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

Sixty-six women suffering from various grades of hypothalamicovarian failure were treated with the opiate antagonist naltrexoneat doses ranging from 25 to 150 mg per day. This treatment resultedin complete normalization of the menstrual cycle in 49 of 66patients, as indicated by the pattern of circulating levelsof gonadotrophins and ovarian steroids. Five patients failedto respond, three of whom were suffering from primary hypothalamicamenorrhoea. In patients who responded to the administrationof naltrexone, there was a dramatic increase in the amplitudeand frequency of gonadotrophin pulses, reflecting disinhibitionof the hypothalamic gonadotrophin-releasing hormone (GnRH) pulsegenerator. Eighteen pregnancies were achieved in 16 women whowere also treated for infertility, resulting in a cumulativepregnancy rate closely resembling that of a normal population.There were only minor side-effects that could be attributedto the drug. These data demonstrate that chronic administrationof an opiate antagonist will normalize ovarian function in womensuffering from different grades of hypothalamic ovarian failure.The data therefore support the view that suppression of theactivity of the hypothalamic pulse generator, that directs GnRHrelease, is mediated by endogenous opioids. Also, that hypothalamicovarian failure is the consequence of an inappropriate increasein opioid tone impinging on neurons that release GnRH in a pulsatilemanner into the pituitary portal circulation.