CAN TESTOSTERONE ALONE MAINTAIN THE GONADOTROPIN-RELEASING-HORMONE ANTAGONIST-INDUCED SUPPRESSION OF SPERMATOGENESIS IN THE NONHUMAN PRIMATE

The combination of gonadotrophin-releasing hormone (GnRH) antagonist a nd delayed testosterone substitution provides a promising approach tow ards male contraception. However, the GnRH antagonists used clinically so far cause side-effects and have to be administered continuously. W e therefore used the non-human primate model to see whether the GnRH a ntagonist cetrorelix (which exhibits a favourable benefit-to-risk rati o in terms of anti-gonadotrophic action in normal men) induces complet e and reversible suppression of spermatogenesis and whether GnRH antag onist-induced suppression of spermatogenesis can be maintained by test osterone alone. Four groups of adult cynomolgus monkeys (Macaca fascic ularis; five per group) were injected daily with 450 mu g cetrorelix/k g ([N-acetyl-D-2-naphthyl-Ala(1), D-4-chloro-Phe(2), D-pyridyl-Ala(3), D-Cit(6), D-Ala(10)]-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 r estore the ejaculatory response to electrostimulation; group 3 receive d the GnRH antagonist for 18 weeks and testosterone buciclate (TB) was injected during week 6 of GnRH antagonist treatment; group 4 was subj ected to GnRH antagonist administration for 7 weeks and received TB (2 00 mg/animal) during week 6. Under GnRH antagonist treatment alone ser um concentrations of testosterone were suppressed. TB maintained testo sterone 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 significa ntly from week 8 onwards. Group 2 animals were azoospermic during week s 12-18 of GnRH antagonist administration. The TB-replaced groups deve loped 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 producti on compared with group 2 but had maintained the spermatogenic status p resent at week 6 (onset of TB substitution). All inhibitory effects of cetrorelix and/or TB were reversible after cessation of treatment. Th ese findings demonstrate that cetrorelix reversibly inhibits spermatog enesis in a non-human primate model. Although TB maintained the GnRH a ntagonist-induced suppression of spermatogenesis, azoospermia was not achieved. This latter effect may reflect either a direct spermatogenes is-supporting effect of the high dose of TB or the partial recovery of inhibin secretion (indirectly reflecting FSH secretion) or a combinat ion of both. Thus, maintenance of GnRH antagonist-induced spermatogeni c inhibition by testosterone alone appears theoretically possible. Whe ther this regimen will, however, permit the induction of sustained azo ospermia remains to be seen, preferably in human studies.