Dehydroepiandrosterone

Common Name(s): Dehydroepiandrosterone sulfate, DHEA, DHEA-S

Medically reviewed by Drugs.com. Last updated on Feb 1, 2023.

Clinical Overview

Use

Long-term, adequately powered clinical trials are lacking to support therapeutic use of dehydroepiandrosterone (DHEA) and its metabolite dehydroepiandrosterone sulfate (hereafter referred to as DHEA-S) supplementation. A Polish Menopause and Andropause Society (PMAS) position statement on DHEA supplementation in pre- and postmenopausal women (2020) states that DHEA supplementation is effective in females with adrenal insufficiency treated long-term with exogenous glucocorticoids, postmenopausal females with low bone mineral density (BMD) and/or osteoporosis, and premenopausal females with sexual disorders and low libido and is probably effective in females with obesity and insulin resistance, females with depression and anxiety, postmenopausal females with hypoactive sexual disorders, and as part of assisted reproductive therapy in females with diminished ovarian reserves. DHEA is recommended as third-line monotherapy or adjunctive therapy for treatment of major depressive disorder (MDD) by Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines, and limited data suggest a potential role for DHEA as an anxiolytic.

Dosing

Major depressive disorder: DHEA doses ranging from 30 to 450 mg/day for 6 to 8 weeks have been commonly used in clinical studies.

Polish Menopause and Andropause Society recommendations: The PMAS position statement on DHEA supplementation in pre- and postmenopausal females provides the following daily dosing recommendations and titration ranges:

• Adrenal insufficiency: 25 mg/day orally titrated to 50 mg/day.

• Anxiety and depression (females): 30 mg/day orally titrated to 60 mg/day, then to 90 mg/day, then to 450 mg/day.

• Assisted reproductive therapy in females with diminished ovarian reserve: 75 mg/day orally.

• Obesity and insulin resistance (females): 25 mg/day orally titrated to 50 mg/day, then to 100 mg/day.

• Postmenopausal females:

  • Low BMD and/or osteoporosis: 25 mg/day orally titrated to 50 mg/day, then to 100 mg/day.

  • Hypoactive sexual disorders: 10 mg/day orally titrated to 50 mg/day, then to 90 mg/day, then 300 mg/day, then 450 mg/day.

• Premenopausal females with sexual disorders and low libido: 75 mg/day orally.

Contraindications

Use of DHEA or DHEA-S is not recommended in breast or prostate cancer.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. DHEA supplementation has been evaluated for use in improving oocyte production in infertility.

Interactions

Supraphysiologic serum DHEA-S levels due to DHEA supplementation have been documented to interfere with commercially available progesterone assays, yielding false-positive increases in serum progesterone. Drug interactions are possible with estrogen derivatives and testosterone.

Adverse Reactions

Studies in adrenal insufficiency suggest DHEA is generally well tolerated. However, data from long-term studies are lacking. Observed adverse effects include mania and hypomania, acne, hirsutism, gynecomastia, testicular changes, increased blood pressure, and decreased HDL levels.

Use caution in individuals with psychiatric disorders; agitation, confusion, anxiety, paranoia, and suicidal thoughts have been reported. Use of hormones such as DHEA may cause erythrocytosis. Use caution in individuals with diabetes, as DHEA may increase insulin resistance or sensitivity. Use caution in individuals with liver dysfunction, as DHEA may exacerbate this condition. Use caution in individuals with polycystic ovarian syndrome, as DHEA may worsen this condition.

Toxicology

No data.

