women. In hyperprolactinemic mice, we previously demonstrated that hypothalamic kisspeptin (Kp) expression was diminished and that Kp administration restored hypothalamic GnRH release, gonadotropin secretion, and ovarian cyclicity, suggesting that Kp neurons could also play a role in hPRL-HA.Objective:To study the effect of Kp-10 on the gonadotropic-ovarian axis in women with hPRL-HA.Patients:Two women (32 and 36 years old) with chronic hPRL-HA (prolactin: between 94 and 102 and 98 and 112 ng/mL, respectively) caused by cabergoline-resistant microprolactinomas.Interventions:Cabergoline was discontinued 6 months before inclusion. Blood samples were taken every 10 minutes for 12 hours during 2 consecutive days to evaluate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Serum estradiol (E2), testosterone (T), and inhibin B (IB) levels were also measured. Vehicle or Kp-10 (1.5 μg/kg/h) was infused intravenously for 12 hours.Results:Kp-10 induced a significant increase in LH and FSH levels and increased LH pulses. E2, T, and IB serum levels were also significantly increased.Conclusions:In this exploratory study, we demonstrated that administration of Kp-10 reactivated gonadotropin secretion in women with hPRL-HA and increased ovarian activity. Our data suggest that, as in rodents, GnRH deficiency in hPRL-HA is also mediated by an impairment of hypothalamic Kp secretion. Kp-10 or its analogues could have therapeutic application as an alternative approach to restore ovarian function and fertility in women with hPRL-HA resistant to dopamine agonists and in whom pituitary surgery is not possible.

Inhibitory Effect of Submaximal Doses of Ghrelin on Gonadotropin Secretion in Women

Inhibitory Effect of Submaximal Doses of Ghrelin on Gonadotropin Secretion in Women

Inhibitory Effect of Submaximal Doses of Ghrelin on Gonadotropin Secretion in Women

The effect of ghrelin on gonadotropin secretion has been equivocal. Recent data have shown an inhibitory effect of repeated injections of ghrelin on nocturnal LH and FSH secretion in women. The aim of this study was to investigate the effect of submaximal doses of ghrelin on the diurnal secretion of gonadotropins. Ten normally cycling women received 2 consecutive dosages of ghrelin (0.15 μg/kg and 0.30 μg/kg) intravenously in the early and late follicular phases of the cycle. Saline was injected in the preceding cycle. Blood samples in relation to ghrelin or saline administration (time 0 and 90 min) were taken at -15, 0, 30, 90, 120, 150, and 180 min. Serum estradiol concentrations were significantly higher in the late than in the early follicular phase. Following ghrelin administration, serum LH and FSH levels decreased significantly, in relation to the saline injection, in the late (p<0.01), although FSH values showed a within the group decrease also in the early follicular phase (p<0.05). The study suggests a differential action of ghrelin on diurnal gonadotropin secretion throughout the follicular phase of the cycle.

Evaluation of ovarian function in 35–40-year-old women with polycystic ovary syndrome

ObjectiveTo assess gonadotrophin secretion, ovarian steroid production and ovarian reserve in PCOS women during the onset of reproductive decline, in order to characterize their ovarian function at this age. Study designForty PCOS patients and 35 healthy women (35–40 years of age) were included. Clinical history, anthropometry, transvaginal ultrasound and a leuprolide acetate test (10μg/kg s.c.) were performed. Gonadotrophins, steroid hormones, SHBG, inhibin B and AMH were determined. ResultsBasal and peak LH levels were similar in both groups. Basal and peak FSH levels were significantly higher in the control group. Androgens, peak oestradiol, ovarian volume, antral follicle count and AMH levels were significantly higher in PCOS patients. ConclusionThese observations suggest that during late reproductive age, gonadotrophin secretion in women with PCOS is clearly different from that observed in control women and may also differ from that of younger PCOS patients. New features like normal LH and lower FSH levels associated with a higher ovarian reserve may give a different reproductive profile to these women.

