Reduction of Gonadotropin-Releasing Hormone Pulse Frequency Is Associated with Subsequent Selective Follicle-Stimulating Hormone Secretion in Women with Polycystic Ovarian Disease*

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Abstract
Polycystic ovarian disease (PCO) is characterized by hyperandrogenism, ovulatory dysfunction, and altered gonadotropin secretion. Mean plasma FSH concentrations are low, while LH is elevated in a majority of patients. LH pulsatile secretion has been shown to occur at rapid follicular phase frequencies (approximately one pulse per h) in PCO, suggesting persistent rapid frequency GnRH secretion in this disorder. Anovulatory women with PCO were given estradiol (E2; Estraderm skin patches) and progesterone (P; vaginal suppositories) to produce midluteal concentrations for 21 days. The aim was to determine if E2 and P would slow LH (GnRH) pulse frequency and if this would result in augmented FSH secretion and follicular development after withdrawal of E2 and P. Plasma LH was measured every 10 min for 8 h before1 during (days 10 and 20), and 7 days after withdrawal of E2 and P (day 28). On each of these study days FSH was measured hourly, and E2 and P were measured every 2 h. After sampling, GnRH (25 and 250 ng/kg, iv) was given to assess pituitary responsiveness. Follicular development was monitored by vaginal ultrasound through day 34 of the study. Basal LH frequency was 8.5 ± 0.5 pulses/8 h (mean ± sem). During E2 and P, LH pulse frequency fell to 3.3 ± 1.0 (10 days) and 2.3 ± 0.8 (20 days), 39% and 27% of the basal value, respectively, and subsequently increased to 5.6 ± 0.7 (66% of basal) 7 days after withdrawal of E2 and P. LH pulse amplitude (basal, 7.2 ± 1.5 IU/L) was not reduced until day 20, but remained suppressed (3.9 ± 1.1 IU/L) on day 28. As a result, mean LH (basal, 21.0 ± 3.5 IU/L) fell progressively during E2 and P, to 3.8 ± 1.2 IU/L on day 20, and remained low (39% of basal) 7 days after steroid withdrawal. Mean plasma FSH (basal, 7.1 ± 0.9 IU/L) also fell during steroid administration, but in contrast to LH, had risen to 93% of the basal value by 7 days after E2 and P. LH release in response to exogenous GnRH revealed marked initial responses which did not decrease until day 20, but remained suppressed (8% of basal) after withdrawal of E2 and P. FSH responses were also suppressed on day 20, but had increased to 75% of the basal value by day 28. Initiation of follicular development occurred in all patients, and the lead follicle measured 12.3 ± 0.8 mm 13 days post-E2 and P. Ovulation occurred in one patient. These data show that luteal concentrations of E2 and P slow the frequency of LH (GnRH) pulses and normalize the ratio of LH/FSH in plasma in women with PCO. Subsequently, selective FSH secretion and follicular development occurred after steroid withdrawal. This suggests that the rapid GnRH pulse frequency and abnormalities of plasma gonadotropins in PCO are consequent upon low plasma levels of luteal steroids or lowered hypothalamic sensitivity to the inhibitory effects of E2 and P on pulsatile GnRH secretion. The data also suggest that administration of E2 and P may provide a physiological approach to normalizing gonadotropin secretion and inducing early follicular development in women with PCO.

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