Source

Many nonprescription preparations of DHEA are developed in China and are likely to contain DHEA derived from diosgenin that has been extracted from the root of wild yam (Dioscorea villosa). Other commercial preparations contain synthetically derived DHEA. These supplements are not regulated by the US Food and Drug Administration (FDA) and are exempt from pharmaceutical quality standards; wide variations in DHEA content among products have been described.(Olech 2005, Webb 2006)

History

DHEA was first isolated by the German biochemist Adolf Butenandt in the 1930s. Claims of supplementary DHEA being the "fountain of youth" hormone have arisen 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. Although its use is prohibited under the World Anti-Doping Code and the National Collegiate Athletic Association, several high-profile athletes have tested positive for DHEA.(Maninger 2009, Webb 2006) The FDA banned over-the-counter sales of DHEA in 1985; however, since the passage of the Dietary Supplement Health and Education Act of 1994, DHEA has been widely available and marketed as a dietary supplement.(Webb 2006)

Chemistry

DHEA is a precursor in the production of sex hormones.(Olech 2005) It is produced endogenously in the adrenal gland from cholesterol, but can also be synthesized in neurons, glial cells, and the ovaries.(Fouany 2013, Grimley Evans 2006, Maninger 2009) Both DHEA and its main metabolite DHEA-S are major circulating hormones in the body. Levels vary according to age, peaking in early adulthood and generally declining to 10% to 20% between 70 and 80 years of age, although there is great individual variability in these changes.(Genazzani 2007, Maninger 2009, Mazat 2001) In females, exogenous DHEA results in greater increases in systemic androgens, while in males, DHEA use results in increases in both systemic estrogens and androgens, with greater influence on estrogens.(Samaras 2013) Factors that influence circulating DHEA-S levels include alcohol intake, body mass index (BMI), ethnicity, nutritional status, sex, smoking status, thyroid function, and use of concomitant medications (eg, corticosteroids).(Olech 2005) Autoregulation mechanisms and local tissue requirements can result in sex hormone levels in peripheral tissues that differ considerably from what would be expected based on circulating levels.(Samaras 2013)

Uses and Pharmacology

The sulfate derivative of DHEA (DHEA-S) has been shown to act as a noncompetitive antagonist of gamma-aminobutyric acid receptors, as well as a positive allosteric modulator of N-methyl-D-aspartate receptors. In humans, neuroprotective, antioxidant, antihypertensive, and anti-inflammatory effects have also been reported. Serum DHEA levels peak 60 to 480 minutes after administration.(Fouany 2013)

Note: Studies conducted in nonprimate animals have limited applicability in humans because the levels of circulating DHEA-S are different; rodents have very little circulating DHEA.(Bovenberg 2005, Genazzani 2007, Maninger 2009)

Adrenal insufficiency

Clinical data

The PMAS position statement on supplementation with DHEA in pre- and postmenopausal females (2020) concluded that based on current evidence, DHEA supplementation is effective in females with adrenal insufficiency treated long-term with exogenous glucocorticoids. Dosing recommendation is 25 mg/day orally titrated to 50 mg/day.(Rabijewski 2020)

Ageing

Clinical data

Using insulinlike growth factor 1 (IGF-1) as a surrogate biomarker for the aging process, a systematic review and meta-analysis of pooled data from 24 randomized controlled trials (N=1,429) evaluated the impact of DHEA supplementation. Results showed IGF-1 levels were significantly increased following DHEA supplementation (weighted mean difference [WMD], 16.36 ng/mL; 95% CI, 8.99 to 23.74; P=0). Heterogeneity among trials was significant. Subgroup analyses revealed significant increases in IGF-1 for females, doses of 50 mg/day, supplementation duration of more than 12 weeks, healthy participants, and those older than 60 years. Additionally, a nonlinear dose-response analysis revealed a greater increment in IGF-1 levels with supplementation up to 20 weeks (P=0.023).(Xie 2020)

Assisted reproduction

Clinical data

Limited clinical studies have been conducted in females with diminished ovarian reserves. Reviews of the studies have concluded that DHEA supplementation increases the number of oocytes produced, hence increasing the chance of pregnancy. The rate of miscarriage has also been found to be diminished, possibly by reducing aneuploidy. Reported adverse events are androgenic in nature but also include 1 case report of seizure. One study suggests that most babies born after maternal DHEA treatment are male, possibly related to increases in intrafollicular testosterone or other androgen levels in females taking DHEA; however, corroboration of more studies is needed.(Gleicher 2011, Mamas 2009, Narkwichean 2013, Wiser 2010) A small, controlled study in patients with primary ovarian insufficiency found increases in antral follicle count and ovarian volume but no significant changes in follicle-stimulating hormone (FSH) or anti-Mullerian hormone levels.(Yeung 2013)

