Organizational versus activational effects of sex steroid hormones

The study of sex differences in the brain grew out of our understanding of how gonadal hormones influence sexual differentiation of the body with regard both to primary sexual differences between males and females (the differentiation of the sexual organs) and to the development of secondary sexual differences (body fat distribution, muscle development, breast development, differences in hair distribution). In the case of sexual differentiation of the body, it is clear that exposure of males to various testicular secretory products, including testosterone, during early prenatal development leads to sexual differentiation of the internal and external genitalia. Later activation of the reproductive axis at puberty, with a sustained increase in circulating testosterone, then leads to the development of secondary sexual characteristics. Thus, testosterone has both organizational and activational influences on the sexual differentiation of the body. Organizational effects of gonadal hormones are conceptualized as resulting from the early influence of gonadal hormones on structural development that do not require continued hormone exposure to maintain sexual differentiation. Activational effects are conceptualized as later stimulation of reversible influences on sexual differentiation that require continued exposure to gonadal hormones to maintain sex differences.

The concept that sex steroid hormones have important and permanent organizational effects on the developing brain was originally postulated on the basis of experimental findings that treatment of developing mice with testosterone produced permanent effects on reproductive capacity (Barraclough and Leathern, 1954), with early treatment with testosterone blocking later activation of ovulation by estradiol. A similar coordination of early and later influences of gonadal steroid hormones on reproductive behavior was first reported by Phoenix and coworkers (1959). These investigators found that exposure of female guinea pigs to testosterone in the prenatal period increased the likelihood of animals' displaying masculine sexual behaviors in adulthood, and simultaneously decreased the likelihood of their displaying feminine sexual behaviors. These observations formed the basis for the hypothesis that, during early brain development, exposure to sex steroids can have long-lasting, organizational effects that will influence CNS neuronal activity and behavior throughout life. Although there are exceptions, it is now recognized that for a multitude of diverse actions of sex steroid hormones on the brain there are specific "critical" periods in early brain development when sex steroid hormone exposure has permanent organizational effects on the regions of the brain mediating these actions (Cooke et al., 1998; MacLusky and Naftolin, 1981).

In general, exposure of males to testicular hormones during prenatal and early postnatal periods leads both to masculinization of some tissues and functions (masculine changes in genital structure, copulatory behavior, and other behaviors characteristic of males) and to defeminization of other tissues and functions (ovulatory competence, feminine sexual behaviors such as lordosis, and other behaviors characteristic of females). Because the various steroid-sensitive tissues of the body and brain have differing critical periods for the organizational effects of testosterone, in some congenital syndromes and under some experimental conditions certain tissues of the body and brain may become masculinized while others do not. Thus, it is often important to consider the degree of masculinization or feminization of specific tissues and functions.

In rodents, the critical period for steroid hormonemediated organization of brain regions and sexually dimorphic behaviors appears to be postnatal, with most effects occurring during the first 10 days of life. In primates, sexual differentiation of the brain occurs pre-natally, over an extended period in midgestation (Phoenix, Goy, and Resko, 1968).

In contrast to the organizational effects of sex steroid hormones on the neural circuits that control behavior, the more common actions of sex steroids on behavior in adulthood are often conceptualized as activational effects. That is, sex steroid treatment causes a temporary and reversible change in neural function and behavior. An example of an activational effect of a sex steroid on behavior is the rapid increase in display of female sexual receptive behavior, lordosis, that occurs in female rats after a brief exposure to elevated estrogen.

Despite the useful conceptual framework of early organizational effects and later activational effects of steroid hormones on neural function, there are clear examples in which effects of steroid hormones in adulthood cause major long-term structural reorganization of the brain. For example, castration of male hamsters and rats in adulthood has been shown to lead to dramatic decreases in neural size and dendritic branching within the medial amygdala, with testosterone treatment in adulthood reversing these changes (Cooke et al., 1998; Gomez and Newman, 1991). Another example of long-term organizational effects of steroid hormones in adulthood is the neurotrophic effects of testosterone on substance P-containing neurons of the medial nucleus of the amygdala and the bed nucleus of the stria terminalis in the rat (Malsbury and McKay, 1994). Male rats have almost twice the area of substance P-containing neurons in these brain regions compared to females, and this sexually dimorphic difference is dependent on the maintenance of adult levels of testosterone. Castrating males in adulthood leads to a dramatic decrease in the area of substance P-containing neurons.

A great many actions of steroid hormones on the brain require both early organizational and later activational effects of the hormones, but this is not true in all cases. The ventromedial hypothalamus (VMH) is a sexually dimorphic nucleus that plays key roles in the control of feminine reproductive behaviors, including maternal behavior and lordosis in rats (Madeira and Lieberman, 1995; Pfaff, 1980). The VMH is significantly larger in males than in females, but individual cell nuclei are larger in females (Dorner and Staudt, 1969). These differences depend on organizational effects of steroid hormones in the first few days of postnatal life, such that castration of males on postnatal day 1, but not postnatal day 7, reduces the volume of the VMH to that of control females (Dorner and Staudt, 1969). In adulthood the VMH is a critical site for the induction of lordosis behavior in response to elevations in estradiol and progesterone (Pfaff, 1980). Estradiol treatment of female rats leads to a number of acute changes in the

VMH, including an increase in protein synthesis and an increase in dendritic spines in VMH neurons, and induction of progesterone receptors and receptors for another reproductive hormone oxytocin (McEwen, 1991). Subsequent progesterone exposure leads to changes in the location of oxytocin receptors and makes the estra-diol-primed female sensitive to oxytocin-induced lordosis (McEwen, 1991). Some of these acdons depend on both the organizational and activadonal effects of steroid hormones on VMH neurons. For example, estradiol increases dendritic spines in VMH neurons in the female, but the VMH neurons in the male are refractory to this action of estradiol (Frankfurt et al., 1990; McEwen, 1991). Also, estradiol treatment sensitizes this nucleus to actions of progesterone in females, but not in males (Rainbow, Parsons, and McEwen, 1982). Other actions of estradiol in this nucleus depend only on acute estradiol exposure. For example, estradiol induces oxytocin receptors in the VMH in adulthood in both female and male rats (Coirini, Johnson, and McEwen, 1989). These contrasts highlight the need for specificity when determining the contributions organizational versus activational actions of a sex steroid hormone, both in reference to the particular action of a steroid hormone and the cell type upon which it is acting.

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