Can testosterone alone maintain the gonadotrophin-releasing hormone antagonist-induced suppression of spermatogenesis in the non-human primate?
The combination of gonadotrophin-releasing hormone (GnRH) antagonist and delayed testosterone substitution provides a promising approach towards male contraception. However, the GnRH antagonists used clinically so far cause side-effects and have to be administered continuously. We therefore used the non-human primate model to see whether the GnRH antagonist cetrorelix (which exhibits a favourable benefit-to-risk ratio in terms of anti-gonadotrophic action in normal men) induces complete and reversible suppression of spermatogenesis and whether GnRH antagonist-induced suppression of spermatogenesis can be maintained by testosterone alone. Four groups of adult cynomolgus monkeys (Macaca fascicularis; five per group) were injected daily with 450 micrograms cetrorelix/kg ([N-acetyl-D-2-naphthyl-Ala1, D-4-chloro-Phe2, D-pyridyl-Ala3, D-Cit6, D-Ala10]-GnRH). Group 1 received the GnRH antagonist for 7 weeks followed by vehicle administration for another 11 weeks; group 2 was treated with GnRH antagonist for the entire 18 weeks with each animal receiving a single testosterone implant during weeks 11-18 to restore the ejaculatory response to electrostimulation; group 3 received the GnRH antagonist for 18 weeks and testosterone buciclate (TB) was injected during week 6 of GnRH antagonist treatment; group 4 was subjected to GnRH antagonist administration for 7 weeks and received TB (200 mg/animal) during week 6. Under GnRH antagonist treatment alone serum concentrations of testosterone were suppressed. TB maintained testosterone levels two- to fourfold above baseline levels in groups 3 and 4 and prevented the recovery of LH secretion for about 20 weeks after GnRH antagonist withdrawal, whereas inhibin levels increased significantly from week 8 onwards. Group 2 animals were azoospermic during weeks 12-18 of GnRH antagonist administration. The TB-replaced groups developed azoospermia or became severely oligozoospermic. Quantitation of cell numbers by flow cytometry during weeks 6 and 18 revealed that TB (groups 3 and 4) had prevented a further decline of germ cell production compared with group 2 but had maintained the spermatogenic status present at week 6 (onset of TB substitution). All inhibitory effects of cetrorelix and/or TB were reversible after cessation of treatment. These findings demonstrate that cetrorelix reversibly inhibits spermatogenesis in a non-human primate model. Although TB maintained the GnRH antagonist-induced suppression of spermatogenesis, azoospermia was not achieved. This latter effect may reflect either a direct spermatogenesis-supporting effect of the high dose of TB or the partial recovery of inhibin secretion (indirectly reflecting FSH secretion) or a combination of both.(ABSTRACT TRUNCATED AT 400 WORDS)
Weinbauer
G F
GF
Institute of Reproductive Medicine, Westfälische Wilhelms-Universität (WHO Collaborating Centre for Research in Human Reproduction), Münster, Germany.
Limberger
A
A
Behre
H M
HM
Nieschlag
E
E
D000818:Animals; D003864:Depression, Chemical; D004343:Drug Implants; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007265:Inhibins / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D013091:Spermatogenesis / Q000187:drug effects*; D013739:Testosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology
D004343:Drug Implants; C050320:testosterone 4-n-butylcyclohexylcarboxylic acid; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007265:Inhibins; C062876:cetrorelix