A 2016 meta-analysis of pooled data from 2 studies (N=99)(Narkwichean 2013, Wiser 2010) found adjuvant use of DHEA supplementation had no effect on the number of oocytes and clinical pregnancy rates in females with poor response to ovarian stimulation.(Jeve 2016) Another systematic review and meta-analysis explored DHEA efficacy data from a larger sample of patients (8 studies [N=647]), specifically those in whom in vitro fertilization (IVF) or intracytoplasmic sperm injection failed due to diminished ovarian reserve or poor response. The systematic review showed that DHEA did not increase the number of oocytes retrieved compared with controls; however, a significant increase in pregnancy rate was observed (P=0.02). Significance remained (P<0.001) for increased clinical pregnancy rate after removal of the study with the highest relative heterogeneity. DHEA was not found to have a significant effect on implantation or spontaneous abortion rates.(Li 2015) Reports of increased progesterone subsequent to DHEA administration in females with low ovarian reserve(Strauss 2014) should be interpreted cautiously, as the resulting serum DHEA-S level has been demonstrated to cross-react with 3 commercially available progesterone assays (Immulite 2000, eCobas, Centaur), yielding false-positive increases in serum progesterone.(Forman 2015, Franasiak 2016)

The British Fertility Society Policy and Practice Committee 2015 evidence-based guidelines and recommendations for good clinical practice do not support the routine use of DHEA as an adjuvant in IVF cycles based on a lack of robust evidence of benefit.(Nardo 2015) The PMAS position statement on supplementation with DHEA in pre- and postmenopausal females (2020) concluded that based on current evidence, DHEA supplementation is probably effective in females with infertility due to diminished ovarian reserve. The recommended daily dose is 75 mg orally.(Rabijewski 2020)

Asthma

Clinical data

Circulating DHEA-S levels are lower among patients with asthma, leading to studies to evaluate effects of DHEA replacement therapy in asthma.(Kasperska-Zajac 2010) When nebulized DHEA-S (70 mg/day) was evaluated in a study of patients with moderate to severe asthma, no effects on forced expiratory volume at 1 second or peak expiratory flow rate were demonstrated; however, a difference over placebo was shown using the Asthma Control Questionnaire.(Wenzel 2010)

Bone mineral density

Clinical data

Pooled data from healthy adults in a meta-analysis of 3 randomized controlled trials (N=289) showed no beneficial effects on total body BMD or on specific measures for lumbar spine, femoral neck, total hip (for males), or trochanter (for males) with DHEA supplementation (ie, 50 mg/day for 6 to 12 months) compared with placebo. In contrast, in females, total hip BMD (standardized mean difference [SMD], −0.5; 95% CI, −0.95 to −0.04; P=0.03) and trochanter BMD (SMD, −0.55; 95% CI, −1.1 to 0; P=0.05) were significantly lower with placebo than DHEA, with moderate heterogeneity observed among data pooled from the 3 studies (N=148) that reported these outcomes. For bone turnover markers, IGF-1 levels were lower in the placebo group compared with the DHEA group, with a significant difference observed in females but not males (SMD, −2.61; 95% CI, −4.85 to −0.38; P=0.02); however, heterogeneity was very high. Meanwhile, an increase in serum bone-specific alkaline phosphatase was observed in males receiving placebo compared with those receiving DHEA (SMD, 0.5; 95% CI, 0.02 to 0.97; P=0.04; no heterogeneity).(Lin 2019)

In postmenopausal females, DHEA-S has been shown to stimulate osteoblasts; however, results regarding improvements in bone density have been equivocal, with only a small effect demonstrated in some studies. The quality of evidence for the majority of studies was low due to imprecision and risk of bias.(Alkatib 2009, Bovenberg 2005, Elraiyah 2014, Genazzani 2010, Grimley Evans 2006, Olech 2005, Panjari 2010)

