Sex Differences in Acute Neuroendocrine Responses to Stressors in Rodents and Humans

Abstract

Sex differences in the neuroendocrine response to acute stress occur in both animals and humans. In rodents, stressors such as restraint and novelty induce a greater activation of the hypothalamic-pituitary-adrenal axis (HPA) in females compared to males. The nature of this difference arises from steroid actions during development (organizational effects) and adulthood (activational effects). Androgens decrease HPA stress responsivity to acute stress, while estradiol increases it. Androgenic down-regulation of HPA responsiveness is mediated by the binding of testosterone (T) and dihydrotestosterone (DHT) to the androgen receptor, as well as the binding of the DHT metabolite, 3β-diol, to the β form of the estrogen receptor (ERβ). Estradiol binding to the α form of the estrogen receptor (ERα) increases HPA responsivity. Studies of human sex differences are relatively few and generally employ a psychosocial paradigm to measure stress-related HPA activation. Men consistently show greater HPA reactivity than women when being evaluated for achievement. Some studies have found greater reactivity in women when being evaluated for social performance. The pattern is inconsistent with rodent studies but may involve the differential nature of the stressors employed. Psychosocial stress is nonphysical and invokes a significant degree of top-down processing that is not easily comparable to the types of stressors employed in rodents. Gender identity may also be a factor based on recent work showing that it influences the neural processing of positive and negative emotional stimuli independent of genetic sex. Comparing different types of stressors and how they interact with gender identity and genetic sex will provide a better understanding of sex steroid influences on stress-related HPA reactivity.

Figure 1.

Effects of testosterone (T) and its metabolites on hypothalamic-pituitary-adrenal (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 androgen receptors (ARs), estrogen receptor α (ERα), estrogen receptor β (ERβ), and γ-aminobutyric acid (GABA) receptors. Binding of ARs or ERβ is expected to decrease the HPA axis and behavioral stress responses. In contrast, actions at ERα increase the HPA axis response to stress. 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. (The figure and legend are reprinted from Zuloaga et al. 2020 under the terms of a Creative Commons Attribution 4.0 International License.)