Bromocriptine response in normoprolactinemic patients with polycystic ovary disease: a preliminary report.
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Recent work has suggested that a central deficiency or defect of dopamine may contribute significantly to the inappropriate gonadotropin secretion commonly associated with polycystic ovary disease. To evaluate this hypothesis, 2.5 to 5 mg of the dopamine agonist bromocriptine was administered daily to patients with polycystic ovary disease. Prolactin (PRL) levels were normal in all cases and there was no evidence of galactorrhea. All patients had failed to conceive while on clomiphene citrate. Seven patients were treated for a total of nine cycles. Ovulation occurred in four cycles, and two of these patients conceived. In five cycles, no ovulation occurred. Among ovulatory cycles, PRL levels declined, but not to undetectable levels. There was also a periovulatory drop in dehydroepiandrosterone sulfate. Levels of luteinizing hormones rose initially and then dropped to below baseline postovulation. Among anovulatory cycles, PRL fell to undetectable levels and dehydroepiandrosterone sulfate was unaffected. Luteinizing hormone levels rose initially and then dropped slightly. In both ovulatory and anovulatory cycles, follicle-stimulating hormone (FSH) levels remained low. These preliminary data suggest: 1) bromocriptine appears capable of altering gonadotropin secretion in polycystic ovary disease, and 2) variable results on ovulation in polycystic ovary disease may reflect the diverse etiology of the pathophysiology of polycystic ovary disease and/or choosing inappropriate dosages of bromocriptine.Keywords:
Polycystic ovarian disease
Anovulation
Galactorrhea
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Plasma prolactin (PRL) was measured in 34 patients with polycystic ovary syndrome (PCO) before and after the intravenous administration of 200 micrograms of thyrotropin-releasing hormone (TRH). The results were compared with those from 30 normal female volunteers. The distinctive features of PCO were elevated plasma concentrations of luteinizing hormone (LH), testosterone and androstenedione and increased 24-hour urinary estrogen excretion. Abnormal secretion of PRL was observed in ten patients with PCO. Hyperprolactinemia was detected in five patients, and the prolactin response to TRH was exaggerated or prolonged in five normoprolactinemic patients with PCO. A statistically significant correlation was found between mean prolactin concentrations and the mean plasma dehydroepiandrosterone sulphate (DHEAS) concentration (r = 0.67, p less than 0.01). These data suggest that a significant portion of women with PCO syndrome have abnormalities of PRL secretion.
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Administration of 4 mg of the antiprogestagen RU486 to 4-day-cyclic rats over 8 consecutive days starting on the day of estrus (Day 1) induced and anovulatory cystic ovarian condition with endocrine and morphological features similar to those exhibited in polycystic ovarian disease (PCO). To determine whether the RU486-treated rat responds in an analogous fashion to therapies similar to those that have been used to treat human PCO, RU486-treated rats were injection on Days 5 and 7 with 1) 1 mg of an LHRH antagonist (LHRHa), 2) 5 IU of human FSH (hFSH), 3) 2 mg of the antiandrogen flutamide (FLU), 4) 1 mg of the antiestrogen tamoxifen (TMX), or 5) 1 mg of the dopamine agonist bromocriptine (BRC). Controls were intact cyclic rats decapitated on estrus and rats injected with RU486 and the corresponding vehicles (saline or 70% ethanol) used with LHRHa, hFSH, FLU, TMX, and BRC injections. RU486-treated rats were decapitated on Day 9, and the serum concentrations of LH, FSH, prolactin (PRL), testosterone (T), and estradiol-17 β (E2) were determined. Pituitary and ovary weight, number of follicular cysts, size of the corpora lutea, and rates of follicular growth and atresia were also noted. Finally, the ovulatory response to ovine LH (oLH) in rats treated with RU486 and injected with various doses of hFSH (5, 10, or 20 IU) was evaluated. While administration of LHRHa and of TMX decreased the serum concentrations of LH, T and E2 and the LH/FSH and T/E2, ratios, and injections of BRC and of FLU increased the serum concentration of LH and T, the administration of hFSH (10 IU) to RU486-treated rats increased only the serum levels of E2. All treatments decreased, though in different degrees, both the number of cysts and the rate of follicular atresia, and stimulated follicular growth. The positive effects on follicular growth and atresia were significantly higher in those rats injected with hFSH. Moreover, RU486-treated rats injected with different doses of hFSH ovulated in a dose-dependent manner in response to oLH. Rates deprived of the actions of progesterone through the administration of the antiprogestagen RU486 had 1) endocrine and morphologic alterations comparable to those observed in women with PCO, 2) analogous responses to therapies similar to those that have been used to treat human PCO, and 3) an ovulatory response to combined treatment with FSH and LH. These results establish the fundamental adequacy of using the RU486-treated rat as a PCO model.
