Do androgens directly regulate gonadotropin secretion in the polycystic ovary syndrome?

This study was designed to investigate whether androgens directly, independent of their aromatization to estrogens, disrupt gonadotropin secretion in hyperandrogenic women with the polycystic ovary syndrome (PCO). Pulsatile gonadotropin release and gonadotroph sensitivity to GnRH were determined on consecutive study days basally and during a primed continuous infusion of testosterone (T; n = 4; 100 micrograms/h; twice the mean production rate of T in PCO) or dihydrotestosterone (DHT; n = 5; 50 micrograms/h). To determine if the gonadotropin secretory changes during T infusion were secondary to spontaneous variation, four patients had two consecutive basal studies, and all patients received DHT on the third study day. T infusion that increased mean plasma T levels from 76 +/- 12 (+/- SE) to 315 +/- 28 ng/dl produced no significant changes in the amount or pattern of LH release or in LH sensitivity to GnRH. Mean plasma FSH levels decreased slightly but significantly during T infusion (basal, 242 +/- 29 vs. T 226 +/- 30 ng/ml LER-907; P less than 0.05 by two-tailed paired t test), but the pulsatile pattern of FSH release and FSH sensitivity to GnRH did not change. DHT infusion increased plasma DHT levels from 17 +/- 3 to 244 +/- 31 ng/dl, but did not alter the mean levels, pulsatile patterns, or sensitivity to GnRH of LH or FSH. These data suggest that androgens do not directly alter gonadotropin release in PCO. Thus, regulation of the hypothalamic-pituitary axis in women with PCO is different from that in men despite chronic exposure to hyperandrogenemia.     

MODIFICATION BY SEX STEROIDS OF LHRH RESPONSE IN THE POLYCYSTIC OVARY SYNDROME

Exogenously administered oestradiol or progesterone was found to induce augmentation of LH and FSH release in response to LHRH administration in patients with the polycystic ovary (PCO) syndrome. The effect of oestradiol upon LH release in the patients was significantly less than the augmented release induced in normal women (P < 0.02). In contrast, progesterone induced a significantly greater LH release in PCO patients than normal women studied during the early follicular phase (P < 0.001) but less than that in normal women studied during the mid-follicular phase of the cycle (P < 0.01). The effects on FSH release in the PCO patients were less marked but similar to those in normal women with comparable basal steroid levels. The results suggest that both oestradiol and progesterone can modify the hypothalamic-pituitary axis in the PCO syndrome in a manner similar to that observed in normal women and a failure of these ‘positive feedback’ mechanisms does not appear to be the cause of the ovulatory deficiency in this syndrome.     

Impaired LH release following exogenous estrogen administration in patients with amenorrhea-galactorrhea syndrome.

Serum gonadotropin levels were determined in 10 patients with the amenorrhea-galactorrhea syndrome before and following acute iv administration of synthetic LH-releasing hormone (LHRH) or conjugated estrogens, in order to clarify the hypothalamic derangements in the gonadotropin secretion in patients with hyperprolactinemia. The basal prolactin (PRL) levels were elevated in all the patients, and blunted responses to 500 mug of iv synthetic thyrotropin-releasing hormone (TRH) injection were found in 9 out of the 10 patients. The basal levels of LH and FSH were subnormal in 2 and 3 patients, respectively, while those in the remaining patients were normal or slightly elevated. Normal or excessive responses of gonadotropins to 100 mug of iv LHRH were observed in most patients, 9 for LH and 10 for FSH out of 10 patients. In 10 normal cyclic women at the mid-follicular phase (D7-9) and 10 hypothalamic amenorrhea patients without galactorrhea, LH release was found 48 to 72 h after the iv injection of 20 mg conjugated estrogens (Premarin). This LH release following Premarin injection was completely abolished in the patients with amenorrhea-galactorrhea. These data seem to indicate that in patients with hyperprolactinemia, tonic secretion of gonadotropin is maintained fairly well, while of the positive feedback effect of Premarin on the release of LH is impaired. It is suggested that impaired LH release may be partly responsible for anovulation and amenorrhea in patients with hyperprolactinemia.     

