To evaluate the suitability of the sc route for the pulsatile delivery of GnRH, plasma GnRH, LH, and FSH levels were measured by RIA in five women with hypothalamic amenorrhea after sc injection of single doses of 2.5, 5, and 10 micrograms GnRH. The results were compared with those obtained after bolus iv injection of 10 micrograms GnRH. After sc injection, plasma GnRH levels rose to a dose-related maximum after 5-10 min and fell to less than 10% of the peak value by 90 min. The mean plasma disappearance half-time was 24 min (range, 18-30 min). After bolus iv injection, an initial rapid phase of disappearance (t1/2, 2.8 min) was followed by a slower phase (t1/2, 33 min), falling within the 95% confidence intervals for the disappearance half-time after sc administration (12-36 min). The patterns of LH response to sc and iv GnRH were similar, with maximum levels reached between 20 and 30 min after injection, then declining to 50-69% of the peak value by 90 min after sc injection and 61% of the peak value 90 min after iv injection. There was no significant difference between peak LH responses to 10 micrograms iv and sc doses of GnRH [15.2 +/- 2.5 (+/- SEM) vs. 13.2 +/- 2.2 IU/L]. Subcutaneous administration of three consecutive GnRH pulses at 90-min intervals to four women resulted in gonadotropin responses to each GnRH pulse. We conclude that sc GnRH administration results in pulsatile plasma GnRH and gonadotropin responses, the latter resembling those seen after iv GnRH. These results confirm the suitability of the sc route for pulsatile GnRH delivery.