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Differential Regulation of Luteinizing Hormone, Follicle-Stimulating Hormone, and Free -Subunit Secretion from the Gonadotrope by Gonadotropin-Releasing Hormone (GnRH): Evidence from the Use of Two GnRH Antagonists^*

JANET E. HALL, RANDALL W. WHITCOMB, JEAN E. RIVIER, WYLIE W. VALE and WILLIAM F. CROWLEY, JR

Reproductive Endocrine Unit and the Vincent Memorial Research Laboratories, and the Departments of Medicine and Gynecology, Massachusetts General Hospital Boston, Massachusetts 02114
the Salk Institute for Biological Studies La Jolla, California 92037

Address requests for reprints to: Dr. J. E. Hall, Reproductive Endocrine Unit, Vincent Memorial Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts 02114.

To examine the differential regulation of glycoprotein hormone secretion from the gonadotrope by GnRH, the Nal-Glu GnRH antagonist was administered to euthyroid women in the early follicular phase (days 1–5) of the menstrual cycle, and the results compared to previous studies with the Nal- Arg GnRH antagonist. After a 4-h period of baseline sampling at a frequency of every 10 min, a single sc dose of the GnRH antagonist was administered to each subject. Frequent sampling continued for 8 h, followed by hourly sampling for a further 16 h. LH, FSH, and free -subunit were measured serially in assays with high specificity.

There was a 90% concordance of LH and free -subunit pulses during the baseline sampling period. Pulsatile secretion of LH and free -subunit was immediately abolished at the highest dose of the Nal-Glu antagonist for at least 8 h. The maximum percent suppression of LH after administration of the Nal-Glu GnRH antagonist was 70 ± 4%, 80 ± 4%, and 83 ± 1% at doses of 15, 50, and 150 µg/kg, respectively, compared to 51 ± 10%, 70 ± 5%, and 69 ± 5% at doses of 50, 150, and 500 µg/kg Nal-Arg antagonist. Decreases in FSH were 28 ± 2%, 32 ± 7%, and 39 ± 2%, with increasing doses of the Nal-Glu antagonist compared with 25 ± 6%, 17 ± 6%, and 28 ± 4% reductions at increasing doses of the Nal-Arg antagonist. Free -subunit decreased 22 ± 4%, 23 ± 4%, and 28 ± 3% at increasing doses of the Nal-Glu antagonist and 12 ± 4%, 27 ± 4%, and 30 ± 7% with increasing doses of the Nal-Arg antagonist. For the Nal- Glu antagonist, suppression of LH was greater than that of FSH and free -subunit at all doses (P < 0.001), while FSH suppression was greater than that of free -subunit at the highest dose only (P < 0.05). For the Nal-Arg antagonist, LH suppression was greater than that of FSH or free -subunit at all doses (P > 0.01), and FSH suppression exceeded that of free -subunit at the 50 µg/kg dose. Suppression of LH was greater with the Nal-Glu antagonist than with the Nal-Arg antagonist at doses of 50 and 150 µg/kg (P < 0.05), and FSH suppression was greater with the Nal-Glu antagonist at 150 µg/kg (P < 0.01), while the degrees of maximum suppression were similar for the two different GnRH antagonists for free -subunit.

We conclude that 1) GnRH receptor blockade eradicates the pulsatile nature of both LH and free -subunit secretion; 2) GnRH antagonism differentially suppresses LH, FSH, and free -subunit, suggesting differential regulation of these three hormones, which are secreted from the gonadotrope in response to GnRH; and 3) the Nal-Glu antagonist is a more potent GnRH antagonist than the Nal-Arg antagonist in this model.

^* This work was supported by NIH Grants HD-15080, HD-3-2837, HD-15788, HD-13527, and RR-01066. A portion of this research was conducted at the Clayton Foundation for Research, CA.

Supported in part by a fellowship from the Medical Research Council of Canada.

Clayton Foundation Investigator.

Received April 17, 1989.

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