Altered neuroendocrine regulation of gonadotropin secretion in women distance runners

We tested the hypothesis that the neuroendocrine control of gonadotropin secretion is altered in certain women distance runners with secondary amenorrhea. To this end, we quantitated the frequency and amplitude of spontaneous pulsatile LH secretion during a 24-h interval in nine such women. The ability of the pituitary gland to release LH normally was assessed by administration of graded bolus doses of GnRH during the subsequent 8 h. Compared to normally menstruating women, six of nine amenorrheic distance runners had a distinct reduction in spontaneous LH pulse frequency, with one, three, six, five, four, or two pulses per 24 h (normal, 8-15 pulses/24 h). This reduction in LH pulse frequency occurred without any significant alterations in plasma concentrations of estradiol and free testosterone or 24-h integrated serum concentrations of LH, FSH, or PRL. Moreover, in long-distance runners, the capacity of the pituitary gland to release LH was normal or accentuated in response to exogenous pulses of GnRH. In the six women athletes with diminished spontaneous LH pulsatility, acute ovarian responsiveness also was normal, since serum estradiol concentrations increased normally in response to the GnRH-induced LH pulses. Although long-distance runners had significantly lower estimated percent body fat compared to control women, specific changes in pulsatile gonadotropin release did not correlate with degree of body leanness. In summary, certain long-distance runners with secondary amenorrhea or severe oligomenorrhea have unambiguously decreased spontaneous LH pulse frequency with intact pituitary responsiveness to GnRH. This neuroendocrine disturbance may be relevant to exercise-associated amenorrhea, since pulsatile LH release is a prerequisite for cyclic ovarian function. We speculate that such alterations in pulsatile LH release in exercising women reflect an adaptive response of the hypothalamic pulse generator controlling the intermittent GnRH signal to the pituitary gland. The basis for amenorrhea in the remaining runners who have normal pulsatile properties of LH release is not known.     

Classification of secondary amenorrhea based on distinct hormonal patterns.

Patients with secondary amenorrhea have been classified into 4 clincal groups. In order to further investigate these 4 groups, LH, FSH, and estradiol (E2) were measured at 15 min intervals for 4 h in 21 patients with secondary amenorrhea. Patients within each group had similar hormonal patterns, but there was a distinct variation among the groups. Three patients in group 1 (polycystic ovaries [PCO]) had elevated basal levels of only LH with marked irregular fluctuations. Seven patients in group II (hypothalamic-pituitary dysfunction) had normal basal levels of LH, FSH, and E2. Only LH showed oscillations of varying mahnitude and frequency. Eight patients in group III (hypothalamic-pituitary failure) had low or low-normal levels of LH, FSH, and low E2 with minimal or absent fluctuations. Three patients in group IV (ovarian failure) had high basal levels of FSH and LH and irregular fluctuations. This study confirmed the rationality of separating patients with secondary amenorrhea into 4 different groups. In addition, it was found that in group III patients, the total amount of LH secreted in a 4-hour period of time appears to be insufficient to stimulate E2 production from the ovary even when a single sample was found to be in the normal range.     

Calcium antagonists and hormone release. II. Effects of verapamil on basal, gonadotropin-releasing hormone- and thyrotropin-releasing hormone-induced pituitary hormone release in normal subjects

Although it has been well established that Ca2+ plays an essential role in the release of several hormones, very little is known of the interactions between Ca2+ and secretagogues in the process of pituitary hormone release. One possible way of studying the mechanism of action of hypothalamic releasing hormones is to study how organic calcium antagonists affect their action. Consequently, we infused the commonly used calcium antagonist, verapamil, into 20 normal subjects (10 men and 10 women; aged 19-37 yr) and studied its effects on both basal pituitary hormone levels and augmented hormonal release induced by gonadotropin-releasing hormone (GnRH) and TRH. Verapamil, infused at a rate of 5 mg/h for 3 h, induced a significant and marked suppression of circulating LH and FSH levels in both men and women. By the end of the infusion, the suppression of release was greater for LH (60%) than for FSH (54%). After the termination of the infusion, plasma gonadotropin concentrations returned progressively to basal levels within 2 h. Verapamil was also capable of blunting the peak incremental gonadotropin response to GnRH. Although the basal TSH concentration was apparently unaffected by verapamil, the incremental TSH response to TRH was significantly inhibited in both men and women. Verapamil infusion did not affect either the basal PRL concentration or the PRL response to TRH. Our data provide evidence that verapamil exerts different effects on the release of pituitary hormones in normal subjects. It inhibits the centrally mediated as well as the peripherally mediated gonadotropin release and blunts the TSH response to TRH. On the contrary, verapamil does not seem to affect basal or TRH-mediated PRl release. The use of organic calcium antagonists in experimental models in vitro as well as in vivo appears to offer a promising tool for further studies on the mechanism of action of secretagogues in the process of hormone release.     

