In functional hypothalamic amenorrhea, failure of ovulation probably results from deficient hypothalamic secretion of gonadotropin-releasing hormone (GnRH). We treated 14 infertile women in whom this condition was resistant to clomiphene with pulses of 5 to 15 Î¼g of GnRH administered subcutaneously by portable pumps at 90-minute intervals in 36 cycles of treatment. Ovulation occurred in 30 cycles (83 per cent) and was followed by normal luteal function in 24. Singleton pregnancy occurred after 13 (54 per cent) of these cycles. Ovarian ultrasound consistently showed a single dominant follicle, and follicular-phase levels of gonadotropins and urinary estrone glucuronide were in the normal range in all cycles of treatment except two in which mild ovarian overstimulation occurred. Plasma profiles of GnRH and luteinizing hormone were highly pulsatile after subcutaneous administration of GnRH, and mean peak plasma levels of GnRH were comparable to those in pituitary portal blood. We conclude that treatment with low-dose subcutaneous pulses of GnRH is a safe, effective, and physiologic method of restoring reproductive function in hypothalamic amenorrhea and that it has advantages over gonadotropin therapy.