Non-androgenic testicular mediation of androphilia in male mice with global overexpression of androgen receptors

•Global androgen receptor overexpression (CMV-AR) increases androphilia in male mice.•Gonadectomy (GDX) of CMV-AR male mice restores gynephilic partner preference.•GDX with testosterone restores gynephilic olfactory preference in these mice.•Results support an inhibitory activational effect of testes on behavior. Sexual attraction is robustly sexually differentiated among mammalian species. Gonadal androgens acting perinatally and in adulthood are required for male-typical preference for female sexual cues. Recent evidence suggests that at the high extent of AR signaling, male mice show an increased preference for same-sex odor cues. These findings were found only in mice that overexpress AR globally in all tissues (CMV-AR), whereas neural AR overexpression (Nestin-AR) did not affect sexual preference. The present studies investigated the endocrine basis of this phenotype and examined whether preference for male or female stimulus animals (partner preference) was also affected in these transgenic animals. We manipulated adult gonadal hormones in male mice that overexpress AR globally and males that overexpress AR only in neural tissue. We replicate the finding that androphilia is increased in gonadally intact CMV-AR males, and these males exhibited reduced neural activation in response to estrus female odors. Testosterone treatment of gonadectomized CMV-AR males was sufficient to induce a gynephilic olfactory preference, while a gynephilic partner preference was induced with gonadectomy alone. These findings suggest that altered sexual preference of CMV-AR male mice is mediated by inhibitory activational functions of the testes. Together, these results suggest that at the high extent of AR signaling, non-neural AR via the gonads, can promote androphilia.