Is human brain masculinization estrogen receptor-mediated? Reply to Luoto and Rantala.

Human genetic males are unlike rodent males in that neither the ability to convert testosterone to estrogen nor a functional estrogen receptor (ER) appears necessary for male-typical behavior, but a functional androgen receptor (AR) is required. Brain masculinization is probably mainly AR-mediated in human genetic males. ER binding may nevertheless have important masculinizing or defeminizing effects in human genetic females. Probably the strongest available evidence on this issue is derived from females exposed to synthetic estrogens in utero due to their mother's treatment with DES. As we review, the totality of evidence from this population indicates little or no effect of estrogens on sexuality in genetic females. In addition, if brain masculinization were ER-mediated in humans, it seems unlikely that sex hormone-binding globulin would bind estrogens so effectively as to prevent them from masculinizing the brain. In sum, current evidence suggests that estrogen plays a limited role in masculinizing the human brain and behavior.