The effect and possible mode of action of alpha-melanocyte-stimulating hormone on gonadotropin release in the ovariectomized rat: an in vivo and in vitro analysis

This study was designed to examine the possible effects of alpha MSH on gonadotropin release. Injection of alpha MSH into the third ventricle of the brain and sampling at 5, 10, 15, 30, and 60 min postinjection produced a significant lowering of plasma LH, but not of FSH, in conscious ovariectomized (OVX) rats. The minimum effective dose was 1 microgram. This procedure did not affect plasma levels of LH or FSH in estradiol benzoate-primed, OVX rats. Multiple blood sampling every 10 min before and after intraventricular injection of alpha MSH (2 micrograms) produced a significant reduction in the area under the secretion curve of LH. Intravenous injection of alpha MSH had little effect; however, a slight lowering of plasma LH occurred in OVX rats after a 50-micrograms dose. The effect of alpha MSH on LH release was blocked by pretreatment of the animals with alpha-methyl-paratyrosine, an inhibitor of catecholamine synthesis, as well as by pretreatment with an iv injection of spiroperidol, a dopamine receptor blocker. The peptide failed to alter basal or K+-stimulated LHRH release from median eminence fragments of OVX rats incubated in vitro. Alpha MSH had no effect on LHRH-induced LH release in vivo and failed to alter the release of FSH and LH from hemipituitaries of OVX rats or dispersed cells from OVX, estradiol benzoate-primed rats in vitro. It is concluded that alpha MSH exerts an inhibitory effect on LH release by an action on the hypothalamus, probably via activation of the tuberoinfundibular dopaminergic system.     

Hypothalamic dysfunction

A pulsatile GnRH stimulus is required to maintain gonadotropin synthesis and secretion. The frequency and amplitude of GnRH pulses determine gonadotropin subunit gene expression and secretion of pituitary LH and FSH. Rapid frequency (more than 1 pulse per h) GnRH pulses favor LH while slower frequencies favor FSH secretion. During ovulatory cycles, an increase in GnRH frequency during the follicular phase favors LH synthesis prior to the LH surge, while following ovulation, luteal steroids slow GnRH pulses to favor FSH synthesis. Thus, a changing frequency of GnRH stimulation of the gonadotrope is one of the mechanisms involved in differential gonadotropin secretion during ovulatory cycles. In hypothalamic amenorrhea a majority of women exhibit a persistent slow frequency of LH (GnRH) pulses, which reflects excess hypothalamic opioid tone and can be temporarily reversed by opioid antagonists. At the other end of the spectrum, in polycystic ovarian syndrome, LH (GnRH) pulses are persistently rapid and favor LH synthesis, hyperandrogenism and impaired follicular maturation. Administration of progesterone can slow GnRH pulse secretion, favor FSH secretion and induce follicular maturation. Thus, the ability to change the pattern of GnRH secretion is an important factor in the maintenance of cyclic ovulation, and loss of this function leads to anovulation and amenorrhea.     

Effect of aging on serum gonadotropin levels in healthy subjects and patients with nonfunctioning pituitary adenomas