The PMAS position statement on supplementation with DHEA in pre- and postmenopausal females (2020) concluded that based on current evidence, DHEA supplementation is effective in postmenopausal females with low BMD and/or osteoporosis. Dosing recommendation is 25 mg/day orally titrated to 50 mg/day, then to 100 mg/day.(Rabijewski 2020)

Cancer

DHEA is a weak androgen, and adrenal androgens are associated with an increased risk of cancer, especially of the breast and prostate. Until rigorous laboratory and clinical studies have been conducted, use of DHEA-S in cancer prevention cannot be supported.(Arnold 2009, Matsuzaki 2006)

Animal and in vitro data

The relevance of effects of DHEA in rodent models of cancer is unclear.(Arnold 2005, Arnold 2009) Epidemiological data are inconclusive regarding the role of DHEA and DHEA-S in cancer. Some studies suggest that age-related declines in DHEA-S, testosterone, and estrogen are protective for hormone-sensitive cancers. Other studies correlate elevated DHEA-S with decreased rates of cancer.(Arnold 2005, Arnold 2009, Matsuzaki 2006)

CNS effects

Clinical data

DHEA supplementation may be of benefit in posttraumatic stress disorder and in addiction by improving abstinence.(Maninger 2009, Yadid 2010)

The role of exogenous DHEA in depression remains unclear. A correlation between low DHEA levels and increased symptoms of depression in older females has been suggested; 2 well-designed studies showed modest effects.(Olech 2005)

CANMAT clinical guidelines for the management of MDD in adults (2016) recommend DHEA as third-line monotherapy in mild to moderate MDD based on level 2 evidence (at least 1 randomized controlled trial with adequate sample size and/or meta-analysis with wide confidence intervals) and as adjunctive therapy based on level 3 evidence (small-sample randomized clinical trials, nonrandomized controlled prospective studies, case series, or high-quality retrospective studies). DHEA dosages commonly used in research of MDD range from 30 to 450 mg/day, with treatment lasting 6 to 8 weeks.(Ravindran 2009, Ravindran 2016)

One small randomized, placebo-controlled, 6-month pilot study (N=21 evaluable) evaluated the effects of DHEA 100 mg/day in community-dwelling patients with anorexia nervosa. Beck Depression Inventory score at 3 and 6 months and BMI at month 4 were improved in the treatment group compared with placebo. There were no differences between treatment groups for Eating Disorders Inventory and Clinical Global Improvement Scale scores.(Bloch 2012)

Uncontrolled studies conducted in patients with schizophrenia in the 1950s reported an improved sense of well-being (ie, improvement in energy, insight, self-confidence, emotionality, vitality, adjustments to environment, school and occupational performance, anxiety, depression, apathy, withdrawal) with DHEA supplementation; however, data from more recent clinical trials are limited and equivocal.(Maninger 2009) Some evidence exists of altered DHEA-S circulating levels in patients with schizophrenia; it is possible that differences in baseline levels between patients with schizophrenia and healthy matched controls may account for equivocal results of clinical studies.(Ritsner 2011) In one study evaluating therapeutic potential in schizophrenia, DHEA dosages of 150 mg/day over 12 weeks improved negative symptoms (loss of interest, energy, and humor), with no effect on hallucinations or delirium.(Ritsner 2011) Another study used DHEA 200 mg/day for 6 weeks and found no superiority over placebo in treating negative or positive symptoms of schizophrenia.(Maninger 2009)

