One-hundred-and-thirty-eight women suffering from hypothalamic or hyperandrogenic ovarian failure were treated with daily doses of 25-150 mg of the opiate antagonist naltrexone for 4-100 weeks. In patients with hypothalamic ovarian failure, treatment with naltrexone alone was followed by an increase of gonadotrophins and by normalization of the menstrual cycle in approximately 70% of patients. Eight of 10 patients who did not respond to naltrexone and had not previously ovulated in response to clomiphene administration exhibited ovulatory cycles when both compounds were administered. Twenty-four pregnancies were achieved in 22 women, corresponding to an overall pregnancy rate of 26%, with a cumulative pregnancy rate closely resembling that of a normal population. In contrast, in hyperandrogenic insulin-resistant patients, the pattern of gonadotrophin secretion did not seem to change dramatically during naltrexone treatment. However, the rise of insulin in plasma following an oral load of glucose (oGTT) was blunted considerably, resulting in normalization of previously elevated circulating insulin levels. Since the time course of plasma glucose after oGTT did not appear to be affected by treatment, this indicates an increase in insulin sensitivity (or a decrease in insulin resistance) during naltrexone therapy. Side-effects of naltrexone treatment were negligible in patients with hypothalamic ovarian failure. Hyperandrogenic patients, however, did experience more intense and prolonged side-effects, such as nausea and dizziness.(ABSTRACT TRUNCATED AT 250 WORDS)
A total of 12 women (24.2 +/- 1.6 years old, BMI 36.7 +/- 1.5 Kg/m2) with hyperandrogenism (HA) and with normal glucose tolerance test were studied to evaluate the involvement of endogenous opioids in the pathophysiology of insulin secretion and insulin sensitivity in HA by administering naltrexone, an oral opioid receptor antagonist. Six patients received naltrexone orally (75 mg daily) and another six received placebo for 12 weeks (double-blind study). Before and after therapy a frequently sampled intravenous glucose tolerance test (FSIVGTT) was performed. The insulin sensitivity index (SI) was determined by Bergman's program. SHBG, DHEAS, testosterone, free androgen index (FAI) and plasma concentrations of IGF-I and IGFBP-1 were determined in 3 basal samples, before and after therapy. Treatment with naltrexone in hyperandrogenic patients resulted in a decrease in fasting insulin concentrations of 40% and C-peptide concentrations of 50% (p < 0.05). Insulin and C-peptide from the FSIVGTT displayed a similar pattern with a fall in the area under the curve under naltrexone treatment of 34% for insulin and 35% for C-peptide. Insulin sensitivity did not change under naltrexone (1.26 +/- 0.19 vs 1.32 +/- 0.32 10(-4) x min(-1)/(uU/ml)) or placebo (0.95 +/- 0.19 vs 1.12 +/- 0.28 10(-4) x min(-1)/(uU/ml)) administration. However, glucose effectiveness increased significantly with naltrexone (2.231 +/- 0.002 vs 3.354 +/- 0.006 x 10(-2) min(-1)). Glucose (fasting and area under the curve) was not modified significantly after naltrexone administration. Baseline hormone levels were similar in the two groups, and they did not change after long-term treatment with naltrexone or placebo. In conclusion, these results support the hypothesis of elevated opioid tonus and increased insulin secretion as a possible mechanism of hyperinsulinism in a group of hyperandrogenic women of ovarian origin. This alteration could act as an additional factor in the pathogenesis of insulin resistance found in an important proportion of these patients.
The pulsatile gonadotrophin secretion in hyperandrogenaemic women was examined, following short-term androgen antagonism induced by flutamide, a specific androgen receptor blocker. Flutamide was administered to seven hyperandrogenaemic women and five normal cycling women, at a dose of 250 mg on the evening of day 1, followed by daily doses of 750 mg for 6 days. Blood samples were collected at 10 min intervals for 8 h before (day 1) and during treatment (days 2 and 6). Gonadotrophin and prolactin concentrations were measured in all samples while sex hormone concentrations were analysed in selected samples. Flutamide administration to hyperandrogenaemic women was followed by a decrease in luteinizing hormone (LH) pulse amplitude (P < 0.05), associated with an apparent decline in mean LH concentrations. Follicle stimulating hormone (FSH) showed a significant fall after 6 days of treatment (P < 0.05). Total testosterone, free testosterone, androstenedione and dihydroepiandrosterone sulphate were significantly decreased during flutamide administration, while sex-hormone-binding globulin and oestradiol were not affected. Normal women showed no significant changes in the above mentioned parameters. These results demonstrate that short-term androgen receptor blockade with flutamide reduces gonadotrophin secretion and androgen concentration in hyperandrogenaemic women. Since flutamide is devoid of intrinsic hormonal activity, it is suggested that the observed hormonal changes are secondary to the androgen blockade.
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