LHRH antagonists suppress pituitary and go-nadal function by competing with endogenous LHRH for binding to gonadotroph receptors. To determine the mechanism of suppression of gonadotropin secretion we studied the effects of a single dose of a LHRH antagonist on the pulsatile activity of serum bioactive LH (Bio-LH), immunoreactive LH (IR-LH), α-subunit, and testosterone for 24 h in normal men. The LHRH antagonist, Nal-Glu ([Ac-D2Nal1, D4ClPhe2, D3Pal3, Arg5, DGlu6-(AA), DAla10]LHRH) was given as a single sc injection of 5 mg to five normal men. Blood samples were collected every 10 min during a 10-h baseline period and for 14 h after administration of the antagonist. IR-LH, α-subunit, and testosterone were measured in triplicate, and Bio-LH in duplicate. Pulses were then evaluated using Cluster analysis; all replicates were entered in the pulse analysis. After administration of the Nal-Glu antagonist, IR-LH levels decreased (P < 0.001) from 2.81 ± 0.06 at baseline to a nadir of 0.75 ± 0.02 U/L. Bio-LH levels followed the same pattern, decreasing by 89% (P < 0.001) from 4.54 ± 0.13 to a nadir of 0.51 ± 0.13 U/L 6.8 h after the injection of Nal-Glu. In contrast, serum α-subunit levels did not change (P > 0.05) during the 14-h period after antagonist administration (0.85 ± 0.01 and 0.75 ± 0.01 μg/L before and after Nal-Glu, respectively). Serum testosterone levels decreased by more than 80%, from 17.6 ± 0.2 at baseline to a mean nadir of 3.3 ± 0.7 nmol/L 12.8 h after Nal-Glu administration. Pulse frequency and the number of significant pulses remained the same for all of the measured hormones during the 10-h baseline period and the 14 h after Nal-Glu administration. In contrast, the pulse amplitude of IR-LH, Bio-LH, and testosterone decreased significantly after injection of the antagonist. The pulse amplitude of the α-subunit also declined, albeit not significantly. Coincidence analysis revealed that during both the 10-h baseline and the 14-h post-Nal-Glu period there was a highly significant (P < 10−5) nonrandom synchrony between peaks of IR-LH, Bio-LH, α-subunit, and testosterone. These results suggest that coordinate pulsatile secretion of IR-LH, Bio-LH, and testosterone persists after the administration of 5 mg Nal-Glu LHRH antagonist. These pulses are of low amplitude, resulting in overall reduction of serum gonadotropin and testosterone levels, while α-subunit release remains unaffected. Consequently, we infer that even small amounts of effective endogenous LHRH are sufficient to couple pulsatile hormone release within the hypothalamo-pituitary-gonadal axis in men.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Clinical Biochemistry
- Biochemistry, medical