Review: neuroestrogen regulation of socio-sexual behavior of males

Abstract

It is thought that estrogen (neuroestrogen) synthesized by the action of aromatase in the brain from testosterone activates male socio-sexual behaviors, such as aggression and sexual behavior in birds. We recently found that gonadotropin-inhibitory hormone (GnIH), a hypothalamic neuropeptide, inhibits socio-sexual behaviors of male quail by directly activating aromatase and increasing neuroestrogen synthesis in the preoptic area (POA). The POA is thought to be the most critical site of aromatization and neuroestrogen action for the regulation of socio-sexual behavior of male birds. We concluded that GnIH inhibits socio-sexual behaviors of male quail by increasing neuroestrogen concentration beyond its optimal concentration in the brain for expression of socio-sexual behavior. On the other hand, it has been reported that dopamine and glutamate, which stimulate male socio-sexual behavior in birds and mammals, inhibit the activity of aromatase in the POA. Multiple studies also report that the activity of aromatase or neuroestrogen is negatively correlated with changes in male socio-sexual behavior in fish, birds, and mammals including humans. Here, we review previous studies that investigated the role of neuroestrogen in the regulation of male socio-sexual behavior and reconsider the hypothesis that neuroestrogen activates male socio-sexual behavior in vertebrates. It is considered that basal concentration of neuroestrogen is required for the maintenance of male socio-sexual behavior but higher concentration of neuroestrogen may inhibit male socio-sexual behavior.

Keywords: aggressive behavior; aromatase; dopamine; glutamate; gonadotropin-inhibitory hormone; neuroestrogen; sexual behavior; socio-sexual behavior.

Figure 1

Model of the intracellular mechanism of GnIH and its receptor (GPR147), glutamate and its receptor, dopamine that may control male socio-sexual behavior by regulating the activity of aromatase and neuroestrogen synthesis in the brain. GPR147 is expressed on aromatase immunoreactive cells in the brain. GPR147 is coupled to G_αi protein that inhibits the activity of adenylate cyclase (AC) and decreases cAMP production and the activity of protein kinase A (PKA). Inhibition of AC/cAMP/PKA pathway may thus decrease phosphorylated aromatase and increase dephosphorylated aromatase. 17β-estradiol (E2) synthesized from androgen such as testosterone (T) by aromatase in the brain especially in the preoptic area (POA) regulates male aggression. It has been previously demonstrated that aromatase activity is rapidly down-regulated by phosphorylation, and this down-regulation is blocked by kinase inhibitors. The administration of GnIH activates aromatase by decreasing phosphorylated aromatase, and stimulates neuroestrogen synthesis in the brain. Aromatase activity and estrogen concentration in the brain especially in the POA are low in the morning when the birds are active, but aromatase activity and E2 concentration gradually increased until the evening when the birds became inactive. E2 release in the POA also increased in the evening. Finally, centrally administered E2 at higher doses in the morning inhibited aggressive behavior. These results suggest that GnIH inhibits aggressive behavior by directly activating aromatase and increasing neuroestrogen synthesis in the brain beyond its optimum concentration for the expression of aggressive behavior. Glutamate was shown to decrease the activity of aromatase by phosphorylation, and dopamine may act as an alternative substrate for aromatase to compete with testosterone and prevent its transformation into estrogens. Glutamate and dopamine may thus facilitate male socio-sexual behavior by decreasing the activity of aromatase and maintaining the optimum concentration of neuroestrogen for the expression of male socio-sexual behavior.