A small, double-blind, randomized, placebo-controlled trial (N=29) investigated the effect of DHEA on neural regulation of emotions. A single oral dose of DHEA 400 mg was administered 120 minutes prior to neuroimaging in right-handed healthy young males (18 to 34 years of age). Memory accuracy for emotional stimuli was significantly reduced with DHEA compared with placebo (P=0.029), suggesting a reduction in emotional reactivity encoding; this effect was negatively correlated with serum DHEA (P=0.005). Additionally, magnetic resonance imaging results revealed that activity was reduced in regions of the brain associated with negative emotion and increased in regions linked to emotion regulatory control with DHEA compared with controls. These results suggest a possible role for DHEA in anxiety and depressive disorders.(Sripada 2013) In a behavioral and electrophysiological study in 21 healthy females 18 to 26 years of age with normal anxiety levels, DHEA and DHEA-S levels were shown to be related to brain processing under negative emotional contexts, suggesting potential modulation of emotionally negative information processing.(do Vale 2015)

The PMAS position statement on supplementation with DHEA in pre- and postmenopausal females (2020) concluded that based on current evidence, DHEA supplementation is probably effective in females with depression and anxiety. Dosing recommendation is 30 mg/day orally titrated to 60 mg/day, then to 90 mg/day, then to 450 mg/day.(Rabijewski 2020)

Circulating DHEA levels in older populations are only 10% to 20% of those in young adults, and some but not all observational studies suggest patients diagnosed with dementia have lower circulating DHEA-S levels.(Genazzani 2007, Grimley Evans 2006, Maninger 2009, Olech 2005) This observation has led to the suggestion that DHEA supplementation might prevent or slow the decline in cognitive function with age; however, there is currently no positive evidence to support this use.(Bovenberg 2005, Grimley Evans 2006, Maninger 2009, Merritt 2012, Sorwell 2010)

Erectile dysfunction

Clinical data

In a study of DHEA treatment (50 mg orally for 6 months) for erectile dysfunction in patients with different organic etiologies, results suggest oral DHEA may be beneficial in patients with erectile dysfunction who have hypertension or those without organic etiology. DHEA treatment had no impact on erectile dysfunction in patients with diabetes mellitus or with neurological disorders.(Reiter 2001)

Immune effects

Animal data

In animal studies of experimental sepsis and trauma, DHEA decreased splenocyte proliferation and increased circulating NK cells and CD8+ lymphocytes; therefore, a role in managing critical illness has been suggested.(Oberbeck 2010)

Clinical data

Correlations between reduced circulating DHEA-S levels and urticaria and other immune-related disorders have led to proposals for DHEA supplementation. However, clinical trials are largely lacking.(Buford 2008, Kasperska-Zajac 2008, Kasperska-Zajac 2011) In a review of clinical trials, no effect of DHEA supplementation was found in well-established rheumatoid arthritis in one study; however, decreased disease activity was observed in another study of patients with inflammatory bowel disease, although the study was not placebo controlled.(Hazeldine 2010)

Metabolic effects (lipids/insulin)

Clinical data

Studies evaluating the effect of DHEA supplementation on lipid profiles have produced equivocal results. Trials used varying dosages (from 25 to 1,600 mg/day) and include heterogenous populations, making meta-analysis difficult. Some studies report decreases in total cholesterol as well as decreased HDL cholesterol; other studies report no effect. While it is possible that certain subpopulations may experience greater metabolic benefit with DHEA supplementation, specific populations have not been identified.(Davis 2011, Olech 2005, Panjari 2010, Tchernof 2004) Similarly, results for body composition and body fat distribution outcomes are inconsistent.(Olech 2005, Tchernof 2004)

The role of exogenous DHEA in insulin sensitivity is unclear. Some studies report a modest effect, while a greater number show no effect.(Talaei 2010, Tchernof 2004) In one study, DHEA-S supplementation did not improve insulin response in hypopituitary hypoadrenalism.(McHenry 2012) In a study in obese pre- and postmenopausal females, DHEA-S produced reductions in both obesity parameters (weight, BMI, body fat, leptin) and in metabolic syndrome parameters (waist circumference, blood glucose, blood pressure) in postmenopausal females; in premenopausal females, the effects of DHEA-S were limited to decreases in obesity parameters.(Gómez-Santos 2012) A meta-analysis of randomized, controlled trials demonstrated an overall significant reduction in fasting plasma glucose after DHEA administration (WMD, −2.185 mg/dL [P=0.029]; n=613), no effect on insulin levels (n=541), and no effect on insulin resistance (ie, HOMA-IR). Heterogeneity was significant only for the fasting glucose analysis.(Wang 2020)

