What is DHEA (Dehydroepiandrosterone) sulfate?

What is DHEA Sulfate (DHEAS)?

DHEA sulfate (DHEAS) is the sulfated form of dehydroepiandrosterone (DHEA), representing the most abundant circulating steroid hormone in humans, primarily produced by the adrenal cortex and serving as an inactive precursor that is converted to active sex steroids (testosterone and estrogen) in peripheral tissues. 1, 2

Biochemical Characteristics

• DHEAS is produced through enzymatic sulfation of DHEA by sulfotransferase in the liver and adrenal glands, making it more water-soluble and extending its half-life in circulation compared to DHEA 2, 3

• DHEAS serves as the most reliable measure of adrenal androgen production, unlike testosterone which is influenced by sex hormone-binding globulin (SHBG) levels 1

• The hormone reaches maximum circulating concentrations between ages 20-30 years, followed by a steady decline at approximately 2% per year, a phenomenon termed "adrenopause" 1, 3

Clinical Significance in Diagnosis

Role in PCOS Diagnosis

• DHEAS is considered a second-line diagnostic marker for polycystic ovary syndrome (PCOS), not a routine first-line test, with pooled sensitivity of 0.75 and specificity of 0.57 for detecting biochemical hyperandrogenism 1

• The 2023 International PCOS Guidelines recommend measuring DHEAS only when first-line androgen markers (total testosterone, calculated free testosterone, or free androgen index) are negative but clinical suspicion remains high 1

• Elevated DHEAS occurs in 33% of non-classic PCOS patients overall, with racial variation showing 20% in White women and 33% in Black women when adjusted for age and race normative values 1

• DHEAS has poorer diagnostic specificity than testosterone-based markers, bringing additional costs and risk of overdiagnosis 1

Age-Related Reference Ranges

• Normal DHEAS levels vary significantly by age: for women aged 20-29 years, levels >3800 ng/mL are considered elevated; for ages 30-39 years, >2700 ng/mL is abnormal 1

• DHEAS measurement has more diagnostic value in premenopausal than postmenopausal women due to the age-related decline in production 1

Physiological Functions

Hormone Precursor Activity

• DHEAS acts as an indirect precursor to both estrogen and testosterone through peripheral tissue conversion, functioning as a prohormone rather than having direct hormonal activity 2, 4

• The hormone exerts effects through multiple mechanisms: downstream conversion to sex steroids, neuromodulation via GABA-A and NMDA receptors, improvement in endothelial cell function, and possibly through cell membrane-bound receptors 5, 3

Systemic Effects

• DHEA/DHEAS demonstrate immunomodulatory actions by increasing monocytes, T cells expressing TCRγδ, and natural killer cells in elderly populations 6

• The hormones exhibit neuroprotective, anti-inflammatory, and immune-modulating effects beyond their role as sex steroid precursors 3, 4

Clinical Applications of DHEA Supplementation

FDA-Approved Indication

• Intravaginal DHEA (prasterone) is FDA-approved for treating vaginal dryness and dyspareunia in postmenopausal women, showing significant improvements in sexual desire, arousal, pain, and overall sexual function 7, 8

• The typical dosing for women ranges from 10-50 mg daily, with 25 mg being a common starting dose, and treatment efficacy should be monitored through serum DHEAS, androstenedione, and testosterone levels 7

Special Populations

• In women with adrenal insufficiency, DHEA supplementation restores DHEAS and androstenedione levels, reduces total cholesterol, improves well-being and sexual satisfaction, and prevents bone mineral density loss 6

• For breast cancer patients on aromatase inhibitors with vaginal atrophy not responding to non-hormonal treatments, vaginal DHEA is an option, though it should be used with caution as DHEA increases circulating androgen levels 7, 8

Safety Considerations and Contraindications

• DHEA should be used with caution in patients with hormone-dependent cancers due to its conversion to sex steroids 7

• Men with breast cancer should not use DHEA supplementation 7

• Women on aromatase inhibitor therapy require careful consideration before DHEA use, as it increases circulating androgen levels that could potentially be converted to estrogens 7

Diagnostic Testing Considerations

When to Order DHEAS

• Order DHEAS when evaluating suspected PCOS only after first-line androgen markers are negative but clinical suspicion persists based on symptoms like hirsutism, acne, or menstrual irregularity 1

• Measure DHEAS when ruling out non-classical congenital adrenal hyperplasia or adrenal/ovarian tumors in women with markedly elevated androstenedione (>10.0 nmol/L) 1

• DHEAS can be used to screen for adrenal suppression as a side effect of corticosteroid therapy 6

Assay Method Considerations

• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides superior accuracy compared to direct immunoassays for measuring DHEAS, with pooled sensitivity of 0.82 versus 0.67 for immunoassays 1

• Direct immunoassay methods are widely available but less accurate, particularly at the low concentrations relevant for clinical decision-making 1

Common Clinical Pitfalls

• Ordering DHEAS as a routine first-line test for PCOS leads to unnecessary costs and potential overdiagnosis due to its lower specificity (0.57) compared to testosterone-based markers 1

• Failing to adjust reference ranges for age results in misinterpretation, as DHEAS declines progressively after age 30 1

• Interpreting isolated DHEAS elevation without considering clinical context and other androgen markers can lead to incorrect PCOS diagnosis 1

• Not recognizing that DHEAS levels can be influenced by medications, particularly corticosteroids which suppress adrenal production 6