The goals of this study were to determine whether women with idiopathic hypogonadotropic hypogonadism (IHH) respond to pulsatile GnRH replacement therapy with exaggerated glycoprotein free alpha-subunit (FAS) levels, as reported in GnRH-deficient men, and to determine whether this pattern is unique to congenital GnRH deficiency or is also characteristic of patients with hypogonadotropic hypogonadism caused by other factors. GnRH was administered i.v. at a physiologic frequency and dose (75-100 ng/kg.bolus) to women with IHH (n = 11; n = 6 with anosmia); acquired GnRH deficiency secondary to treatment for cranial tumors (AHH; n = 7); and secondary hypothalamic amenorrhea (HA; n = 8). Results were compared with 24 normal cycling women. Gonadotropins, sex steroids, and FAS levels were measured in samples drawn daily across induced or normal menstrual cycles in patients or normal women, respectively. Samples were drawn at the same time of day and were collected 45 min after a GnRH bolus in patients. All women ovulated in response to pulsatile GnRH. There were no differences in the patterns of LH or gonadal steroid secretion between any of the patient groups (IHH, AHH, and HA). The patterns of LH and FSH secretion in the induced patient cycles were not different from normal women, with the exception of lower midcycle FSH levels in IHH women (P < 0.002). However, the daily dynamic secretion of FAS was exaggerated in IHH (compared with AHH, HA, and normal) women (P < 0.002). The increase in FAS levels in IHH was dependent on cycle stage, with the greatest difference observed during the early (P < 0.005) and midfollicular phase (P < 0.05) and the early luteal phase (P < 0.05). There was no difference in FAS between groups during the late follicular phase, at the midcycle, or in the midluteal and late luteal phase. This exaggerated FAS response to GnRH replacement in IHH was demonstrated in repeat cycles in two patients. Conclusions are: 1) Women with IHH respond to pulsatile GnRH replacement with an exaggerated secretion of FAS, which seems to be modified by gonadal factors; 2) this exaggerated FAS response, which is similar to that seen in GnRH-deficient men, is unique to congenital GnRH deficiency, and it is not observed in patients with acquired or secondary hypogonadotropic hypogonadism, suggesting that IHH patients may be missing a factor, in addition to GnRH, which normally restrains FAS secretion; and 3) the FAS response may prove to be a useful marker to distinguish constitutional delay of puberty from congenital GnRH deficiency.