Dehydroepiandrosterone (DHEA)
1. Identity, Nomenclature, and Chemical Nature
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is also known by the systematic chemical names 3-beta-hydroxyandrost-5-en-17-one, dehydroisoandrosterone, trans-dehydroandrosterone, Δ5-androsten-3-β-ol-17-one, and by the pharmaceutical generic name prasterone. It is one of the most abundant circulating steroids in humans.
DHEA is the most abundant steroid hormone in humans and is produced mainly by the adrenal cortex as an inactive sulfate ester (DHEA-S). Notably, 75–90% of DHEA production comes from the adrenal cortex, and 10–25% of DHEA is produced in the testis or ovaries. DHEA is produced in the adrenal glands, the gonads, and the brain, and it functions as a metabolic intermediate in the biosynthesis of the androgen and estrogen sex steroids both in the gonads and in various other tissues. However, DHEA also has a variety of potential biological effects in its own right, binding to an array of nuclear and cell surface receptors, and acting as a neurosteroid and modulator of neurotrophic factor receptors.
DHEA sulfate, the 3β-sulfate ester of DHEA, was isolated from urine in 1944 and was found by Baulieu to be the most abundant steroid hormone in human plasma in 1954. Dehydroepiandrosterone-sulfate (DHEA-SO4) of adrenal origin is the major C19 steroid in the serum.
Common Names and Synonyms
- 3β-Hydroxy-Androst-5-Ene-17-One; Androstenolone; Dehydroepiandrosterone; Déhydroépiandrostérone (French); DHEA-S; GL701; Prasterone.
- From its discovery in 1934 until 1959, DHEA was referred to by a number of different names in the literature, including dehydroandrosterone, transdehydroandrosterone, dehydroisoandrosterone, and androstenolone. The name dehydroepiandrosterone, also known as DHEA, was first proposed by Fieser in 1949, and subsequently became the most commonly used name of the hormone.
2. Natural Sources and Commercial Preparation
DHEA is not found in foods and cannot be derived from dietary consumption of plant sources. Food does not contain DHEA, but it is synthesized in the human body; in the laboratory it can be prepared by various chemical constituents obtained from plant sources, including extracts of wild yam — specifically Mexican yam — which can be processed in laboratories for the production of DHEA.
DHEA (3β-hydroxyandrost-5-en-17-one), also known as prasterone, is an important endogenous steroid hormone and a precursor in the synthesis of other steroidal drugs. Current routes toward DHEA and DHEA acetate are typically based on the selective degradation of yam-derived diosgenin to 16-dehydropregnenolone acetate, followed by oxime formation and rearrangement.
The starting source material for commercial DHEA is a class of plant hormones called sterols extracted from wild yams that are grown commercially. The most common plant sterol is diosgenin, which has a molecular structure very similar to DHEA. Diosgenin is converted to DHEA in the laboratory by removing several side chains through various chemical reactions.
Critical clarification: Since the DHEA precursor diosgenin is also found in soy and wild yams, these foods are sometimes advertised as a natural source of DHEA. However, the conversion of diosgenin into DHEA is not believed to occur in the body, so consuming wild yam or diosgenin is unlikely to increase DHEA levels. The modern use of wild yam in the United States is based on a fundamental misconception: that it contains women's hormones such as progesterone and DHEA. In reality, there is no progesterone, DHEA, or any other hormone in wild yam, nor does wild yam contain any substances that have progesterone-like or estrogen-like effects.
Available Dosage Forms
In addition to the body's natural production, DHEA can be made synthetically in a laboratory. The synthetic version is sold as a tablet, capsule, powder, topical cream, or gel in supplements or as a medication called Prasterone. Prasterone, also known as dehydroepiandrosterone (DHEA) and sold under the brand name Intrarosa among others, is a medication as well as over-the-counter dietary supplement; it is taken by mouth, by application to the skin, through the vagina, or by injection into muscle.
In the United States, DHEA is sold as an over-the-counter supplement, and as a medication called prasterone. In almost all countries except the U.S., DHEA is treated as a controlled anabolic steroid. In the U.S., DHEA is exempt from the Controlled Substances Act, which means it is treated differently from other steroids.
