Endocrinology & Internal Medicine & Gynecology
DHEA-S (dehydroepiandrosterone sulfate)
Dehydroepiandrosterone sulfate (DHEA-S) is the most abundant circulating steroid in adult humans - its plasma concentration exceeds that of cortisol by a factor of 100 to 500. It is a weak androgen, produced almost entirely (95 %) by the reticular zone of the adrenal cortex, under the control of ACTH (pituitary adrenocorticotropin); the remaining 5 % originate from the gonads (ovaries and testes). DHEA is sulfated to DHEA-S in the liver and the adrenal gland itself - sulfation considerably increases its plasma half-life (7-10 hours for free DHEA vs. 10-20 hours for DHEA-S) and solubility, making DHEA-S a stable circulating reservoir and the reference biological marker of adrenal androgen activity. DHEA-S is itself biologically inactive - it acts as a peripheral precursor converted in target tissues (skin, liver, adipose tissue, muscle, brain) into active androgens (testosterone, dihydrotestosterone - DHT) and estrogens (estradiol, estrone) via the enzymes 3β-HSD, 17β-HSD and aromatase. ACTH is the main regulator of DHEA-S secretion - but unlike cortisol, DHEA-S does not exert negative feedback on the hypothalamic-pituitary axis, making it an almost exclusively adrenal marker. DHEA-S exhibits a highly characteristic physiological variation throughout life: its level rises at birth (fetal DHEA-S - massive fetal zone of the adrenal cortex), falls in the first weeks of life, gradually rises again from 6-8 years of age (adrenarche - first biological sign of puberty) to reach a peak around 20-30 years of age, then declines inexorably by 2-3 % per year (adrenal senescence - adreno-pause) until reaching 10-20 % peak values after 80 years of age. DHEA-S measurement is indicated in the evaluation of hyperandrogenism (hirsutism, acne, androgenetic alopecia, virilization), precocious puberty, congenital adrenal hyperplasia, adrenal tumors and adrenal insufficiency.
Reference values by age and gender
| Population | DHEA-S - normal values | Clinical remarks |
|---|---|---|
| Female - 18-29 years | 65-380 µg/dL (1.8-10.3 µmol/L) | Peak around 20-25 years; values comparable to those for men at the same age |
| Female - 30-39 years | 45-270 µg/dL (1.2-7.3 µmol/L) | Onset of progressive physiological decline |
| Female - 40-49 years | 32-240 µg/dL (0.9-6.5 µmol/L) | 50 % decline from peak; symptoms of female andropause possible |
| Female - 50-59 years | 26-200 µg/dL (0.7-5.4 µmol/L) | Menopause: DHEA-S becomes the main source of intra-tissular estrogens (intracrinology) |
| Female - ≥60 years | 13-130 µg/dL (0.4-3.5 µmol/L) | Very low values; relationship studied with sarcopenia, frailty and cognition |
| Men - 18-29 years | 280-640 µg/dL (7.6-17.3 µmol/L) | Maximum values; men have slightly higher levels than women due to a minor gonadal contribution |
| Men - 30-49 years | 120-520 µg/dL (3.2-14.1 µmol/L) | Progressive decline; andropause: DHEA-S is a marker of adrenal aging |
| Male - ≥50 years | 45-370 µg/dL (1.2-10.0 µmol/L) | 70-80 % reduction from peak at age 80 |
| Children - adrenarche (6-9 years) | 10-100 µg/dL - progressive rise | Adrenarche corresponds to maturation of the reticular zone; first biological sign of puberty - precedes gonadarche (gonadal activation) by 2 years |
| Pregnant women (3rd trimester) | Values reduced by 30-50 % | Increased hepatic metabolic clearance (enzymatic induction by placental estrogens) - not to be interpreted without this context |
Note: reference values vary according to laboratory and assay method (immunoassay vs. liquid chromatography-mass spectrometry - LC-MS/MS - reference method). Always interpret according to the values of the laboratory involved.
