Aging in men selectively lowers DHEA-S while cortisol stays relatively preserved

Normal aging in men is characterized by a unique, highly selective divergence in adrenal steroid hormone production. Rather than representing a generalized failure of the adrenal gland, this transition involves a dramatic decline in adrenal androgens alongside the relative preservation of glucocorticoids.

Clinical evidence of divergent steroid trajectories

• Severe androgen decline: Circulating DHEA-S concentrations peak in early adulthood and decline progressively, dropping to just 10% to 20% of young-adult values by age 70.
• Preserved glucocorticoid production: In contrast to the steep fall in DHEA-S, basal and morning cortisol levels remain highly preserved or slightly elevated in older men, leading to a significantly increased cortisol-to-DHEA-S ratio.

Mechanistic explanations

• Structural regression: This selective decline, known as adrenopause, is driven by the progressive thinning and regression of the adrenal zona reticularis (the androgen-producing layer) while leaving the cortisol-producing zona fasciculata structurally and functionally intact.
• Enzymatic shift: This structural regression is accompanied by a functional decrease in the 17,20-lyase activity of the CYP17A1 enzyme and its cofactor, cytochrome b5, which selectively impairs the androgenic pathway.

Differentiation from adrenal insufficiency

• Intact HPA axis function: Because clinical adrenal insufficiency is defined by a pathological deficiency in cortisol, preserved cortisol production directly rules out global adrenal failure.
• Diagnostic confirmation: A standard ACTH stimulation test demonstrating a normal peak cortisol response (typically ≥ 18 µg/dL) confirms intact glucocorticoid reserve, distinguishing benign age-related adrenopause from a pathological disease state.

Bottom line

• In aging men, the steep decline in DHEA-S paired with stable cortisol production represents a selective adrenal androgen decline (adrenopause) due to targeted zona reticularis regression, rather than a broad or pathological adrenal insufficiency.