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

Abstract

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 g/kg) to 11 women with PCOS. The response to GnRH receptor blockade was compared with data from regularly cycling women (n ϭ 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 g/kg of the GnRH antagonist was administered sc every 24 h for 3 days (n ϭ 7) and continued for 7 days in 3 subjects.LH levels decreased in a dose-dependent fashion after administration of the GnRH antagonist (P Ͻ 0.0001), with a maximum percent inhibition of 83 Ϯ 2%. At all except the 5 g/kg dose, mean LH levels remained significantly lower than baseline for up to 20 h post antagonist (P Ͻ 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 Ϯ 2%, which was significantly less than that of LH (P Ͻ 0.001). Testosterone (T) levels fell significantly within 4 h of antagonist administration, with maximum percent inhibition of 39 Ϯ 3% occurring at 8 h. In the patients in whom 150 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 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. (J Clin Endocrinol Metab 83: 2343-2349, 1998 W HILE polycystic ovary syndrome (PCOS) is a heterogeneous disorder for which several pathogenic mechanisms have been proposed (1-4), abnormal gonadotropin secretion is a dominant feature in a large subgroup. Such patients are characterized by increased serum levels of LH in association with normal or low levels of FSH, resulting in an elevated LH/FSH ratio (5-10).The relative contributions of the pituitary and hypothalamus to the abnormal gonadotropin secretory dynamics in PCOS have been difficult to quantify. The increase in LH pulse amplitude characteristic of PCOS (6,7,9,(11)(12)(13)(14) may represent either enhanced pituitary sensitivity or in...

The Efficacy of Metformin Treatment on Insulin Resistance and Hyperandrogenism in Lean Women with Polycystic Ovary Syndrome: A Literature Review

“…Elevated LH levels due to higher LH pulse amplitudes are also well documented in PCOS. This is possibly due to the increased sensitivity of the pituitary gland to GnRH [77][78][79], although it is unclear whether this hypothalamicpituitary hyperactivity is intrinsic in PCOS [77,80]. Insulin signalling has been shown to be an indirect factor on LH synthesis in PCOS, as insulin can have direct effects on GnRH neurons and stimulate GnRH gene expression [25,26].…”

The relationship between hormonal levels and hematological parameters in cystic ovarian syndrome

“…On the other hand, FSH (follicle-stimulating hormone) production is favored as it supports the expansion of follicles for the upcoming menstrual cycle [ 13 ]. The source of LH (luteinizing hormone) hypersecretion in PCOS (polycystic ovary syndrome) is more likely attributed to greater pituitary sensitivity to GnRH (gonadotropin-releasing hormone) or alterations in GnRH secretion patterns rather than increased GnRH secretion itself.…”

Ovulation induction techniques in women with polycystic ovary syndrome

“…As opposed to normal cycling hormone concentrations in ovulating women, women with PCOS are often described as being in a "hormonally steady state, " with both gonadotropin and sex steroid concentrations similar to those seen in early follicular phase (4). Increased Luteinizing Hormone (LH) levels are a result of abnormal LH secretory dynamic due to increased LH pulse frequency and pulse amplitude (5)(6)(7)(8), where decreased FSH levels results from the increase in Gonadotropin Releasing Hormone (GnRH) pulse frequency, the negative feedback effects of chronically elevated estrone concentrations and increased inhibin B levels (9, 10). These changes often result in an increased LH/FSH ratio (11-13).…”