The PMAS position statement on supplementation with DHEA in pre- and postmenopausal females (2020) concluded that based on current evidence, DHEA supplementation is probably effective in females with obesity and insulin resistance. Dosing recommendation is 25 mg/day orally titrated to 50 mg/day, then to 100 mg/day.(Rabijewski 2020)

Physical strength

Clinical data

Data regarding the effect of supplemental DHEA on muscle strength or physical function in older patients (50 years of age and older) are inconclusive.(Baker 2011) A meta-analysis of DHEA-S use in older males found a small reduction in body fat that was dependent on DHEA conversion to testosterone and estradiol.(Corona 2013) A small, controlled trial in young healthy males found that DHEA supplementation (100 mg/day during 5 days of exercise training) reduced muscle soreness and serum creatine kinase levels.(Liao 2013)

Postexercise testosterone

Clinical data

A small, double-blind, randomized, placebo-controlled, crossover trial (N=16) investigated the effects of oral DHEA supplementation (single dose of 50 mg the night before high-intensity interval training) on testosterone levels in young and middle-aged males. Baseline free testosterone was approximately 75% lower in middle-aged males (mean age, 49 years) compared with young males (mean age, 21 years). Compared with placebo, mean free testosterone levels after the exercise challenge increased significantly with DHEA supplementation in both middle-aged and young males (from 2.76 to 9.99 pg/mL and from 9.22 to 19.4 pg/mL, respectively [P<0.05 for each]). Likewise, the free testosterone to cortisol ratio was significantly increased during the recovery period with DHEA compared with placebo. Little to no effect on levels of cortisol, total testosterone, or luteinizing hormone was observed with DHEA.(Liu 2013)

Postmenopausal effects

Clinical data

Reviews of clinical trials and 2 meta-analyses of DHEA supplementation found no convincing evidence to support use for treatment of postmenopausal symptoms in females with intact adrenal function. The quality of evidence for the majority of studies was low due to imprecision and risk of bias.(Alkatib 2009, Bovenberg 2005, Elraiyah 2014, Genazzani 2010, Grimley Evans 2006, Olech 2005, Panjari 2010) Sexual function, well-being, quality-of-life measures, depressed mood, anxiety and distress, metabolic parameters (lipid profile, carbohydrate metabolism), body weight, BMI, and cognition were among the outcomes measured. DHEA-S has been shown to stimulate osteoblasts; however, results for improvements in bone density have been equivocal, with only a small effect demonstrated in some studies. In a meta-analysis of data from 23 trials (N=1,188), subgroup analyses were conducted based on study design (parallel vs crossover) and duration of follow-up (less than 12 months vs 12 months or longer; range: 1.5 to 24 months) to explain between-study heterogeneity; no significant subgroup interactions were found. The most commonly used DHEA daily dose ranged from 50 to 100 mg, but some studies have used doses up to 1,600 mg/day. Results suggest a benefit from DHEA-S supplementation may be observed in older females with low circulating DHEA, but not in older males. Fracture rates were not reported in the studies.(Christiansen 2011, Elraiyah 2014, Grimley Evans 2006, Olech 2005)

A pilot study in 7 healthy, nonobese, postmenopausal females showed positive correlations between DHEA-S, estrone, and androstanediol glucuronide after daily administration of DHEA 50 mg supplementation for 3 weeks. Increases were also observed in testosterone and estradiol but were highly variable. Oral DHEA supplementation disrupted preexisting androgen/estrogen balance, causing an unpredictable hyperandrogenism compared with placebo. Effects on sleep appeared to depend on the relative conversion of DHEA to estradiol versus testosterone; therefore, supplementation may result in either sleep inhibition or sleep stimulation. Little to no effect was observed on growth hormone secretion, prolactin, thyroid function, adrenocorticotropic hormone, and cortisol profiles.(Caufriez 2013)

