Dehydroepiandrosterone

DHEA also called Dehydroepiandrosterone, Androstenolone, Prasterone, 3b-hydroxyandrost-5-en-17-one, 3Beta-hydroxy-5-androsten-17-one, are adrenal steroid precursor hormones (prohormones) with weak androgenic effects that is converted into male sex hormones (androgens) and/or female sex hormones (estrogens) in peripheral tissues in your body to exert their effects ¹⁾, ²⁾. Dehydroepiandrosterone sulphate (DHEAS) has a long half-life and provides a stable pool of circulating DHEA ³⁾. DHEA and DHEAS are involved in the development of male sexual characteristics at puberty. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are made and secreted primarily by the zona reticularis of the adrenal glands (adrenal cortex) in response to adrenocorticotropic hormone (ACTH) ⁴⁾. The ovaries also synthesize DHEA; however, the ovaries lack the enzyme DHEA-sulphotransferase so that dehydroepiandrosterone sulphate (DHEAS) is almost exclusively synthesized and secreted by the adrenal glands. Furthermore, dehydroepiandrosterone (DHEA) is claimed to be synthesized in the human brain as well ⁵⁾. In fact, DHEA concentrations in the human brain have been shown to be higher than that in circulation, while DHEAS concentrations are lower ⁶⁾, ⁷⁾, which not only supports the theory of local synthesis, but also testifies to the importance of this hormone in the central nervous system (brain and spinal cord) ⁸⁾. DHEA can also be made in a laboratory; this man-made synthetic form is known as prasterone ⁹⁾. Although DHEA and DHEAS are secreted in greater quantities, androstenedione is qualitatively more important since it is more readily converted to testosterone in peripheral tissues ¹⁰⁾. Roughly, the relative androgenic potency of DHEA, androstenedione, testosterone, and dihydrotestosterone (DHT) are 5:10:100:300, respectively ¹¹⁾. As ACTH is the main regulator of adrenal androgen production in adults, both DHEA and androstenedione exhibit circadian periodicity in concert with ACTH and cortisol and their plasma concentrations increase rapidly following ACTH administration; also, they are suppressed by glucocorticoid administration. Because of its slow metabolic clearance, DHEAS does not exhibit diurnal rhythm variation.

The production of DHEA and DHEAS start increasing in boys and girls around the age of 6 to 8 years as a consequence of the maturation of the zona reticularis of the adrenal cortex and this increase in adrenal androgens is known as adrenarche and the concomitant clinical appearance of pubic hair is known as pubarche ¹²⁾, ¹³⁾. DHEA and DHEAS levels rise steadily and peak in the second to third decade of life (serum DHEAS concentration can be as high as 10 μM in young adults) ¹⁴⁾, ¹⁵⁾, ¹⁶⁾, ¹⁷⁾. Thereafter there is a progressive decline by around 2%-5% each year with advancing age, such that levels decrease by 80%-90% in the eighth to ninth decade of life ¹⁸⁾. In a healthy aged 65- to 81-yr-old population, plasma DHEAS concentration is 2.2 µM in women and 3.3 µM in men ¹⁹⁾. However, the interindividual variability across adulthood is substantial, and the normal range of serum DHEA and DHEAS is therefore very wide at each decade of life ²⁰⁾. DHEAS levels in women in their mid 70s are about 77% lower than women in their third decade of life, with age alone explaining about 30% of the variation in DHEAS levels ²¹⁾. Despite the overall decline in DHEAS with age, levels across the menopausal transition vary according to the transitional phase ²²⁾. Between the early and late perimenopause, DHEAS appears to increase on average by 3.95% in most women and then decline to levels seen in the early perimenopause by the late postmenopause ²³⁾. Women who do not exhibit this rise in DHEAS across the menopause have lower levels as they enter menopause ²⁴⁾. Overall Chinese women tend to have higher DHEAS levels and African-American women have lower DHEAS levels than Caucasian women ²⁵⁾. To compensate for the decrease in aged people, over-the-counter DHEA sulfate supplements are available and are sometimes promoted as an anti-aging therapy. But there is no reliable evidence to support these anti-aging claims of DHEA supplements. In fact, DHEA supplements may cause serious side effects. If you have questions about DHEA supplements, talk to your health care provider.

The potential clinical roles of dehydroepiandrosterone (DHEA) and its metabolite dehydroepiandrosterone sulfate (DHEAS) have been studied extensively, as previous epidemiologic and prospective studies found DHEA or DHEAS levels seem to go down as people get older and indicate an inverse relation between low circulating levels of dehydroepiandrosterone (DHEA) and its metabolite dehydroepiandrosterone sulphate (DHEAS) with a host of aging-associated pathologies such as sexual dysfunction, degenerative disorders and increased frailty, mood defects, poor sense of well-being and mortality from all causes in the elderly, attributing to DHEA or DHEAS anti-aging properties ²⁶⁾, ²⁷⁾, ²⁸⁾, ²⁹⁾, as well as higher risk of hospital admission ³⁰⁾, poor muscle strength ³¹⁾ and mobility ³²⁾, ³³⁾, and higher prevalence of frailty ³⁴⁾, insulin resistance, obesity, cardiovascular disease ³⁵⁾ and mortality from cardiovascular disease ³⁶⁾. At the same time, a positive relation between higher levels of DHEAS and better health and well-being was documented ³⁷⁾. Furthermore, animal (primarily rats) studies have suggested many beneficial effects of DHEA treatment, including improved immune function and prevention of atherosclerosis, cancer, diabetes, and obesity. Therefore, the therapeutic role of DHEA replacement as an anti-aging factor for the prevention and/or treatment of the above conditions was studied; however, recent systematic reviews of the reports do not seem promising ³⁸⁾, ³⁹⁾, ⁴⁰⁾, ⁴¹⁾, ⁴²⁾, ⁴³⁾, ⁴⁴⁾, ⁴⁵⁾.

• Thinning of vaginal tissue (vaginal atrophy). A prescription DHEA product is available for vaginal atrophy. Using vaginal inserts containing DHEA can reduce pain during sex by up to 15% after menopause.
• Aging. In theory, taking DHEA supplements to maintain DHEA levels could slow the aging process, possibly improving well-being, cognitive function and body composition. But so far research hasn’t proved this to be true. More studies are needed to better understand whether DHEA supplementation can counteract some of the effects of aging.
• Aging skin. Taking DHEA by mouth or applying it to the skin might improve skin appearance after menopause and in people over the age of 60 years. A small study suggested that taking DHEA supplements might improve skin hydration and firmness, and decrease aging spots in elderly adults.
• Depression. Changes in levels of DHEA have been linked to depression. Several preliminary studies show improvement in depression symptoms when taking DHEA as a dietary supplement, but more research is needed. Taking 30-500 mg of DHEA by mouth daily seems to improve symptoms of depression. Lower doses don’t seem to help.
• Inability to become pregnant within a year of trying to conceive (infertility). Taking DHEA by mouth before in-vitro fertilization (IVF) might improve the chances of pregnancy and having a baby. But it’s not clear if taking DHEA helps prevent miscarriage after IVF.
• Osteoporosis. Study findings on the effects of DHEA supplementation in the treatment of osteoporosis are mixed. More research is needed to determine whether taking DHEA supplements improves bone density in older adults with low DHEA.

DHEA levels seem to be lower in people with depression, Alzheimer’s disease and after menopause ⁴⁶⁾, ⁴⁷⁾, ⁴⁸⁾, ⁴⁹⁾, ⁵⁰⁾, ⁵¹⁾, ⁵²⁾, ⁵³⁾, ⁵⁴⁾.

There is interest in using DHEA for a number of health purposes (e.g., for aging and aging related problems such as body shape, bone strength, muscle strength, physical performance or quality of life in people older than 60 or memory and thinking skills [cognitive function] in healthy older people, people with HIV, or in healthy young adults), but there isn’t enough reliable information to say whether it might be helpful. The authors of a Cochrane Systematic Review regarding the supplementation of DHEA in peri- and post-menopausal women, questioned the effectiveness of DHEA in women, and concluded that the overall quality of the studies analyzed was moderate to low and that the study outcomes were inconsistent and could not be pooled to obtain an overall effect due to the diversity of the measurement methods employed ⁵⁵⁾. Without exception, all recent reviews of the available data regarding DHEA replacement for the management of aging-related disorders do not support its use in clinical practice ⁵⁶⁾, ⁵⁷⁾, ⁵⁸⁾, ⁵⁹⁾, ⁶⁰⁾, ⁶¹⁾, ⁶²⁾, ⁶³⁾.

There’s no scientific evidence to support taking DHEA to improve exercise or athletic performance. DHEA is banned by the National Collegiate Athletic Association (NCAA), the International Olympic Committee (IOC) and the World Anti-Doping Agency (WADA) ⁶⁴⁾, ⁶⁵⁾. Don’t confuse DHEA with 7-alpha-hydroxy-DHEA, 7-beta-hydroxy-DHEA, and 7-keto-DHEA. These are all different forms of DHEA but are not the same as DHEA.

DHEA supplementation has historically been used in the treatment of reproductive-related diseases, particularly in women, where it has been shown to alleviate menopause-related pathologies such as vaginal tissue thinning (vaginal atrophy) ⁶⁶⁾. DHEA supplements are also used for aging skin, depression, infertility, muscle strength, heart disease, erectile dysfunction (ED), and many other conditions, but there is no good scientific evidence to support many of these other uses ⁶⁷⁾, ⁶⁸⁾, ⁶⁹⁾, ⁷⁰⁾, ⁷¹⁾, ⁷²⁾, ⁷³⁾, ⁷⁴⁾, ⁷⁵⁾, ⁷⁶⁾, ⁷⁷⁾, ⁷⁸⁾. Studies have shown quality control of DHEA supplement to often be low.

As an ingredient in dietary supplement products, DHEA is mostly marketed for bodybuilding as a “testosterone booster” (which it is not) or for nootropic (“cognitive enhancer”) actions. 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. DHEA might eventually prove to have benefits in treating people diagnosed with certain conditions, such as adrenal insufficiency and lupus. However, further studies are needed.

DHEA is considered as a hormone in Europe and available only by prescription, while in the United States DHEA is considered as a nutritional supplement and is sold over the counter without a prescription. This difference has no scientific foundation and is mostly a matter of declaration ⁷⁹⁾. Most DHEA supplements are made in laboratories from a substance called diosgenin, a plant sterol found in soy and wild yams. DHEA supplements were taken off the U.S. market in 1985 because of their unproven safety and effectiveness, but were reintroduced as a dietary supplement after the Dietary Supplement Health and Education Act was passed in 1994 ⁸⁰⁾. At present, questionable over-the-counter DHEA preparations lacking pharmacokinetic and pharmacodynamic data are widely used in the United States ⁸¹⁾, ⁸²⁾. There is no standard dosage of DHEA replacement; some studies have used between 25 and 200 milligrams a day, or sometimes even higher amounts. DHEA in current preparations has a long half-life ⁸³⁾, which allows a single intake a day. Target levels of DHEA are around the middle of normal range for healthy young subjects, measured in a blood sample 24 hour after the last intake ⁸⁴⁾.