Kisspeptin-10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback

Does sex-steroid feedback influence gonadotrophin responses to kisspeptin-10? Gonadotrophin response to kisspeptin-10 is enhanced in sex-steroid deficient post-menopausal women and suppressed in women taking pharmacological doses of exogenous estrogen and progestogen. Kisspeptin, a novel hypothalamic neuropeptide, stimulates gonadotrophin secretion by stimulating GnRH secretion and has been shown in animal models to play a pivotal role in mediating sex steroid feedback. As estrogen feedback occurs at both the hypothalamus and the pituitary levels, we hypothesized that the stimulatory effect of kisspeptin-10 in women would be dependent on prevailing sex steroid milieu. An experimental study of a novel neuropeptide in women-10 in the early follicular phase, 6 post-menopausal and 8 taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Gonadotrophin secretion was followed for 60 min after kisspeptin administration. The gonadotrophin response to intravenous kisspeptin-10 (0.3 µg/kg) in women in the early follicular phase was compared with that in the presence of low endogenous sex steroids/high gonadotrophin secretion (post-menopausal women) and in women taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Area under the curve (AUC) of gonadotrophin secretion sampled at 15 min intervals over 60 min before and after kisspeptin-10 was analysed. Kisspeptin-10 stimulated LH secretion in follicular (ΔAUC 2.3 ± 0.8 IU/l h, P = 0.009), post-menopausal (5.3 ± 0.9 IU/l h P 0.002) and progestogen (2.6 ± 0.8 IU/l h P 0.05) groups but not in women taking combined pill (0.9 ± 0.4 IU/l h P 0.13). FSH secretion was significantly increased only in post-menopausal women (ΔAUC 2.6 ± 0.8 IU/l h P = 0.03) with changes of <0.5 IU/l h observed in the other three groups. Both LH and FSH responses in post-menopausal women were significantly larger than the other groups (one-way ANOVA analysis of ΔAUC; LH (P = 0.012) and FSH (P = 0.001)]. This study only assessed acute responses to an intravenous bolus of kisspeptin-10 administration, and the impact of continuous exposure to kisspeptin-10 on LH pulse frequency in women remains to be studied to fully understand the translational potential. Gonadotrophin secretion in women is stimulated by kisspeptin-10. These results suggest that the pituitary gonadotrope is a functionally important locus of estrogen feedback in women and also inform potential translational applications of kisspeptin in reproductive endocrine disorders. Medical Research Council (UK). None.

Sensitive and specific markers for insulin resistance, hyperandrogenemia, and inappropriate gonadotrophin secretion in women with polycystic ovary syndrome: a case-control study from Bahrain

BackgroundIn women with polycystic ovary syndrome (PCOS), despite a high prevalence of insulin resistance, hyperandrogenemia, and disturbances in the secretion of gonadotrophin, the principal causes of biochemical abnormalities and the best endocrine markers for PCOS have not been fully identified.Subjects and methodsSerum levels of insulin, glucose, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, estrogen, sex hormone-binding capacity (SHBG), and other related indices such as homeostasis model assessment, insulin glucose ratios, LH/FSH ratios, and the free androgen index (FAI) were determined and compared in women with PCOS (n = 50) and women without PCOS (n = 50).ResultsIn multivariate logistic regression analyses, among all insulin resistance indices, only hyperinsulinemia (odds ratio [OR] = 2.6; confidence interval [CI]: 1.3–5.2; P = 0.008) was significantly and independently associated with PCOS when adjusted for body mass index (BMI), hyperandrogenemia, and LH/FSH ratios. The LH/FSH ratio (OR = 5.4; CI: 1.2–23.0, P = 0.03) was the only marker among those indices for inappropriate gonadotrophin secretion that significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. Among those indices for hyperandrogenemia, FAI (OR = 1.1; CI: 1.0–2.7; P = 0.02) and SHBG (OR = 1.2; CI: 1.2–3.4; P = 0.03) were significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. In addition, receiver operating characteristic analysis showed that the best predictive markers for PCOS were insulin (area under the curve [AUC] = 0.944; CI: 0.887–0.989), FAI (AUC = 0.932; CI: 0.895–0.993), SHBG (AUC = 0.924; CI: 0.87–0.978), and LH/FSH ratios (AUC = 0.906; CI: 0.821–0.965).ConclusionFor insulin and LH/FSH ratios, FAI, and SHBG seemed the best predictors and markers for insulin resistance, inappropriate gonadotrophin secretion, and hyperandrogenemia, respectively, with high sensitivity and specificity for identifying Bahraini women with and without PCOS.