OBJECTIVE: Nonfunctioning pituitary adenomas (NFPA), which represent about one-quarter of human pituitary tumors, occur in middle or old age. Determination of gonadotropin levels, which are not expected to be high during the early postmenopause in normal women and which are low in women with NFPA, is important to distinguishing hypogonadal status due to the normal decline of gonadal function from that due to hypothlalamic-pituitary dysfunction. The aim of the study was to verify whether this difference still persists in old subjects, despite the physiological decline of gonadotropins in the last decades of life. DESIGN AND METHODS: The study included 154 healthy subjects (aged 50-104 years) and 47 patients with NFPA (aged 50-80 years). Blood samples were collected after an overnight fast and hormone levels were measured by two immunofluorimetric assays. RESULTS: In healthy women the highest serum levels of gonadotropins were present in the 50-60 year age group, with a slight but progressive age-associated decrease in serum FSH and LH being observed thereafter. In healthy men serum gonadotropin levels were stable up to 70 years, increased up to 75-85 years and thereafter gradually decreasing. Female patients with NFPA showed levels of gonadotropins which were far lower than controls. Only three patients had levels of both FSH and LH above the 2.5 centile for normal subjects. A high sensitivity and specificity of gonadotropin measurements (about 90%) for the diagnosis of NFPA was observed in female patients aged 50-80 years. In male subjects, a large overlap of gonadotropin values in NFPA and controls, namely over the 50-70 years age range, was observed. CONCLUSIONS: Our study demonstrates that despite the gradual decline of gonadotropin levels in healthy postmenopsausal women, the reduction of both FSH and LH persists in old patients with NFPA, suggesting that measurement of gonadotropin levels could prove useful in the evaluation of pituitary lesions even in old women. More subtle differences seem to occur in male subjects.     

FAILURE OF POSITIVE FEEDBACK IN NORMAL MEN AND SUBJECTS WITH TESTICULAR FEMINIZATION

The abdity of the hypothalamic-pituitary unit to release luteinizing hormone (LH) in response to oestrogen Cpositive feedback) was studied in normal men and women and in subjects with testicular feminization or XY gonadal dysgenesis. Ethinyloestra-diol (200 μg a day for 3 days) given orally to six regularly menstruating women during the early to mid follicular phase of the cycle evoked an LH surge which started between 48 and 72 h after the initiation of treatment. A similar positive feedback effect on the secretion of follicle-stimulating hormone (FSH) could not be demonstrated. In eight normal men there was no evidence for a stimulatory effect of ethinyl-oestradiol (in doses of 200 μg or 500 μg a day for 3 days) on gonadotrophin release even though the levels of plasma ethyloestradiol in men on the higher dosage regime were greater than those found in women. Changes of peripheral LH, but not FSH, in men were inversely related to plasma ethinyloestradiol concentrations. A patient with XY pure gonadal dysgenesis exhibited a female type of LH release in response to ethinyloestradiol administration (200 μg a day for 3 days), but two patients with the syndrome of testicular feminization failed to release LH. The results suggest that normal adults of the two sexes differ in their ability to respond to ethinyloestradiol administration with LH release. The female response in XY gonadal dysgenesis emphasizes the importance of testicular secretions for the suppression of positive feedback whereas the male type of response in cases of testicular feminization indicates that testosterone does not represent the central mediator of this testicular function. The reported observations are compatible with the concept that the organizing action of the testes on positive feedback is mediated through 17β-oestradiol.     

Pulsatile secretory characteristics of allopregnanolone, a neuroactive steroid, during the menstrual cycle and in amenorrheic subjects

OBJECTIVE: To investigate whether allopregnanolone, a neuroactive steroid involved in modulating behavioural and neuroendocrine functions, shows episodic secretion in eumenorrheic women, during the follicular and luteal phases of the menstrual cycle, and in women with stress-induced amenorrhea. PATIENTS: Six eumenorrheic women and 14 women with hypothalamic amenorrhea were enrolled for the present study. METHODS: All subjects underwent hormonal evaluation in baseline conditions and a pulsatility study to determine LH, cortisol and allopregnanolone episodic release. Eumenorrheic subjects were investigated twice, in the follicular phase (days 3-7) and in the luteal phase (days 18-22) of the menstrual cycle. LH, FSH, prolactin, estradiol, phosphate, DHEA, allopregnanolone and cortisol levels were evaluated in each case. RESULTS: In healthy women, serum gonadotropin and gonadal steroid levels were significantly lower (P<0.01 and P<0.05 respectively) than those in amenorrheic subjects. Allopregnanolone was higher in amenorrheic subjects and during the luteal phase, compared with the follicular phase, of eumenorrheic subjects (P<0.01). Pulse analysis revealed a significant episodic discharge of allopregnanolone in all subjects (follicular phase 6.5+/-0.3 peaks/6 h and luteal phase 5.5+/-0.4 peaks/6 h, hypothalamic amenorrhea 7.0+/-0.7 peaks/6 h) with higher pulse amplitude in amenorrheic subjects and during the luteal phase compared with the follicular phase of the eumenorrheic subjects (P<0.05). Moreover, the specific concordance index demonstrated that allopregnanolone is coupled with LH only during the luteal phase of the cycle and with cortisol during both phases. Allopregnanolone-cortisol coupling was also observed in amenorrheic subjects. CONCLUSIONS: Allopregnanolone is secreted episodically. Both the ovary and adrenal glands release this steroid hormone and it shows temporal coupling with LH only during the luteal phase, with cortisol during both the studied phases of the menstrual cycle in eumenorrheic women and again with cortisol in hypothalamic amenorrheic patients.     

