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Review
. 2020 Jul 29;11(1):44.
doi: 10.1186/s13293-020-00319-2.

Roles for androgens in mediating the sex differences of neuroendocrine and behavioral stress responses

Damian G Zuloaga  1 , Ashley L Heck  2 , Rose M De Guzman  1 , Robert J Handa  3
Affiliations
Review

Roles for androgens in mediating the sex differences of neuroendocrine and behavioral stress responses

Damian G Zuloaga et al. Biol Sex Differ. .

Abstract

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.

Keywords: Androgen receptor; Anxiety; Depression; Estrogen; Estrogen receptor; Glucocorticoids; HPA axis; Hypothalamus; Testosterone.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Sex differences in HPA axis response to stress. Adult male versus female rodents have decreased HPA axis responses to acute stressors characterized by decreased paraventricular nucleus (PVN) neuronal activation and corticotropin-releasing hormone (CRH) gene expression, decreased pituitary expression of the proopiomelanocortin (POMC) precursor for adrenocorticotropin (ACTH), and decreased ACTH and corticosterone (CORT) responses to acute stressors. Males also have enhanced negative feedback (red arrow) resulting from their reduced corticosteroid-binding globulin (CBG) levels, their increased PVN glucocorticoid receptor (GR) gene expression, and their increased neuronal activation in limbic regions that inhibit the HPA axis. The sun symbol indicates neuronal activation
Fig. 2
Fig. 2
Effects of testosterone (T) and its metabolites on HPA axis and behavioral stress responses. This figure describes enzymes involved in the conversion of T and its metabolites and predicted effects produced by binding AR, ERα, ERβ, and GABA receptors. Binding of AR or ERβ is expected to decrease HPA axis and behavioral stress responses. In contrast, actions at ERα increase the HPA axis response to stress while effects on anxiety-like behaviors are mixed and depend on reproductive status among other factors. Effects of 3α-diol on the HPA axis are currently unknown. HSD = hydroxysteroid dehydrogenase; 3α-Diol = 5α androstane 3α, 17β Diol; 3β Diol = 5α androstane 3β, 17β Diol, RL-HSD = 11-cis-retinol dehydrogenase like 3α-HSD
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