Androgen regulation of behavioral stress responses and the hypothalamic-pituitary-adrenal axis

Abstract

Testosterone is a powerful steroid hormone that can impact the brain and behavior in various ways, including regulating behavioral and neuroendocrine (hypothalamic-pituitary-adrenal (HPA) axis) stress responses. Early in life androgens can act to alter development of brain regions associated with stress regulation, which ultimately impacts the display of stress responses later in life. Adult circulating androgens can also influence the expression of distinct genes and proteins that regulate stress responses. These changes in the brain are hypothesized to underlie the potent effects of androgens in regulating behaviors related to stress and stress-induced activation of the HPA axis. Androgens can induce alterations in these functions through direct binding to the androgen receptor (AR) or following conversion to estrogens and subsequent binding to estrogen receptors including estrogen receptor alpha (ERα), beta (ERβ), and G protein-coupled estrogen receptor 1 (GPER1). In this review, we focus on the role of androgens in regulating behavioral and neuroendocrine stress responses at different stages of the lifespan and the sex hormone receptors involved in regulating these effects. We also review the specific brain regions and cell phenotypes upon which androgens are proposed to act to regulate stress responses with an emphasis on hypothalamic and extended amygdala subregions. This knowledge of androgen effects on these neural systems is critical for understanding how sex hormones regulate stress responses.

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

Figure 1.. Framework for effects of androgen actions throughout the lifespan on behavioral stress responses and the HPA axis in rodents.

Androgens likely act during the perinatal period primarily via conversion to 17β-Estradiol by the enzyme aromatase and subsequent binding to ERα. Binding to ERα during this period can affect expression levels of AR and ERs, thus influencing sensitivity to hormones at other periods in the lifespan. Androgen binding to AR may also exert some organizational effects during the perinatal period to ultimately influence later display of stress responses. Androgens can potentially act during the perinatal period to permanently organize specific brain regions and cell types (e.g. CRF, vasopressin, OT, and their cognate receptors) to regulate stress responses. In a second developmental period (puberty) increased levels of androgens and their binding to ARs and ERs can also influence development of stress-regulating brain structures to organize stress responses. Following exposure to early life and pubertal androgens, androgens released in adulthood can act through ARs and ERs (after conversion) to influence expression levels of stress-related genes and proteins to facilitate the activational effects of androgens on behavioral stress responses and the HPA axis. A decline in androgens with aging in some species should result in lesser binding to ARs and ERs to influence aging-related changes in stress responses. Androgen-induced changes in the HPA axis can also influence behavioral stress responses, and to some extent, the reverse also occurs. Dashed arrows indicate a lesser level or response relative to filled arrows. Figure created with BioRender.com.

Figure 2.. Actions of testosterone (T), metabolites, and sex hormone receptors on behavioral stress responses and the HPA axis.

This figure describes primarily adult (activational) effects of testosterone and its metabolites and their actions through androgen and estrogen receptors. Testosterone can be converted to 17β-Estradiol to produce effects on different estrogen receptors including ERα, ERβ, and GPER1. Testosterone can also act directly via AR or produce more potent action through AR following conversion to dihydrotestosterone (DHT). DHT can also be converted to 3β-diol which has a high affinity for ERβ. Binding of AR and ERβ generally reduces behavioral stress responses and HPA axis activation. Recent evidence suggests binding to GPER1 also produces similar stress-reducing effects although this conclusion is based on relatively fewer studies on GPER1, hence the asterisk (*). Binding to ERα has generally been shown to increase activation of the HPA axis although effects on behavioral stress responses are mixed, with some studies indicating elevated versus decreased stress reactivity. These varying results appear dependent on various factors including reproductive status and the brain region in which binding occurs. Robert J. Handa is shown here due to his tremendous contributions to studies that encompass this figure, perhaps most notably his studies on ERβ. HSD = hydroxysteroid dehydrogenase; 3β-diol = 5α androstane 3β, 17β-Diol. Figure created with BioRender.com.