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

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Abstract
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 the 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 .alpha.-subunit were measured serially in assays with the high specificity. There was a 90% concordance of LH and free .alpha.-subunit pulses during the baseline sampling period. Pulsatile secretion of LH and free .alpha.-subunit was immediately abolished at the highest dose of 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 .mu.g/kg, respectively, compared to 51 .+-. 10%, 70 .+-. 5%, and 69 .+-. 5% at doses of 50, 150, and 500 .mu.g/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 .alpha.-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, suppresion of LH was greater than that of FSH and free .alpha.-subunit at all doses (P < 0.001), while FSH suppression was greater that that of FSH or free .alpha.-subunit at all doses (P > 0.01), and FSH suppression exceeded that of free .alpha.-subunit at the 50 .mu.g/kg dose. Suppression of LH was greater with the Nal-Glu antagonist than with the Nal-Arg antagonist at doses of 50 and 150 .mu.g/kg (P < 0.05), and FSH suppression was greater with the Nal-Glu antagonist at 150 .mu.g/kg (P < 0.01), while the degrees of maximum suppression were similar for the two different GnRH antagonists for free .alpha.-subunit. We conclude thaat GnRH receptor blockade eradicates the pulsatile nature of both LH and free .alpha.-subunit secretion. GnRH antagonism differentially suppresses LH, FSH, and free .alpha.-subunit, suggesting differential regulation of these three hormones, which are secreted from the gonadotrope in response to GnRH. The Nal-Glu antagonist is a more potent GnRH antagonist than the Nal-Arg antagonist in this model.

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