Sex Differences in Neuroendocrine Stress Responses
Summary
Stress engages a dynamic neuroendocrine network centred on the hypothalamic–pituitary–adrenal (HPA) axis, culminating in the release of glucocorticoids that orchestrate systemic adaptation. Males and females exhibit marked distinctions at each level of this axis, from hypothalamic corticotropin-releasing hormone (CRH) synthesis through adrenal steroidogenesis to feedback sensitivity in target tissues. Organisational effects of gonadal hormones during development establish divergent neural circuits, while activational effects in adulthood modulate responsiveness to acute and chronic challenges. Oestrogens enhance CRH transcription and potentiate glucocorticoid responses under certain conditions, whereas androgens exert both direct and indirect inhibitory actions on HPA activity. Sex chromosomes further shape receptor expression, epigenetic landscapes and stress-sensitive neurotransmitter systems. These biological differences underpin sex biases in vulnerability to affective and metabolic disorders, influence immune regulation and may determine treatment response. Recent advances have begun to unravel molecular mechanisms by which steroidogenic enzymes, neuropeptide co-transmitters and intracellular signalling cascades confer sex-specific regulation of stress pathways, highlighting opportunities for targeted interventions and precision medicine.
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Sex Differences in Neuroendocrine Stress Responses publication trend
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Technical terms
Hypothalamic–pituitary–adrenal (HPA) axis: The neuroendocrine system coordinating stress responses via hypothalamic CRH release, pituitary ACTH secretion and adrenal glucocorticoid production.
Glucocorticoids: Steroid hormones (e.g. cortisol, corticosterone) that regulate metabolism, immune function and stress adaptation.
Corticotropin-releasing hormone (CRH): A hypothalamic peptide that stimulates pituitary adrenocorticotropic hormone (ACTH) release.
Pregnenolone: A precursor in the steroidogenic cascade from cholesterol to glucocorticoids and sex steroids, influencing central stress regulation.
Androgen receptor (AR): A nuclear receptor that mediates effects of testosterone and dihydrotestosterone on gene transcription and HPA function.
Steroidogenic pathway: The enzymatic sequence in adrenal and gonadal tissues converting cholesterol into active steroids.
References
- The hypothalamic steroidogenic pathway mediates susceptibility to inflammation-evoked depression in female mice. Journal of Neuroinflammation (2023).
- The adipose tissue keeps the score: priming of the adrenal-adipose tissue axis by early life stress predisposes women to obesity and cardiometabolic risk. Frontiers in Endocrinology (2024).
- Roles for androgens in mediating the sex differences of neuroendocrine and behavioral stress responses. Biology of Sex Differences (2020).
- Sexual Dimorphism in Glucocorticoid Stress Response. International Journal of Molecular Sciences (2021).
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