Previous studies have shown that the end products of DHEA supplementation depend on the patient’s gender, with a non-symmetrical transformation of DHEA favoring androgens in women and estrogens in men ⁸⁵⁾, ⁸⁶⁾, ⁸⁷⁾. The above refer to oral administration of DHEA supplements; percutaneous administration of DHEA seems to provoke similar increases in both estrogens and androgens in the two genders ⁸⁸⁾.

DHEA supplements are generally well tolerated in studies using oral or percutaneous administration, with daily doses ranging from 25 mg to 1,600 mg. In women DHEA when administered orally is mainly converted to androgen metabolites. As a result, some minimal androgenic adverse effects have been reported, including mild acne, seborrhea (a red, itchy rash and white scales skin), facial hair growth, and ankle swelling ⁸⁹⁾, ⁹⁰⁾, ⁹¹⁾.

Figure 1. DHEA Biosynthesis

Figure 2. Metabolism of DHEA

Footnote: Metabolism of exogenously administered dehydroepiandrosterone (DHEA).

Abbreviations: DHEA = Dehydroepiandrosterone; DHEAS = Dehydroepiandrosterone sulfate.

[Spurce ⁹²⁾ ]

Figure 3. Adrenal gland androgens

[Source ⁹³⁾ ]

Figure 4. Adrenal androgens summary

[Source ⁹⁴⁾ ]

How does DHEA work?

The exact mechanism of action and clinical role of DHEA and DHEAS remain unclear ⁹⁵⁾, ⁹⁶⁾. As DHEA has minor steroidogenic activity, it acts predominantly by conversion to androgens and estrogens in peripheral target tissues (Figure 1 and 2). It also functions as a neurosteroid and acts via receptors for N methyl-D aspartate receptors (NMDA) and gamma amino butyric acid alpha (GABAα), peroxisome proliferator-activated receptor α (PPARα), or receptors for pregnane X, androstanol, and estrogen receptor β ⁹⁷⁾.

About 75%-90% of DHEA is produced by the zona reticularis of the adrenal gland while the rest is produced in the ovaries and the brain ⁹⁸⁾. DHEA sulfated form, dehydroepiandrosterone sulfate (DHEAS), is exclusively synthesized by the adrenals. DHEA has a shorter half-life and is secreted in a pulsatile manner, mirroring the circadian rhythm of corticotrophin (ACTH). In contrast, dehydroepiandrosterone sulfate (DHEAS) has a longer half-life and relatively more stable levels across the day, providing a continuous reservoir of DHEA.

The production of DHEA and DHEAS start increasing in boys and girls around the age of 6 to 8 years as a consequence of the maturation of the zona reticularis of the adrenal cortex and this increase in adrenal androgens is known as adrenarche and the concomitant clinical appearance of pubic hair is known as pubarche ⁹⁹⁾, ¹⁰⁰⁾. DHEA and DHEAS levels rise steadily and peak in the second to third decade of life ¹⁰¹⁾, ¹⁰²⁾, ¹⁰³⁾. Serum DHEA concentration is around 20 nM in young adults and decreases with age to 7 nM ¹⁰⁴⁾. Thereafter there is a progressive decline by around 2%-5% each year with advancing age, such that levels decrease by 80%-90% in the eighth to ninth decade of life ¹⁰⁵⁾. However, the interindividual variability across adulthood is substantial, and the normal range of serum DHEA and DHEAS is therefore very wide at each decade of life ¹⁰⁶⁾. DHEAS levels in women in their mid 70s are about 77% lower than women in their third decade of life, with age alone explaining about 30% of the variation in DHEAS levels ¹⁰⁷⁾. Despite the overall decline in DHEAS with age, levels across the menopausal transition vary according to the transitional phase ¹⁰⁸⁾. Between the early and late perimenopause, DHEAS appears to increase on average by 3.95% in most women and then decline to levels seen in the early perimenopause by the late postmenopause ¹⁰⁹⁾. Women who do not exhibit this rise in DHEAS across the menopause have lower levels as they enter menopause ¹¹⁰⁾. Overall Chinese women tend to have higher DHEAS levels and African-American women have lower DHEAS levels than Caucasian women ¹¹¹⁾.

In adult women, dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid hormone, with daily production rates being approximately 8 to 16 mg/day, which are almost exclusively adrenal glands ¹¹²⁾. DHEAS is formed from DHEA in the highly specialized zona reticularis of the adrenals, which has high sulfuryl transferase activity. The hydrophilic DHEAS is the major circulating form of DHEA and is interconverted in various tissues with DHEA by DHEA sulfotransferases and hydroxysteroid sulfatases ¹¹³⁾. In premenopausal women, the production rate of DHEA is approximately 6–8 mg/day. Approximately 50% of DHEA is secreted by the adrenal glands, with the ovaries producing approximately 1 to 2 mg of DHEA per day; the remaining DHEA production occurs in peripheral tissues ¹¹⁴⁾. In contrast, the production of testosterone (T) in premenopausal women is approximately 0.2 to 0.25 mg/day, which is about 25–40 times less than that of DHEA and even much lower than that of DHEAS ¹¹⁵⁾. The ovaries of some postmenopausal women continue to produce some testosterone (T), but not DHEA ¹¹⁶⁾, ¹¹⁷⁾. In the circulation, DHEAS and DHEA are found in low micromolar and low nanomolar concentrations, respectively. Rosenfeld et al. ¹¹⁸⁾ reported a circulating half-life of 1 to 3 hours for DHEA and 10 to 20 hours for DHEAS. Sex hormone-binding globulin (SHBG) weakly binds DHEA but not DHEAS ¹¹⁹⁾.

Regular exercise is known to increase DHEA production in the body ¹²⁰⁾, ¹²¹⁾. Calorie restriction has also been shown to increase DHEA in rhesus monkeys ¹²²⁾. Some theorize that the increase in endogenous DHEA brought about by calorie restriction is partially responsible for the longer life expectancy known to be associated with calorie restriction ¹²³⁾.

Peripherally, DHEA appears to exert its primary effects through its estrogenic and androgenic metabolites because a unique DHEA receptor has not been characterized. However, DHEA has been shown to exhibit weak agonist effects on the estrogen receptors (ER) α and β and be a weak antagonist of the androgen receptor (AR) ¹²⁴⁾. There is evidence that DHEA is synthesized within the brain and may act locally as an excitatory neurosteroid by antagonizing the actions of the gamma-aminobutyric acid type A receptor (GABAα) and stimulating the N-methyl-d-aspartate receptor (NMDA), peroxisome proliferator-activated receptor α (PPARα), or receptors for pregnane X, androstanol, and estrogen receptor β ¹²⁵⁾, ¹²⁶⁾, ¹²⁷⁾. A putative plasma membrane-bound G coupled receptor activated by DHEA has been identified on bovine aortic endothelial cells ¹²⁸⁾, ¹²⁹⁾. Liu et al. ¹³⁰⁾ subsequently have shown that physiological concentrations of DHEA activate this plasma membrane receptor on vascular endothelial cells and stimulate endothelial proliferation and angiogenesis through extracellular signal-regulated kinase 1/2-mediated mechanisms.

DHEA and DHEAS can be converted to many different metabolites; Figure 2 depicts some of the more important ones. DHEA and DHEAS are metabolized in extragonadal target tissues such as the brain, bone, and body fat either by aromatization to estrone or by 5α-reduction to testosterone (T), with the testosterone (T) being converted to either estradiol or 5 alpha-dihydrotestosterone (DHT) in the same cells ¹³¹⁾. The transformation of DHEA into active androgens and estrogens depends upon the level of expression of the various steroidogenic and metabolizing enzymes in each cell type. With the increase in aromatase gene expression in body fat with age ¹³²⁾, ¹³³⁾, older women potentially have greater capacity to synthesize estrone from DHEA and DHEAS. Furthermore, the ultimate effects of the complex metabolism of DHEA and DHEAS will involve the absolute levels of each metabolite, their receptor content within the target cell, the presence and levels of specific coactivator and corepressor proteins that modify the transcriptional response, and the up- or down-regulation of receptor levels by other hormones ¹³⁴⁾.

DHEA uses

DHEA has most often been used by adults at a dose of 50 mg by mouth daily for up to 1 year. DHEA is also available in topical creams and vaginal products. Speak with a healthcare provider to find out what type of product and dose might be best for a specific condition.

Data from epidemiologic and prospective studies indicate an inverse relation between low circulating levels of dehydroepiandrosterone (DHEA) and its metabolite dehydroepiandrosterone sulphate (DHEAS) and a host of aging-associated pathologies such as sexual dysfunction, mood defects, and poor sense of well-being ¹³⁵⁾, ¹³⁶⁾, as well as higher risk of hospital admission ¹³⁷⁾, poor muscle strength ¹³⁸⁾ and mobility ¹³⁹⁾, ¹⁴⁰⁾, and higher prevalence of frailty ¹⁴¹⁾, insulin resistance, obesity, cardiovascular disease ¹⁴²⁾ and mortality from cardiovascular disease ¹⁴³⁾. At the same time, a positive relation between higher levels of DHEAS and better health and well-being was documented ¹⁴⁴⁾. Furthermore, animal (primarily rodent) studies have suggested many beneficial effects of DHEA treatment, including improved immune function and prevention of atherosclerosis, cancer, diabetes, and obesity. Therefore, the therapeutic role of DHEA replacement as an anti-aging factor for the prevention and/or treatment of the above conditions was studied; however, recent systematic reviews of the reports do not seem promising ¹⁴⁵⁾, ¹⁴⁶⁾, ¹⁴⁷⁾, ¹⁴⁸⁾, ¹⁴⁹⁾, ¹⁵⁰⁾, ¹⁵¹⁾, ¹⁵²⁾.

• Thinning of vaginal tissue (vaginal atrophy). A prescription DHEA product is available for vaginal atrophy. Using vaginal inserts containing DHEA can reduce pain during sex by up to 15% after menopause.
• Aging. In theory, taking DHEA supplements to maintain DHEA levels could slow the aging process, possibly improving well-being, cognitive function and body composition. But so far research hasn’t proved this to be true. More studies are needed to better understand whether DHEA supplementation can counteract some of the effects of aging.
• Aging skin. Taking DHEA by mouth or applying it to the skin might improve skin appearance after menopause and in people over the age of 60 years. A small study suggested that taking DHEA supplements might improve skin hydration and firmness, and decrease aging spots in elderly adults.
• Depression. Changes in levels of DHEA have been linked to depression. Several preliminary studies show improvement in depression symptoms when taking DHEA as a dietary supplement, but more research is needed. Taking 30-500 mg of DHEA by mouth daily seems to improve symptoms of depression. Lower doses don’t seem to help.
• Inability to become pregnant within a year of trying to conceive (infertility). Taking DHEA by mouth before in-vitro fertilization (IVF) might improve the chances of pregnancy and having a baby. But it’s not clear if taking DHEA helps prevent miscarriage after IVF.
• Osteoporosis. Study findings on the effects of DHEA supplementation in the treatment of osteoporosis are mixed. More research is needed to determine whether taking DHEA supplements improves bone density in older adults with low DHEA.

