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Box CThe Actions of Sex Hormones

Sex hormones, which include progestagens, androgens, and estrogens, are all steroids derived from a common precursor, cholesterol (see Figure 30.1). Despite the tendency to speak of these hormones as female or male, it is not really correct to think of estrogens as female and androgens as male; females and males synthesize both estrogens and androgens, and estrogens are the effective agonist in both sexes (see text). What is important is the receptors available to bind the two steroids when they are in the circulation. The brain has receptors for all these sex steroids, but the distribution of each receptor type is slightly different in females and males. For example, a higher level of estrogen receptors occurs in the arcuate, dorsomedial nucleus, and ventrolateral nucleus of the hypothalamus of females than in males.

Because sex steroids are lipids, they do not need special membrane receptors to enter cells; they simply diffuse through the lipid bilayer of the membrane. However, neurons and other cells have the capacity to select, concentrate, and retain specific steroids by means of receptors and binding proteins in the cytoplasm and nucleus. Different areas of the adult brain have different steroid receptor patterns, with overlapping distributions of receptor types. Thus, particular brain regions can be targets for the actions of different classes of steroids. For instance, estradiol receptors are sparsely distributed in the neocortex of the rat, but are prevalent in preoptic and hypothalamic areas and the anterior pituitary (figure A). Conversely, whereas receptors for 5-α-dihydrotestosterone (5-DHT) are found only in certain nuclei in the septum and hypothalamus, both estradiol and 5-DHT receptors are abundant in the frontal, prefrontal, and cingulate areas of the cortex. Some neurons express receptors for more than one steroid. Thus, all neurons with progesterone receptors also express estrogen receptors. As a result, hormones can have a synergistic effect; for example, certain reproductive behaviors brought on by progesterone can be enhanced if estrogen is given first.

Steroids can have a direct effect on neural activity by altering the permeability of the membrane to neurotransmitters and their precursors, or by altering the functioning of the neurotransmitter receptors (figure B). This type of effect has a latency to onset of seconds to minutes. As a consequence of these actions, sex steroids can modulate the efficacy of neural signaling.

Sex steroids can also have an indirect effect on neural activity by forming noncovalent bonds with steroid receptors or by indirectly affecting other signaling pathways. Binding to a steroid receptor causes a conformational change that allows the receptor to bind to specific DNA recognition elements called hormone responsive elements. Steroid receptor coactivators, members of a family of coactivators that modulate the activity of steroid receptors, can enhance the effects of steroids by opening up chromatin structure, or by stabilizing the preinitiation complex at the promoter. Consequently, hormones can alter gene expression, leading to changes in the synthesis of specific proteins (see figure B). Such hormonal actions have a latency to onset of minutes to hours.

Most sexually dimorphic differences in the brains of females and males are thought to arise by the indirect actions of hormones on gene expression.

(A) Distribution of estradiol-sensitive neurons in a sagittal section of the rat brain. Animals were given radioactively labeled estradiol; dots represent regions where the label accumulated. In the rat, most estradiol-sensitive neurons are located in the preoptic area, hypothalamus, and amygdala. (B) Steroids have direct and indirect effects on neurons. Dashed line shows direct effects of hormones on the pre- or postsynaptic membrane, which alter neurotransmitter release and affect neurotransmitter receptors. Solid line shows indirect effects of hormones, which act at the level of the nucleus to alter protein synthesis. (A after McEwen, 1976; B after McEwen et al., 1978.)