Does low DHEA-S in older adults indicate reduced precursor supply for estrogen and testosterone?

Dehydroepiandrosterone sulfate (DHEA-S) serves as the primary reservoir for the synthesis of sex hormones in peripheral tissues, a process that becomes particularly critical in older adults.

Mechanistic pathways of steroid conversion

DHEA-S is synthesized in the zona reticularis of the adrenal cortex and released into circulation at high concentrations. Although DHEA-S is biologically inactive at androgen and estrogen receptors, it acts as a stable prohormone reservoir.

• Intracellular uptake: Circulating DHEA-S enters peripheral cells through organic anion transporting polypeptides (OATP).
• Enzymatic activation: Once inside the cell, steroid sulfatase (STS) converts DHEA-S into DHEA. This is followed by conversion into androstenedione via 3β-hydroxysteroid dehydrogenase (3β-HSD).
• Downstream synthesis: Androstenedione serves as the gateway to both androgens and estrogens. It is converted to testosterone by 17β-HSD enzymes, and subsequently into estrogens (estrone and estradiol) via the enzyme aromatase (CYP19A1).

Clinical evidence in older populations

In older adults, the decline of DHEA-S—often referred to as adrenopause—significantly impacts the availability of sex steroid precursors.

• Precursor depletion: Because postmenopausal women and older men rely almost exclusively on the peripheral conversion of adrenal precursors for their sex steroid needs, a low DHEA-S level (e.g., < 50–100 µg/dL in individuals over 70) represents a fundamental reduction in the building blocks available for hormone synthesis.
• Correlation with testosterone: Evidence from large cohort studies (such as the Rancho Bernardo Study) shows that DHEA-S and testosterone levels often decline in parallel. In postmenopausal women, adrenal-derived androgens can contribute significantly to the total circulating androgen pool.
• Estrogen considerations: While low DHEA-S limits the substrate available for estrogen production, the correlation between DHEA-S and estradiol in the elderly is often weak. This is because estradiol levels in older women are uniformly low, and their variation is driven more by peripheral aromatase activity in adipose tissue than by the absolute supply of DHEA-S.

Safety and practical considerations

• Intracrinology: The conversion of DHEA-S occurs locally within tissues (skin, bone, brain, and adipose tissue). This "intracrine" system allows tissues to regulate their own hormonal environment independently of systemic levels.
• Diagnostic value: In a 73-year-old female, measuring DHEA-S provides a clearer picture of adrenal androgenic output than measuring testosterone alone, as DHEA-S has a longer half-life and lacks significant diurnal variation.

Bottom line

Low DHEA-S in older adults directly reflects a reduced supply of the primary adrenal precursor used for peripheral sex hormone synthesis. This reduction is strongly associated with lower testosterone levels, though its impact on circulating estradiol is less pronounced due to the compensatory role of peripheral aromatization in body fat.