There is interest in using DHEA for a number of other purposes (e.g., for aging and aging related problems such as body shape, bone strength, muscle strength, physical performance or quality of life in people older than 60 or memory and thinking skills [cognitive function] in healthy older people, people with HIV, or in healthy young adults), but there isn’t enough reliable information to say whether it might be helpful. The authors of a Cochrane Systematic Review regarding the supplementation of DHEA in peri- and post-menopausal women, questioned the effectiveness of DHEA in women, and concluded that the overall quality of the studies analyzed was moderate to low and that the study outcomes were inconsistent and could not be pooled to obtain an overall effect due to the diversity of the measurement methods employed ¹⁵³⁾. Without exception, all recent reviews of the available data regarding DHEA replacement for the management of aging-related disorders do not support its use in clinical practice ¹⁵⁴⁾, ¹⁵⁵⁾, ¹⁵⁶⁾, ¹⁵⁷⁾, ¹⁵⁸⁾, ¹⁵⁹⁾, ¹⁶⁰⁾, ¹⁶¹⁾.

There’s no scientific evidence to support taking DHEA to improve exercise or athletic performance. The National Collegiate Athletic Association (NCAA), the International Olympic Committee (IOC) and the World Anti-Doping Agency (WADA) prohibit the use of DHEA in athletic competitions.

DHEA and infertility

DHEA has been found to improve ovarian steroidogenesis and also leads to an increase in insulin-like growth factor 1 (IGF-1) which is speculated to have a favorable effect on oocyte quality and follicular development ¹⁶²⁾, ¹⁶³⁾. In a randomized prospective study by Wiser et al ¹⁶⁴⁾, they enrolled 33 women with poor ovarian reserve (17 in the DHEA group and 16 in the control group) and observed the effects of DHEA supplementation on in vitro fertilization (IVF). Patients in the DHEA group had a significantly higher live birth rate as compared to controls ¹⁶⁵⁾. In a meta-analysis by Qin et al ¹⁶⁶⁾, they included nine studies and observed that clinical pregnancy rates were significantly increased in women with diminished ovarian reserve supplemented with DHEA. However, when the analysis was restricted to randomized control trials, there was no significant difference in pregnancy rates. In a recent meta-analysis by Schwarze et al ¹⁶⁷⁾, they included five studies with a total of 910 individuals with diminished ovarian reserve, of which 413 received DHEA. They observed that DHEA supplementation was associated with significantly improved pregnancy rates and decreased abortion frequency ¹⁶⁸⁾. There was no effect on the number of oocytes retrieved. Hence, the results have been largely conflicting and it is difficult to draw any conclusions as the definitions for diminished ovarian reserve, stimulation protocols used, and dosing and duration of DHEA varied notably between studies ¹⁶⁹⁾. Taken together, it implies that DHEA may have a role in the peri-implantation period but have less impact on ovulation induction/oocytes retrieval ¹⁷⁰⁾. Future randomized controlled trials planned with primary endpoints of implantation success in such group of subjects, may yield a favorable role for DHEA supplementation.

Genitourinary syndrome of menopause

Genitourinary syndrome of menopause, a term first introduced in 2014, is a relatively common entity with a prevalence ranging from 27% to 82%. Genitourinary syndrome of menopause encompasses symptoms ranging from vulvovaginal dryness and painful intercourse (dyspareunia) to urinary urgency and pain or a burning sensation when urinating (dysuria), and leads to significant impairment in quality of life and sexual function ¹⁷¹⁾. In a randomized prospective double-blind placebo-controlled trial by Labrie et al ¹⁷²⁾, the efficacy of 0.5% intravaginal DHEA in women with genitourinary syndrome of menopause was assessed. They observed that vaginal DHEA (Prasterone) significantly relieved painful intercourse (dyspareunia) with improvement in vaginal secretions and epithelial integrity. Prasterone was first approved by the FDA in 2016 for the treatment of dyspareunia due to genitourinary syndrome of menopause ¹⁷³⁾. Recent North American Menopause Society guidelines suggest vaginal DHEA as an alternative agent in individuals with genitourinary syndrome of menopause symptoms after the initial use of non-hormonal agents ¹⁷⁴⁾.

DHEA and Sexual dysfunction

Serum levels of DHEA and DHEAS start declining from the third decade, leading to decreased androgen levels. From epidemiologic studies sexual function problems are common among women and increase with increasing age ¹⁷⁵⁾, ¹⁷⁶⁾, ¹⁷⁷⁾. The sex steroid hormones estrogens and androgens seem to play an important role in the sexual life of women; androgens affect the reusability, pleasure, and intensity of orgasm in women and are particularly implicated in the neurovascular smooth muscle response of swelling and lubrication, whereas estrogens contribute to vulval and vaginal congestive response and affect mood and sexual responses ¹⁷⁸⁾. Conditions such as menopausal symptoms, loss of libido, vulvovaginal atrophy-related sexual dysfunction, and poor sense of well-being seen in menopausal and peri-menopausal women were related to the age-associated decline in sex steroids ¹⁷⁹⁾. Furthermore, interventional studies in postmenopausal women with estrogens have shown much improvement on vaginal atrophy and vasomotor symptoms ¹⁸⁰⁾, ¹⁸¹⁾, ¹⁸²⁾, ¹⁸³⁾; there is also much clinical evidence for the efficacy of transdermal testosterone treatment for low sexual function in women ¹⁸⁴⁾, ¹⁸⁵⁾, ¹⁸⁶⁾, ¹⁸⁷⁾, ¹⁸⁸⁾, ¹⁸⁹⁾.

Given that a) the adrenal steroids are the most abundant sex steroids in post-menopausal women and provide a large reservoir of precursors for the intracellular production of androgens and estrogens in non-reproductive tissues, b) DHEA levels decline with age, c) pre- and post-menopausal women with lower sexual responsiveness have lower levels of serum DHEAS ¹⁹⁰⁾ and d) treatment of postmenopausal women with estrogen and testosterone have shown some improvement in sexual function, it was proposed that restoring the circulating levels of DHEA to those found in young women may improve sexual function and well-being in postmenopausal women ¹⁹¹⁾. In a randomized, double-blind, placebo-controlled trial by Panjari et al ¹⁹²⁾, 93 post-menopausal women with low libido were included and the effect of DHEA on sexual function was assessed. They observed that there was no significant improvement in sexual function with regard to the primary outcome measures which included the change in total satisfying sexual events and the Sabbatsberg Sexual Self-Rating Scale total score. There was no significant change in secondary outcome measures as well, which included measures of well-being and quality of life ¹⁹³⁾.

A recent review of the available data concluded that current evidence does not support the routine use of DHEA in women with adrenal insufficiency ¹⁹⁴⁾. Furthermore, the more recent placebo-controlled randomized trials that are of superior design compared to the early trials, as they use validated measures of sexual function, have larger sample sizes, and are of longer duration, failed to document any significant benefit of oral DHEA therapy on well-being or sexual function in women ¹⁹⁵⁾, ¹⁹⁶⁾, ¹⁹⁷⁾, ¹⁹⁸⁾, ¹⁹⁹⁾. It has been hypothesized that the efficacy of DHEA to improve sexual function might be dependent on the route of its administration. In women, androgens and estrogens are produced from DHEA in the vagina tissue. As vaginal atrophy and dryness are common symptoms of estrogen deficiency during menopause, causing dyspareunia and sexual dysfunction ²⁰⁰⁾, a possible benefit that emerged is that vaginally administered DHEA may improve the postmenopausal vaginal atrophy-related sexual dysfunction ²⁰¹⁾ without increasing the circulating levels of estrogen above the postmenopausal range ²⁰²⁾, ²⁰³⁾, ²⁰⁴⁾, ²⁰⁵⁾, ²⁰⁶⁾. Despite initial promising, beneficial effects on sexual function, again, even with intravaginally administered DHEA, a study failed to show significant benefits ²⁰⁷⁾.

In a systematic review and meta-analysis of 28 studies of DHEA therapy in 1273 post-menopausal women, DHEA therapy did not improve sexual function, quality of life, or menopausal symptoms and was associated with androgenic side effects ²⁰⁸⁾. It is to be noted that these studies had a duration less than 3 months. Also, oral DHEA was used in all of these, and there are no studies on percutaneous DHEA. Currently, the Endocrine Society guidelines recommend against the use of DHEA for sexual dysfunction and other related indications because of a lack of long-term safety efficacy data ²⁰⁹⁾.

DHEA and Erectile dysfunction

In men lower circulating levels of DHEA was related to erectile dysfunction. A double-blind, placebo-controlled study that enrolled men with erectile dysfunction treated with oral DHEA 50 mg daily has shown some promise for improving sexual performance in men who had low DHEA blood levels ²¹⁰⁾. However, high-quality studies have demonstrated inconsistent results regarding DHEA supplementation for improving sexual function, libido, and erectile dysfunction. Although research in this area is promising, additional well-designed studies are required ²¹¹⁾.

DHEA and Adrenal insufficiency

Adrenal insufficiency is associated with reduced androgen levels which have been suggested to have multiple effects including loss of libido, reduced energy, and consequently decreased quality of life despite optimal glucocorticoid replacement when compared to a healthy population ²¹²⁾, ²¹³⁾, ²¹⁴⁾. DHEA supplementation has been suggested as a potential add-on therapy to conventional adrenal replacement therapy with glucocorticoids and mineralocorticoids to mitigate these effects ²¹⁵⁾. However, the exact physiological roles of DHEA still remain unclear and the routine therapy of individuals with adrenal insufficiency is still controversial ²¹⁶⁾.

Some authors reported significant improvements of mood, well-being, sexual thoughts, libido, interest, and satisfaction following DHEA replacement, particularly in females ²¹⁷⁾, ²¹⁸⁾, ²¹⁹⁾, ²²⁰⁾. In a randomized double-blind placebo-controlled study by Binder et al ²²¹⁾, they included 23 young women with secondary hypoadrenalism and observed significant improvements in pubic hair growth and psychological well-being. In a subsequent meta-analysis by Alkatib et al ²²²⁾ which included 10 studies in women with either primary or secondary adrenal insufficiency, DHEA supplementation lead to minor improvements in quality of life. However, there was no effect on sexual function or anxiety ²²³⁾.

Other analyses of DHEA administration in women with primary and secondary adrenal insufficiency have resulted in inconsistent and unreproducible results ²²⁴⁾. Currently, the Endocrine Society Clinical Practice Guidelines suggest that DHEA replacement (25–50 mg as a single oral dose in the morning) may be considered in women with adrenal insufficiency with low energy levels, low libido and depressive symptoms despite optimal glucocorticoid and mineralocorticoid replacement ²²⁵⁾. Monitoring is done by clinical and biochemical markers such as measurement of DHEAS, testosterone, androstenedione, and sex hormone-binding globulin (SHBG) 24 hour after the last DHEA dose. If the patient fails to report a sustained, beneficial effect of replacement after 6 months, the treatment should be discontinued ²²⁶⁾.

DHEA and Anorexia nervosa

DHEA levels have also been implicated to play a role in low bone mass in anorexia nervosa. In a randomized control trial by Gordon et al ²²⁷⁾, which compared the effects of DHEA vs conventional hormone replacement therapy in young women with anorexia nervosa, they observed that while hip bone mineral density (BMD) increased significantly with both therapies, DHEA therapy was associated with increased bone formation markers. DHEA therapy in addition was associated with significant improvement in psychological parameters. However, in a recent systematic review and meta-analysis ²²⁸⁾, DHEA treatment was not found to be associated with improvement in bone mineral density (BMD) compared with placebo after adjustment for weight gain. Therefore, while DHEA does play a role in the bone pathology in anorexia nervosa, evidence with treatment remains sparse and further randomized trials are needed.

