Sexual differentiation

Sexual differentiation in mammals is linked to the composition of the sex chromosomes. In the genetic male, the sexually determining region (Sry) gene on the Y chromosome promotes the differentiation of the testis from the indifferent gonad, resulting in the production of two critical hormonal signals, testosterone and anti-Mullerian hormone (Arnold, 2004; Breedlove andHampson, 2002; Goy and McEwen, 1980; McCarthy, 1994). These hormones initiate the differentiation of the reproductive tracts and genitalia. Anti-Mullerian hormone supports the regression of the Mullerian duct resulting in the initial defeminiza-tion of the reproductive system. Testosterone promotes the development of the male-typical Wolffian ducts and the male genitalia resulting in the masculiniza-tion of the reproductive system. Thus, genetic sex (XX orXY) determines gonadal phenotype, from which derives the process of sexual differentiation into the male or female phenotype, or gender. Gonadal secretions then form the basis for the sexual differentiation of the reproductive system and the brain.

It is important to note that the process of sexual differentiation is mediated by multiple intracellular pathways and is therefore subject to variation. For example, testosterone is subject to intracellular metabolism by 5a-reductase into 5a-dihydrotestosterone, which binds to androgen receptors with a higher affinity than does testosterone. The formation of 5a-dihydrotestosterone from testosterone within reproductive tissues can enhance the process of virulization of the male genitalia. The differential expression of the androgen receptor or of factors regulating the downstream effect of the androgen receptor on gene expression or protein-protein interactions could likewise modulate the degree of masculinization. A familial reductase deficiency common in the Dominican Republic (Imperato-McGinley, 1979) results in the severely limited levels of 5a-dihydrotestosterone and in incomplete masculinization. It is reasonable to assume that the process of masculinization admits to degrees, even at the more rudimentary level of the reproductive tract and genitalia. Such variation is evident in cases of testicular feminization (or androgen insensitivity) or congenital adrenal hyperplasia, in which varying levels of androgen sensitivity (tfm) or androgen exposure (CAH) result in varying degrees of masculinization. The latter case is interesting since it affects the sexual differentiation of genetic females.

Successful reproduction requires the appropriate genitalia and endocrine organs, as well as the necessary "software," in the form of hypothalamic and pituitary secretions that regulate reproductive function and corticolimbic brain systems that influence sexual motivation and parental care of the offspring. Predictably, gonadal hormones also support the sexual differentiation of hypothalamic-pituitary-gonadal (HPG) axis. The essential gender difference in mammalian HPG function is the positive surge in hypothalamic gonadotrophin-releasing hormone (GnRH) in response to estrogen. This GnRH surge supports the pulse of pituitary luteinizing hormone (LH) essential for ovulation. The capacity for such positive feedback effects of estrogen is lost in the male rodent (although not in all male mammals) as a function of perinatal testosterone exposure (Levine, 1997). In genetic females, perinatal testosterone exposure results in the loss of the LH surge and the capacity for ovulation. Similarly, males castrated in early life retain the capacity for an estrogen-induced LH surge. Thus, HPG function in the adult is subject to the developmental influences of gonadal hormones in early life.

A comparable scenario is apparent in the sexual differentiation of sexual behavior in the rodent. As the female rat transits from diestrus to proestrus, there occurs a prolonged and increasing exposure to estrogen that ultimately triggers an LH surge and an increase in circulating levels of progesterone. These hormonal signals render the female sexually receptive and promote the classic lordosis reflex in response to male mounts (Kow and Pfaff, 1998). The female is unresponsive at other points in the cycle. The female pattern of behavior is coordinated with ovulation and the sexual differentiation of female sexual behavior follows the same pattern of influences as that observed for the HPG axis. Thus, as first suggested by Pheonix et al. (1959) in studies with guinea pigs, androgens act during perinatal development to "organize" the sexual differentiation of sexual behaviors. Females exposed to increased levels of perinatal androgens fail to exhibit lordosis in response to male mounting even when primed appropriately with estrogen and progesterone. Males castrated at birth retain the capacity to exhibit lordosis in response to estrogen and progesterone priming. This chapter refers largely to studies with rodents, and particularly the rat. Nevertheless, similar hormone-dependent mechanisms of neural and behavioral differentiation are observed in amphibians (Kelley, 1997), birds (Balthazart and Ball, 1995), and reptiles (Godwin and Crews, 1997).

Sex differences in phenotype are also analyzed at the level of the supporting neuroanatomy (Madeira and Lieberman, 1995; Simerly, 2002). The medial preoptic area (MPOA) of the rat is essential for the expression of male sexual behavior. Studies of Gorski et al. (1980) reveal a sexually dimorphic region of the MPOA that is significantly larger in male than in female rats. The gender difference in the size of the sexually dimorphic nucleus of the MPOA is androgen sensitive. The nucleus is significantly smaller in males castrated at birth, and equivalent in size in females treated with androgens in late fetal and early postnatal life (Gorski, 1984). The gender difference in the MPOA is apparent in early postnatal life and is associated with an increase in neurogenesis in the males (Jacobson et al., 1985) as well as an increased rate of neuron death in the females (Davis et al., 1996; McCarthy et al., 1997). In mice, ablation of bax, a member of the Bcl-2 family of proteins that is required for cell death in developing neurons, eliminates the sex differences in cell number in various hypothalamic and limbic regions (Forger et al., 2004).

An important issue here is the original observation that the absence of exposure to anti-Mullerian hormone or testosterone is associated with the development of the female-typical reproductive system. This idea led many in reproductive biology to assume that the female phenotype in mammals is virtually a "default option." However, studies focusing on processes of sexual differentiation that occur later in development appear to provide support for an active process of feminization (Fitch and Denenberg, 1998; Simerly et al., 1997; Stewart and Cygan, 1980; Toran-Allerand, 1981, 1995). For example, in the mouse, there is an increased number of tyrosine hydroxylase-positive neurons in the anteroventral paraventricular (AVPV) nucleus in the female compared with the male (Simerly et al., 1997). In an estrogen receptor a (ERa) knockout mouse, the number of tyrosine hydroxylase neurons are significantly reduced suggesting an estrogen-dependent process of feminization in a brain region that regulates gonadotropin-releasing hormone (GnRH) activity. These and comparable findings represent a critical conceptual advance that suggests the possibility of variation in the expression of traits that define female reproduction. These findings are also entirely consistent with studies of within-gender variation in females in both behavior and endocrine function (see below).

These findings provide a brief outline of the biological basis for sexual differentiation in mammals based on research largely with rodent models. Biological studies have traditionally focused on the essential question of the factors that lead to the development of male- or female-typical patterns of physiology and behavior for any particular species. The cascade of genomically driven events, including organ differentiation and accompanying hormonal secretions, form the basis for the process of sexual differentiation. It is important to note that the processes by which genomic sex is translated into organogenesis and differentiation, and the subsequent downstream hormonal effects on specific target tissues are subject to modification by environmental regulation on, for example, various enzymatic pathways. Such effects could then result in variations in the expression of gender-specific patterns of reproductive function. Studies in ecology, evolutionary biology, and human psychology reveal variation in multiple reproductive functions within members of the same sex and species. These variations reflect plasticity in reproductive phenotypes. The basic theme of this chapter is that the process of sexual differentiation in mammals can be influenced by environmental influences, particularly by parental effects. Indeed, these effects appear to derive from a fundamental biological theme whereby environmental conditions prevailing during conception and development can regulate the development of reproductive systems, including behavior.

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