Does adrenal DHEA-S decline with age and supply the precursor for peripheral androgen and estrogen synthesis in postmenopausal women?

In postmenopausal women, the adrenal gland serves as the primary source of hormonal precursors that maintain local steroid concentrations across various tissues. Research into dehydroepiandrosterone (DHEA) and its sulfate form (DHEA-S) confirms their role as critical prohormones during the postmenopausal years.

Age-related decline in adrenal DHEA-S

Adrenal production of DHEA-S undergoes a physiological decline known as adrenopause, which begins between the ages of 30 and 40. This trajectory continues through the postmenopausal years, though the rate of decline varies by stage.

• Mechanistic drivers: The decline is primarily caused by atrophy of the zona reticularis in the adrenal cortex and a reduction in the activity of the enzyme CYP17A1, which is essential for androgen synthesis.
• Postmenopausal stability: Longitudinal data, such as from the Study of Women’s Health Across the Nation (SWAN), indicate that while levels decrease over the long term, DHEA-S often stabilizes or plateaus during the immediate transition following the final menstrual period (FMP). Unlike the rapid drop in ovarian estrogens, the adrenal decline is gradual.

Peripheral synthesis of sex steroids

Following the cessation of ovarian function, nearly 100% of sex steroids in postmenopausal women are derived from adrenal DHEA and DHEA-S through a process termed "intracrinology."

• Androgen synthesis: Peripheral tissues (such as muscle, skin, and bone) convert DHEA into active androgens like testosterone and dihydrotestosterone (DHT) using local enzymes (3β-HSD and 17β-HSD). Tracer studies suggest approximately 2–5% of circulating DHEA is converted directly into testosterone.
• Estrogen synthesis: DHEA serves as the substrate for estrone (E1) and estradiol (E2) production. It is first converted to androstenedione and then transformed into estrogens via the aromatase enzyme. Tracer data show a conversion efficiency of approximately 0.5–1.5% for estradiol.
• Local regulation: This peripheral conversion allows specific tissues to regulate their own hormonal environments locally without increasing systemic circulating levels of active estrogens or androgens.

Bottom line

In postmenopausal women, DHEA-S production declines as part of general adrenal aging, though it remains relatively stable during the immediate years after menopause. DHEA is the essential precursor for virtually all peripheral androgen and estrogen synthesis in the postmenopausal state, providing a localized source of sex steroids after ovarian function has ceased.