3. Historical Discovery and Research Background
The first naturally occurring androgen, androsterone, was isolated from policemen's urine by Butenandt and Tscherning in 1931; the second — dehydroepiandrosterone (DHEA) — was isolated similarly by the same group in 1934. DHEA was discovered, via isolation from male urine, by Adolf Butenandt and Hans Dannenbaum in 1934, and the compound was isolated from human blood plasma by Migeon and Plager in 1954.
For decades after its discovery, DHEA was considered to be an inactive compound that served mainly as an intermediate in the production of androgens and estrogens from cholesterol. The discovery of "oestrus-producing" hormones was a major research breakthrough in biochemistry and pharmacology during the early part of the 20th century. The elucidation of the molecular weight and chemical structure of major oxidative metabolites of DHEA led to significant research into its biosynthesis and metabolism.
There is no documented traditional or ethnobotanical use of DHEA as an isolated compound, because it was only identified through 20th-century biochemistry. Unlike herbal medicines, DHEA has no traditional use in plant form. Claims of supplementary DHEA being the "fountain of youth" hormone arose largely from the observation that endogenous levels of the hormone decline with age and from anecdotal descriptions of enhanced energy and well-being in patients treated with DHEA for adrenal insufficiency. Interest in supplementation grew substantially in the 1990s following epidemiological observations linking low DHEA levels to various age-related conditions.
4. Endogenous Physiology: Production, Levels, and Age-Related Decline
The biosynthesis of dehydroepiandrosterone (DHEA) from cholesterol involves only two enzymes, both cytochrome P450s. The conversion of cholesterol to pregnenolone is mediated by cholesterol side-chain cleavage enzyme (CYP11A1), which is found in the mitochondria. The cleavage of pregnenolone to DHEA requires both the 17alpha-hydroxylase and 17,20-lyase activities of CYP17, which is found in the endoplasmic reticulum.
In the smooth endoplasmic reticulum, steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) hydroxylates pregnenolone at the C-17 position, followed by the cleavage of the bond between C-17 and C-20 to produce DHEA. CYP17A1 works in conjunction with NADPH-dependent cytochrome P450 reductase (CPR) as an electron source and microsomal cytochrome b5 (CYB5A), increasing the activity of CYP17A1 by 10-fold.
Astrocytes and neurons express P450c17 and synthesize DHEA from pregnenolone. Astrocytes also have the capacity to metabolize DHEA into sex steroid hormones. The production of DHEA by astrocytes is not limited to cerebral cortex, as hypothalamic astrocytes produce DHEA at a level 3 times higher than that produced by cortical astrocytes.
Between the ages of 20 and 60 years, serum DHEA sulfate (DHEAS) levels decline approximately 70%, reflecting the overall decrease in adrenal production of DHEA. Adrenal production of DHEA begins during puberty and peaks at around 20 years old. At approximately age 25, serum DHEA begins to decline rapidly, so that by age 75 DHEA level is approximately 80% lower than at 20 years old.
The synthesis of androgens and estrogens from DHEAS becomes increasingly important as gonadal sex hormone production declines with aging. It has been estimated that DHEAS is the precursor for all estrogens and androgens in postmenopausal women and 40% in older men.
5. Key Active Compounds and Mechanisms of Action
5.1 Prohormone / Sex Steroid Conversion
DHEA functions as a metabolic intermediate in the biosynthesis of the androgen and estrogen sex steroids both in the gonads and in various other tissues. DHEA is potentiated locally via conversion into testosterone and dihydrotestosterone (DHT) in the skin and hair follicles. DHEA is a weak estrogen. In addition, it is transformed into potent estrogens such as estradiol in certain tissues such as the vagina, and thereby produces estrogenic effects in such tissues.
5.2 Neurosteroid Activity
DHEA is the most abundant neurosteroid synthesized de novo in the central nervous system. Despite extensive evidence supporting the modulatory effects of DHEA on various membrane receptors, including the GABA-A, NMDA, and sigma-1 receptors, the precise mechanism underlying its action in the nervous system has not yet been fully elucidated.
