DIFFERENTIAL REGULATION OF LUTEINIZING-HORMONE, FOLLICLE-STIMULATING-HORMONE, AND FREE ALPHA-SUBUNIT SECRETION FROM THE GONADOTROPE BY GONADOTROPIN-RELEASING HORMONE (GNRH) - EVIDENCE FROM THE USE OF 2 GNRH ANTAGONISTS

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 α-subunit were measured serially in assays with high specificity. There was a 90% concordance of LH and free α-subunit pulses during the baseline sampling period. Pulsatile secretion of LH and free α-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 α-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 α-subunit at all doses (P < 0.001), while FSH suppression was greater than that of free α-subunit at the highest dose only (P < 0.05). For the Nal-Arg antagonist, LH suppression was greater than that of FSH or free α-subunit at all doses (P > 0.01), and FSH suppression exceeded that of free α-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 α-subunit. We conclude that 1) GnRH receptor blockade eradicates the pulsatile nature of both LH and free α-subunit secretion; 2) GnRH antagonism differentially suppresses LH, FSH, and free α-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. © 1990 by The Endocrine Society.