What is dehydroepiandrosterone (DHEA)?

What is DHEA (Dehydroepiandrosterone)?

DHEA is an adrenal steroid prohormone that serves as a precursor to testosterone and estrogen, produced primarily in the adrenal cortex and converted to active sex steroids in peripheral tissues. 1, 2

Biochemical Identity and Production

• DHEA is a 19-carbon steroid hormone that is the most abundant circulating steroid in primates, present in blood at concentrations second only to cholesterol 3, 4
• It is predominantly synthesized in the zona reticularis of the adrenal cortex through the cholesterol-pregnenolone pathway 5, 4
• DHEA can be converted to DHEA-sulfate (DHEAS) by the enzyme sulfotransferase in the liver and adrenal glands, with DHEAS serving as the most reliable measure of adrenal androgen production 1, 5
• It is lipophilic in nature, allowing it to cross cell membranes and act in peripheral tissues 5

Physiological Role and Mechanism

• DHEA is not itself a hormone but rather a prohormone that must be converted to active sex steroids (testosterone and estrogen) in target tissues 4
• All enzymes required to transform DHEA into androgens and/or estrogens are expressed in a cell-specific manner in peripheral target tissues, allowing local control of sex steroid levels according to tissue-specific needs—a process termed "intracrinology" 4
• DHEA acts as a direct precursor of testosterone and can also be produced in peripheral tissues, making it independent of sex hormone-binding globulin (SHBG) influences 1
• It exhibits neuroactive properties through modulation of GABA-A, NMDA, and sigma-1 receptors, contributing to neuroprotection, synaptic plasticity, and mood regulation 2, 3

Age-Related Decline

• DHEA secretion follows a characteristic age-related pattern, reaching maximum circulating concentrations between 20 and 30 years of age, followed by a steady gradual decline at approximately 2% per year 1, 5
• This age-related decline is termed "adrenopause" and has prompted interest in supplementation to mitigate age-related symptoms 2
• High levels of plasma circulating DHEA are suggested as a marker of human longevity, while decreased levels are associated with adrenal insufficiency, severe systemic diseases, acute stress, and anorexia 3

Clinical Applications

In Primary Adrenal Insufficiency (PAI)

• In women with PAI, adrenal androgen can be replaced by oral DHEA tablets (10–50 mg), typically 25 mg as a single daily dose guided by serum DHEAS, androstenedione, and testosterone levels measured in the morning prior to DHEA ingestion 1
• A pragmatic approach is to offer female patients with persistent lack of libido and/or low energy levels despite optimized glucocorticoid and mineralocorticoid replacement a 6-month trial of DHEA replacement, which can be continued if clinically effective 1
• There is only limited objective evidence of clinical benefit from large studies, and long-term effects remain unknown, so use should be cautious 1

In PCOS Diagnosis

• DHEAS is considered a second-line diagnostic androgen marker for PCOS, not a routine diagnostic biomarker 1
• High concentrations of DHEAS have been reported in 33% of non-classic PCOS patients, with variability depending on age (more valuable in pre- than post-menopausal women) 1
• The 2023 International PCOS Guidelines recommend considering DHEAS only in cases with negative first-line diagnostic biomarkers and strong clinical suspicion, as it brings additional costs and risk of overdiagnosis due to poorer specificity than testosterone, calculated free testosterone, or free androgen index 1

In Postmenopausal Women

• After menopause, all estrogens and almost all androgens are made locally in peripheral tissues from DHEA, affecting bone formation, adiposity, muscle, insulin and glucose metabolism, skin, libido, and well-being 4
• Intravaginal DHEA has shown potential benefits in treating genitourinary syndrome of menopause (GSM), including improved vaginal health, lubrication, and sexual function, appearing safer than systemic estrogen therapy especially for women with estrogen sensitivity 2

Measurement and Laboratory Considerations

• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the reference standard for measuring DHEA, with superior selectivity and accuracy compared to immunoassays 6, 7
• DHEA measurements should be performed in the morning prior to any supplementation to ensure accurate assessment of endogenous levels 1
• 11-Deoxycortisol, androstenedione, and DHEA are superior to cortisol for assessing adrenal vein sampling selectivity, with selectivity indices 5-6 fold higher than cortisol 7

Important Caveats

• DHEA is classified as a dietary supplement in some countries, leading to increasing recreational misuse in healthy people despite limited evidence for benefit in this population 3
• No specific intranuclear receptor for DHEA has been identified, though highly specific membrane receptors have been detected in endothelial cells, heart, kidney, liver, and brain 3
• The therapeutic effects of DHEA supplementation are inconsistent across different human systems, mainly due to heterogeneous receptor distribution, various action pathways, and distinct tissue responses 2