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 males rendered irreversibly infertile by
CDB-4022; levels increased transiently and returned to baseline in rats protected by
acyline pretreatment. These data indicate that pretreatment with
acyline was able to prevent irreversible
infertility in CDB-4022-treated rats, whereas posttreatment with
acyline did not promote spermatogonial differentiation, as has been observed by others in rats that received
GnRH analogs and various other testicular toxicants. Suppression of ITT and possibly rFSH by
acyline appeared to be crucial in preventing irreversible
infertility induced by
CDB-4022. In this regard, our results are similar to those of investigators who have studied other testicular toxicants. Continued development of
CDB-4022 as a potential
male contraceptive will depend largely on its safety profile and whether its antispermatogenic activity is reversible in primates.