DHEA and Inflammatory bowel disease (IBD)

DHEA has anti-inflammatory properties ²²⁹⁾, ²³⁰⁾. DHEA levels appear to be low in people with ulcerative colitis and Crohn’s disease, irrespective of the patient’s age ²³¹⁾, ²³²⁾. A phase 2 small pilot trial in patients with active inflammatory bowel disease refractory to other drugs, treated with 200 mg dehydroepiandrosterone per day orally for 56 days showed that DHEA may decrease the clinical activity of the disease and may even cause a remission ²³³⁾. More studies are needed before saying for sure whether DHEA helps inflammatory bowel disease (IBD) or not.

DHEA and Autoimmune diseases

DHEA has been found to modulate inflammatory responses by blunting the production of pro-inflammatory cytokines, downregulating complement activation via the generation of C1 inhibitor, and enhancing T-cell and NK cell cytotoxicity ²³⁴⁾. In accordance, DHEAS levels have also been found to be decreased in multiple autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), autoimmune hypothyroidism, fibromyalgia, and polymyalgia rheumatica ²³⁵⁾, ²³⁶⁾, ²³⁷⁾.

In a randomized double-blind placebo-controlled study by Nordmark et al ²³⁸⁾, they included 41 women with systemic lupus erythematosus (SLE) on steroids and assessed the efficacy of DHEA supplementation. They observed significant improvement in some domains of health-related quality of outcome measures which included an improvement in mental health. There was also an improvement in sexual well-being while there was no improvement in other domains such as physical function, general health, or vitality.

Similarly, DHEA levels have also been found to be low in Sjogren’s syndrome, which has been hypothesized as a potential cause of fatigue in these individuals. In a multicenter randomized controlled trial by Virkki et al ²³⁹⁾, they included 107 individuals with primary Sjogren’s syndrome and assessed the efficacy of DHEA administration on several measures of fatigue. They observed that DHEA supplementation at a dose of 50 mg significantly improved measures of fatigue but a similar improvement was observed with placebo as well ²⁴⁰⁾. Their results were similar to an earlier study by Hartkamp et al ²⁴¹⁾, and hence the authors suggested cognitive behavioral interventions in these individuals. In autoimmune hypothyroidism, Shukla et al ²⁴²⁾ investigated the relationship between DHEAS levels and arthralgias in individuals with primary hypothyroidism. They assessed 73 individuals with subclinical hypothyroidism and observed that DHEAS levels < 43.6 mcg/dL significantly predicted early rheumatoid changes in individuals with primary hypothyroidism ²⁴³⁾. They postulated the inhibition of 11-β HSD1, a possible bystander effect due to hypothalamic-pituitary-axis suppression and its immunosuppressive effects as some of the mechanisms to explain the effects. Therefore, there is some evidence to suggest a potential role of DHEA in multiple immunological diseases, and clinical interventions targeting this area merit further investigation.

DHEA and Systemic Lupus Erythematosus (SLE)

Several randomized controlled clinical studies have reported that regardless of the patient’s age, taking DHEA (50-200mg/day) along with other medications improves quality of life for people with mild to moderate SLE, decreases corticosteroid requirements, and reduces the frequency of flare-ups, though it probably does not change the overall course of their disease ²⁴⁴⁾, ²⁴⁵⁾, ²⁴⁶⁾. A study had shown DHEA replacement may increase bone mass in women with lupus ²⁴⁷⁾. A 2007 report in the Cochrane Database of Systematic Reviews ²⁴⁸⁾ suggests a “modest but clinically significant impact” of DHEA replacement on health-related quality of life in the short-term for people with SLE; the impact on disease activity was inconsistent. Long- term outcomes and safety remain unstudied.

DHEA and Rheumatoid arthritis (RA)

DHEA levels have been found to be low in people with rheumatoid arthritis ²⁴⁹⁾, ²⁵⁰⁾ and decrease further with glucocorticoid therapy ²⁵¹⁾. Considering the well-demonstrated immune-suppressive activities exerted by the adrenal androgens and their derivatives ²⁵²⁾, ²⁵³⁾, the use of DHEA as potential therapy for management of male and female rheumatoid arthritis patients was studied. Preliminary data from animal studies showed benefits of DHEA treatment in collagen-induced arthritis ²⁵⁴⁾, ²⁵⁵⁾. However, in carefully controlled human clinical trials, DHEA treatment produced only modest benefits ²⁵⁶⁾, probably with the exception of female-treated RA patients who benefit the most by DHEA replacement ²⁵⁷⁾. The noted discrepancy in benefits from DHEA treatment between animals and humans may be related to the low endogenous DHEA in rodents relative to humans because of low levels of cytochrome P450 17α-hydroxylase ²⁵⁸⁾, but also because of different DHEA metabolism between species; remarkably, in rodents DHEA has many highly oxygenated metabolites and a surprisingly complex metabolism that results in production of a multitude highly oxygenated species that may exert the beneficial effects on arthritis ²⁵⁹⁾.

DHEA as Anti-ageing agent

Concomitant to its potential multiple actions on well-being, sexual function, and cognition, early interest in DHEA came about with it being promoted as the “fountain of youth hormone.” In the DHEAge study by Baulieu and colleagues ²⁶⁰⁾, they observed the effects of DHEA supplementation at 50 mg daily for a year in 280 older men and women (age 60-79, 140 each). While there was some improvement in some parameters such as sexual function in women over 70 years of age, BMD at the femoral neck, and skin indices, there was no difference in libido, BMD, or sexual function in men ²⁶¹⁾. Moreover, there was no difference in body composition or muscle strength in women. Thereafter, in a double-blind randomized placebo-controlled study by Nair et al ²⁶²⁾, they investigated the effects of DHEA administration in 87 elderly men with low levels of DHEAS and bioavailable testosterone and 57 elderly women with low DHEAS levels. There was no improvement in body composition, quality of life, physical performance, or insulin supplementation with DHEA supplementation ²⁶³⁾. Similarly, there have been studies that have found no effects of DHEA supplementation on sexual function or well-being parameters ²⁶⁴⁾, ²⁶⁵⁾. Taken together, studies have argued against the use of DHEA as a cure-all elixir and the lack of long-term safety data does not justify the use of DHEA in healthy elderly individuals.

DHEA in Muscle strength, physical function and performance

The increasing incidence of fractures with advancing age has been related, among other factors, with the aging-related reduced muscle mass and strength, that increase the tendency for falling ²⁶⁶⁾. A body of evidence exists on the effect of circulating DHEA or DHEAS on various markers of strength and physical function in older individuals. Studies in elderly individuals support a positive relation between DHEA blood levels and muscle mass ²⁶⁷⁾, muscle strength ²⁶⁸⁾, ²⁶⁹⁾, and mobility ²⁷⁰⁾, as well as better self-reported ²⁷¹⁾ and objectively assessed physical function ²⁷²⁾, and measured peak volume of oxygen consumed per minute ²⁷³⁾ in elderly with higher DHEA or DHEAS concentrations. In this direction, higher DHEAS levels were associated with increased bone mass density (BMD) in both men ²⁷⁴⁾ and post-menopausal women and inversely related to risk for falls ²⁷⁵⁾. Finally, low DHEAS levels have been associated with a higher prevalence of frailty, a geriatric syndrome of loss of reserve characterized by weight loss, fatigue, weakness, and vulnerability to adverse events ²⁷⁶⁾, ²⁷⁷⁾, and low back pain in both genders and slow rehabilitation of low-back pain in women ²⁷⁸⁾, ²⁷⁹⁾, ²⁸⁰⁾.

Reports from interventional studies support a therapeutic role of DHEA replacement in aging-associated musculoskeletal defects. For example, DHEA exerted positive effects on muscle strength, body composition ²⁸¹⁾, ²⁸²⁾, ²⁸³⁾, and physical performance ²⁸⁴⁾, as well as on bone mass density (BMD) in both lumbar spine and the hip ²⁸⁵⁾, ²⁸⁶⁾, ²⁸⁷⁾, ²⁸⁸⁾, ²⁸⁹⁾, ²⁹⁰⁾, ²⁹¹⁾, ²⁹²⁾ when administered to post-menopausal women and elderly people over a period of 52 weeks. The above positive effects on musculoskeletal system were attributed to the DHEA-related increase of insulin-like growth factor-1 (IGF-1) levels ²⁹³⁾, ²⁹⁴⁾ and bioavailability (decrease of insulin growth factor binding protein-1 [IGFBP-1]) ²⁹⁵⁾ in both men and women and/or to the increase of androgen levels mostly in women ²⁹⁶⁾, ²⁹⁷⁾, ²⁹⁸⁾. Some other data also suggest aromatase activity of primary human osteoblasts converting DHEA to estrone ²⁹⁹⁾, while it was shown in vitro that DHEA inhibits apoptosis and promotes proliferation of rat osteoblasts through MAPK signaling pathways, independently from androgen and estrogen effects ³⁰⁰⁾. The above support a positive effect of DHEA on bone through conversion to estrogens, but also independently from its hormonal end-products. Other studies, however, failed to show a beneficial effect of DHEA supplementation on muscle function ³⁰¹⁾, ³⁰²⁾, ³⁰³⁾ or on BMD ³⁰⁴⁾, ³⁰⁵⁾, ³⁰⁶⁾; of note all these studies were conducted over a shorter period (26 weeks only). Whether these conflicting data result from DHEA’s mild/moderate effect or from great differences between study designs, such as short duration of treatment and small number of participants, is difficult to say ³⁰⁷⁾. Overall, the effect of DHEA supplementation on bone mass density (BMD) is small in relation to other treatments for bone loss, and no fracture data are available. Therefore, its therapeutic utility in rehabilitation and/or fracture/frailty prevention and treatment protocols for older patients remains unclear.

A recent systematic review ³⁰⁸⁾ of the literature concluded that overall, the benefit of DHEA on muscle strength and physical function in older adults remains inconclusive ³⁰⁹⁾, ³¹⁰⁾. Some measures of muscle strength may improve, although DHEA does not appear to routinely benefit measures of physical function or performance. Therefore, consensus has not been reached. Further large clinical trials are necessary to better identify the clinical role of DHEA supplementation in this population.

DHEA and Age-Related Cognitive Decline

The incidence of dementia increases exponentially with increasing age in both men and women ³¹¹⁾. The number of elderly people nowadays is the fastest growing segment of the population, which means the related personal, social, and economic burdens of dementia are extremely high and could increase dramatically over the next few decades. It has been proposed that DHEA and DHEAS may exert neuroprotective effects in the brain mainly through DHEA-dependent neural stem cell stimulation, genomic activity modulation, and upregulation of androgen receptor levels ³¹²⁾, ³¹³⁾, as well as via the DHEA-induced inhibition of pro-inflammatory factor production, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) ³¹⁴⁾ that are involved in the pathogenesis of the amyloid plaques of Alzheimer disease ³¹⁵⁾. Higher serum levels of DHEAS have been related to more favorable cognitive function in older people, such as better concentration and working memory ³¹⁶⁾, ³¹⁷⁾ and higher scores on the Mini Mental State Examination (MMSE) ³¹⁸⁾. In this direction, low DHEA or DHEAS levels in particular brain regions were thought to play a role in the development of Parkinson disease, which is the second most common neurodegenerative disorder, just behind Alzheimer’s disease ³¹⁹⁾, while DHEA administration showed some beneficial effect in a primate model of Parkinson disease ³²⁰⁾, ³²¹⁾. Inverse relations between DHEAS levels in saliva ³²²⁾ and circulation ³²³⁾ and some domains of memory impairment were also documented, supporting the hypothesis that DHEA supplementation may improve cognition in the elderly; yet solid evidence of associations between the endogenous levels of DHEA or DHEAS and measures of cognitive function is lacking.

