Figure 1.

Organizational-activational hypothesis. (A) The testes are active during perinatal development providing testosterone for central aromatase (Aro) to produce estrogen (E) within the brain. Estrogen organizes the brain by binding to ERs, leading to the masculinization and defeminization of the brain. By contrast, the perinatal ovary is quiescent. In utero, the brain is protected from estrogens that may enter via maternal circulation by the presence of α-fetoprotein that binds estrogen. The role of the GPER1 in this organizational period is largely unknown. For a detailed review, the reader is referred to (8) and references therein. (B) The organized neural substrate is activated following puberty when the gonads become active. Estrogen is released from the ovaries and testosterone (T) from the testes, which is then aromatized to estrogen in the brain. The availability of cholesterol (Ch) and presence of steroidogenic enzymes within the brain also allows for the de novo production of neuroestrogens. Estrogens activate neural circuits to express behaviors through activating second messenger pathways such as MAPK acutely and recruiting transcriptional coactivators such as fos and jun to regulate non-ERE containing promoters. This could be via multiple ERs, including GPER1 (9). Alternatively, the classical nuclear hormone receptors, ERα/β can translocate to the nucleus to directly bind estrogen-response-elements in DNA to regulate gene transcription. Both these pathways result in modulation of behaviors in both males and females.