Editorial: stressing the importance of sex.

Neuroendocrine responses to stress, particularly those mediated by the hypothalamic-pituitary-adrenocortical (HPA) axis, can differ significantly between males and females in many species. In laboratory rats and mice, for example, basal and stress-induced hormone secretions in the HPA axis are generally higher in females than in males in a variety of experimental situations (1, 2). Female rodents also exhibit alterations in basal and stress-induced HPA activity across the ovulatory cycle, with highest levels observed during the preovulatory period (3, 4). Which mechanisms govern the sex-specific secretion of stress hormones, and what is the adaptive significance of these phenomena? Although definitive answers to these questions have not yet been obtained, tantalizing clues—such as those provided by Speert et al. (5) in this issue of Endocrinology—suggest that sex hormones may play a key role in sculpting the features of stress hormone responses in ways that may optimally coordinate the activity of the reproductive and stress responsive systems. The activity of the HPA axis is sexually differentiated despite the fact that both sexes are endowed with the same basic physiological response transduction system. In both females and males, stressful stimuli evoke neural and hormonal signals that activate CRH neurons in the paraventricular nucleus, prompting release of CRH into the hypophysial portal vasculature. The CRH is conveyed to the anterior pituitary gland, where it can bind receptors on corticotrophs, and thereby stimulate synthesis and secretion of ACTH. In turn, ACTH binds its cognate receptors in zona fasciculata cells in the adrenal cortex and stimulates production of glucocorticoids. Feedback regulation in the axis is exerted by integrated effects of glucocorticoids on corticotrophs to suppress CRH-stimulated ACTH secretion and on hypothalamic neurons and limbic structures to suppress neurosecretion of CRH. In addition to its role in eliciting activity in the HPA axis, CRH is also released at synaptic endings within the central nervous system (CNS), where the peptide likely contributes to behavioral stress responses, anxiogenesis, and central activation of autonomic responses. Both the postsynaptic and pituitary actions of CRH are transduced by one or both of the known G protein-coupled receptors for the peptide, the type 1 CRH receptor (CRH-R1) and the type 2 CRH receptor (CRH-R2). Other neuropeptides that play major roles in stress responses include the urocortins (6), which can bind CRH receptors with differing affinities compared with CRH itself and thereby modulate CRHmediated responses and/or activate alternate response patterns at central and/or pituitary sites. Vasopressin is also known to act through its own receptors to amplify the actions of CRH in the stimulation of ACTH secretions (7). A most interesting player in the HPA axis is the CRHbinding protein (CRH-BP), a glycoprotein identified by Vale and colleagues in 1991 (8) on the basis of its ability to bind CRH and attenuate CRH’s actions at CRH receptors. Consistent with its purported function, anatomical studies demonstrate expression of CRH-BP at locations of CRH synthesis and release sites (9), including limbic and basal forebrain structures and anterior pituitary corticotrophs (10). Genetic manipulations of CRH-BP expression have also provided evidence supporting CRH-BP’s role in tempering CRH actions at both central and adenohypophysial sites (11). The most potent inducers of CRH-BP expression appear to be those processes that mediate activation of HPA activity: stress (12), CRH (13), and glucocorticoids (12). The latter observations in particular have provided support for the idea that CRH-BP functions as a feedforward inhibitor in the HPA axis—an endocrine device that is engaged in concert with the activation of the HPA axis—and thereby limits the duration of HPA activation by prompting a quicker return of the system to basal homeostatic levels of activity. Is it possible that differences in CRH-BP expression in males vs. females may account for the sexual differentiation of HPA axis activity, or at least some aspects of it? Speert et al. (5) examined this possibility in their studies, reasoning that higher basal ACTH levels and more robust ACTH and corticosterone responses to stress in females may be a consequence of lower CRH-BP expression. They further hypothesized that the heightened circadian peaks of ACTH and glucocorticoid secretion that are known to occur in proestrus females (3, 4) may result from an ability of preovulatory ovarian estrogen secretions to suppress CRH-BP production, thereby disinhibiting the actions of CRH on pituitary corticotrophs. As is often the case in well-designed and carefully executed studies, their results unequivocally disprove their hypothesis, and in so doing they raise a most interesting, and perhaps more illuminating, alternative scenario. Because the expression of CRH-BP is clearly higher in females than in males, and it is stimulated by estrogen, it may instead be the case that CRH-BP expression is up-regulated to ensure that HPA activity is rapidly returned to basal levels after having been stimulated and is kept at a lower level for several additional hours (see Ref. 3) before it begins its daily ascent throughout the hours of the following estrous morning. This begs the question: What is the adaptive significance of sharply higher stress hormone secretions in late proestrous, followed by a period of HPA quiescence? The answer to the foregoing question may be tied to the larger issue of the functional relationship between HPA axis and neuroendocrine systems that govern reproduction. Indeed, the differentiated patterns of HPA activity in the two sexes may be less about stress and more about . . . well, sex. Specifically, the female pattern of HPA activation may have particular functional significance with respect to the cyclic manifestation of behavioral estrus. In response to preovulatory gonadal steroid secretions, female rats exhibit a period Abbreviations: CNS, Central nervous system; CRH-BP, CRH-binding protein; HPA, hypothalamic-pituitary-adrenocortical; HPG, hypothalamic-hypophysial gonadal. 0013-7227/02/$15.00/0 Endocrinology 143(12):4502–4504 Printed in U.S.A. Copyright © 2002 by The Endocrine Society doi: 10.1210/en.2002-221041