Absence of Circadian Rhythms of Gonadotropin Secretion in Women

Diurnal rhythms of LH and FSH have been reported in normal women, but it is unclear whether these reflect underlying circadian control from the suprachiasmatic nucleus and/or external influences. The aim of this study was to determine whether endogenous circadian rhythms of LH, FSH, and the glycoprotein free α-subunit (FAS) are present in reproductive-aged women. Subjects were studied in the early follicular phase using a constant routine protocol in a Clinical Research Center at an academic medical center. Subjects were healthy, normal-cycling women aged 23-29 yr (n = 11). Temperature data were collected, and blood samples were assayed for LH, FSH, FAS, and TSH. Core body temperature and TSH were best fit by a sinusoid model, indicating that known circadian rhythms were present in this population. However, the patterns of FSH, LH, and FAS over 24 h were best fit by a linear model. Furthermore, there were no differences in LH and FAS interpulse intervals or pulse amplitudes between evening, night, and morning. Under conditions that control for sleep/wake, light/dark, activity, position, and nutritional cues, there is no circadian rhythm of LH, FSH, or FAS in women during the early follicular phase despite the presence of endogenous rhythms of TSH and core body temperature. These studies indicate that endogenous circadian control does not contribute to previously reported diurnal rhythms in reproductive-aged women and emphasizes the importance of environmental cues in controlling normal reproductive function.

Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women With Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis

Background: Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown. Aim: The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA. Methods: We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed. Results: On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from ba...

Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis

Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown. The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA. We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed. On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 +/- 3.5 IU/liter; FSH, 9.1 +/- 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 +/- 2.2 IU/liter, P < 0.05; FSH, 0.5 +/- 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed. Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.

Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis

ABSTRACT Background Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown. Aim The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA. Methods We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed. Results On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 ± 3.5 IU/liter; FSH, 9.1 ± 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 ± 2.2 IU/liter, P &amp;lt; 0.05; FSH, 0.5 ± 0.5 IU/liter, P &amp;lt; 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed. Conclusion Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.

Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis

Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis

Effect of ghrelin on gonadotrophin secretion in women during the menstrual cycle

It has been suggested that ghrelin may affect reproduction in animals by decreasing pituitary LH secretion. The role of ghrelin on LH secretion in women has not been investigated. Our aim was to assess the effect of ghrelin administration on basal and GnRH-induced LH secretion during the menstrual cycle. Normally cycling women (n = 10) received on Day 3 of three consecutive cycles a single bolus i.v. of either ghrelin (1 microg/kg, cycle 1) or GnRH (100 microg, cycle 2) or GnRH plus ghrelin (cycle 3). In cycle 1, ghrelin was also injected in late follicular and mid-luteal phase of the cycle. Saline was injected in a preceding cycle (cycle 1, control). Blood samples were taken before drugs or saline injection (time 0) as well as at -15, 15, 30, 45, 60, 75, 90 and 120 min. Plasma ghrelin levels increased rapidly, peaking at 15 or 30 min (P < 0.001), then decreased steadily, approaching pre-injection levels at 120 min. Serum FSH, LH, estradiol and progesterone levels remained unchanged. The stimulating effect of GnRH on LH and FSH secretion was unaffected by ghrelin injection. In contrast to saline, ghrelin stimulated a significant increase in growth hormone levels. Under these experimental conditions, our results demonstrate for the first time the inability of a bolus of ghrelin to affect basal and GnRH-induced LH and FSH secretion. It is suggested that ghrelin does not play a major physiological role in gonadotrophin secretion in women.

Inappropriate gonadotropin secretion in polycystic ovary syndrome

To evaluate inappropriate gonadotropin secretion in women with polycystic ovary syndrome (PCOS). Retrospective study. Academic tertiary center. A total of 373 women were classified into three groups: [1] healthy control women (n = 48); [2] women who were positive for PCOS risk factor; and [3] women with PCOS (n = 251). None. Gonadotropin levels, LH-FSH ratio, body mass index, and clinical and/or biochemical presentations of PCOS. The area under the receiver operating characteristic curve, used to predict PCOS for the LH-FSH ratio, showed similar diagnostic performance to total T and average ovarian volume. The LH-FSH ratio exhibits greater observed accuracy than total T and average ovarian volume for evaluation of women with oligomenorrhea or anovulation. An LH-FSH ratio of >1 presented the best combination of sensitivity and specificity. Body mass index was positively correlated with total T in non-PCOS and PCOS groups; however, body mass index was negatively correlated with LH in PCOS but showed no correlation in non-PCOS subjects. The LH-FSH ratio is a valuable diagnostic tool in evaluating women with PCOS and oligomenorrhea or anovulation, and an LH-FSH ratio of >1 may be used as a decision threshold. The link between body mass index and LH may provide clues for further understanding the pathological milieu of PCOS.

