Plasma LH is commonly elevated in women with the polycystic ovary syndrome (PCOS), but the underlying mechanisms are uncertain. We tested the hypothesis that the elevated LH in part reflects a reduced sensitivity of the hypothalamic GnRH pulse generator to suppression by estradiol (E2) and progesterone (P). In an initial protocol, normal controls (beginning on cycle days 8-10) and women with PCOS were given E2 transdermally and P by vaginal suppository (three times daily), to achieve plasma concentrations similar to those in the midluteal phase of an ovulatory cycle, for 21 days. Blood was obtained at 10-min intervals for 12 h before and on days 5, 10, 20, and 28 (7 days after E2 and P were discontinued). LH pulse amplitude and LH pulse frequency were suppressed in both PCOS and normal controls, but LH pulse frequency fell more rapidly in controls and was lower by day 10 (P < 0.05). Based on this time course a dose-response study was performed, in which E2 in constant dosage and varying concentrations of P were administered for 7 days. Pulsatile LH release was appraised on days 1 and 7. The frequency of LH pulse secretion was reduced in controls and was lower than that in patients with PCOS on day 7 (P < 0.0001). Plasma P concentrations of 13-15 ng/mL suppressed LH pulse frequency to a similar degree in PCOS and controls. In contrast, lower concentrations (P < 10 ng/mL) were more effective in suppressing GnRH/LH pulse frequency in controls (by > 45% of basal) than in PCOS (< 40%; P < 0.01). The data indicate that E2 and P can inhibit the activity of the hypothalamic GnRH pulse generator in women with PCOS. However, higher plasma concentrations of P were required to reduce GnRH/LH pulse frequency in PCOS compared to controls, suggesting an insensitivity of the GnRH pulse generator to suppression by E2 and P. These results suggest that an abnormality in the regulation of hypothalamic GnRH secretion is present in PCOS and may be a factor in the etiology of the disorder in adolescence.