Graphs Built From Reported Results

Key claims & evidence (concise, fully inline-cited)

• Age-related decline: Circulating DHEA/DHEAS peaks in young adulthood (≈20–30 y) then declines markedly with age — by ~70 y levels are often ≈20% of peak and by extreme old age may be only a few percent of young-adult values (illustrated above) — based on a narrative synthesis of human data and population estimates. DHEA/DHEAS age-pattern review
• Pharmacokinetics difference: DHEA has a short plasma half-life (~1–3 h) and very rapid apparent clearance, whereas DHEAS is long‑lived (~13.7 h reported) with far slower clearance due to protein binding and renal handling — this explains why DHEAS often reflects adrenal output better than DHEA. DHEA/DHEAS pharmacokinetics
• Tissue intracrinology & receptors: DHEA/DHEAS are adrenal steroid precursors that can be taken up and locally converted into active androgens/estrogens via STS, 3β-HSD, 17β-HSD and related enzymes (intracrine production) and can also act via multiple receptor classes (ER, AR, PPARs, NMDA/GABA/sigma-1 membrane signaling). The intracrine model helps explain tissue‑specific actions and inconsistent systemic effects of oral DHEA. Intracrine metabolism & receptor targets
• Clinical heterogeneity: Controlled trials show intravaginal DHEA can improve genitourinary syndrome of menopause endpoints (vaginal maturation, symptoms) while oral DHEA trials show inconsistent results for libido, metabolic markers, mood, and muscle/bone outcomes — evidence quality varies and many studies are small or short-duration. Clinical trial heterogeneity (intravaginal vs oral)
• Immune modulation (in vitro): DHEA shows dose-dependent immunomodulatory effects: in human PBMCs high concentrations inhibited T-cell proliferation while lower concentrations enhanced B-cell responses — in vitro findings that require careful translation to in vivo immune effects. In vitro immune modulation by DHEA
• Population association — liver fibrosis cohort: In a large retrospective cohort of 2,369 men with LOH-like symptoms, mean DHEA‑S decreased progressively across FIB‑4 quintiles (Q1→Q5: 284.8 → 168.7 μg/dL), with higher FIB‑4 also linked to worse urinary/sexual symptom scores after adjustment — observational association, not causal. FIB-4 cohort DHEA-S association

Limitations, blindspots & counterpoints (brief)

• Many claims derive from heterogeneous trials, in vitro/animal models, or observational cohorts — causal claims require randomized, adequately powered, long-term trials in targeted tissues (reviewed in the main citation above). Review limitations and heterogeneity
• In vitro dose-response effects (e.g., immune cell proliferation) may not map to physiologic concentrations achieved in vivo; careful PK/PD mapping is required. In vitro vs in vivo limitations

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