Neuroactive steroids exert rapid neuromodulatory effects in the brain by interacting with GABA(A), NMDA, and sigma-1 receptors. At the sigma-1 receptor level, DHEA (3beta-hydroxy-5-androsten-17-one) and pregnenolone act as agonists, whereas progesterone is an efficient antagonist.
Stimulation of the sigma-1 receptor by DHEA improves cognitive function by activating calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C and extracellular signal-regulated kinase in the hippocampus. Sigma-1R stimulation by DHEA in the hippocampal dentate gyrus ameliorates depressive-like behaviors through enhancing neurogenesis via activation of the protein kinase B (Akt)/glycogen synthase kinase-3 beta (GSK-3β)/β-catenin pathway. These findings are from animal models, and their direct applicability to humans remains under investigation.
5.3 Immunomodulatory Actions
There is evidence that DHEA has an immunomodulatory effect as well as an androgenic role. In vitro, DHEA reduces circulating inflammatory drivers such as interleukin-6 and up-regulates interleukin-2.
DHEA is a weak androgen that exerts pleomorphic effects on the immune system. The hormone has no known single receptor, and consequently its mechanism of action on immunocompetent cells remains poorly understood.
5.4 Bone Metabolism
DHEA promotes osteoblast differentiation and proliferation, regulates the RANKL/OPG ratio, and inhibits osteoclastogenesis and bone resorption. Increases in bone mineral density in response to oral dehydroepiandrosterone replacement in older adults appear to be mediated by serum estrogens.
5.5 Adrenarche and Secondary Sexual Development
DHEA and other adrenal androgens such as androstenedione, although relatively weak androgens, are responsible for the androgenic effects of adrenarche, such as early pubic and axillary hair growth, adult-type body odor, increased oiliness of hair and skin, and mild acne.
6. Scientific Evidence by Area of Use
6.1 Adrenal Insufficiency
This represents the clinical area with the strongest evidence base for DHEA replacement. Deficiencies of glucocorticoid and mineralocorticoid in primary adrenal insufficiency (Addison's disease) are well recognized and require lifelong replacement. However, the associated deficiency of DHEA(S) has been investigated only recently, and its possible clinical significance remains controversial. Patients with Addison's disease on optimal glucocorticoid and mineralocorticoid replacement therapy still report a reduced quality of life compared with normal individuals.
DHEA and DHEA sulfate (DHEAS) are the major circulating adrenal steroids and substrates for peripheral sex hormone biosynthesis. In Addison's disease, glucocorticoid and mineralocorticoid deficiencies require lifelong replacement, but the associated near-total failure of DHEA synthesis is not typically corrected. In a double-blind trial, 106 subjects (44 males, 62 females) with Addison's disease were randomized to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months to evaluate its longer-term effects on bone mineral density, body composition, and cognitive function together with well-being and fatigue.
Circulating DHEAS and androstenedione rose significantly in both sexes, with testosterone increasing to low normal levels only in females. DHEA reversed ongoing loss of bone mineral density at the femoral neck (p < 0.05). Multiple clinical trials show that DHEA replacement in this population improves mood, energy, sexual function, and quality of life. Endocrine guidelines from multiple professional societies support DHEA replacement in women with adrenal insufficiency specifically.
6.2 Vaginal Atrophy / Dyspareunia (FDA-Approved Indication)
This is the first agent approved by the Food and Drug Administration (FDA) to treat women experiencing moderate-to-severe pain during sexual intercourse (dyspareunia), a symptom of vulvar and vaginal atrophy (VVA), due to menopause. During menopause, vaginal tissue estrogen levels decrease, which may lead to VVA. Intrarosa is the first FDA-approved product containing the active ingredient prasterone, which is also known as DHEA.
In 2016, the FDA approved prasterone in an intravaginal gel formulation for the treatment of painful sexual intercourse due to vulvovaginal atrophy in the United States under the brand name Intrarosa. This was the first prasterone-containing medication to be approved by the FDA in this country.