Elevated DHEA-S - causes and investigation
| Cause | Mechanism and clinical presentation | Further investigation |
|---|---|---|
| Polycystic ovary syndrome (PCOS) Most frequent cause of female hyperandrogenism |
DHEA-S is elevated in 20-30 % of PCOS (predominantly ovarian hyperandrogenism in the majority, but adrenal contribution in a subgroup); presentation: hirsutism, acne, androgenetic alopecia, oligomenorrhea or amenorrhea, infertility, android obesity, insulin resistance; DHEA-S moderately elevated (typically <600 µg/dL); Rotterdam criteria: 2/3 among oligo-anovulation + clinical or biological hyperandrogenism + polycystic appearance on ovarian ultrasound. | Total and free testosterone + SHBG + free androgen index (FTI = total testosterone/SHBG × 100); 17-OH-progesterone (exclude HCS); prolactin; TSH; pelvic ultrasound; fasting blood glucose + insulin (HOMA-IR); lipid profile |
| Congenital adrenal hyperplasia (CAH) - non-classical forms 21-hydroxylase deficiency (CYP21A2) |
Partial 21-hydroxylase deficiency (non-classical form - NC-HCS - prevalence 0.1-0.2 % in general population, more frequent in certain communities: Ashkenazi Jews 1/27, Yugoslavs 1/50, Hispanics 1/40) → accumulation of 17-OH-progesterone → detour to androgenic pathway (androstenedione → testosterone + DHEA-S); presentation similar to PCOS: hirsutism, acne, oligomenorrhea; elevated DHEA-S with morning 17-OH-progesterone (8h) >2 ng/mL (significant) or >10 ng/mL (diagnostic); ACTH stimulation test (Synacthen 250 µg IV - 17-OH-P assay at 0 and 60 min - stimulated value >10 ng/mL confirms diagnosis) | Morning 17-OH-progesterone fasting (early follicular phase in women); Synacthen test if 17-OH-P 2-10 ng/mL; CYP21A2 genotyping (confirmation and genetic counselling); treatment: low-dose hydrocortisone if symptomatic hyperandrogenism or desire for pregnancy. |
| Virilizing adrenal tumor Red flag - DHEA-S >700-800 µg/dL |
Adrenocortical carcinoma (ACC) or adrenal adenoma secreting : very high DHEA-S (>700 µg/dL in women, >800 µg/dL in men - alarm threshold); rapid, progressive virilization (clitoromegaly, phallomegaly, muscular hypertrophy, deep voice, temporal baldness) occurring within a few months - abrupt onset unlike benign causes; CCS may co-secrete several hormones (cortisol + androgens) → associated signs of Cushing's disease; CCS is rare (1-2/million/year) but has a poor prognosis if discovered late (5-year survival: 35-60 % stages I-II vs <10 % stages III-IV) | Adrenal CT with contrast (mass >4 cm, heterogeneous appearance, spontaneous density >10 HU, slow washout - suspected malignancy); adrenal MRI if in doubt (loss of signal in opposition phase - lipid-rich adenoma) ; 24h urinary free cortisol + dexamethasone braking test (associated cortisol hypersecretion); FDG-PET (metastatic extension - CCS); full Cushing's workup if clinically suggestive; no biopsy (risk of seeding + diagnosis often clinico-radiologically sufficient). |
| Adrenal Cushing's syndrome / Hypercortisolism | Paradoxically, in Cushing's syndrome caused by a cortisol-secreting adrenal adenoma, DHEA-S is often depressed (suppression of the reticular zone by autonomic hypercortisolism) - but in Cushing's disease (ACTH-secreting pituitary adenoma) or ectopic ACTH secretion, DHEA-S may be elevated (stimulation of the reticular zone by excess ACTH); simultaneous elevation of DHEA-S and cortisol points to an ACTH-dependent cause | 24h cortisoluria + nocturnal salivary cortisol × 2 + 1 mg dexamethasone braking test (at midnight); morning plasma ACTH (undetectable ACTH → adrenal autonomic; elevated ACTH → pituitary or ectopic origin); pituitary MRI; thoracoabdominal CT (ectopic source). |
| Premature adrenarche | Precocious elevation of DHEA-S before age 8 in girls or age 9 in boys (normal adrenarche ≥6 years) without other pubertal signs (no breast development, no increase in testicular volume) → isolated premature pubic and/or axillary hair growth; DHEA-S in Tanner stage II-III values for age but without excessive statural acceleration or significant bone advancement; diagnosis of exclusion: exclude HCS, adrenal tumor, central precocious puberty | Bone age (X-ray of left wrist); 17-OH-progesterone (exclude HCS); LH/FSH/estradiol (exclude central precocious puberty); GnRH test if basal LH high; adrenal CT if DHEA-S very high for age |
| Medicines and supplements | Exogenous DHEA supplementation (sold over the counter in the US as a dietary supplement, illegal as an OTC drug in Canada) → elevation of DHEA-S and peripheral androgens (testosterone, DHT) - possible virilizing effect in women; androgenic anabolic steroids (AAS) → may elevate DHEA-S depending on molecule; metformin (slight reduction of DHEA-S in PCOS); oral contraceptives (reduction of DHEA-S by adrenal suppression) | Systematic drug and supplement history prior to DHEA-S interpretation; discontinue supplementation 4-6 weeks prior to assay if possible |
