Dissociating antifertility effects of GnRH-antagonist from its adverse effects on mating behavior in male rats

Antagonist analogues of gonadotropin-releasing hormone (GnRH-A) alone inhibit spermatogenesis in experimental animals, but concomitant decline in serum testosterone leads to abolition of mating behavior. We assessed if the antifertility effects of GnRH-A could be dissociated from its effects on mating behavior by combining it with a small dose of androgen. Seven groups of six adult male Wistar rats were treated for 70 days as follows: I) controls, II) GnRH-A alone (250 μg/day), III) GnRH-A + 0.05 mg testosterone enanthate (TE), IV) GnRH-A + 0.15 mg TE, V) GnRH-A + 0.50 mg TE, VI) GnRH-A + 1.50 mg TE, and VII) GnRH-A alone (recovery group). Testes, prostate, and seminal vesicle weights were markedly reduced by GnRH-A treatment alone. Doses of TE required to maintain prostate and seminal vesicle weights were between 0.15 and 0.50 mg. Testis weights were not restored to normal even by the highest dose of TE. Intratesticular sperm counts were markedly decreased by GnRH-A treatment and restored only at the highest dose of TE (1.50 mg). Five out of six animals in group II, six out of six animals in group III, and one out of six in group IV were azoospermic. When mated with normal females, all animals in groups I and VI were fertile, all animals in groups II, III, and IV were infertile, whereas only four out of six animals in group V were fertile. All measures of mating behavior were impaired by GnRH-A treatment and restored by the smallest dose of TE (0.05 mg). Histological examination of the testes revealed spermatogenic arrest and complete absence of sperm in groups II, III, and IV. Group V and VI had normal spermatogenesis qualitatively. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations were markedly inhibited by GnRH-A treatment alone. Addition of graded concentrations of TE to GnRH-A led to a dose-dependent increase in serum FSH. We conclude 1) that GnRH-A treatment markedly inhibits LH and FSH and induces azoospermia in male rats and 2) the dose of testosterone required to maintain mating behavior in this model is much lower than that required to maintain spermatogenesis. These data suggest feasible application of combined GnRH-A and androgen treatment for male contraception.