No studies with DHEA replacement, either acute administration or chronic (up to 12 months) supplementation, have shown a benefit in cognitive function in healthy elderly populations ³²⁴⁾, ³²⁵⁾, ³²⁶⁾, ³²⁷⁾, ³²⁸⁾, ³²⁹⁾, ³³⁰⁾. Furthermore, DHEA supplementation failed to show any benefit in patients with Alzheimer’s disease ³³¹⁾ and had only minimal beneficial effect on specific cognitive domains such as the verbal fluency in older women with mild to moderate cognitive impairment ³³²⁾. Remarkably, some other studies have shown a negative effect of DHEAS replacement on cognitive performance ³³³⁾, ³³⁴⁾, ³³⁵⁾. It should be noted however, that most studies included only small groups of patients and were up to a yearlong, which is probably not enough time to address the potential role of DHEA or DHEAS in neurodegenerative disorders.

DHEA supplementation in Depression

The prevalence of depression increases in cohorts of the elderly and has been independently related to high morbidity and mortality ³³⁶⁾. In the central nervous system, DHEA is considered a neurosteroid with a wide range of functions. Animal studies demonstrated several DHEA-modulated neurotransmitters, including dopamine, glutamate, and c-amino butyric acid ³³⁷⁾, as well as DHEA-induced increased activity of serotonin (5-hydroxytryptamine) neurons ³³⁸⁾, providing the cellular basis for a potential antidepressant effect of DHEA. Furthermore, typical neuroleptic-like effects of DHEA were displayed amphetamine-induced schizophrenia models in mice suggesting potential role of DHEA replacement in the treatment of schizophrenia ³³⁹⁾.

Previous studies suggested a strong relation between low levels of DHEA or DHEAS and major depression in children and adolescents ³⁴⁰⁾, as well as adults and the elderly ³⁴¹⁾, ³⁴²⁾. On the contrary, higher DHEAS levels were positively associated with depressive symptoms during the menopausal transition ³⁴³⁾ and depression in patients with major depression ³⁴⁴⁾, ³⁴⁵⁾; whether the elevated DHEAS levels in the above studies represent increased adrenal activity that could explain the depressive symptoms is not clear, as cortisol was not measured. Moreover, successful treatment of depression was followed by reductions in both DHEAS ³⁴⁶⁾, ³⁴⁷⁾, ³⁴⁸⁾ and DHEA levels ³⁴⁹⁾, making the relation between DHEA or DHEAS and depression even more confusing.

Several interventional studies have shown that DHEA replacement may improve negative and depressive symptoms ³⁵⁰⁾, ³⁵¹⁾, ³⁵²⁾, ³⁵³⁾, ³⁵⁴⁾. In women with adrenal insufficiency, oral DHEA replacement significantly improved the overall well-being, as well as scores for depression and anxiety ³⁵⁵⁾; similar results were found in the management of the negative symptoms of schizophrenia ³⁵⁶⁾. Recent placebo-controlled randomized trials, however, failed to demonstrate a beneficial effect of DHEA therapy on mood, quality of life, perceptions of physical and emotional health, and life satisfaction in postmenopausal women ³⁵⁷⁾, ³⁵⁸⁾, ³⁵⁹⁾. However, recent data have suggested that increased circulating DHEA and DHEAS levels may predict SSRI-associated remission in major depression ³⁶⁰⁾. Therefore, the therapeutic role of DHEA on mood disorders remains unclear.

DHEA supplementation in Schizophrenia

DHEA has also been found to play a role in the pathophysiology of schizophrenia. It has been suggested to modulate neuronal differentiation and synaptogenesis. Additionally, it also interacts with multiple hormone receptor systems including gamma-aminobutyric acid, glutamate, and dopamine ³⁶¹⁾. In a systematic review and meta-analysis by Misiak et al ³⁶²⁾, which included 19 studies, DHEAS levels were found to be significantly elevated in individuals with schizophrenia.

DHEA and Psychosocial Stress

It has long been suggested that long-term psychosocial stress may cause or contribute to different diseases and symptoms, including atherosclerosis ³⁶³⁾, coronary heart disease ³⁶⁴⁾ and acute coronary events ³⁶⁵⁾, as well as accelerated aging ³⁶⁶⁾, ³⁶⁷⁾. Whether DHEA or DHEAS levels are related to psychological stress or not is still debatable. Exposure to prolonged psychosocial stress has been related to reduced ³⁶⁸⁾, ³⁶⁹⁾, ³⁷⁰⁾ or elevated levels of DHEA or DHEAS ³⁷¹⁾, while some other studies failed to show any clear association in any direction ³⁷²⁾, ³⁷³⁾. A recent study by Lennartsson et al. ³⁷⁴⁾ demonstrated that DHEA and DHEAS levels are markedly lower in individuals that report perceived stress at work than in individuals who report no perceived stress at work. Whether this is of clinical importance is not clear.

DHEA and ADHD

Some research has shown that DHEA levels are too low in people with attention-deficit/hyperactivity disorder (ADHD), and treatment with methylphenidate or bupropion (stimulant type of medications) normalizes DHEA levels ³⁷⁵⁾.

DHEA and Cardiovascular disease (CVD)

Cardiovascular disease (CVD) is the broad term for problems with the heart and blood vessels and its prevalence increases with advancing age ³⁷⁶⁾. Cardiovascular disease (CVD) is often due to atherosclerosis. Cardiovascular disease (CVD) occurs when fat and cholesterol build up in blood vessel (artery) walls. This buildup is called plaque. Over time, plaque can narrow blood vessels and cause problems throughout the body. If an artery becomes blocked, it can lead to heart attack or stroke. Low androgen levels have been related to atherogenic profile in men ³⁷⁷⁾, ³⁷⁸⁾, while data from acute coronary units have shown a transient fall of the testosterone levels in the first 24 hours after heart attack (myocardial infarction) ³⁷⁹⁾, ³⁸⁰⁾, which probably deprives these patients of testosterone’s pro-fibrinolytic activity ³⁸¹⁾, ³⁸²⁾ and may actually result in increased 30-day mortality rate following acute heart attack ³⁸³⁾; the above findings suggest a strong relation between sex steroid hormones and cardiovascular disease morbidity and mortality. Many studies have previously documented a significant inverse relation between low DHEA or DHEAS levels and key elements involved in the development of atherosclerosis and cardiovascular disease, including carotid artery intima-media thickness ³⁸⁴⁾, ³⁸⁵⁾, oxidative stress ³⁸⁶⁾, ³⁸⁷⁾ and endothelial dysfunction ³⁸⁸⁾, independent of other coronary risk factors. Low DHEAS levels ³⁸⁹⁾, ³⁹⁰⁾, ³⁹¹⁾ were also predictive of severe coronary atherosclerosis on coronary angiography ³⁹²⁾, but also of earlier cardiac allograft vasculopathy development in heart transplant patients ³⁹³⁾.

These findings are suggestive of anti-atherogenic and cardioprotective effect of DHEA or DHEAS. Numerous epidemiological studies have, therefore, looked at the specific relation between plasma levels of adrenal androgens and cardiovascular disease. Most have shown that low plasma levels of DHEA or DHEAS were clearly associated with increased incidence of atherosclerotic vascular diseases ³⁹⁴⁾, ³⁹⁵⁾, ³⁹⁶⁾, ³⁹⁷⁾ and cardiovascular morbidity ³⁹⁸⁾, ³⁹⁹⁾, ⁴⁰⁰⁾, independently from classic cardiovascular risk factors, as well as with increased cardiovascular disease-related mortality in elderly men but not in postmenopausal women, unless they had pre-existing coronary disease ⁴⁰¹⁾, ⁴⁰²⁾, ⁴⁰³⁾, ⁴⁰⁴⁾, ⁴⁰⁵⁾, ⁴⁰⁶⁾.

The plasma levels of DHEA were also inversely associated with the progression ⁴⁰⁷⁾ and prognosis of heart failure ⁴⁰⁸⁾, at least in men. The exact pathophysiologic background is still more or less unclear. Some preliminary data in patients with type 2 diabetes mellitus suggest that the adrenal androgens may increase the generation of activated protein C, an important anticoagulant protein that protects from acute coronary events ⁴⁰⁹⁾. Furthermore, DHEA may directly stimulate eNOS phosphorylation/activation in endothelial cells and nitric oxide (NO) production ⁴¹⁰⁾, ⁴¹¹⁾, ⁴¹²⁾, which in turn induces vasodilation, and preserves myocardial perfusion ⁴¹³⁾. DHEA may also exert anti-inflammatory actions ⁴¹⁴⁾, ⁴¹⁵⁾, through which it may alleviate endothelial dysfunction, atherogenesis ⁴¹⁶⁾, and the acute thrombotic complications of atheroma ⁴¹⁷⁾, ⁴¹⁸⁾, ⁴¹⁹⁾, ⁴²⁰⁾ enhanced by systemic inflammation. The protective effects of DHEA on endothelium were also shown in several in vitro studies in which DHEA increased endothelial proliferation ⁴²¹⁾ and protected endothelial cells against apoptosis ⁴²²⁾, ⁴²³⁾. Finally, DHEA can alleviate oxidative stress and inflammation in vascular smooth muscle cells via ERK1/2 and NF-κB signaling pathways, although it has no effect on their phenotype transition ⁴²⁴⁾.

However, other studies have failed to show a significant relation between DHEA or DHEAS and cardiovascular disease. In men for example, myocardial infarction occurrence was not altered by DHEAS levels, and acute myocardial infarctions were seen in patients with either low or high DHEAS levels ⁴²⁵⁾, ⁴²⁶⁾. Similarly in women, lower DHEAS levels in ischemic heart disease patients versus control were observed in some studies, but not in others ⁴²⁷⁾, ⁴²⁸⁾, ⁴²⁹⁾. The reasons that account for the discrepancies among the above studies are not clear. It can be argued that smoking could be a possible confounding variable for both DHEAS levels and cardiovascular disease, as smoking increases DHEA-S levels but also increases the incidence of adverse cardiovascular events ⁴³⁰⁾, ⁴³¹⁾. The discrepancies among the above studies may also be attributed to population variability; for example, in the study by Mazat et al. ⁴³²⁾ the relative risk of an 8-year mortality associated with low DHEAS was 3.4 times higher in males under 70 years compared to older men (odds ratio of 6.5 versus 1.9). Finally, DHEAS was checked just once in some retrospective studies, often several years before the adverse cardiovascular events ⁴³³⁾.

