Sustained inhibition of sperm production and inhibin secretion induced by a gonadotrophin-releasing hormone antagonist and delayed testosterone substitution in non-human primates (Macaca fascicularis).
Since the concomitant administration of a gonadotrophin-releasing hormone (GnRH) antagonist and testosterone suppresses sperm production only incompletely, the feasibility of treatment with a GnRH antagonist and delayed testosterone supplementation for sustained suppression of sperm production in a non-human primate model was investigated. Adult cynomolgus monkeys (Macaca fascicularis; five/group) received daily s.c. injections of the GnRH antagonist [N-acetyl-D-2-naphthyl-Ala1,D-4-chloro-Phe2, D-pyridyl-Ala3,nicotinyl-Lys5,D-nicotinyl-Lys6, isopropyl-Lys8,D-Ala10]-GnRH of either 450 or 900 micrograms/kg for 18 weeks. During week 6 of the GnRH antagonist treatment, all monkeys were given a single i.m. injection of 40 mg of a long-acting testosterone ester (testosterone-trans-4-n-butylcyclo-hexanecarboxylate; 20-Aet-1). Within 1 week, serum LH bioactivity was suppressed in both groups and remained low throughout the entire treatment period. Similarly, concentrations of serum testosterone declined precipitously. During week 6, substitution with testosterone restored concentrations of serum testosterone into the pretreatment range. Concentrations of serum inhibin declined within 1 week and remained suppressed during the period of treatment with the GnRH antagonist. Testicular volumes were reduced to approximately 25% of pretreatment values in both groups by week 8 and stayed in that range during the remaining period of administration of the GnRH antagonist. During the first 6 weeks of administration of the GnRH antagonist, the ejaculatory response to electrostimulation and the volume of the ejaculates diminished with time.(ABSTRACT TRUNCATED AT 250 WORDS)
Weinbauer
G F
GF
Max Planck Clinical Research Unit for Reproductive Medicine, University of Münster, Federal Republic of Germany.
Khurshid
S
S
Fingscheidt
U
U
Nieschlag
E
E
D000818:Animals; D004334:Drug Administration Schedule; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D007265:Inhibins / Q000097:blood*; D007986:Luteinizing Hormone / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D009845:Oligospermia / Q000139:chemically induced*; D010906:Pituitary Hormone-Releasing Hormones / Q000037:antagonists & inhibitors*; D013076:Sperm Count / Q000187:drug effects; D013737:Testis / Q000473:pathology; D013739:Testosterone / Q000008:administration & dosage* / Q000097:blood; D015431:Weight Loss / Q000187:drug effects
D010906:Pituitary Hormone-Releasing Hormones; C062272:LHRH, N-Ac-2-naphthyl-Ala(1)-4-chloro-Phe(2)-pyridyl-Ala(3)-nicotinyl-Lys(5,6)-isopropyl-Lys(8)-AlaNH2(10)-; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007265:Inhibins; D007986:Luteinizing Hormone