To compare the efficacy and safety of ovulation induction with exogenous gonadotropins vs. pulsatile GnRH in patients with hypogonadotropic amenorrhea, results from 30 patients in 111 cycles of gonadotropins and 41 patients in 118 cycles of pulsatile GnRH were analyzed retrospectively. Exogenous gonadotropins were administered using an individually adjusted protocol, using a starting dose of 150 IU. Pulsatile GnRH was delivered iv at a physiological frequency based upon our normative data. The doses administered ranged from 75-250 ng/kg. Preovulatory serum estradiol (E2) and luteal phase progesterone (P) levels were compared to those in normal cycling women (n = 87). The mean body mass index, age, and baseline gonadotropin levels were similar in the two groups. Overall ovulatory rates and conception rates per cycle and per patient were not significantly different between the two groups. However, the cumulative chance of conception after six cycles of treatment by life table analysis appeared to be higher with pulsatile GnRH treatment (96%) than with exogenous gonadotropins (72%). The risk of multiple gestation was also higher with exogenous gonadotropins (14.8% vs. 8.3%), although this was not statistically significant. All higher order multiple gestations (triplets or more) occurred in the gonadotropin-treated group. More than two dominant follicles were seen on ultrasound in 47.6% of gonadotropin-treated cycles compared to 18.9% of cycles with pulsatile GnRH treatment (P < 0.01). Three or more follicles were seen in 16.6% of the gonadotropin cycles compared to 5.4% with pulsatile GnRH (P < 0.05). No case of severe ovarian hyperstimulation was observed in either group, although the mean luteal phase ovarian size was significantly higher in the gonadotropin group (P < 0.05). Mean peak preovulatory E2 levels were significantly higher in the gonadotropin group (1684.5 +/- 124.4 vs. 1315.3 +/- 74.9 pmol/L; P < 0.05). The mean luteal phase P level 1 week after ovulation was significantly higher than normal in the gonadotropin group (84.9 +/- 10.8 vs. 61.1 +/- 3.2 nmol/L; P < 0.05), but was not significantly different from that in the pulsatile GnRH group (70.3 +/- 6.0 nmol/L). We conclude that pulsatile GnRH, when compared to exogenous gonadotropins, results in high rates of ovulation and conception, but a decreased risk of multiple folliculogenesis, higher order multiple gestations, and ovarian enlargement.(ABSTRACT TRUNCATED AT 400 WORDS)