Evidence for increased dopaminergic and opioid activity in patients with hypothalamic hypogonadotropic amenorrhea

The functional activity of endogenous opioids and dopamine (DA) was assessed by analyzing gonadotropin and prolactin responses to DA receptor antagonist (metoclopramide) and the opioid receptor antagonist (naloxone) in selected patients with hypothalamic hypogonadotropic amenorrhea and in normal cycling women. 8 amenorrheic and 9 normal women during the low estrogen (early follicular) phase of menstrual cycle were studied. Simultaneous blood sampling and agent infusion was performed via 2 indwelling catheters after an overnight fast. Those receiving metoclopramide (10 mg intravenous bolus) and those receiving naloxone (1.6 mg/h for 4 hours) had blood samples withdrawn at various intervals. The 8 amenorrheic patients weighed significantly less (P .01) and had significantly lower mean basal serum luteinizing hormone (LH) (P .0001) and prolactin (P .01) than normal women. Metoclopramide administered to normal women induced no significant changes in pituitary gonadotropin levels. In contrast, 4 of 8 hypogonadotropic amenorrhea patients responded to metoclopramide with a significant mean net change of LH (P .05); a concomitant rise in follicle stimulating hormone (FSH) was also seen but was not statistically significant. The other 4 showed no response, as in normal women. Prolactin response to metoclopramide was reduced uniformly in all 8 patients, independent of LH responders or nonresponders. Naloxone in normal women showed no response. However, a clear increment of mean LH in response to naloxone was observed in the same 4 hypogonadotropic amenorrhea patients who also responded to metoclopramide. Mean LH nearly doubled; FSH levels showed no significant changes. Those other 4 patients who had no response to metoclopramide also had no response to naloxone. The 4 LH nonresponders with significantly (P .01) lower mean basal prolactin levels compared with normal women showed greater than l00% increase in prolactin levels by Hour 3 of naloxone infusion; in contrast, the LH responders showed no changes in prolactin levels in response to naloxone infusion.     

Luteinizing hormone pulsatility in patients with major ovarian hyperandrogenism

Hyperandrogenism and ovulatory dysfunction are common in women with either polycystic ovary (PCOS) or ovarian virilizing tumor. However, contrasting with the numerous studies that have extensively described gonadotropin secretory abnormalities, principally increased LH pulse amplitude and frequency, few studies have concerned gonadotropin secretion in patients with ovarian virilizing tumors; low gonadotropin levels have occasionally been reported, but never extensively studied. The goal of the present study was to further evaluate the pulsatility of LH secretion in women with ovarian virilizing tumor compared with that of PCOS patients. Eighteen women with major hyperandrogenism (plasma testosterone level >1.2 ng/ml) were studied (5 women with ovarian virilizing tumor, 13 women with PCOS, and 10 control women). Mean plasma LH level, LH pulse number and amplitude were dramatically low in patients with ovarian tumors when compared to both PCOS (p<0.001) and controls (p<0.001). In case of major hyperandrogenism, LH pulse pattern differs markedly between women with ovarian virilizing tumor or PCOS, suggesting different mechanisms of hypothalamic or pituitary feedback.     