The PMAS position statement on supplementation with DHEA in pre- and postmenopausal females (2020) concluded that based on current evidence, DHEA supplementation is effective in postmenopausal females with low BMD and/or osteoporosis and is probably effective in postmenopausal females with hypoactive sexual disorders. Dosing recommendations are 25 mg/day orally titrated to 50 mg/day, then to 100 mg/day for low BMD/osteoporosis, and 10 mg/day orally titrated to 50 mg/day, then to 90 mg/day, then 300 mg/day, then 450 mg/day for hypoactive sexual disorders.(Rabijewski 2020)

Sexual dysfunction

Clinical data

The PMAS position statement on supplementation with DHEA in pre- and postmenopausal females (2020) concluded that based on current evidence, DHEA supplementation is effective in premenopausal females with sexual disorders and low libido. The recommended daily dose is 75 mg orally.(Rabijewski 2020)

Systemic lupus erythematosus

Clinical data

The use of DHEA in systemic lupus erythematosus is controversial and based on observed effects of DHEA and DHEA-S on the immune system and enhanced autoantibody production by estrogen and suppression by androgens.(Bovenberg 2005, Olech 2005)

A Cochrane review of 7 studies evaluating the use of DHEA in mild to moderate systemic lupus erythematosus showed little clinical effect, with only one study showing stabilization or improvement over placebo (8% more patients). The review showed modest, clinically relevant increases in health-related quality-of-life measures, but the long-term effect (longer than 1 year) of DHEA supplementation is unknown.(Crosbie 2007, Hazeldine 2010) The use of DHEA in more severe lupus is not supported because it exerts DHEA antiglucocorticoid effects.(Olech 2005)

Trauma

Clinical data

A phase 2, randomized cross-sectional study (ADaPT trial) is underway in adult patients with trauma and older females with femur neck fracture to assess the effects of 3 DHEA doses (50 mg, 100 mg, or 200 mg) administered orally or sublingually once daily for 3 days during the second week after injury. The primary outcome is to determine the optimal dose to restore serum DHEA levels to at least 15 nmol/L and thereby minimize subsequent clinical deterioration.(Bentley 2021)

Dosing

DHEA is available as oral preparations, intraoral sprays, and transdermal creams and gels.(Olech 2005)

Orally administered DHEA has a low bioavailability (less than 10%), and intravenous DHEA is subject to rapid hepatic clearance. Transdermal and subcutaneous routes offer greater bioavailability. Oral DHEA is converted to inactive DHEA-S, which can then act as a reservoir for the body to utilize. In a pharmacokinetic study, DHEA 200 mg/day given to healthy males for 1 week resulted in a DHEA level of 1 mcg/dL and a DHEA-S level of 400 mcg/dL.(Olech 2005)

Exercise training–induced muscle damage

100 mg/day orally of DHEA supplementation was administered over 5 days in a study in young males undergoing exercise training.(Liao 2013)

Major depressive disorder

DHEA doses ranging from 30 to 450 mg/day for 6 to 8 weeks have been used commonly in clinical studies.(Ravindran 2016)

Polish Menopause and Andropause Society recommendations

The PMAS position statement on DHEA supplementation in pre- and postmenopausal females provides the following daily dosing recommendations and titration ranges (Rabijewski 2020):

Adrenal insufficiency

25 mg/day orally titrated to 50 mg/day.

Anxiety and depression (females)

30 mg/day orally titrated to 60 mg/day, then to 90 mg/day, then to 450 mg/day.

Assisted reproductive therapy in females with diminished ovarian reserve

75 mg/day orally.

Obesity and insulin resistance (females)

25 mg/day orally titrated to 50 mg/day, then to 100 mg/day.

Postmenopausal females

Low BMD and/or osteoporosis

25 mg/day orally titrated to 50 mg/day, then to 100 mg/day.

