Hormone-like behavioral effects of levonorgestrel and its metabolites in the male rat

Abstract

Levonorgestrel (LNG), a contraceptive progestin, exhibits, besides its progestational activity, other hormone-like effects at the peripheral level. To assess whether LNG and its metabolites exert androgenic and/or estrogenic actions at the central nervous system (CNS), their effects on male sexual behavior in castrated rats were examined. LNG, 5α-dihydro LNG (5αLNG), and the 3α,5α- and 3β,5α-tetrahydro derivatives of LNG (3αLNG and 3βLNG, respectively) were administered for 3 weeks either alone (1000 μg/day) or in combination (300 μg/day) with 5α-dihydrotestosterone (DHT, 300 μg/day) or with estradiol-17β (E 2, 5 μg/day). Copulatory behavior was assessed twice per week and sex accessory organs weights recorded at the end of treatments. LNG restored full copulatory behavior comparable to that of testosterone treated animals, although with a slight delay, whereas 5αLNG induced male sexual behavior in a significantly lower number of subjects. 3βLNG and 3αLNG induced mounting but failed to restore intromission and ejaculation. Combined LNG+E 2 treatment fully activated mounting and intromission, but ejaculation was only partially restored. Combined 5αLNG+E 2 treatment and the combinations of 3αLNG or 3βLNG with E 2 were significantly less effective, activating fewer intromissions and ejaculations. 3αLNG and 5αLNG, in combination with DHT, restored male sexual behavior. LNG, but not its metabolites, induced a significant increase on the weight of sex accessory organs. The overall results demonstrated that high doses of LNG induce a potent androgen agonistic behavioral effect and that its A-ring reduction diminishes this potency and enables a shift towards a weak estrogen-like effect.