Perinatal hormonal exposure and the development of neuroendocrine regulatory processes

Abstract

The concept that certain sexual differences in brain function are established by exposure of the brain to a particular hormonal environment during early perinatal development of the intrinsically female, or at least undifferentiated, brain is reviewed. Since sexual differentiation of the brain is a normal function of the neonatal testis, it had been (1) assumed that the ovary is hormonally quiescent perinatally and (2) argued that the effectiveness of exogenous estrogen in masculinizing the brain is a pharmacological oddity. However, recent studies from several laboratories indicate that endogenous estrogen levels in perinatal plasma are very high. Since a peculiar estrogen‐binding protein is present in the neonatal rat, it may be that the high plasma titers of estrogen, whatever their source, are sequestered by this protein and prevented from exerting a masculinizing action. The importance of this putative protective mechanism is emphasized by the currently popular view that estrogen is the effective molecular form of the masculinizing hormone. Although the generally accepted model of sexual differentiation of the brain includes the concept of a limited critical period of hormone sensitivity, treatment of the perinatal female with low doses of androgen delays the onset of anovulatory sterility until well beyond puberty. It is possible that the postpubertal animal that exhibits the delayed anovulation syndrome may represent a model of sexual differentiation extended into adulthood. Results are presented to document that there are age‐related changes in the ability of gonadal steroids to facilitate LH release in these animals, changes that appear to be related to perinatal steroid exposure. Finally, although several subtle morphological sex differences have been observed in the brain, we now report the existence of a marked sex difference in the extent and volume of the medial preoptic nucleus, a difference that can be detected by observation of histological sections even with the naked eye. The functional significance of this gross sex difference, the medial preoptic nucleus being larger in the male, is unknown. Not only is the functional activity of the hypothalamus complex, but the process of sexual differentiation may apply to several functions not readily classified as sexual in nature. Nevertheless, it is evident that the chemical environment during perinatal development in the rat can exert permanent functional and perhaps morphological effects.