Whether exogenously administered DHEA could reduce key elements involved in the generation and progression of the atherosclerotic process was addressed in humans with atherosclerosis and experimental animal models. The human studies have shown a beneficial effect of DHEA on angiographic evidence of atherosclerosis and improvement of vascular endothelial function ⁴³⁴⁾, ⁴³⁵⁾, ⁴³⁶⁾. Several animal studies have also clearly demonstrated the inhibitory effect of orally administered DHEA on atherosclerosis and plaque progression ⁴³⁷⁾, ⁴³⁸⁾ as well as beneficial effects on ischemia–reperfusion injury in the microcirculation ⁴³⁹⁾, ⁴⁴⁰⁾ and cardiac dysfunction ⁴⁴¹⁾, ⁴⁴²⁾. Arterial stiffness, which is also considered a risk factor for cardiovascular disease, significantly improved after DHEA replacement in both elderly men and women ⁴⁴³⁾, ⁴⁴⁴⁾. Whether the above findings could be translated into DHEA administration in clinical practice for the reduction of cardiovascular disease morbidity and/or mortality is not well documented and supported by current reports. However, since DHEA is a well-tolerated molecule and an inexpensive drug, additional large multi-centric clinical studies could address its role in the prevention and/or management of cardiovascular disease.

DHEA and Cerebrovascular disease

Stroke is the third-leading cause for disability worldwide ⁴⁴⁵⁾; therefore, early risk stratification for an optimized allocation of health care resources is imperative. The ischemic strokes that account for the great majority of all stroke cases (87 percent) occur as a result of acute obstruction of atherosclerotic blood vessels supplying blood to the brain ⁴⁴⁶⁾. Considering DHEAS has neuroprotective and antiatherosclerotic properties ⁴⁴⁷⁾, ⁴⁴⁸⁾, ⁴⁴⁹⁾ and its synthesis has been documented in the brain ⁴⁵⁰⁾, ⁴⁵¹⁾, ⁴⁵²⁾, the role of DHEA or DHEAS in acute stroke incidence and outcome was investigated. Interestingly, in women from Nurses’ Health Study, lower DHEAS levels were associated with a greater risk of ischemic stroke ⁴⁵³⁾. In addition, it was suggested that DHEAS levels in the blood may predict the severity and functional outcome of acute strokes ⁴⁵⁴⁾, ⁴⁵⁵⁾. Whether the above findings suggest baseline DHEAS levels could alter stroke management in clinical practice or whether DHEA replacement has a therapeutic potential role in stroke management need to be addressed.

DHEA and Pulmonary hypertension

The previously described vasorelaxant properties of DHEA in systemic circulation were also investigated in pulmonary hypertension in animal models and in humans. Several studies have shown that DHEA replacement could effectively prevent and reverse hypoxic pulmonary hypertension, pulmonary arterial remodeling, and right ventricular hypertrophy in rats ⁴⁵⁶⁾, ⁴⁵⁷⁾ in a dose-dependent manner ⁴⁵⁸⁾ and also prevent the age-related frailty induced by hypoxic pulmonary hypertension in older mice ⁴⁵⁹⁾. The effect of DHEA is selective to the pulmonary circulation since the systemic blood pressure was not altered. It was shown that the beneficial effects of DHEA on pulmonary hypertension were at least partly independent of its conversion to estrogen/testosterone and eNOS activation. Some of the potential molecular mechanism by which DHEA promotes pulmonary artery relaxation appears to involve K+ channel activation, upregulation of soluble guanylate cyclase ⁴⁶⁰⁾, ⁴⁶¹⁾, ⁴⁶²⁾, downregulation of hypoxia inducible factor 1a (HIF-1a) ⁴⁶³⁾, and by NADPH oxidation-elicited subunit dimerization of protein kinase G 1α ⁴⁶⁴⁾.

DHEA may inhibit and reverse chronic hypoxia-induced pulmonary hypertension in rats. Little is known, however, about the effects of DHEA on the pulmonary circulation in humans. The levels of DHEA or DHEAS in patients with pulmonary hypertension over time have not been determined, but the recent Multi-Ethnic Study of Atherosclerosis (MESA) – Right Ventricle (RV) Study found that higher DHEA levels were associated with increased right ventricle mass and stroke volume in women ⁴⁶⁵⁾. Another prospective study suggested a strong inverse correlation between natural DHEA/DHEA-S blood levels and the ten-year mortality in old male smokers and ex-smokers ⁴⁶⁶⁾. Prompted by the experimental findings in the pulmonary circulation, a recent study investigated whether DHEA can improve the clinical and hemodynamic status of patients with pulmonary hypertension associated to chronic obstructive pulmonary disease; eight patients with the disease were treated with DHEA (200mg daily orally) for 3 months. The results were very promising as DHEA treatment significantly improved the pulmonary hemodynamics and the physical performance of the patients, without worsening gas exchange, as do other pharmacological treatments of pulmonary hypertension ⁴⁶⁷⁾.

Putting together the above evidence, there are experimental data to support the beneficial role of DHEA treatment in models with pulmonary hypertension, but only a few studies supporting its beneficial effect in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease. Further clinical studies would probably clarify its therapeutic role in the management of pulmonary hypertension in clinical practice.

DHEA and Obesity

Animal studies support a beneficial effect of DHEA administration on obesity ⁴⁶⁸⁾, ⁴⁶⁹⁾, ⁴⁷⁰⁾. In humans, two sets of longitudinal analyses of studies with women in menopausal transition showed that elevated DHEAS level is negatively related to body mass index (BMI) ⁴⁷¹⁾, ⁴⁷²⁾. On the other hand, baseline analyses by Santoro et al ⁴⁷³⁾ did not find much association between DHEAS and body mass index (BMI), waist-hip ratio, or waist. Childhood obesity is associated with higher levels of DHEAS ⁴⁷⁴⁾. Similarly, a 2-year, placebo-controlled, randomized, double-blind study involving elderly men and women with low levels of DHEAS, showed no significant effect of DHEA replacement (75 mg per day orally) on body composition measurements ⁴⁷⁵⁾. Interestingly, a, recent meta-analysis of intervention studies showed that DHEA supplementation in elderly men can induce only a small positive effect on body composition which is strictly dependent on DHEA conversion into its bioactive metabolites such as androgens or estrogens ⁴⁷⁶⁾. Putting together these results, current data regarding DHEA effect on BMI contradict each other, and its usage in clinical practice for body weight management is not suggested or recommended at the present.

DHEA and Cholesterol levels

In women, the effects of sex steroids on lipid profile differ according to the steroid treatment (estrogen or androgen) and to the route of administration. Thus, oral methyltestosterone lowers high-density lipoprotein (HDL)-cholesterol ⁴⁷⁷⁾, and oral estrogen increases HDL-cholesterol and triglycerides and lowers low-density lipoprotein (LDL)-cholesterol and total cholesterol ⁴⁷⁸⁾, ⁴⁷⁹⁾, while transdermal estradiol and transdermal testosterone have little or no effect on lipids ⁴⁸⁰⁾. Combined oral estrogen and methyltestosterone is associated with lowering of HDL-cholesterol ⁴⁸¹⁾, ⁴⁸²⁾. Considering that DHEA can be converted intracellularly to estrogens and androgens, the effect on the lipid profile could be mixed and may vary between individuals. Most of the recent well-designed studies, addressing this issue report no association or even an adverse association (at least in women) ⁴⁸³⁾, ⁴⁸⁴⁾ between plasma levels of DHEA ⁴⁸⁵⁾, ⁴⁸⁶⁾ or DHEA administration ⁴⁸⁷⁾, ⁴⁸⁸⁾, ⁴⁸⁹⁾, ⁴⁹⁰⁾, ⁴⁹¹⁾ and the lipid profile.

DHEA and Insulin resistance

DHEA may at least theoretically improve endothelial function ⁴⁹²⁾, and ameliorate local/systemic inflammation ⁴⁹³⁾, ⁴⁹⁴⁾ and oxidative stress ⁴⁹⁵⁾, ⁴⁹⁶⁾, ⁴⁹⁷⁾. These effects in association with DHEAS’s inverse relation with body mass index (BMI) ⁴⁹⁸⁾, ⁴⁹⁹⁾, ⁵⁰⁰⁾, ⁵⁰¹⁾ would most probably suggest beneficial effect of DHEA or DHEAS supplement on insulin sensitivity ⁵⁰²⁾. This hypothesis was confirmed by reports from animal studies in which DHEA replacement had a beneficial effect on insulin sensitivity ⁵⁰³⁾, ⁵⁰⁴⁾. In human studies, however, the results are rather inconsistent. In some studies, the lower levels of DHEA seen with aging have been associated with impaired glucose tolerance, insulin resistance, and diabetes ⁵⁰⁵⁾, ⁵⁰⁶⁾, while in another ⁵⁰⁷⁾ exactly the opposite relation was shown as higher levels of DHEA were associated with impaired glucose tolerance and diabetes mellitus in post-menopausal women. The truth regarding DHEA or DHEAS and insulin resistance and its associated conditions gets even more complicated considering conflicting results from interventional studies with DHEA replacement. Therefore, an ameliorating effect of long-term treatment with DHEA on insulin resistance was described in a group of middle-aged hypo-adrenal women treated with DHEA ⁵⁰⁸⁾, but also in groups of elderly men ⁵⁰⁹⁾ and postmenopausal women ⁵¹⁰⁾, ⁵¹¹⁾, ⁵¹²⁾, ⁵¹³⁾, ⁵¹⁴⁾ replaced with DHEA. The DHEA dose used ranged between 25 and 100 mg/day oally and the duration of treatment varied between 3 and 12 months; in one study transdermal DHEA was used ⁵¹⁵⁾. Most other interventional studies addressing this issue, failed to demonstrate any significant effect of DHEA on insulin resistance/sensitivity ⁵¹⁶⁾, ⁵¹⁷⁾, ⁵¹⁸⁾, ⁵¹⁹⁾, ⁵²⁰⁾, ⁵²¹⁾ and so did a recent review of the available data regarding use of DHEA in women with adrenal insufficiency ⁵²²⁾. Mortola and Yen ⁵²³⁾ reported worsening insulin resistance with DHEA replacement in postmenopausal women; in this study however, the number of participants was small (n=6), the duration of treatment short (28 days), and the DHEA dosage supraphysiological (1600 mg/day orally). Putting together the above, the relation between DHEA and carbohydrate metabolism is still uncertain.

Is DHEA safe?

DHEA hasn’t been studied enough to know whether it’s safe to take. DHEA has been studied for a number of potential medical uses, but most research studies have been relatively small and for less than 24 months. In women, taking DHEA supplements for months can increase testosterone levels, which can cause acne and facial hair growth, but a variety of other side effects have been noted. Women might develop masculine features, and men might experience breast tenderness or enlargement, aggression, or testicular wasting, but it depends on the amount being taken.

There isn’t enough information about its long-term effects, but DHEA is being explored for possible uses to treat other medical conditions. In general, extensive research is ongoing and, so far, mostly inconclusive. DHEA can be converted into estrogen, so doctors should advise patients with any hormone-sensitive cancer (such as prostate, breast, or ovarian cancer) not to take DHEA.

Don’t use DHEA if you’re pregnant or breastfeeding.

Consider avoiding use of DHEA if you have high cholesterol or a condition that affects the supply of blood to the heart (ischemic heart disease). DHEA might reduce high-density lipoprotein (HDL), or “good,” cholesterol levels.