Low DHEA-S - causes and significance
- Primary adrenal insufficiency (Addison's disease): autoimmune (70-80 % - anti-21-hydroxylase antibodies), infectious (tuberculosis, histoplasmosis), infiltrative (sarcoidosis, amyloidosis, hemochromatosis) or hemorrhagic (Waterhouse-Friderichsen syndrome - meningococcemia) destruction of the adrenal glands → global insufficiency of the three cortical zones → collapsed DHEA-S + low cortisol + low aldosterone (hyponatremia + hyperkalemia) ; DHEA-S is a sensitive marker of zona reticular involvement and can be lowered very early, even before full cortisolic involvement - useful as a marker of early partial adrenal insufficiency
- Secondary (pituitary) adrenal insufficiency: ACTH deficiency (pituitary adenoma, pituitary surgery or radiotherapy, head trauma, Sheehan's syndrome) → insufficient stimulation of the reticulated zone → low DHEA-S with low cortisol but normal aldosterone (aldosterone is mainly controlled by the renin-angiotensin system - not by ACTH); absence of typical Addison's hyponatremia-hyperkalemia
- Prolonged (iatrogenic) corticosteroid therapy: exogenous corticosteroids suppress pituitary ACTH by negative feedback → atrophy of the reticular zone → collapsed DHEA-S; DHEA-S remains low for several months after prolonged corticosteroid therapy has been discontinued and may serve as a marker of recovery of the corticotropic axis.
- Physiological aging (adrenopause): DHEA-S declines by 2-3 % per year after age 30 - 80-90 % reduction in values between ages 25 and 80 (adrenopause); supplementation studies in the elderly (DHEAge study - Baulieu 2000, NEJM) have not demonstrated clear clinical benefits on cognition, muscle mass, sexuality or mortality in general populations - DHEA supplementation is not recommended outside documented adrenal insufficiency
- Severe chronic stress and critical illnesses: DHEA-S can be transiently lowered during severe acute illnesses (sepsis, major surgery) - «cortisol priority» phenomenon → reduction of DHEA synthesis in favor of cortisol in states of extreme stress (partially shared synthesis pathway)
- Anorexia nervosa and severe undernutrition: reduced activity of the reticular zone in the context of profound undernutrition; to be distinguished from true adrenal insufficiency - cortisol often remains normal or elevated in anorexia nervosa (functional hypercortisolism)
ℹ️
DHEA-S is the biological reference marker of adrenal origin hyperandrogenism: a DHEA-S >700 µg/dL in women or >800 µg/dL in men should lead to the urgent elimination of a virilizing adrenal tumor (adrenocortical carcinoma or secretory adenoma) by adrenal imaging (CT or MRI). Conversely, normal DHEA-S with clinical hyperandrogenism points to an ovarian origin (PCOS, secretory ovarian tumor) or peripheral origin (local conversion of androgens in target tissues - skin, hair follicle). DHEA-S does not no significant circadian variation (unlike cortisol) and no variation with the menstrual cycle - it can be taken at any time of the day, regardless of the phase of a woman's cycle.
Signs requiring urgent consultation
Consult your physician or go to the emergency room if hyperandrogenism is associated with a rapid and progressive virilization (clitoromegaly, deep voice, marked muscular hypertrophy, frontal baldness occurring in weeks to months) with a DHEA-S >700 µg/dL in women - a virilizing adrenal or ovarian tumor must be rapidly excluded by imaging.
In the event of suspected acute adrenal insufficiency (addisonian crisis) - sudden extreme fatigue, abdominal pain, hypotension, confusion, nausea, hyperpigmentation - call 911 immediately: this is a life-threatening emergency requiring an emergency injection of IV hydrocortisone.
Consult at Clinique Omicron
Clinique Omicron's doctors prescribe and interpret DHEA-S assays as part of a workup for hyperandrogenism (hirsutism, acne, alopecia, menstrual irregularities), precocious puberty or suspected adrenal insufficiency. A full hormonal workup (testosterone, SHBG, 17-OH-progesterone, cortisol, ACTH, prolactin, TSH) is coordinated, and referrals to endocrinologists or gynecologists are made according to the results. Consultations are available at our points of service in Quebec, as well as via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The contents of this page are provided for information purposes only and do not replace the advice of a qualified healthcare professional. Reference values for DHEA-S vary according to laboratory and assay method - any abnormality should be interpreted in its clinical context by a physician.
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