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 ∼ 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. In conclusion, our data demonstrate dramatic effects of the opiate antagonist naltrexone on gonadotrophin secretion in hypothalamic ovarian failure and on insulin resistance and hyperandrogenism, suggesting a critical role of endogenous opioids in the pathogenesis of both disorders. In addition, these findings may provide the basis for new forms of treatment.