Intrarosa is available as a 6.5-mg vaginal insert; the dose is one insert, once daily at bedtime, using the provided applicator. The efficacy of once-daily, intravaginal Intrarosa was established in two 12-week placebo-controlled clinical trials of 406 healthy postmenopausal women (40–80 years of age), who identified moderate-to-severe pain during sexual intercourse as their most bothersome symptom of VVA.
The efficacy of DHEA (Intrarosa) in moderate-to-severe dyspareunia, a menopausal symptom of vulvar and vaginal atrophy, was examined in two primary 12-week placebo-controlled efficacy trials, and all the differences between baseline and endpoints were statistically significant, indicating improvement in the symptoms of vulvar and vaginal atrophy after treatment with 6.5 mg of Intrarosa.
Evidence strength: Strong for this indication, based on multiple RCTs supporting FDA approval. Local intravaginal delivery minimizes systemic hormone exposure.
6.3 Bone Mineral Density
DHEA levels decline dramatically with age, concurrent with the onset of osteoporosis, suggesting a role for DHEA supplementation in preventing age-related bone loss. A randomized, placebo-controlled trial examined the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism, and body composition in 225 healthy adults aged 55 to 85 years.
DHEA treatment increased serum DHEA and DHEA sulfate levels to concentrations seen in young adults. Testosterone, estradiol, and insulin-like growth factor (IGF-1) levels increased in women (all p<0.001), but not men, receiving DHEA.
Studies of DHEA therapy in older adults suggest sex-specific effects on bone mineral density (BMD) and body composition. Pooled analyses of data from four double-blinded, randomized controlled trials enrolled women (n=295) and men (n=290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months.
Studies indicate that DHEAS is associated with increased BMD and decreased fracture risk, suggesting that it plays a protective role by enhancing bone mass. In elderly individuals with low androgen levels, DHEA supplementation increases sulphated DHEA and oestradiol levels and improves bone mineral density, particularly in the ultra-distal radius of women and the femoral neck of men. However, the clinical use of DHEA remains debated due to inconsistent study results. Its effects on bone health may vary based on factors such as age, gender, and health conditions, emphasising the need for further research.
Evidence strength: Moderate; pooled RCT data suggest BMD benefits especially in women and elderly populations with low baseline androgen levels, but results are not uniformly consistent across trials.
6.4 Cognitive Function
A positive correlation between DHEA-S blood levels and global cognition was found in women and men. Other positive correlations between DHEA-S and working memory, attention, and verbal fluency were found only in women. These are observational/epidemiological correlations and do not establish causation.
However, intervention data are less encouraging. The results of a clinical trial (the DAWN trial) provide no evidence for a beneficial effect of supplementation with 50 mg daily of DHEA on cognitive function in healthy older adults. Likewise, there were no beneficial effects of DHEA supplementation on quality of life, including mood, perceptions of physical and emotional health, life satisfaction, or sexual function.
Studies found little evidence of a beneficial effect of DHEA supplementation on cognitive function of middle-aged or older adults who do not have dementia.
Evidence strength: Weak to null for cognitive enhancement in healthy older adults based on controlled trial data; epidemiological associations do not translate into demonstrated supplementation benefit in RCTs.
6.5 Depression and Mood
Some research suggests that DHEA may be helpful in treating depression. Some evidence indicates that it may relieve depression (although not as a first-line treatment). Altered DHEA/DHEAS levels have been implicated in neurodegenerative disorders and depression, with emerging evidence supporting their potential therapeutic value.
Evidence strength: Preliminary; some small RCTs show modest benefit in specific populations (e.g., midlife depression), but the evidence base is not robust enough to support routine clinical use.
6.6 Systemic Lupus Erythematosus (SLE)
DHEA is a naturally occurring inactive steroid which may possess disease activity modifying properties as well as the ability to reduce flares and steroid requirements in SLE. Androgens and DHEA are reduced (by approximately 50%) in women with SLE, especially those with active disease, and are further reduced by corticosteroid administration.