Use of DHEA also might worsen psychiatric disorders and increase the risk of mania in people who have mood disorders.

DHEA also might cause oily skin, acne and unwanted, male-pattern hair growth in women (hirsutism).

• When taken by mouth, DHEA is possibly safe when used short-term ⁵²⁴⁾. DHEA has been used safely for up to 2 years, usually in doses of 50 mg daily ⁵²⁵⁾. DHEA is possibly unsafe when used in high doses or long-term ⁵²⁶⁾. Do not use DHEA in doses higher than 50-100 mg daily or for a long period of time. Using higher doses or using it long-term can increase the risk of serious side effects including cancer ⁵²⁷⁾. DHEA is a hormone that can affect how estrogen works in the body. If you have any condition that might be made worse by estrogen, do not use DHEA. Hormone-sensitive conditions such as breast cancer, uterine cancer, ovarian cancer, endometriosis, or uterine fibroids.
• When applied to the skin, DHEA is possibly safe when used appropriately. DHEA cream has been used safely for up to 1 year.
• When applied into the vagina, DHEA is possibly safe when used appropriately. DHEA vaginal inserts have been safely used for up to 3 months.

Pregnancy and breast-feeding

DHEA is possibly unsafe when taken during pregnancy or breast-feeding. It can cause higher than normal levels of a male hormone called androgen. This might be harmful to the baby. Do not use DHEA if you are pregnant or breast-feeding.

Diabetes

DHEA can affect how insulin works in the body. If you have diabetes, monitor your blood sugar carefully if you are taking DHEA.

High cholesterol

DHEA might lower high-density lipoprotein (HDL or “good”) cholesterol, especially in females. If you have high cholesterol or heart disease, talk with your doctor before taking DHEA.

Liver problems

DHEA might make liver problems worse. Do not use DHEA if you have liver problems.

Depression and mood disorders

DHEA might cause excitability, impulsiveness, and irritability in people with mood disorders. If you have a mood disorder, talk to your healthcare provider before taking DHEA.

Polycystic ovary syndrome (PCOS)

Don’t use DHEA if you have PCOS. Taking DHEA might make polycystic ovary syndrome (PCOS) worse.

Interactions with other medications

• Estrogens. DHEA might increase estrogen levels in your body. Taking DHEA along with estrogen might cause too much estrogen in your body and cause symptoms of excess estrogen, such as nausea, headache and insomnia.
• Testosterone. Taking DHEA with testosterone might cause too much testosterone in your body. This might increase the effects and side effects of testosterone. Combining DHEA and testosterone might cause symptoms such as low sperm count and enlarged breasts in men (gynecomastia) and the development of typically male characteristics in women.
• Fulvestrant (Faslodex). Estrogen-sensitive cancers are cancers that are affected by estrogen levels in the body. Fulvestrant is used for estrogen-sensitive cancers. DHEA might increase estrogen in your body and decrease the effects of fulvestrant for treating cancer. Do not take DHEA if you are taking fulvestrant.
• Medications changed by the liver (Cytochrome P450 3A4 (CYP3A4) substrates). Some medications are changed and broken down by the liver. DHEA might change how quickly the liver breaks down these medications. This could change the effects and side effects of these medications.
• Medications for depression (Antidepressant drugs). There is some concern that taking DHEA along with antidepressant drugs might increase the risk for serious side effects. Speak with a healthcare provider before taking DHEA if you are taking an antidepressant.
• Selective serotonin reuptake inhibitors (SSRIs). Use of DHEA with this type of antidepressant might cause manic symptoms.
• Antipsychotics. Use of DHEA with antipsychotics such as clozapine (Clozaril, Versacloz, others) might reduce the drug’s effectiveness.
• Carbamazepine (Tegretol, Carbatrol, others). Use of DHEA with this drug used to treat seizures, nerve pain and bipolar disorder might reduce the drug’s effectiveness.
• Valproic acid. Use of DHEA with this medication used to treat seizures and bipolar disorder might reduce the drug’s effectiveness.
• Medications for estrogen sensitive cancers (Aromatase inhibitors). The body changes DHEA to estrogen in the body. Aromatase inhibitors are used to help lower estrogen levels in the body. Taking DHEA might decrease the effects of aromatase inhibitors.
• Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs). DHEA might slow blood clotting. Taking DHEA along with medications that also slow blood clotting might increase the risk of bruising and bleeding.
• Tamoxifen (Nolvadex). Estrogen-sensitive cancers are cancers that are affected by estrogen levels in the body. Tamoxifen is used to help treat and prevent these types of cancer. DHEA increases estrogen levels in the body and might decrease the effects of tamoxifen. Do not take DHEA if you are taking tamoxifen.
• Triazolam (Halcion). DHEA might decrease how quickly the body breaks down triazolam. Taking DHEA with triazolam might increase the effects and side effects of triazolam, causing excessive sedation and affecting your breathing and heart rate.
• Lithium. Use of DHEA with lithium might reduce the drug’s effectiveness.
• Tuberculosis vaccine. Taking DHEA might reduce the effects of the tuberculosis vaccine. Do not take DHEA if you are receiving a tuberculosis vaccine.
• Herbs and supplements that might slow blood clotting. DHEA might slow blood clotting and increase the risk of bleeding. Taking it with other supplements with similar effects might increase the risk of bleeding in some people. Examples of supplements with this effect include garlic, ginger, ginkgo, nattokinase, and Panax ginseng.
• Licorice. Taking licorice increases levels of DHEA in the body. Taking licorice with DHEA might increase the side effects of DHEA.

DHEA side effects

The major concerns with DHEA revolve around its ability to convert to androgen and estrogen metabolites. Reported androgenic side effects of DHEA are usually mild and might include mild acne, facial hair growth, upset stomach and seborrhea ⁵²⁸⁾. DHEA also might cause oily skin, acne and unwanted, male-pattern hair growth in women (hirsutism). DHEA has also been associated with a pro-atherogenic state with decreased high-density lipoprotein (HDL) or “good,” cholesterol levels ⁵²⁹⁾, ⁵³⁰⁾. It has also been seen that DHEA leads to proliferation of breast cancer cells via stimulation of estrogen receptors ⁵³¹⁾ Hence, there have been concerns with the use of DHEA in hormone dependent cancers including breast cancer, endometrial cancer, and prostate cancer ⁵³²⁾, ⁵³³⁾. Currently, there is limited evidence on the long-term safety data and caution needs to exercised.

As long as long-term safety data for DHEA supplementation are lacking, the American Cancer Society advices caution in its use in people who have cancer, especially types of cancer that respond to hormones, such as certain types of breast cancer, prostate cancer, ovarian cancer and endometrial cancer ⁵³⁴⁾. If you have any form of cancer or are at risk of cancer, don’t use DHEA.

Don’t use DHEA if you’re pregnant or breastfeeding.

Consider avoiding use of DHEA if you have high cholesterol or a condition that affects the supply of blood to the heart (ischemic heart disease). DHEA might reduce high-density lipoprotein (HDL), or “good,” cholesterol levels.

Use of DHEA also might worsen psychiatric disorders and increase the risk of mania in people who have mood disorders.

DHEA-sulfate test

Dehydroepiandrosterone sulfate test or DHEAS blood test checks how much DHEA-sulfate (DHEAS) is in your blood. DHEA-sulfate (DHEAS) is a male sex hormone (androgen) that is found in both men and women. Dehydroepiandrosterone Sulfate (DHEAS) is a steroid precursor hormone (prohormone) made by your adrenal glands with weak androgenic effects that is converted into male sex hormones (androgens) and/or female sex hormones (estrogens) in peripheral tissues in your body to exert their effects ⁵³⁵⁾, ⁵³⁶⁾. The DHEA-sulfate test is generally done to check how well your adrenal glands are working and to look into conditions that might cause hormone production to be off.

Although DHEA-sulfate is the most abundant hormone in the body, its exact function is still not known. DHEA-sulfate (DHEAS) plays an important role in making the male sex hormone testosterone and androstenedione and the female sex hormone estrogen. DHEA-sulfate (DHEAS) is also responsible for the onset of sexual differentiation in males and females and the development of secondary male physical characteristics at puberty such as a deep voice and facial hair.

• In men, the DHEA-sulfate (DHEAS) male hormone effect may not be important if testosterone level is normal.
• In women, DHEA contributes to normal libido and sexual satisfaction.
• DHEA may also have effects on the immune system.

DHEA-sulfate (DHEAS) is mostly made in the adrenal glands, two small glands located above your kidneys (Figure 1). They help control heart rate, blood pressure, and other body functions. Smaller amounts of DHEAS are made in a man’s testicles and in a woman’s ovaries. If your DHEAS levels are not normal, it may mean there is a problem with your adrenal glands or sex organs (testicles or ovaries).

The DHEA-sulfate (DHEAS) test is used to determine whether or not your adrenal glands are functioning properly and to detect adrenal tumors or cancers ⁵³⁷⁾. DHEAS blood test also helps determine the cause of masculine (male) physical characteristics in girls and women (virilization) or early puberty in boys (precocious puberty). DHEA-sulfate test can help figure out what’s causing your irregular periods, excessive hair growth (hirsutism), infertility, and a decreased sex drive (low libido) ⁵³⁸⁾. DHEAS test is also used to find out if someone has a growth in their adrenal gland, congenital adrenal hyperplasia, diagnosis of hyperandrogenism (in conjunction with measurements of other sex steroids) or polycystic ovary syndrome (PCOS) or to assess delayed puberty or premature adrenarche. Babies may also need testing if they have genitals that are not clearly male or female in appearance (ambiguous genitalia). Boys may need this test if they have signs of early puberty (precocious puberty). People on long-term glucocorticoid medicine can also use the DHEAS test to check how well their adrenal glands are working or to rule out Cushing’s syndrome. It is an important test for people who think their male sex hormones (androgens) or female sex hormones (estrogens) might be out of order.

A DHEA-sulfate (DHEAS) test is most often used to ⁵³⁹⁾:

• Find out if your adrenal glands are working right
• Diagnose adrenal glands tumors or cancers
• Diagnose disorders of the testicles or ovaries
• Find out the cause of early puberty in boys
• Find out the cause of excess body hair growth (hirsutism) and development of masculine features in women and girls (virilization)

A DHEAS test is often done along with other sex hormone tests. These include testosterone tests for men and estrogen tests for women.

The DHEAS test is ordered along with tests for testosterone and several other male hormones (androgens) to ⁵⁴⁰⁾:

• Evaluate whether the adrenal glands are working properly
• Distinguish between DHEAS-secreting conditions caused by the adrenal glands and those that originate in the testicles — or rarely, in the ovaries (ovarian tumors)
• Help diagnose tumors in the outer layer (cortex) of the adrenal gland (adrenocortical tumors) and adrenal cancers
• Help diagnose congenital adrenal hyperplasia and enlargement of the adrenal glands (hyperplasia) in adults

In women, DHEAS levels are often measured, along with other hormones such as follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estrogen, and testosterone, to help diagnose polycystic ovary syndrome (PCOS) and rule out other causes of infertility, lack of menstrual period (amenorrhea), and excess hair on the face and body (hirsutism).

DHEAS levels may be ordered with other hormones to investigate and diagnose the cause of the development of masculine physical characteristics (virilization) in young girls and early (precocious) puberty in young boys.

