Treatment with naltrexone in hypothalamic ovarian failure: induction of ovulation and pregnancy

Sixty-six women suffering from various grades of hypothalamic ovarian failure were treated with the opiate antagonist naltrexone at doses ranging from 25 to 150 mg per day. This treatment resulted in complete normalization of the menstrual cycle in 49 of 66 patients, as indicated by the pattern of circulating levels of gonadotrophins and ovarian steroids. Five patients failed to respond, three of whom were suffering from primary hypothalamic amenorrhoea. In patients who responded to the administration of naltrexone, there was a dramatic increase in the amplitude and frequency of gonadotrophin pulses, reflecting disinhibition of the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator. Eighteen pregnancies were achieved in 16 women who were also treated for infertility, resulting in a cumulative pregnancy rate closely resembling that of a normal population. There were only minor side-effects that could be attributed to the drug. These data demonstrate that chronic administration of an opiate antagonist will normalize ovarian function in women suffering from different grades of hypothalamic ovarian failure. The data therefore support the view that suppression of the activity of the hypothalamic pulse generator, that directs GnRH release, is mediated by endogenous opioids. Also, that hypothalamic ovarian failure is the consequence of an inappropriate increase in opioid tone impinging on neurons that release GnRH in a pulsatile manner into the pituitary portal circulation.