Differential regulation of gonadotropin secretion by testosterone in the human male: absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion.

Studies of sex steroid regulation of gonadotropin secretion in the human male have focused primarily on the respective site(s) of negative feedback of testosterone (T) and estradiol (E(2)). The use of pharmacological doses of sex steroids in these studies has precluded conclusions about the relative roles of T and E(2) in gonadotropin feedback. Thus, the aims of the present study were to 1) determine the relative contributions of T vs. E(2) to the sex steroid component of gonadotropin regulation, and 2) distinguish the feedback effects of T that that are direct (i.e. mediated by the androgen receptor) vs. indirect (mediated by aromatization to E(2)). Two experimental interventions were used: 1) inhibition of aromatization by a selective aromatase inhibitor to examine the impact of selective E(2) withdrawal; and 2) acute medical castration to examine the effect of ablating both T and E(2). Sixteen normal (NL) men (mean age, 30.5 +/- 2.2 yr) were studied. Nine NL subjects were treated with the aromatase inhibitor, anastrozole (10 mg, orally, daily, for 5 days). Twelve NL men underwent medical castration with ketoconazole (1-g loading dose followed by 400 mg, orally, four times a day for 5 days). Ketoconazole-treated subjects received concomitant treatment with dexamethasone (0.5 mg twice daily) to prevent the development of adrenal insufficiency. Single blood samples were drawn daily between 0800-1000 h. To ensure that dexamethasone was not altering the gonadotropin response to sex steroid ablation by a direct pituitary effect, five GnRH-deficient men (mean age, 37.6 +/- 3.9 yr) underwent GnRH dose-response studies at baseline and after treatment with dexamethasone (0.5 mg twice daily). Aromatase blockade caused significant lowering of E(2) (33 +/- 3 to 14 +/- 1 pg/mL; P: < 0.0005) with a corresponding increase in T levels (563 +/- 42 to 817 +/- 81 ng/dL; P: < 0.05). Treatment with ketoconazole resulted in equivalent suppression of E(2) (41 +/- 4 to 14 +/- 1 pg/mL; P: < 0.0005), but also induced castrate levels of T (491 +/- 28 to 40 +/- 3 ng/dL; P: < 0.0005). Both treatment regimens were associated with a significant increase in gonadotropin levels. For LH, the percent increase in serum levels after castration was almost 3-fold greater than that seen after selective E(2) withdrawal (275 +/- 23% with ketoconazole vs. 95.6 +/- 21% with anastrozole; P: < 0.005). Despite the divergent changes in T levels with these two maneuvers (a marked decrease after ketoconazole and a significant increase with anastrozole), the percent rise in FSH levels was similar in the two protocols (91 +/- 6% vs. 71 +/- 7%, respectively; P: = NS). Inhibin B levels were unchanged after selective E(2) withdrawal (156 +/- 23 vs. 176 +/- 19 pg/mL), but decreased slightly with ketoconazole (156 +/- 15 to 131 +/- 11 pg/mL; P: < 0.05). In contrast to the effects of glucocorticoid administration on gonadotropin secretion in women, no significant changes were observed in the GnRH-deficient men treated with dexamethasone in terms of mean LH levels (19.8 +/- 3.2 vs. 23.3 +/- 5.4 IU/L), mean LH pulse amplitude after GnRH (16.0 +/- 2.5 vs. 19.0 +/- 5.1 IU/L), or mean FSH levels (8.0 +/- 1.9 vs. 9.2 +/- 2.4 IU/L, pre vs. post). These studies provide evidence of differential regulation of gonadotropin secretion by T in the human male. T exerts both direct and indirect feedback on LH secretion, whereas its effects on FSH appear to be mediated largely by aromatization to E(2). From these data we conclude that in terms of sex steroid feedback, E(2) is the predominant regulator of FSH secretion in the human male.

Ovarian regulators of gonadotropin secretion.

Great progress in the ovarian mechanisms that control gonadotrophin secretion in women has recently been achieved. Estradiol (E2) is the main component of the ovarian negative effect on basal gonadotropin secretion during the normal menstrual cycle. However, nonsteroidal substances such as inhibins and activins that can affect follicle-stimulating hormone (FSH) secretion in vitro may also participate in the control of FSH secretion in vivo. Recent evidence has shown that the ovaries also produce another nonsteroidal substance, named gonadotropin surge-attenuating factor (GnSAF), that specifically attenuates GnRH-induced LH secretion and the endogenous LH surge in superovulated women. It is possible that during the normal menstrual cycle GnSAF controls the amplitude of the midcycle LH surge by antagonizing the stimulating effect of E2 on the pituitary.