An initial workup in adults might also include total testosterone and bioavailable testosterone. Depending on results, this may be supplemented with measurements of sex hormone-binding globulin (SHBG) and occasionally other androgenic steroids (eg, 17-hydroxyprogesterone).

What do the DHEA-sulfate test results mean?

A DHEA-sulfate (DHEAS) test is most often used to ⁵⁴¹⁾:

• Find out if your adrenal glands are working right
• Diagnose adrenal glands tumors or cancers
• Diagnose disorders of the testicles or ovaries
• Find out the cause of early puberty in boys
• Find out the cause of excess body hair growth (hirsutism) and development of masculine features in women and girls (virilization)

A DHEAS test is often done along with other sex hormone tests. These include testosterone tests for men and estrogen tests for women.

The DHEAS test is ordered along with tests for testosterone and several other male hormones (androgens) to ⁵⁴²⁾:

• Evaluate whether the adrenal glands are working properly
• Distinguish between DHEAS-secreting conditions caused by the adrenal glands and those that originate in the testicles — or rarely, in the ovaries (ovarian tumors)
• Help diagnose tumors in the outer layer (cortex) of the adrenal gland (adrenocortical tumors) and adrenal cancers
• Help diagnose congenital adrenal hyperplasia and enlargement of the adrenal glands (hyperplasia) in adults

In women, DHEAS levels are often measured, along with other hormones such as follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estrogen, and testosterone, to help diagnose polycystic ovary syndrome (PCOS) and rule out other causes of infertility, lack of menstrual period (amenorrhea), and excess hair on the face and body (hirsutism).

DHEAS levels may be ordered with other hormones to investigate and diagnose the cause of the development of masculine physical characteristics (virilization) in young girls and early (precocious) puberty in young boys.

DHEAS normal range

Normal blood levels of DHEA-sulfate can differ by sex and age. Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or test different specimens. Talk to your health care provider about the meaning of your specific test results.

Normal DHEA-sulfate levels in females

Typical normal DHEA-sulfate ranges for females are ⁵⁴³⁾:

• Ages 18 to 19: 145 to 395 micrograms per deciliter (µg/dL) or 3.92 to 10.66 micromoles per liter (µmol/L)
• Ages 20 to 29: 65 to 380 µg/dL or 1.75 to 10.26 µmol/L
• Ages 30 to 39: 45 to 270 µg/dL or 1.22 to 7.29 µmol/L
• Ages 40 to 49: 32 to 240 µg/dL or 0.86 to 6.48 µmol/L
• Ages 50 to 59: 26 to 200 µg/dL or 0.70 to 5.40 µmol/L
• Ages 60 to 69: 13 to 130 µg/dL or 0.35 to 3.51 µmol/L
• Ages 69 and older: 17 to 90 µg/dL or 0.46 to 2.43 µmol/L

Normal DHEA-sulfate levels in males

Typical normal DHEA-sulfate ranges for males are ⁵⁴⁴⁾:

• Ages 18 to 19: 108 to 441 µg/dL or 2.92 to 11.91 µmol/L
• Ages 20 to 29: 280 to 640 µg/dL or 7.56 to 17.28 µmol/L
• Ages 30 to 39: 120 to 520 µg/dL or 3.24 to 14.04 µmol/L
• Ages 40 to 49: 95 to 530 µg/dL or 2.56 to 14.31 µmol/L
• Ages 50 to 59: 70 to 310 µg/dL or 1.89 to 8.37 µmol/L
• Ages 60 to 69: 42 to 290 µg/dL or 1.13 to 7.83 µmol/L
• Ages 69 and older: 28 to 175 µg/dL or 0.76 to 4.72 µmol/L

High DHEA-sulfate levels

If your DHEAS blood test results show high levels of DHEA sulfate (DHEAS), it may mean you have one of the following conditions:

• Congenital adrenal hyperplasia, an inherited disorder of the adrenal glands
• A tumor of the adrenal gland. It may be benign (noncancerous) or cancerous.
• Polycystic ovary syndrome (PCOS). PCOS is a common hormone disorder affecting childbearing women. It is one of the leading causes of female infertility. About 25% to 50% of women with PCOS have elevated DHEAS.
• Body changes of a girl in puberty happening earlier than normal.
• Rarely, an ovarian tumor that produces DHEA-sulfate.

A high dehydroepiandrosterone sulfate (DHEAS) blood level may indicate that excess DHEA sulfate (DHEAS) production is causing or contributing to your symptoms. Elevated DHEA-sulfate levels can cause symptoms or signs of hyperandrogenism in women. However, an increased level of DHEAS is not diagnostic of a specific condition. Most mild to moderate elevations in DHEAS levels are idiopathic (unknown cause). It usually indicates the need for further testing to pinpoint the cause of the hormone imbalance. However, pronounced elevations of DHEA-sulfate with levels of 600 micrograms per deciliter (µg/dL) or more may be indicative of androgen-producing adrenal tumors. DHEA sulfate (DHEAS) levels are elevated in more than 90% of patients with adrenal tumors, usually well above 600 mcg/dL. This is particularly true for androgen-secreting adrenal carcinomas (adrenal gland cancer), as they have typically lost the ability to produce down-stream androgens, such as testosterone ⁵⁴⁵⁾. By contrast, androgen-secreting adrenal adenomas (adrenal benign tumors) may also produce excess testosterone and secrete lesser amounts of DHEAS ⁵⁴⁶⁾.

In small children, congenital adrenal hyperplasia (CAH) due to 3 beta-hydroxysteroid deficiency is associated with very high levels of DHEA sulfate (DHEAS) production, often 5- to 10-fold elevations. Lesser elevations may be observed in 21-hydroxylase deficiency (the most common form of congenital adrenal hyperplasia) and 11 beta-hydroxylase deficiency. By contrast, steroidogenic acute regulatory protein or 17 alpha-hydroxylase deficiencies are characterized by low DHEA-sulfate levels. Consequently, DHEAS testing should not be used as the primary
tool for congenital adrenal hyperplasia (CAH) diagnosis. Similarly, discovering a high DHEA sulfate (DHEAS) level in an infant or child with symptoms or signs of possible congenital adrenal hyperplasia (CAH) should prompt additional testing, as should the discovery of very high DHEAS levels in an adult. In the latter case, adrenal tumors need to be excluded and additional adrenal steroid profile testing may assist in diagnosing congenital adrenal hyperplasia (CAH). If you have questions about your results, talk to your doctor.

Girls below the age of 7 to 8 and boys before age 8 to 9, who present with early development of pubic hair, or, in boys, penile enlargement, may be suffering from either premature adrenarche or premature puberty or both ⁵⁴⁷⁾. Measurement of DHEAS and androstenedione, alongside determination of sensitive estradiol,total testosterone and bioavailable testosterone or free testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels will allow correct diagnosis in most cases ⁵⁴⁸⁾. In premature adrenarche, only the adrenal androgens, chiefly DHEA sulfate (DHEAS), will be above prepubertal levels, whereas early puberty will also show a fall in sex hormone-binding globulin (SHBG) levels and variable elevations of gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and gonadal sex-steroids above the prepuberty reference range.

Many drugs and hormones can result in changes in DHEA sulfate (DHEAS) levels. Whether any of these secondary changes in DHEAS levels are of clinical significance and how they should be related to the established normal reference ranges is unknown ⁵⁴⁹⁾. In most cases, the drug-induced changes are not large enough to cause diagnostic confusion, but when interpreting mild abnormalities in DHEAS levels, drug and hormone interactions should be taken into account. Examples of drugs that may increase DHEA sulfate (DHEAS) levels include metformin, troglitazone, prolactin, many neuroleptic drugs (by indirect implication)), danazol, calcium channel blockers (eg, diltiazem, amlodipine), and nicotine ⁵⁵⁰⁾.

Low DHEA-sulfate levels

If your DHEAS blood test results show low levels of DHEA sulfate (DHEAS), it may mean you have one of the following conditions:

• Adrenal gland disorders that produce lower than normal amounts of adrenal hormones, including adrenal insufficiency and Addison disease
• Hypopituitarism, a condition in which the pituitary gland does not make enough pituitary hormones
• Taking glucocorticoid medicines (Cushing’s syndrome)

If you have questions about your results, talk to your doctor.

Many drugs and hormones can result in changes in DHEA sulfate (DHEAS) levels. Whether any of these secondary changes in DHEAS levels are of clinical significance and how they should be related to the established normal reference ranges is unknown ⁵⁵¹⁾. In most cases, the drug-induced changes are not large enough to cause diagnostic confusion, but when interpreting mild abnormalities in DHEAS levels, drug and hormone interactions should be taken into account. Examples of drugs and hormones that can reduce DHEA sulfate (DHEAS) levels include: insulin, oral contraceptive drugs,
corticosteroids, central nervous system agents that induce hepatic enzymes (eg, carbamazepine, clomipramine, imipramine, phenytoin), many antilipemic drugs (eg, statins, cholestyramine), dopaminergic drugs (eg, levodopa/dopamine, bromocriptine), fish oil, and vitamin E ⁵⁵²⁾.

DHEA sulfate levels normally decline with age in both men and women. The production of DHEA and DHEAS start increasing in boys and girls around the age of 6 to 8 years as a consequence of the maturation of the zona reticularis of the adrenal cortex and this increase in adrenal androgens is known as adrenarche and the concomitant clinical appearance of pubic hair is known as pubarche ⁵⁵³⁾, ⁵⁵⁴⁾. DHEA and DHEAS levels rise steadily and peak in the second to third decade of life (serum DHEAS concentration can be as high as 10 μM in young adults) ⁵⁵⁵⁾, ⁵⁵⁶⁾, ⁵⁵⁷⁾, ⁵⁵⁸⁾. Thereafter there is a progressive decline by around 2%-5% each year with advancing age, such that levels decrease by 80%-90% in the eighth to ninth decade of life ⁵⁵⁹⁾. In a healthy aged 65- to 81-yr-old population, plasma DHEAS concentration is 2.2 µM in women and 3.3 µM in men ⁵⁶⁰⁾. However, the interindividual variability across adulthood is substantial, and the normal range of serum DHEA and DHEAS is therefore very wide at each decade of life ⁵⁶¹⁾. DHEAS levels in women in their mid 70s are about 77% lower than women in their third decade of life, with age alone explaining about 30% of the variation in DHEAS levels ⁵⁶²⁾. Despite the overall decline in DHEAS with age, levels across the menopausal transition vary according to the transitional phase ⁵⁶³⁾. Between the early and late perimenopause, DHEAS appears to increase on average by 3.95% in most women and then decline to levels seen in the early perimenopause by the late postmenopause ⁵⁶⁴⁾. Women who do not exhibit this rise in DHEAS across the menopause have lower levels as they enter menopause ⁵⁶⁵⁾. Overall Chinese women tend to have higher DHEAS levels and African-American women have lower DHEAS levels than Caucasian women ⁵⁶⁶⁾. To compensate for the decrease in aged people, over-the-counter DHEA sulfate supplements are available and are sometimes promoted as an anti-aging therapy. But there is no reliable evidence to support these anti-aging claims of DHEA supplements. In fact, DHEA supplements may cause serious side effects. If you have questions about DHEA supplements, talk to your health care provider.