Membrane estrogen receptor alpha rapidly regulates male mice sexual behavior

Introduction/Aim:
The activation of male sexual behavior depends on brain aromatization of testosterone into an estrogen. Estrogens exert slow genomic effects (hours/days) by binding to nuclear estrogen receptors but also rapid effects (seconds/minutes) by acting on membrane-associated receptors (including G-protein coupled estrogens receptor 1 [GPER1] or the nuclear receptors themselves following palmitoylation) to activate intracellular signaling pathways. Rapid effects of estrogens have been described on reproductive behavior of rodents but the identity of the receptor involved is not known. In mice, estrogen receptor alpha (ERα) plays a major role in the control of male sexual behavior but whether these effects involve membrane triggered-actions remains unclear. In this study, we used a mouse model carrying a mutation at the palmitoylation site of ERα making it unable to traffic to and signal from the membrane (C451A-ERα) to investigate the role of membrane estrogen receptor alpha (mERα) in the motivational and copulatory aspects of male sexual behavior.

Methods/Results:
Sexually experienced and gonadally intact C451A-ERα and wild-type male mice were tested for sexual motivation using the partner preference test and for sexual performance by measuring the frequencies and latencies of mounts, intromissions and ejaculations observed during a 30 minutes interaction with a receptive female. Both aspects of behavior were tested 10 minutes after single subcutaneous injections of estetrol (E4), a natural estrogen acting as an antagonist of mER or the aromatase inhibitor 1,4,6-Androstatriene-3,17-dione (ATD). In both genotypes, ATD acutely decreased both sexual performance and the time spent by males near the female, confirming the key role of aromatization in the rapid control of male sexual performance and extended this conclusion to sexual motivation. On the other hand, E4 rapidly decreased sexual performance in wild-type males, but it had no effect on the sexual performance of C451A-ERα males. Moreover, E4 did not affect time spent near the female in both genotypes.

Conclusions :
These data indicate that E4 rapidly inhibits sexual performance, but not sexual motivation. Since this rapid effect of E4 is prevented in mice invalidated for mERα, this demonstrates the role of mERα in the regulation of rapid effects of neuroestrogens on sexual performance in mice. Finally, the persistence of the effect of ATD on behavior in C451A-ERα mice suggests that another estrogen receptor, such as ERβ or GPER1, could also regulate both aspects of male sexual behavior.