Increased gonadotropin responsiveness to gonadotropin-releasing hormone during fasting in normal subjects

To investigate whether food deprivation affects hormone release from pituitary gonadotrophs, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses to intravenous (IV) administration of 50 micrograms gonadotropin-releasing hormone (GnRH) were determined in 12 healthy subjects (six women and six men) after an overnight fast and after a fasting period of 56 hours. In the female participants, these GnRH tests were performed early in the follicular phase of the menstrual cycle. Blood glucose declined during the fast from 4.4 +/- 0.1 (mean +/- SEM) to 3.3 +/- 0.1 mmol/L (P less than .001). LH and FSH responsiveness to GnRH--as reflected by hormone incremental areas--increased from 1973 +/- 256 to 3267 +/- 450 (IU/L X min) for LH (P less than .001), and from 376 +/- 44 to 705 +/- 112 (IU/L X min) for FSH (P less than .01). When control studies were carried out in nonfasted subjects in exactly the same way as in the fasted participants, the gonadotropin responsiveness to GnRH did not change significantly between the tests. To explore possible mechanisms behind the increased gonadotropin responsiveness in fasted subjects, six of the above mentioned healthy women were given nine small oral doses of glucose (each dose 0.5 g/kg) during an additional 56-hour fast to prevent blood glucose from falling significantly during the period of food deprivation. This did not change the hormone response pattern at all, since both the LH and the FSH responses to GnRH increased significantly during the glucose-supplemented fasting period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of alpha 1-adrenergic blockade on pulsatile luteinizing hormone, follicle-stimulating hormone, and prolactin secretion in polycystic ovary syndrome

Central noradrenergic mechanisms may participate in the regulation of pulsatile gonadotropin secretion in women with the polycystic ovary syndrome (PCO). To examine this possibility we measured serum LH, FSH, and PRL concentrations at 10-min intervals and total testosterone and 17 beta-estradiol at 60-min intervals for 8 h basally and during the infusion of the alpha 1-adrenoceptor antagonist thymoxamine (10 micrograms/kg X min) in 10 young women with PCO. Mean and integrated serum LH concentrations as well as LH pulse frequency were not significantly altered (P = NS) during the thymoxamine infusion. However, we found an increase in LH pulse amplitude as both net (P less than 0.002) and percent (P less than 0.002) increment, as well as mean LH peak values (P less than 0.05) during alpha 1-adrenergic blockade. There were no significant changes in pulsatile FSH and PRL secretion or gonadal sex steroids during these experimental conditions. These data suggest that in PCO patients, 1) brain noradrenergic mechanisms do not play a stimulatory role in regulating the frequency of pulsatile LH secretion, 2) central noradrenergic activity inhibits LH pulse amplitude, and 3) PRL and FSH pulsatility are not altered by central noradrenergic blockade.     

Luteinizing hormone secretion is not influenced by insulin infusion in women with polycystic ovary syndrome despite improved insulin sensitivity during pioglitazone treatment

It has been reported in women with polycystic ovary syndrome (PCOS) that LH secretion is not altered by insulin infusion. To determine whether insulin resistance may have precluded an effect of insulin, pulsatile LH secretion and gonadotropin responses to GnRH were examined in PCOS women (n = 9) before and after pioglitazone treatment (45 mg/d) for 20 wk in the presence and absence of a hyperinsulinemic euglycemic clamp (80 mU/m2.min). Frequent blood samples were obtained for 12 h (every 10 min) as well as during sequential administration of GnRH at doses of 2, 10, and 20 microg over 12 h. A significant (P < 0.05) improvement in insulin sensitivity was seen in the subjects after treatment. Mean LH levels, LH pulse frequency and amplitude, as well as gonadotropin responses to GnRH were not influenced by pioglitazone, either with or without insulin infusion. We conclude that in PCOS women, inappropriate gonadotropin release does not appear to be a consequence of hyperinsulinemia.     

The effects of continuous androgen secretion on the hypothalamic-pituitary axis in woman: evidence from a luteinized thecoma of the ovary

Hyperandrogenic states in women are often accompanied by disruption of gonadotropin secretion. However, the role of androgens per se in the pathogenesis of this abnormality is poorly understood. We report a woman with a virilizing ovarian tumor in whom the effects of continuous androgen secretion on the hypothalamic-pituitary axis were investigated in detail. A 29-yr-old woman with previously normal reproductive function, including prior fertility, was evaluated for amenorrhea and hirsutism. She had elevated peripheral serum levels of testosterone (T; 337-500 ng/dl) and androstenedione (A; 258-353 ng/dl). Her serum LH level was above the normal follicular phase range and was hyperresponsive to LHRH, whereas the FSH level was below normal early follicular phase levels and increased minimally in response to LHRH. A luteinized thecoma of the left ovary, shown by catherization of the ovarian venous blood to be secreting both T and A, was removed. Postoperatively, serum T and A levels returned to normal, and the patient had a normal ovulatory menstrual cycle in the 30 days after the operation, documented by daily determinations of plasma estradiol, progesterone, and gonadotropin levels. A repeat LHRH test in the follicular phase of the second postoperative menstrual cycle was completely normal. This case indicates that the characteristic abnormalities of gonadotropin secretion observed in hyperandrogenic states such as polycystic ovarian disease can result from chronic androgen secretion by an ovarian tumor and that normal folliculogenesis and gonadotropin secretion can be promptly restored by the elimination of the androgen excess.     

