A multicenter trial was undertaken to assess the ability of pulsatile gonadotropin-releasing hormone to restore physiologic ovulatory function in women with diminished or absent pulsatile gonadotropin-releasing hormone secretion. In 109 women with primary and secondary hypothalamic amenorrhea, pulsatile gonadotropin-releasing hormone (Lutrepulse [gonadorelin acetate] for Injection) was extremely effective, resulting in ovulation in 91% and 96% of patients, respectively. Overall complications of intravenous line placement ranged from 0% to 11% (mean = 7%). A 12% incidence of multiple pregnancy was noted, and a single case of ovarian hyperstimulation was reported in a woman who also received clomiphene citrate. Pulsatile gonadotropin-releasing hormone treatment appears to be of at least comparable efficacy to human menopausal gonadotropins, with the added benefit of reduced overall risks for the patient with hypothalamic amenorrhea.