Serum levels of DHEA are decreased in patients with inflammatory diseases including lupus, and these levels seem to correlate inversely with disease activity. Following encouraging studies demonstrating beneficial effects of DHEA supplementation in murine lupus models, several clinical studies have tested the effect of DHEA in lupus patients. DHEA treatment could improve overall quality-of-life assessment measures and glucocorticoid requirements in some lupus patients with mild to moderate disease.
In animal studies, supplementation of DHEA has shown clear anti-inflammatory effects on the immune system and beneficial effects in lupus-prone mice have been observed. DHEA plasma concentrations are subnormal in a subset of subjects with SLE.
Evidence strength: Moderate signals from multiple RCTs in mild-to-moderate SLE, particularly for quality of life and steroid-sparing effects; however, a Cochrane review found insufficient evidence to recommend DHEA as standard treatment, and further large trials are needed.
6.7 Fertility and Assisted Reproduction
Benefits of DHEA supplementation have been reported in connection with IVF outcomes. In women with diminished ovarian reserve, DHEA treatment has been related to amelioration of outcome parameters of in vitro fertilization (IVF) such as peak estradiol level, numbers and quality of embryos, and reduced miscarriage rates. Nevertheless, in the absence of randomized studies, DHEA cannot be recommended as a routine protocol in advanced reproductive age.
In several countries, DHEA is sold over the counter as a food supplement. Analysis of commercially available DHEA products found that DHEA content ranged from 0 to 150% of the labelled amount.
Evidence strength: Preliminary; observational and small prospective studies show promise in women with diminished ovarian reserve, but rigorous large RCTs are lacking. Current evidence does not support routine clinical recommendation.
6.8 Body Composition, Muscle Strength, and Athletic Performance
Research on the effects of DHEA on muscle strength and physical performance had mixed results, but most studies indicate DHEA supplementation has no effect on muscle strength in younger or older adults. Many athletes claim that DHEA builds muscle and enhances athletic performance, but the use of DHEA is banned by numerous professional sports organizations.
The World Anti-Doping Agency classes DHEA as a banned substance in sports. The National Collegiate Athletic Association has banned DHEA use among athletes.
Studies at lower doses (50 mg/day) have reported effects suggesting preservation of insulin sensitivity in post-menopausal women, increased muscle mass and strength, and decreased fat mass in men (but not in women), and decreased platelet aggregability.
Evidence strength: Mixed; some positive signals in specific populations (older men, adrenal insufficiency) but not consistently demonstrated in healthy younger adults. Banned in competitive sports.
6.9 Anti-Aging and General Well-Being
In theory, taking DHEA supplements to maintain DHEA levels could slow the aging process, possibly improving well-being, thinking skills, and body composition. But so far research hasn't proved this to be true. There's little evidence to support antiaging claims.
Though supplementation shows potential benefits, especially in conjunction with resistance training, results remain discrepant. Current evidence has revealed that the therapeutic effects of DHEA supplementation are inconsistent in different human systems among different studies. The diversity of results is mainly due to heterogeneous receptor distribution, various action pathways, and distinct tissue responses in different systems. Further research is needed to define its efficacy and dosage across various systems.
Evidence strength: Weak; broad "anti-aging" claims are unsupported by current RCT evidence in healthy adults without documented deficiency.
7. Dosages Reported in Clinical Studies
The following dosages appear in peer-reviewed studies and clinical trials; they are reported descriptively from those sources and do not constitute dosing recommendations:
- DHEA has been used in controlled human studies at doses up to 1600 mg/day for four weeks, and at much lower doses (50 mg/day) for as long as six months, in subjects up to age 70.
- A randomized, placebo-controlled trial examined the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density, bone metabolism, and body composition in 225 healthy adults aged 55 to 85 years.
- A double-blind trial randomized 106 subjects with Addison's disease to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months.
- Intrarosa (for vaginal atrophy) is available as a 6.5-mg vaginal insert; the dose is one insert, once daily at bedtime.
- The DAWN trial used 50 mg daily oral DHEA replacement for 1 year to examine cognitive function and quality of life.
