Can low DHEA-S cause lower testosterone in women when SHBG is not elevated?

Dehydroepiandrosterone sulfate (DHEA-S) serves as the primary reservoir for sex steroid synthesis in women, particularly as direct ovarian production fluctuates with age. Synthesized in the adrenal glands, DHEA-S acts as a stable precursor that peripheral tissues utilize to maintain local hormonal balance.

Mechanistic pathways

• Intracrine conversion: Peripheral tissues, including the skin, adipose tissue, and liver, possess the enzymatic machinery required to convert DHEA-S into active androgens. The process begins with the hydrolysis of DHEA-S into DHEA by steroid sulfatase (STS). DHEA is then converted to androstenedione by 3β-hydroxysteroid dehydrogenase (3β-HSD) and subsequently into testosterone via 17β-hydroxysteroid dehydrogenase (17β-HSD).
• Adrenal contribution: In women, approximately 50% of total circulating testosterone is derived from the peripheral conversion of adrenal precursors like DHEA-S. Consequently, a depletion in the DHEA-S pool—often due to aging, adrenal insufficiency, or zona reticularis atrophy—directly limits the substrate available for testosterone biosynthesis.

Role of SHBG and clinical implications

• Bioavailability and binding: Sex Hormone-Binding Globulin (SHBG) is the primary transport protein for testosterone. High levels of SHBG sequester free testosterone, which can mask the true androgenic status by lowering the "free" bioactive fraction even if total production is stable.
• Production vs. sequestration: When SHBG is not elevated, total testosterone levels serve as a more reliable proxy for actual hormone production. In this state, a finding of low testosterone is more likely attributable to a production deficit—such as low DHEA-S precursor availability—rather than excessive protein binding. This confirms that low adrenal androgen output is a primary driver of the patient's low androgen status.

Bottom line

The claim is supported by high-confidence evidence. Low DHEA-S directly contributes to reduced testosterone levels in women because it depletes the precursor pool necessary for peripheral conversion. When SHBG is not elevated, this deficit in production is the most significant factor in low systemic testosterone.