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Estradiol and testosterone are powerful steroid hormones that impact brain function in numerous ways. During development, these hormones can act to program the adult brain in a male or female direction. During adulthood, gonadal steroid hormones can activate or inhibit brain regions to modulate adult functions. Sex differences in behavioral and neuroendocrine (i.e., hypothalamic pituitary adrenal (HPA) axis) responses to stress arise as a result of these organizational and activational actions. The sex differences that are present in the HPA and behavioral responses to stress are particularly important considering their role in maintaining homeostasis. Furthermore, dysregulation of these systems can underlie the sex biases in risk for complex, stress-related diseases that are found in humans. Although many studies have explored the role of estrogen and estrogen receptors in mediating sex differences in stress-related behaviors and HPA function, much less consideration has been given to the role of androgens. While circulating androgens can act by binding and activating androgen receptors, they can also act by metabolism to estrogenic molecules to impact estrogen signaling in the brain and periphery. This review focuses on androgens as an important hormone for modulating the HPA axis and behaviors throughout life and for setting up sex differences in key stress regulatory systems that could impact risk for disease in adulthood. In particular, impacts of androgens on neuropeptide systems known to play key roles in HPA and behavioral responses to stress (corticotropin-releasing factor, vasopressin, and oxytocin) are discussed. A greater knowledge of androgen action in the brain is key to understanding the neurobiology of stress in both sexes.

The chronic variable stress (CVS) paradigm is frequently used to model the changes in hypothalamic pituitary adrenal (HPA) axis function characteristic of many stress-related diseases. However, male C57BL/6 mice are typically resistant to CVS’s effects, making it difficult to determine how chronic stress exposure may alter acute HPA function and regulation in these mice. As social support in rodents can profoundly influence physiological and behavioral processes, including the HPA axis, we sought to characterize the effects of CVS exposure on basal and acute stress-induced HPA axis function in pair- and single- housed adult male mice. Despite all subjects exhibiting decreased body weight gain after six weeks of CVS, the corticosterone response to a novel, acute restraint stressor was enhanced by CVS exclusively in single-housed males. CVS also significantly increased arginine vasopressin (AVP) mRNA in the hypothalamic paraventricular nucleus (PVN) in single-housed males only. Moreover, in single-, but not pair-housed mice, CVS attenuated decreases in circulating OT found following acute restraint. Only the effect of CVS to elevate PVN corticotropin releasing hormone (CRH) mRNA levels after an acute stressor was restricted to pair-housed mice. Collectively, our findings suggest that social isolation reveals effects of CVS on the HPA axis in male C57BL/6 mice.

The hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine network that controls hormonal responses to internal and external challenges in an organism's environment, exhibits strikingly sex-biased activity. In adult female rodents, acute HPA function following a stressor is markedly greater than it is in males, and this difference has largely been attributed to modulation by the gonadal hormones testosterone and estradiol. These gonadal hormones are produced by the hypothalamic-pituitary-gonadal (HPG) axis and have been shown to determine sex differences in adult HPA function after acute stress via their activational and organizational effects. Although these actions of gonadal hormones are well supported, the possibility that sex chromosomes similarly influence HPA activity is unexplored. Moreover, questions remain regarding sex differences in the activity of the HPA axis following chronic stress and the underlying contributions of gonadal hormones and sex chromosomes. The present review examines what is currently known about sex differences in the neuroendocrine response to stress, as well as outstanding questions regarding this sex bias. Although it primarily focuses on the rodent literature, a brief discussion of sex differences in the human HPA axis is also included.