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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 patints, mean serum levels of LH, bioactive LH, androstenedione, testosterone, unbound testosterone, dehydroepiandrosterone sulfate (DHEA-S), and estrone were significantly greater (P < 0.05) than those of normal women, whereas FSH, PRL, dihydrotestosterone, 3α-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 μg, 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.
Gonadotropin
Polycystic ovarian disease
Dihydrotestosterone
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Perphenazine
Anovulation
Galactorrhea
Dopamine antagonist
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Recent work has suggested that a central deficiency or defect of dopamine may contribute significantly to the inappropriate gonadotropin secretion commonly associated with polycystic ovary disease. To evaluate this hypothesis, 2.5 to 5 mg of the dopamine agonist bromocriptine was administered daily to patients with polycystic ovary disease. Prolactin (PRL) levels were normal in all cases and there was no evidence of galactorrhea. All patients had failed to conceive while on clomiphene citrate. Seven patients were treated for a total of nine cycles. Ovulation occurred in four cycles, and two of these patients conceived. In five cycles, no ovulation occurred. Among ovulatory cycles, PRL levels declined, but not to undetectable levels. There was also a periovulatory drop in dehydroepiandrosterone sulfate. Levels of luteinizing hormones rose initially and then dropped to below baseline postovulation. Among anovulatory cycles, PRL fell to undetectable levels and dehydroepiandrosterone sulfate was unaffected. Luteinizing hormone levels rose initially and then dropped slightly. In both ovulatory and anovulatory cycles, follicle-stimulating hormone (FSH) levels remained low. These preliminary data suggest: 1) bromocriptine appears capable of altering gonadotropin secretion in polycystic ovary disease, and 2) variable results on ovulation in polycystic ovary disease may reflect the diverse etiology of the pathophysiology of polycystic ovary disease and/or choosing inappropriate dosages of bromocriptine.
Polycystic ovarian disease
Anovulation
Galactorrhea
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SUMMARY The effects were studied of bromocriptine, 10 mg daily for 1 year, on luteinizing hormone (LH) pulse characteristics in patients with classical polycystic ovarian syndrome (PCOS). All patients were hirsute, had been oligomenorrhoeic since menarche, had LH: FSH ratios of > 3:1, and either elevated serum testosterone (T) or dehydroepiandrosterone sulphate (DHAS) concentrations. In 10 subjects who completed the study menstrual frequency increased from an average of 3‐6 to 8 per year but few of the cycles were ovulatory. Mean (SE) serum testosterone fell from 4‐4 (0‐5) nmol/1 pretreatment to 2‐8 (0‐3) nmol/1 ( P <001) and DHAS from 7‐9 (1‐1) μmol/1 to 5‐4 (1‐1) μmol/1 ( P <0‐05). Serum A4 androstenedione and oestradiol did not change with bromocriptine treatment. Mean serum LH fell from 17‐4 (2‐4) IU/l to 11‐2 (1‐8) IU/l ( P <0‐03) after 12 months of bromocriptine. No pattern of LH pulsatility specific to PCOS was detected during 10 min sampling for an 8 h period prior to dopamine agonist treatment. LH interpeak interval (58 (5‐2) min) and peak amplitude (156 (7‐2%) of mean nadir) in untreated PCOS were similar to that of the mid‐follicular stage of ovulatory cycles, and bromocriptine for 1 year did not alter these variables. We conclude that while bromocriptine reduces serum androgen levels and increases menstrual frequency it has no effect centrally to modify hypothalamic GnRH secretion. The reduction in LH levels by bromocriptine may be the result of diminished gonadotroph sensitivity to GnRH or reduced pituitary stores of LH available for release. Despite the return towards normal of various hormonal characteristics of PCOS, bromocriptine has little place in the management of this condition.
