USE OF A GONADOTROPIN-RELEASING-HORMONE ANTAGONIST AS A PHYSIOLOGICALPROBE IN POLYCYSTIC-OVARY-SYNDROME - ASSESSMENT OF NEUROENDOCRINE ANDANDROGEN DYNAMICS

The majority of patients with polycystic ovary syndrome (PCOS) exhibit an increase in both the frequency and amplitude of LH secretion, whic h is thought to contribute to the hyperandrogenism associated with thi s disorder. The increase in LH pulse amplitude may reflect either enha nced pituitary sensitivity to GnRH and/or an increase in hypothalamic GnRH secretion. To determine whether endogenous GnRH secretion is incr eased in PCOS and to document the degree and time course of androgen s uppression after acute LH inhibition, the Nal-Glu GnRH antagonist was administered sc at 4 doses (5, 15, 50, and 150 mu g/kg) to 11 women wi th PCOS. The response to GnRH receptor blockade was compared with data from regularly cycling women (n = 50) studied in the early and late f ollicular, and early luteal phases. The response to more prolonged GnR H receptor blockade was determined in a subset of patients, in whom 15 0 mu g/kg of the GnRH antagonist was administered sc every 24 h for 3 days (n = 7) and continued for 7 days in 3 subjects. LH levels decreas ed in a dose-dependent fashion after administration of the GnRH antago nist (P < 0.0001), with a maximum percent inhibition of 83 +/- 2%. At all except the 5 mu g/kg dose, mean LH levels remained significantly l ower than baseline for up to 20 h post antagonist (P < 0.002). At all antagonist doses, both the degree and duration of LH suppression were similar in PCOS and normal women. The maximum percent inhibition of FS H was 39 +/- 2%, which was significantly less than that of LH (P < 0.0 01). Testosterone (T) levels fell significantly within 4 h of antagoni st administration, with maximum percent inhibition of 39 +/- 3% occurr ing at 8 h. In the patients in whom 150 mu g/kg of the antagonist was given for 3-7 days, no further suppression of either gonadotropins or T was noted. Our conclusions were: 1) The equivalent susceptibility of LH to submaximal GnRH receptor blockade in normal and PCOS women sugg ests that the elevated LH levels in PCOS are not the result of an incr ease in the quantity of GnRH secreted. These data imply that it is the frequency of GnRH stimulation per se and/or enhanced pituitary sensit ivity to endogenous GnRH that underlie the gonadotropin abnormalities in PCOS; and 2) The rapid suppression of T with increasing GnRH antago nist dose is consistent with acute regulation of T secretion by LH.