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Use of a Gonadotropin-Releasing Hormone Antagonist as a Physiologic Probe in Polycystic Ovary Syndrome: Assessment of Neuroendocrine and Androgen Dynamics¹

National Center for Infertility Research and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Frances Hayes, Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.

The majority of patients with polycystic ovary syndrome (PCOS) exhibit an increase in both the frequency and amplitude of LH secretion, which is thought to contribute to the hyperandrogenism associated with this disorder. The increase in LH pulse amplitude may reflect either enhanced pituitary sensitivity to GnRH and/or an increase in hypothalamic GnRH secretion. To determine whether endogenous GnRH secretion is increased in PCOS and to document the degree and time course of androgen suppression after acute LH inhibition, the Nal-Glu GnRH antagonist was administered sc at 4 doses (5, 15, 50, and 150 µg/kg) to 11 women with PCOS. The response to GnRH receptor blockade was compared with data from regularly cycling women (n = 50) studied in the early and late follicular, and early luteal phases. The response to more prolonged GnRH receptor blockade was determined in a subset of patients, in whom 150 µg/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 decreased in a dose-dependent fashion after administration of the GnRH antagonist (P < 0.0001), with a maximum percent inhibition of 83 ± 2%. At all except the 5 µg/kg dose, mean LH levels remained significantly lower 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 FSH was 39 ± 2%, which was significantly less than that of LH (P < 0.001). Testosterone (T) levels fell significantly within 4 h of antagonist administration, with maximum percent inhibition of 39 ± 3% occurring at 8 h. In the patients in whom 150 µg/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 suggests that the elevated LH levels in PCOS are not the result of an increase in the quantity of GnRH secreted. These data imply that it is the frequency of GnRH stimulation per se and/or enhanced pituitary sensitivity to endogenous GnRH that underlie the gonadotropin abnormalities in PCOS; and 2) The rapid suppression of T with increasing GnRH antagonist dose is consistent with acute regulation of T secretion by LH.

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