To limit excessive glucocorticoid secretion following hypothalamic-pituitary-adrenal (HPA) axis stimulation, circulating glucocorticoids inhibit corticotropin-releasing hormone (CRH) expression in paraventricular nucleus (PVN) neurons. As HPA function differs between sexes and depends on circulating estradiol (E2) levels in females, we investigated sex/estrous stage-dependent glucocorticoid regulation of PVN Crh. Using NanoString nCounter technology, we first demonstrated that adrenalectomized (ADX’d) diestrous female (low E2), but not male or proestrous female (high E2), mice exhibited a robust decrease in PVN CRH mRNA following 2-day treatment with the glucocorticoid receptor (GR) agonist RU28362. Immunohistochemical analysis of PVN CRH neurons in Crh-IRES-Cre;Ai14 mice, where TdTomato fluorescence permanently tags CRH-expressing neurons, showed similarly abundant co-expression of GR-immunoreactivity in males, diestrous females, and proestrous females. However, we identified sex/estrous stage-related glucocorticoid regulation or expression of GR transcriptional coregulators. Out of 17 coregulator genes examined using nCounter multiplex analysis, mRNAs that were decreased by RU28362 in ADX’d mice in a sex/estrous stage-dependent fashion included: GR (males = diestrous females > proestrous females), signal transducer and activator of transcription 3 (STAT3) (males < diestrous = proestrous), and HDAC1 (males < diestrous > proestrous). Steroid receptor coactivator 3 (SRC-3), nuclear corepressor 1 (NCoR1), heterogeneous nuclear ribonucleoprotein U (hnrnpu), CREB binding protein (CBP) and CREB-regulated transcription coactivator 2 (CRTC2) mRNAs were lower in ADX’d diestrous and proestrous females versus males. Additionally, most PVN CRH neurons co-expressed methylated CpG binding protein 2 (MeCP2)-immunoreactivity in diestrous female and male Crh-IRES-Cre;Ai14 mice. Our findings collectively suggest that GR’s sex-dependent regulation of PVN Crh may depend upon differences in the GR transcriptional machinery and an underlying influence of E2 levels in females.

Although prominent sex differences exist in the hypothalamic-pituitary-adrenal axis's response to stressors, few studies of its regulation in the hypothalamic paraventricular nucleus (PVN) have compared both male and female subjects. In this study, we sought to explore sex differences in the acute regulation of PVN neuropeptide expression following glucocorticoid (GC) removal and the underlying role of gonadal hormones. We first examined the effects of short-term adrenalectomy (ADX) on PVN Crh and arginine vasopressin (Avp) expression in mice using in situ hybridization. ADX increased PVN AVP mRNA levels in both sexes. In contrast, PVN CRH mRNA was increased by 2 days after ADX in males only. Both sexes showed increases in CRH mRNA after 4 days. To determine if gonadal hormones contributed to this sex bias, we examined adrenalectomized (ADX'd) and gonadectomized (GDX'd) mice with or without gonadal hormone replacement. Unlike the pattern in intact animals, 2 days following ADX/gonadectomy, CRH mRNA levels did not increase in either sex. When males were given DHT propionate, CRH mRNA levels increased in ADX'd/GDX'd males similar to those observed following ADX alone. To determine a potential mechanism, we examined the coexpression of androgen receptor (AR) immunoreactivity and CRH neurons. Abundant colocalization was found in the anteroventral bed nucleus of the stria terminalis but not the PVN. Thus, our findings reveal a sex difference in PVN Crh expression following the removal of GC-negative feedback that may depend on indirect AR actions in males.

In order to maintain the health and wellbeing of all mammals, numerous aspects of physiology are controlled by neuroendocrine mechanisms. These mechanisms ultimately enable communication between neurons and glands throughout the body and are centrally mediated by neuropeptides and/or steroid hormones. A recent session at the International Workshop in Neuroendocrinology highlighted essential roles for some of these neuropeptide and steroid hormone mediators in the neuroendocrine regulation of stress-, reproduction-, and behavior- related processes. The present review, accordingly, highlights topics presented in this session, including the role of the neuropeptides corticotropin releasing factor and gonadotropin releasing hormone in stress and reproductive physiology, respectively. Additionally, it details an important role for gonadal sex steroids in the development of behavioral sex preference. Overall, this review suggests that the neuroendocrine regulation of numerous physiological processes cannot occur without the involvement of neuropetides and/or steroid hormones.