Can low pregnenolone and low DHEA-S explain low testosterone in women?

The relationship between pregnenolone, dehydroepiandrosterone sulfate (DHEA-S), and testosterone is fundamentally linked through the steroidogenic pathway, where a decline in upstream precursors directly impacts downstream androgen production in women.

Steroidogenic mechanisms

Pregnenolone and DHEA-S serve as the essential foundational precursors for androgen synthesis. Pregnenolone, the initial steroid derived from cholesterol, is converted via the enzyme CYP17A1 into DHEA. In women, DHEA-S acts as a major circulating reservoir, accounting for approximately 90% of adrenal-derived androgens.

• Enzymatic Conversion: In peripheral tissues such as visceral fat, skin, and the ovaries, DHEA-S is hydrolyzed to DHEA by steroid sulfatase (STS).
• Androgen Production: DHEA is then converted to androstenedione by 3β-hydroxysteroid dehydrogenase (3β-HSD) and subsequently into testosterone by 17β-hydroxysteroid dehydrogenase (17β-HSD).
• Intracrine Activity: This intracrine conversion is a critical source of testosterone in postmenopausal women, as peripheral tissues can synthesize active androgens locally from adrenal precursors even when systemic levels appear low.

Clinical correlation in aging

In women aged 60 and older, low levels of pregnenolone and DHEA-S frequently align with low testosterone due to the simultaneous processes of adrenopause and diminished ovarian function.

• Adrenopause: DHEA-S levels exhibit a sharp, age-related decline, often falling by 70–80% from peak levels seen in early adulthood.
• Parallel Decline: Longitudinal data show that while total testosterone declines more gradually than its adrenal precursors, low free testosterone levels are strongly correlated with DHEA-S deficiency in postmenopausal cohorts.
• Pathway Efficiency: Advancing age may also shift steroidogenesis from the efficient Δ5 pathway (utilizing pregnenolone and DHEA) toward less efficient Δ4 pathways, further compounding the reduction in testosterone output when precursor availability is limited.

Bottom line

Low pregnenolone and DHEA-S are physiologically aligned with low testosterone in postmenopausal women because they serve as the primary enzymatic substrates for androgen production; a deficiency in these upstream "building blocks" directly limits the body's capacity for local and systemic testosterone synthesis.