The antigonadotropic activity of a 19-nor-progesterone derivative is exerted both at the hypothalamic and pituitary levels in women.

We have previously shown in postmenopausal women that a 19-nor-progesterone derivative, nomegestrol acetate (NOMA) had a strong antigonadotropic activity and that this effect was not mediated via the androgen receptor. The aim of the present study was to further assess the action of this progestin on gonadotropin secretion in women. To demonstrate at which level of the hypothalamo-pituitary-ovarian axis the gonadotropin inhibition was exerted, 10 normally cycling (NC) women, 3 women with a gonadotropin-independent ovarian function [McCune-Albright (MCA) syndrome], and 5 women with functional hypothalamic amenorrhea (FHA) participated in the study. NC women were treated orally with 5 mg NOMA for 21 days, after one control cycle. Plasma estradiol (E2) and progesterone, LH, and FSH levels were measured during each cycle. A frequent sampling study (every 10 min for 4 h), followed by a classic GnRH test (100 microg, i.v.), was performed on day 11. Women with MCA were studied before, during NOMA, and after long-acting GnRH agonist administration. In women with FHA, pulsatile GnRH (20 microg s.c., every 90 min) was given for two cycles with or without NOMA (5 mg for 21 days). In all NC women, ovulation was suppressed by NOMA. Mean plasma LH levels, LH pulse frequency, and the LH response to exogenous GnRH were significantly decreased. In MCA, neither NOMA nor GnRH agonist modified multiple ovarian cysts on ultrasound or plasma E2, levels which remained elevated, ruling out a direct ovarian effect. In FHA, pulsatile GnRH administration recreated a normal ovulatory menstrual cycle. Addition of NOMA prevented the increase of plasma E2, decreased the amplitude of LH pulses, and prevented ovulation. In view of this unexpected action of NOMA at the pituitary level, seven samples of normal human female pituitaries were tested for the presence of progesterone receptor (PR) using a double labeling immunocytochemical technique. The presence of PR was detected in the seven human pituitary tissues. In addition, PR was found to be expressed only in gonadotroph cells. In conclusion, NOMA, a 19-nor-P derivative, has a potent antigonadotropic activity exerted at the hypothalamic level, inhibiting ovulation in NC women. In women with FHA, NOMA decreased the gonadotropin stimulation induced by pulsatile GnRH administration. According to the presence of PR in gonadotroph cells of normal human pituitaries, 19-nor-progesterone derivatives may also act on the gonadotropin secretion at the pituitary level.

Pulsatile gonadotrophin secretion in women with polycystic ovary syndrome after gonadotrophin-releasing hormone agonist treatment.

In polycystic ovary syndrome (PCOS), increased luteinizing hormone (LH) pulse frequency has been attributed to either the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator or ovarian oestrogen feedback. To address this issue, a detailed examination of pulsatile LH secretion was undertaken during recovery from GnRH agonist (GnRHa) suppression. Each of six women with PCOS and six normal ovulatory women received daily GnRHa treatment for 14 weeks. Frequent blood samples were collected and assayed for gonadotrophins, androgens and oestrogens before, during and up to 4 weeks after treatment. Women with PCOS had higher basal LH pulse frequency and amplitude and increased serum concentrations of LH, androstenedione, testosterone and oestrone than controls. After 3 months of GnRHa treatment, all these parameters were suppressed with no differences observed between the two groups. One week after cessation of GnRHa, LH pulse frequency promptly returned to pre-treatment range with no between-group differences noted, whereas LH pulse amplitude, serum gonadotrophins and ovarian steroids remained maximally suppressed and equivalent in the two groups. Subsequent LH pulse frequency remained constant while LH pulse amplitude and circulating concentrations gradually increased in parallel with a return of serum oestrogen to pre-treatment values. Despite comparable resumption of LH secretion in the two groups, corresponding androgen concentrations in women with PCOS were greater than those of normal ovulatory women. Thus, the immediate restoration of LH pulse frequency after discontinuing GnRHa treatment is largely independent of ovarian oestrogen production and reflects primacy of the GnRH pulse generator in determining basal LH pulse frequency. Equivalent LH pulse frequency rates in the two groups during the recovery period do not suggest an intrinsic hypothalamic-pituitary hyperactivity in PCOS.