THE EFFECT OF GLUCOCORTICOIDS ON CORTICOSTEROID BINDING GLOBULIN

Twenty-three patients with polycystic ovary syndrome and anovulatory infertility have been treated with bromocriptine. All had previously failed to respond to clomiphene. Twenty had normal serum prolactin concentrations and, of these, four (20%) developed regular ovulatory cycles. All three women with moderate hyperprolactinaemia ovulated regularly on bromocriptine so that, overall, seven of 23(30%) responded, which was a significantly higher proportion than that observed during a control period of no treatment. A further eight women ovulated at least once during the study period but these occasional ovulations were no more common during bromocriptine than with either clomiphene or no treatment. No suppression of LH was noted except during the luteal phase of ovulatory cycles and there was no change in the pattern of pulsatile release of LH. Testosterone and androstenedione concentrations remained elevated and unchanged. We conclude that bromocriptine may be expected to induce ovulation in hyperprolactinaemic women with polycystic ovary syndrome but that there is no clear indication for its use in clomiphene-resistant patients with normal serum prolactin concentrations.     

Further delineation of hypothalamic dysfunction responsible for menopausal hot flashes

An association exists between pulsatile LH release and hot flashes (HFs). To further delineate the hypothalamic mechanism(s) responsible for HF, the basal levels and pulsatile release of LH, FSH, estradiol, and estrone and the rate of occurrence of HFs (measured objectively) were evaluated in patients with a defect of GnRH secretion [isolated gonadotropin deficiency (IGD)], patients with abnormalities of afferent input to GnRH neurons [hypothalamic amenorrhea (HA)], and postmenopausal women with severe HFs. Patients with IGD had received estrogens, which were discontinued before study. Patients with HA had experienced regular menses before disease onset, which followed emotional stress or weight loss. Studies were limited to HA patients with estrogen levels in the postmenopausal range. Pulsatile LH release was absent in patients with IGD and was absent or greatly reduced in women with HA. Objectively measured and subjectively experienced HFs occurred in IGD but not in HA patients. These results suggest that HFs are not an obligatory consequence of low endogenous estrogen levels and that the absence of episodic LH and GnRH release (IGD) does not influence the occurrence of HFs. It is possible that the dysfunction of afferent input to GnRH neurons in HA somehow prevents HFs in these women with low endogenous estrogen secretion.     

The effect of bromocriptine on gonadotropin and steroid secretion in polycystic ovarian disease

Use of bromocriptine in some women with polycystic ovarian disease (PCO) has resulted in ovulation induction, although a mechanism has not been established. The purpose of this study was to determine the effect of bromocriptine on gonadotropin and steroid secretion in this disorder. Two groups of seven patients were given bromocriptine at a dose of either 5 mg/day for 2 months or 10 mg/day for 1 month. Ten normal ovulatory women served as controls. In PCO patients, mean serum levels of LH, bioactive LH, androstenedione, testosterone, unbound testosterone, dehydroepiandrosterone sulfate (DHEA-S), and estrone were significantly greater (P less than 0.05) than those of normal women, whereas FSH, PRL, dihydrotestosterone, 3 alpha-androstanediol, and estradiol were not different. Assessment of gonadotropin secretion before and during treatment revealed that basal levels, episodic secretion, and responses to GnRH (25 micrograms, iv) were unaltered by either dose of bromocriptine. Of the remaining hormones, PRL and DHEA-S significantly decreased in response to both doses. There were no changes in the clinical status of patients during treatment. These findings indicate that in PCO patients with normal PRL levels, gonadotropin secretion is unaltered by bromocriptine therapy. The concomitant declines of PRL and DHEA-S confirm previous data reported for this syndrome and suggest a role for PRL in the production of adrenal androgens.