Induction of male sexual behavior by norethisterone: role of its A-ring reduced metabolites.

The estrogenic and androgenic potencies of norethisterone (NET), a synthetic nonaromatizable progestin, and three of its reduced metabolites (5 alpha-NET; 3 alpha, 5 alpha-NET; 3 beta, 5 alpha-NET) were assessed by their ability to restore male sexual behavior in castrated male rats following their chronic administration in combination with either 5 alpha-dihydrotestosterone (DHT) or estradiol (E2), or when given alone. Full restoration of mating was achieved when 3 beta, 5 alpha-NET was administered with DHT, indicating an estrogenic effect of this compound. Lower estrogenic effects were noticed with 3 alpha, 5 alpha-NET and 5 alpha-NET, while NET had very little estrogenic potency. The only effective compound to restore ejaculation, when administered with E2, was NET, indicating its androgen-like intrinsic potency. When administered alone, NET exerted the most potent effect on male behavior, followed by 5 alpha-NET, while the tetrahydro derivatives were ineffective. The observation that NET alone restored male sexual activity at a level identical to that induced by testosterone demonstrated an androgenic-estrogenic activity of this progestin exerted through its intrinsic androgenic effect, and the estrogenic effect of its tetrahydro derivatives. Overall results indicated that the metabolism of NET modulates its mode of action at the brain, and support the concept that both estrogenic and androgenic effects are required for mating activation.