Sexual differentiation of the brain: a model for drug-induced alterations of the reproductive system

Abstract

The process of the sexual differentiation of the brain represents a valuable model system for the study of the chemical modification of the mammalian brain. Although there are numerous functional and structural sex differences in the adult brain, these are imposed on an essentially feminine or bipotential brain by testicular hormones during a critical phase of perinatal development in the rat. It is suggested that a relatively marked structural sex difference in the rat brain, the sexually dimorphic nucleus of the preoptic area (SDN-POA), is a morphological signature of the permanent or organizational action of estradiol derived from the aromatization of testicular testosterone. The SDN-POA of the male rat is severalfold larger in volume and is composed of more neurons than that of the female. The observation that the mitotic formation of the neurons of the SDN-POA is specifically prolonged has enabled us to identify the time course and pathway of neuronal migration into the nucleus. Study of the development of the SDN-POA suggests that estradiol in the male increases the number of neurons which survive a phase of neuronal death by exerting a neurite growth promoting action and/or a direct neuronotrophic action. It may not be possible to extrapolate this trophic effect of estradiol to all other structural sex differences since in the anteroventral periventricular nucleus, steroid exposure reduces the number of immunohistochemically defined dopaminergic neurons. Finally, although it is clear that gonadal hormones have dramatic permanent effects on the brain during perinatal development, even after puberty and in adulthood gonadal steroids can alter neuronal structure and, perhaps as a corollary to this, have permanent effects on reproductive function. For example, in the lightly androgenized rat which exhibits the delayed anovulation syndrome, exposure to estrogen prepubertally delays the onset of ovulatory failure, whereas estrogen exposure peri- or post-pubertally has an inhibitory effect on ovulation. Although the brain may be most sensitive to gonadal hormones or exogenous chemical factors during perinatal development, such sensitivity does not appear limited to this period.