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Evidence of Differential Control of FSH and LH Secretion by Gonadotropin-Releasing Hormone (GnRH) from the Use of a GnRH Antagonist^*

JANET E. HALL, TODD D. BRODIE, THOMAS M. BADGER, JEAN RIVIER, WYLIE VALE, P. MICHAEL CONN, DAVID SCHOENFELD and WILLIAM F. CROWLEY, JR.

Reproductive Endocrine Unit and the Vincent Memorial Research Laboratories Boston, Massachusetts 02114
The Departments of Medicine and Gynecology, Massachusetts General Hospital Boston, Massachusetts 02114
The Salk Institute for Biological Studies La Jolla, California 92037
The Department of Pharmacology, University of Iowa College of Medicine Iowa City, Iowa 52242

Address requests for reprints to: Dr. Janet E. Hall, Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.

The differential regulation of immunoactive FSH and LH secretion by endogenous GnRH was studied using a GnRH antagonist, [Ac-D2Nal¹, D4FPhe², DTrp³, DArg⁶]GnRH (the NAL-ARG antagonist), in normal women in the early follicular phase of the menstrual cycle, and their responses were compared to those in two groups of control women. Pulsatile LH secretion was examined as an index of the completeness of blockade of endogenous GnRH secretion. There was a dose-dependent decrease in both the frequency and amplitude of LH pulses. At the highest dose, LH pulses were completely abolished within 20 min after sc administration of the GnRH antagonist and for a minimum of 8 h in all women. The mean plasma LH levels were reduced within the first 4 h after antagonist administration at all doses (P < 0.001). The duration of LH suppression was influenced by antagonist dose, with a continued effect 24 h after administration of the 500 µg/kg dose only. The maximum degree of LH suppression was 40% after 50 µg/kg (n = 6), 60% after 150 µg/kg (n = 6), and 59% after 500 µg/kg (n = 5). In contrast, plasma immunoreactive FSH levels did not change after these doses of the NAL-ARG GnRH antagonist. The maximum degree of FSH suppression was 16%, and the changes in plasma FSH concentrations were not dose dependent. Serum antagonist concentrations rose within 30 min after its administration to mean peak levels of 7.5 ± 2.1 (±SE), 20.4 ± 6.1, and 151 ± 21 ng/mL after the 50, 150, and 500 µg/kg doses, respectively. The half-time of the disappearance of the NAL-ARG GnRH antagonist from plasma was 8.8 ± 1.5 h. While there were no effects of antagonist administration on hemato-logical, hepatic, or renal function, three women developed urti-caria distant from the site of injection when administered the highest dose.

We conclude that blockade of GnRH receptors by a GnRH antagonist 1) effectively antagonizes the action of GnRH, as assessed by its ability to block pulsatile LH secretion and reduce mean plasma LH levels; and 2) inhibits LH release to a considerably greater degree than FSH release, providing further evidence of possible GnRH-independent FSH secretion.

^* This work was supported by NIH Grants 2HD-RO1-15080, RR-1066, NOl-HD-3-2837, and 2RO1-HD-19899.

Supported by a Fellowship from the Medical Research Council of Canada.

Received January 15, 1988.

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