Estrogen Receptor and Brain Sex Differentiation

Sexual behavior in many mammals is characterized by its dependence on circulating titer of sex hormones and sexual dimorphism. Sexual dimorphism in female and male behavior depends, not on genetic sex but on early actions of sex hormone at a specific period during ontogenesis in each species. The period, termed the critical period for the brain sex differentiation, spans over gestational day 18 to neonatal day 5 in the rat. Testosterone or its aromatization product estradiol organizes or androgenizes the rat brain toward male phenotype. Thus, according to the aromatization hypothesis, binding of circulating estrogen by alpha-fetoprotein prevent this hormone to cross over the blood-brain barrier and female type of rat brain develops in the absence of estrogen. In the males, testosterone enters into the brain and converted to estrogen by an enzyme aromatase. Colocalization of aromatase and estrogen receptor (ER) has been demonstrated in neurons in the preoptic area (POA) and bed nucleus of the stria terminals regions. Ability to exhibit male-like sexual behavior of the testicular feminized rat, that develops as an anatomic female despite its male karyotype due to an androgen receptor deficiency, support that male development of the brain is mediate by ER. Conversely, the male mice genetically altered so that they lack ER alpha generally took the female attitude, showing a high open-field activity and the lack of aggression to intruders in their territory. Endocrine disruptors with estrogenic activity would thus interfere with the process of brain sex differentiation. Brain sex differences can be detected by several different measures. Morphometry revealed sexual dimorphism in the rat POA in its synaptic organization, dendritic branching patterns and the size of particular neuronal groups or the number of neurons it contains. In females more than in males, a significantly larger number of ER beta positive cells has been visualized in the anteroventral periventricular nucleus (AVPV) of the rat POA. Orchidectomy of male neonates or estrogen treatment of female pups reversed the brain sex. Simultaneous visualization of ER beta and ER alpha revealed that 83% of ER beta positive cells in the female AVPV co-express ER alpha, suggesting that the developmental effect of estrogen depends on ER alpha. Aside from brain morphology, sexual difference in the properties of individual neurons effectively dictates sex-specific functions. Neuronal physiology provides clues to subtle effects of organizational effects of sex hormones that defy morphological identification. Estrogen changes thresholds and refractory periods for antidromic …