Can low DHEA-S in women cause low total and free testosterone?

In women, the synthesis of active androgens is heavily dependent on a large circulating pool of precursors, primarily dehydroepiandrosterone sulfate (DHEA-S). This mechanism allows for the production of testosterone in peripheral tissues to maintain metabolic and physiological functions.

Mechanistic pathways of conversion

The process of "intracrinology" allows specific peripheral tissues—such as the skin, adipose tissue, liver, and endometrium—to synthesize androgens locally. This is a multi-step enzymatic process:

• Desulfation: The enzyme steroid sulfatase (STS) converts the inactive reservoir, DHEA-S, into free DHEA.
• Oxidation and Reduction: 3β-hydroxysteroid dehydrogenase (3β-HSD) transforms DHEA into androstenedione, which is then reduced to testosterone by 17β-hydroxysteroid dehydrogenase (17β-HSD).
• Tissue Specificity: This pathway is highly active in the skin, where it supports hair follicles and sebum production, and in adipose tissue, where it influences lipid metabolism.

Clinical evidence and testosterone levels

Low DHEA-S levels, often referred to as adrenal hypoandrogenism, directly impact the availability of substrates for testosterone production.

• Precursor Contribution: In women, approximately 50% to 67% of circulating testosterone is derived from the peripheral conversion of adrenal precursors like DHEA-S and androstenedione, while only 25% to 33% is directly secreted by the ovaries.
• Correlation Findings: Clinical data show that women with low DHEA-S (under 76 μg/dL) are significantly more likely to have low total testosterone (under 16.9 ng/dL).
• Impact of Supplementation: Studies have demonstrated that DHEA supplementation can triple testosterone production in specific tissues and significantly raise serum free testosterone levels, confirming the substrate-product relationship.

Clinical implications for health

As women age and approach the perimenopausal transition (around age 43), the relative importance of this adrenal pathway increases.

• Androgen Deficiency: Because the adrenal pathway provides the majority of the circulating androgen pool, a deficit in DHEA-S is a primary driver of low total and free testosterone.
• Tissue Function: Low levels can affect target organs that rely on local conversion, potentially impacting bone density, muscle mass, and libido.

Bottom line

Low DHEA-S is a primary contributor to low total and free testosterone in women because DHEA-S serves as the essential reservoir for over half of a woman’s circulating androgens through peripheral conversion.