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Hyperprolactinemia is a frequent finding in infertile women with amenorrhea. Bromocriptine is the drug of choice for treatment of hyperprolactinemic amenorrhea. This dopamine agonist is very effective in normalizing raised prolactin levels. Ovulatory menstrual cycles and fertility are then rapidly restored. Bromocriptine therapy represents a major advance in the treatment of anovulatory infertility. Prolactin-secreting pituitary adenomas are common causes of hyperprolactinemia. Neither surgery nor irradiation reliably provides the definitive cure that had been hoped for in patients with prolactin-secreting pituitary tumours. Experience with medical treatment has revealed that induction of ovulation with bromocriptine is remarkably safe both in patients with microtumours and those with macrotumours without suprasellar extension. In the future, it is possible that even the larger macrotumours with suprasellar can be safely managed by medical therapy with bromocriptine. During pregnancy, pituitary tumour complications may arise in women with prolactinomas. However, data accumulated during recent years have shown that induction of ovulation and pregnancy by bromocriptine is remarkably safe in women with both micro- and macroprolactinomas. The risk of permanent sequelae due to rapid tumour enlargement during pregnancy is exceedingly small in properly investigated and carefully supervised women with prolactinomas. Bromocriptine is clearly a must for every infertility clinic. The value of bromocriptine in the treatment of normoprolactinemic amenorrhea, polycystic ovarian disease, luteal insufficiency and ovulatory infertility is not yet proven. However, bromocriptine is extremely effective in normalizing hyperprolactinemia and undoubtedly the drug of choice for treatment of female infertility due to hypersecretion of prolactin.
Anovulation
Galactorrhea
Prolactinoma
Polycystic ovarian disease
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Women with polycystic ovarian syndrome (PCOS) generally are treated with oral contraceptives, "fertility drugs" to induce ovulation, or—when all else fails—surgical wedge resection. But tentative clinical impressions now suggest that dopamine agonists used to treat hyperprolactinemia may become a therapeutic option for these patients. (For discussion of another use of dopamine agonist therapy, see "Galactorrhea Without Hyperprolactinemia" on page 593.) At the recent Endocrine Society meeting in San Francisco, Jon J. Pehrson, MD, a fellow in endocrinology and metabolism at Boston City Hospital, reported that the disease may entail alterations in dopaminergic control of prolactin secretion. Pehrson and Judith L. Vaitukaitis, MD, of Boston University School of Medicine, who is chief of endocrinology at the city hospital, found slightly elevated basal serum prolactin levels in about one third of 42 affected women (none of whom had pituitary tumors or congenital adrenal hyperplasia) during protracted amenorrhea or the early follicular phase
Galactorrhea
Polycystic ovarian disease
Cabergoline
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Anovulation
Galactorrhea
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In order to investigate a possible common role of central dopaminergic mechanisms in the release of PRL and LH in patients with the polycystic ovary syndrome (PCO), plasma LH pulsatile profiles and the response to GnRH were studied in a group of 12 PCO patients before and after 3 months of treatment with bromocriptine, 2.5 mg twice daily. They were divided into two groups of six patients according to the occurrence or not of hyperprolactinemia (plasma PRL, 30.3 +/- 2.7 (SE) ng/ml vs. 9.5 +/- 0.8 (SE) ng/ml). Integrated LH secretion significantly decreased in hyperprolactinemic [2537 +/- 371 (SE) vs. 907 +/- 102 mIU/ml X min] as well as in normoprolactinemic (2847 +/- 460 vs. 901 +/- 152 mIU/ml X min) patients, but there was no difference in the response of the two groups. The LH increment after a bolus injection of 100 micrograms GnRH was reduced (P less than 0.01) to the same extent in both groups. These results indicate a dopaminergic component in the control of LH release in PCO patients, independent of the mechanism governing PRL secretion. Since bromocriptine reduced LH secretion, it may be useful for the management of this condition.
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