piperidines and acyline

Intratesticular testosterone (ITT) is known to play a critical role in the maintenance of spermatogenesis. We have used acyline, a GnRH antagonist, to suppress testosterone (T) production, and acyline and T implants to study the prevention of irreversible infertility induced by CDB-4022. Vehicle or acyline was administered to proven fertile male rats (n = 5/group) at a dose (210 microg/day) that completely suppressed (P < 0.05) T production, as measured by serum T, and testicular function, either before, concurrent with, or after vehicle or a single oral dose of 2.5 mg CDB-4022/kg (Week 0). Vehicle-treated males remained fertile, whereas acyline-treated males exhibited transitory infertility. CDB-4022 alone caused irreversible infertility in all males. Importantly, CDB-4022-treated males recovered fertility when acyline was started before CDB-4022 (Weeks -4 to 0; Weeks -4-9), but not when acyline was administered concurrently with or after CDB-4022 (Weeks 0-9; Weeks 10-19). At the end of this study (Week 34), testes weights, spermatid head counts (SHC), and tubule differentiation indices (TDI) were suppressed (P < 0.05) in infertile CDB-4022-treated males, but in rats that recovered fertility, these parameters were similar (P > 0.05) to those in vehicle-treated males. In addition, serum inhibin B and epididymal androgen-binding protein levels were nondetectable in infertile CDB-4022-treated rats. To test whether suppression of ITT was critical for prevention of CDB-4022-induced infertility, proven fertile rats (n = 7-8/group) received vehicle, acyline alone, or acyline and a T implant for 4 wk before CDB-4022 (Week 0). The T implant increased ITT in acyline-treated rats. Although ITT was lower (P < 0.05) in the T-implanted males than in untreated rats, it was sufficient to sustain spermiogenesis. Serum rFSH levels were also elevated in rats treated with acyline + T as compared with acyline alone during the treatment interval, but rFSH was still lower than in vehicle-treated rats. Rats in all treatment groups were rendered infertile initially, but the acyline + CDB-4022-treated rats recovered fertility by Week 10. In contrast, rats treated with CDB-4022 alone or acyline + T + CDB-4022 remained infertile until at least Week 16. Testes weights, SHC, and TDI were within normal ranges for acyline + CDB-4022-treated rats, but were decreased (P < 0.05) in CDB-4022- or acyline + T + CDB-4022-treated rats. Serum inhibin B levels were nondetectable by Week 1 in mal

Topics: Animals; Female; Indenes; Infertility, Male; Male; Oligopeptides; Piperidines; Rats; Rats, Sprague-Dawley; Recovery of Function; Testis; Testosterone