In general, most human studies involve weak correlations of circulating levels of DHEA and disease outcomes. Further research is needed to define its efficacy and optimal dosage across various systems.
8. Body Systems and Health Areas Associated with DHEA
- Endocrine / Hormonal System: DHEA has various physiological roles in the body, including supporting overall well-being and vitality, modulating the immune system, promoting bone health, and affecting mood and cognitive function. It also plays a role in the development of secondary sexual characteristics during puberty.
- Skeletal System: DHEA plays a key role in various physiological processes including bone health. Its age-related decline is linked to reduced bone density, though the mechanisms by which DHEA affects bone metabolism remain complex.
- Central Nervous System: DHEA is the most abundant neurosteroid synthesized de novo in the central nervous system.
- Immune System: DHEA has an immunomodulatory effect as well as an androgenic role, and both may potentially have benefits in inflammatory conditions. In vitro, DHEA reduces circulating inflammatory drivers such as interleukin-6 and upregulates interleukin-2.
- Reproductive System: DHEA is a weak estrogen, and it is transformed into potent estrogens such as estradiol in certain tissues such as the vagina, thereby producing estrogenic effects in such tissues.
- Skin: Prospects for the clinical use of DHEA are associated with its local effect on the skin, including regeneration and reduction of age-induced atrophy.
- Prostate (oncological concern): DHEA-SO4 of adrenal origin is the major C19 steroid in the serum and is a precursor of intratumoral androgen biosynthesis in patients with advanced prostate cancer following chemical or surgical castration.
9. Safety Considerations and Drug Interactions
9.1 Androgenic and Estrogenic Side Effects
DHEA may result in acne, headache, mood changes, breast enlargement in men, and hairiness in women. Side effects of prasterone in women include symptoms of masculinization like oily skin, acne, increased hair growth, voice changes, and increased sexual desire, headaches, insomnia, and others.
DHEA has been given to over 1,200 patients in clinical trials without severe adverse effects. Known side effects of DHEA include hirsutism (excessive body hair growth), alopecia (hair loss), and acne. In previous studies these side effects were mild, short-lived, and well tolerated.
Other side effects may include slight changes in blood cholesterol, insulin, and triglyceride levels. Additional side effects that may occur include skin rash, breast tenderness or enlargement (in both men and women), oily skin, irregular or abnormal menstruation in women, and lower blood pressure. There is also a possible risk of benign prostatic hyperplasia (BPH) as DHEA has been shown to increase a hormone that may prompt BPH.
9.2 Cancer Risk
Taking high doses of DHEA or using it for a long time might raise the risk of hormone-sensitive cancers, such as prostate and breast cancers, but more research is needed. If you have a type of hormone-sensitive cancer, don't use DHEA.
Estrogen is a metabolite of prasterone. Use of exogenous estrogen is contraindicated in women with a known or suspected history of breast cancer. Intrarosa has not been studied in women with a history of breast cancer.
9.3 Drug Interactions
DHEA may increase bleeding in people taking anticoagulants. DHEA has triggered mania in people taking antidepressants. DHEA may antagonize the anti-estrogenic effects of tamoxifen, aromatase inhibitors (such as anastrozole), and fulvestrant. DHEA may increase the concentrations of triazolam (a benzodiazepine used for sleep), and decrease the effectiveness of bacillus Calmette-Guérin (BCG) vaccination for tuberculosis.
Corticosteroids, birth control taken by mouth, and agents that treat psychiatric disorders may reduce DHEA levels.
9.4 Product Quality and Regulatory Status
Studies have shown quality control of this supplement to often be low. In several countries, DHEA is sold over the counter as a food supplement; however, analysis of commercially available DHEA products (not derived from human sources) found that DHEA content ranged from 0 to 150% of the labelled amount.
Intrarosa is the first FDA-approved product containing the active ingredient prasterone (DHEA). Other forms of DHEA are used in dietary supplements that are not approved by the FDA.
9.5 Contraindications
Intrarosa should not be used in any postmenopausal woman with undiagnosed abnormal genital bleeding. The cause of any persistent or recurring genital bleeding should be evaluated prior to being considered for treatment.
References
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