POLYCYSTIC-OVARY-SYNDROME - EVIDENCE FOR REDUCED SENSITIVITY OF THE GONADOTROPIN-RELEASING-HORMONE PULSE-GENERATOR TO INHIBITION BY ESTRADIOL AND PROGESTERONE

Plasma LH is commonly elevated in women with the polycystic ovary synd rome (PCOS), but the underlying mechanisms are uncertain. We tested th e hypothesis that the elevated LH in part reflects a reduced sensitivi ty of the hypothalamic GnRH pulse generator to suppression by estradio l (E-2) and progesterone (P). In an initial protocol, normal controls (beginning on cycle days 8-10) and women with PCOS were given E-2 tran sdermally and P by vaginal suppository (three times daily), to achieve plasma concentrations similar to those in the midluteal phase of an o vulatory cycle, for 21 days. Blood was obtained at 10-min intervals fo r 12 h before and on days 5, 10, 20, and 28 (7 days after E-2 and P we re discontinued). LH pulse amplitude and LH pulse frequency were suppr essed in both PCOS and normal controls, but LH pulse frequency fell mo re rapidly in controls and was lower by day 10 (P < 0.05). Based on th is time course a dose-response study was performed, in which E-2 in co nstant dosage and varying concentrations of P were administered for 7 days. Pulsatile LH release was appraised on days 1 and 7. The frequenc y of LH pulse secretion was reduced in controls and was lower than tha t 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 P COS and controls. In contrast, lower concentrations (P < 10 ng/mL) wer e more effective in suppressing GnRH/LH pulse frequency in controls (b y >45% of basal) than in PCOS (<40%; P < 0.01). The data indicate that E-2 and P can inhibit the activity of the hypothalamic GnRH pulse gen erator in women with PCOS. However, higher plasma concentrations of P were required to reduce GnRH/LH pulse frequency in PCOS compared to co ntrols, suggesting an insensitivity of the GnRH pulse generator to sup pression by E-2 and P. These results suggest that an abnormality in th e regulation of hypothalamic GnRH secretion is present in PCOS and may be a factor in the etiology of the disorder in adolescence.