Low total testosterone and low DHEA-S reflect reduced ovarian/adrenal androgen production and lower free testosterone.

The relationship between total testosterone, DHEA-S, and the biologically active free testosterone fraction is well-established in female physiology. In a 30-year-old female, these markers serve as specific indicators of the functional output of the endocrine glands and the peripheral tissues that convert precursors into active androgens.

Mechanisms of androgen production

The female androgen pool is derived from three primary sources: direct ovarian secretion, direct adrenal secretion, and the peripheral conversion of pro-hormones.

• DHEA-S as an adrenal marker: DHEA-S is almost exclusively produced (90–100%) by the zona reticularis of the adrenal cortex. Consequently, low DHEA-S is a highly specific biomarker for reduced adrenal androgenic activity.
• Total testosterone sources: Circulating total testosterone is produced roughly 25% by the ovaries (theca cells) and 25% by the adrenal glands. The remaining 50% is synthesized in peripheral tissues (adipose, skin, and liver) through the conversion of precursors, primarily androstenedione and DHEA-S.
• Glandular insufficiency: Low levels of these hormones typically reflect a decline in the steroidogenic capacity of these glands, such as in cases of adrenal insufficiency or reduced ovarian reserve.

Impact on free testosterone levels

Free testosterone (FT) represents the small fraction (typically 1–2%) of testosterone not bound to Sex Hormone-Binding Globulin (SHBG) or albumin. It is the primary driver of androgenic signaling at the cellular level.

• Mathematical dependency: According to the Free Hormone Hypothesis and the Vermeulen equation, the concentration of free testosterone is directly dependent on the total testosterone pool. If total production from the ovaries and adrenals decreases, the available free fraction must also decrease, unless there is a simultaneous and significant drop in SHBG.
• Precursor substrate availability: DHEA-S acts as a critical reservoir for intracrine androgen production. Reduced adrenal output of DHEA-S limits the substrate available for peripheral conversion into testosterone, further contributing to low total and free testosterone concentrations.

Bottom line

Low total testosterone and DHEA-S are reliable indicators of reduced ovarian and adrenal output. Because free testosterone is a subset of the total androgen pool, a reduction in these primary androgens directly diminishes the concentration of biologically active free testosterone.