Persistence of concordant luteinizing hormone (LH), testosterone, and alpha-subunit pulses after LH-releasing hormone antagonist administration in normal men.
LHRH antagonists suppress pituitary and gonadal 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), alpha-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, alpha-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 less than 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 less than 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 alpha-subunit levels did not change (P greater than 0.05) during the 14-h period after antagonist administration (0.85 +/- 0.01 and 0.75 +/- 0.01 microgram/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 alpha-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 less than 10(-5) nonrandom synchrony between peaks of IR-LH, Bio-LH, alpha-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.(ABSTRACT TRUNCATED AT 400 WORDS)
Pavlou
S N
SN
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Veldhuis
J D
JD
Lindner
J
J
Souza
K H
KH
Urban
R J
RJ
Rivier
J E
JE
Vale
W W
WW
Stallard
D J
DJ
D000328:Adult; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000502:physiology; D013737:Testis / Q000502:physiology; D013739:Testosterone / Q000097:blood* / Q000378:metabolism
C057805:LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone