Sex, Stress, and Steroids: Rethinking Cortisol Through a Gendered Lens

Abstract

Cortisol, a vital glucocorticoid hormone, plays an essential role in the body’s stress response, metabolic regulation, immunomodulation, and circadian rhythm maintenance. "Cortisol is synthesized in the adrenal cortex and regulated via the hypothalamic-pituitary-adrenal (HPA) axis in response to stress and circadian cues." While its biological significance has been well established, the effects and patterns of cortisol secretion vary by biological sex, a factor often underrepresented in historical research. This discrepancy has contributed to incomplete understandings of stress-related conditions, such as anxiety and depression, which present differently in males and females. Understanding the sex-specific differences in cortisol reactivity and regulation can shed light on the pathophysiology and treatment of these disorders. In healthy individuals, cortisol follows a circadian rhythm composed of two main phases: the cortisol awakening response (CAR) and the diurnal cortisol slope (DCS). Disruptions in these patterns are linked to negative mental health outcomes. Research has shown that males tend to exhibit higher daytime cortisol levels than premenopausal females, though this sex-based difference declines after age 50, suggesting the influence of estrogen and other sex hormones on cortisol regulation. Estrogenic milieu lowers mean cortisol levels in premenopausal females, with estrogen increasing cortisol-binding globulin (CBG), thereby decreasing levels of active cortisol. These physiological patterns extend into psychopathology: males with depression often exhibit elevated baseline cortisol, while females more frequently show blunted or irregular cortisol responses, a difference that may reflect underlying hormonal or receptor-based mechanisms. At the molecular level, glucocorticoid and mineralocorticoid receptor expression also differs between sexes, influencing how cortisol modulates stress feedback loops. High cortisol levels are a risk factor for both genders, regardless of their receptor affinity, however, low cortisol may be a protective factor for males only. These differences highlight the importance of incorporating sex as a biological variable in both clinical and preclinical cortisol research. Doing so can improve the accuracy of diagnoses, enhance treatment efficacy, and provide a more nuanced understanding of the diverse effects of stress hormones across populations.