Hypoactive sexual disorders

10 mg/day orally titrated to 50 mg/day, then to 90 mg/day, then 300 mg/day, then 450 mg/day.

Premenopausal females with sexual disorders and low libido

75 mg/day orally.

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. DHEA supplementation has been evaluated for use in improving oocyte production in infertility.(Gleicher 2011, Mamas 2009, Wiser 2010)

Interactions

Subsequent to DHEA supplementation, the resulting supraphysiologic serum DHEAS level has been demonstrated to cross-react with 3 commercially available progesterone assays (Immulite 2000, eCobas, Centaur), yielding false-positive increases in serum progesterone. This interference with progesterone immunoassays may impact clinical decision making for IVF.(Forman 2015, Franasiak 2016)

Estrogen derivatives: Avoid combination. Dehydroepiandrosterone may enhance the adverse/toxic effect of estrogen derivatives.(Corona 2013, Davis 2011, Labrie 1997, Legrain 2003, Merritt 2012, Morales 1994, Mortola 1990)

Progesterone: Subsequent to DHEA supplementation, the resulting supraphysiologic serum DHEA-S level has been demonstrated to cross-react with 3 commercially available progesterone assays (Immulite 2000, eCobas, Centaur), yielding false-positive increases in serum progesterone. This interference with progesterone immunoassays may impact clinical decision making for IVF.(Forman 2015, Franasiak 2016)

Testosterone: Avoid combination. Dehydroepiandrosterone may enhance the adverse/toxic effect of testosterone.(Bosy 1998, Bowers 1999, Corona 2013, Davis 2011, Kicman 1990, Labrie 1997, Legrain 2003, Morales 1994, Mortola 1990)

Adverse Reactions

Studies in adrenal insufficiency suggest DHEA is generally well tolerated. However, data from long-term studies are lacking.(Bovenberg 2005, Crosbie 2007, Elraiyah 2014, Grimley Evans 2006) Many observed adverse effects are predictably hormonal in nature: acne and hirsutism in females, gynecomastia and testicular wasting in males, and unfavorable effects on lipid metabolism (decreased HDL levels) and blood pressure in both males and females.(Crosbie 2007, Olech 2005, Ravindran 2016) Other reported infrequent and mild effects include greasy skin, itching of the skin scalp, abundant vaginal discharge, and increased sweat and related odor.(Rabijewski 2020) Mania and hypomania have occurred in patients both with and without a psychiatric history. These reactions appear to be related to higher doses.(Dean 2000, Kline 1999) DHEA supplementation should not be used in hormone-dependent breast and prostate cancers.(Olech 2005) Higher doses have been associated with worsening of prostatitis and increased breast cancer risk.(Ravindran 2016) A single case report of seizure in a female taking DHEA to increase oocyte production exists.(Gleicher 2011, Mamas 2009)

Data collected between 2004 and 2013 from 8 US centers in the Drug-induced Liver Injury Network revealed that 15.5% (130) of hepatotoxicity cases were caused by herbals and dietary supplements, whereas 85% (709) of cases were related to prescription medications. Of the 130 cases of liver injury related to supplements, 65% were from non-bodybuilding supplements and occurred most often in Hispanic/Latino people compared with non-Hispanic White people and non-Hispanic Black people. Liver transplant was also more frequent with toxicity from non-bodybuilding supplements (13%) than with conventional medications (3%) (P<0.001). Overall, the proportion of severe liver injury cases was significantly higher for supplements than for conventional medications (P=0.02). Of the 217 supplement products implicated in liver injury, 175 had identifiable ingredients, of which DHEA was among the 32 (18%) single-ingredient products.(Navarro 2014)

Toxicology

Information in humans is limited. Although DHEA has been demonstrated to be carcinogenic (ie, hepatic tumors) in rodents, relevance in humans has been debated due to hepatic and biliary mechanisms that eliminate the suggested causative peroxisome build-up. Protective effects of DHEA on other cancers have also been demonstrated in rodents.(Matsuzaki 2006, Webb 2006)

Index Terms

• Dioscorea villosa

References

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