Does low DHEA-S and a high cortisol-to-DHEA ratio indicate reduced adrenal androgen reserve and chronic stress-linked lower mood resilience?

The physiological status of the adrenal glands changes significantly with age, particularly in women. In a 73-year-old female, assessing the balance between cortisol and dehydroepiandrosterone sulfate (DHEA-S) provides a window into both structural adrenal health and the functional impact of chronic stress on the brain.

Clinical and Mechanistic Evidence

• Adrenal Androgen Reserve: DHEA-S is a direct biomarker for the functional capacity of the adrenal zona reticularis (ZR). Low levels indicate a "reduced adrenal androgen reserve," reflecting the age-related thinning of the ZR known as adrenopause. Histological studies show that by age 70, ZR volume and cell numbers are significantly diminished, which directly correlates with the sharp decline in serum DHEA-S compared to younger populations.
• Chronic Stress Physiology: The cortisol-to-DHEA ratio (CDR) is an established marker of allostatic load. Chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis often results in a "metabolic shift" where the body prioritizes catabolic cortisol production over anabolic DHEA. This shift is characterized by higher evening cortisol and lower DHEA-S, signaling a state of persistent physiological strain.
• Mood Resilience: A high CDR is strongly associated with lower mood resilience and increased vulnerability to depression and anxiety. This is driven by the loss of DHEA’s "antiglucocorticoid" effects. While cortisol can be neurotoxic to the hippocampus and reduce brain-derived neurotrophic factor (BDNF), DHEA serves as a neuroprotective agent. An elevated ratio means there is insufficient DHEA to buffer the brain against cortisol-driven excitotoxicity and oxidative stress.
• Neurological Implications: High ratios are linked to reduced neuroplasticity and altered limbic system signaling. In older adults, this imbalance is often accompanied by hippocampal atrophy and impaired inhibitory tone on the HPA axis, further reinforcing a cycle of stress vulnerability.

Bottom line

The claim is fully supported. Low DHEA-S is a reliable indicator of reduced adrenal androgen reserve, and an elevated cortisol-to-DHEA ratio serves as a robust biomarker for chronic stress physiology and reduced psychological resilience, particularly in postmenopausal and elderly populations.