DHEA Therapy: Hope or Hype?

By Brinda N. Kalro, MD, FRCOG, DABMA, CCD, Dr. Kalro is Assistant Professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital, Pittsburgh, PA; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Dehydroepiandrosterone (DHEA), first discovered in 1934, is a dietary supplement widely available in pharmacies, health food stores, and via the internet. DHEA is often promoted as a panacea for aging.

Its anti-aging properties are purported to prevent cancer, heart disease, diabetes, and Alzheimer's disease in the elderly, while increasing muscle mass and strength, libido, and mood, and slowing down the aging process. Other perceived benefits include decreased insulin resistance,1 weight loss,2 improved immunomodulatory effects, and possibly beneficial skeletal effects.

Physiology of DHEA and DHEA-S

Circulating DHEA in both men and women is primarily produced by the zona reticularis of the adrenal cortex. In women, 90% of DHEA is adrenal in origin and 10% is from the ovaries. Almost all the DHEA is converted to the sulfated pro-hormone, DHEA-S, in the adrenal gland and the liver, both of which contain sulfotransferase. DHEA-S has a longer half-life and hence degrades more slowly than DHEA, does not bind to protein or albumin, and circulates in the blood in its free form.

DHEA and DHEA-S are converted into active androgens and estrogens in peripheral tissues (hair follicles, prostate, external genitalia, and adipose tissue). DHEA-S is converted in the genital skin in both men and women, to D5-androstenediol, testosterone, androstenedione, and dihydrotestosterone. The conversion is far greater in male genital skin.3

DHEA-S may be directly excreted in the urine, or its sulfate group may be hydrolyzed to yield free DHEA, which is then metabolized to androstenedione. DHEA-S can also undergo hydroxy-lation or reversible 17-b reduction. DHEA-S and its metabolites are cleared more slowly from the serum by the kidney than its non-sulfated analogues. A fraction of DHEA and DHEA-S and their metabolites are excreted in the feces via the biliary tract.4

DHEA levels are low in childhood, increase just prior to and during puberty, peak during the reproductive years, and thereafter gradually decline with age, independent of the cortisol secretion.

In women, DHEA levels peak at age 25, with levels declining steadily after age 30 by about 5% each year. DHEA levels are on average 10-30% less in young women than men and this gender difference declines with age. By age 50 years, women have approximately 50% of their peak DHEA levels,5 becoming almost undetectable by age 70. The fall in secretion of DHEA and DHEA-S by the adrenal gland parallels the decline in formation of androgen and estrogen by steroidogenic enzymes in specific target peripheral tissues.6

In addition to androgen and estrogen receptors, possible sites of action of DHEA and DHEA-S include the GABA-A/benzodiazepine receptor complex (acts as an antagonist); N-methyl aspartate excitatory amino acid receptors (potentiate effects of glutamate); CAR, a novel nuclear hormone-type receptor; a cell surface receptor in vascular endothelial cells that is functionally coupled to G-proteins; and a sigma-1 receptor that binds neuro-steroids and has antidepressant-like effects.7

The DHEA products currently marketed are synthesized in the laboratory by conversion of dioscorea from wild yam, thereby maintaining its classification as a dietary supplement. Dioscorea, a precursor of DHEA production, is also available over the counter, but is not readily bio-converted to DHEA in vivo in humans. DHEA in supplements can be converted to testosterone and estrogen in the body.

Mechanism of Action

The mode of action of DHEA is not very well understood; it perhaps acts as an androgen, estrogen, an anti-glucocortiocoid, or all of these. Compared to other hormones, its circulating levels are quite high and it very likely serves as a pro-hormone or reservoir.

Clinical Trials

Although DHEA therapy has been shown to be beneficial in certain medical conditions in several studies, the existing data are confusing, contradicting, and inconsistent. This is likely due to the wide variation of formulations, doses, and duration of therapies studied, and the different standards used to assess their efficacy. In addition, animals exhibit dramatic effects with DHEA supplementation because they have little to no circulating DHEA; however, animal data cannot and should not be extrapolated to humans.

Adrenal insufficiency. DHEA and DHEA-S production is reduced in patients with primary or secondary adrenal insufficiency, with consequent decreases in circulating androgen levels, particularly in women. DHEA supplementation appears efficacious in women with adrenal insufficiency.8-10

In a study of 24 women with primary adrenal insufficiency receiving adequate glucocorticoid and mineralocorticoid replacement, administration of DHEA 50 mg daily for four months resulted in increased serum androgen concentrations and improved general and psychological well-being and sexuality when compared with placebo.11 In the same study, DHEA replacement had no effect on carbohydrate metabolism, body composition, or exercise capability. Androgenic side effects in most women were mild and transient.

Another study of 50 mg DHEA daily in men and women with adrenal insufficiency reported improved self-esteem and overall sense of well-being with less fatigue and improved mood scores.12

Higher doses of 200 mg daily do not appear to provide additional clinical benefit. Daily doses less than 50 mg are not effective in primary adrenal insufficiency, but appear to be beneficial in secondary adrenal insufficiency.7

Systemic lupus erythematosus. Women with systemic lupus erythematosus (SLE) have low serum levels of DHEA and DHEA-S even prior to replacement with glucocorticoids.13 In patients with SLE, DHEA replacement appears to have a beneficial effect on the overall health-related quality of life,14 bone density,15 cognition,16 disease activity,17,18 and prednisone dosage.19

Depression. Two small series showed some improvement in depression scores in individuals who received DHEA. In the first, 46 patients received 90 mg/d for three weeks followed by 450 mg/d vs. placebo for a further three weeks;20 the other case series included 22 patients with major depression who were given up to 90 mg DHEA daily for six weeks.21 Larger trials with longer duration of therapy are required to corroborate these findings.

Fibromyalgia. Clinical observations reveal abnormal responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis with adrenal hypo-responsiveness and low DHEA/DHEA-S levels in individuals with fibromyalgia. Forty-seven postmenopausal women with fibromyalgia received 50 mg/d of DHEA for three months to restore normal serum levels. No changes were demonstrated in well-being, pain, fatigue, cognition, functional impairment, depression, or anxiety compared to the placebo group, but subjects did report androgenic side effects from therapy.22

Hypopituitarism. Patients with panhypopituitarism and growth hormone (GH) deficiency are profoundly androgen-deficient and have an impaired quality of life. Administration of DHEA 50 mg/d in addition to GH therapy for six months to 51 individuals with hypopituitarism resulted in modest improvement in psychological well-being, more so in female than male patients, when compared to the placebo group.23

Cardiovascular disease. DHEA has been shown to act as a survival factor for vascular endothelial cells and may have beneficial effects on the vascular system. Observational studies of DHEA levels in cardiovascular disease (CVD) in humans are inconsistent; high levels may be associated with lowered CVD risk in men, but may exert the opposite effect in women.

Several epidemiologic studies have shown that there is an inverse correlation between plasma concentrations of DHEA/DHEA-S and CVD mortality in both young and older males and females.24-28 More recent evidence from prospective studies has also shown higher CVD mortality in males with lower DHEA-S levels.29,30

DHEA in physiologic doses of 25-50 mg/d or a slightly higher dose of 100 mg/d resulted in a significant decrease in apolipoprotein A1 and HDL-cholesterol in women, but not in men, possibly a result of increased circulating androgen levels in women but not men.31

Administration of DHEA to women results in a slight decrease in HDL-cholesterol, but its effect on CVD risk is unknown.32,33 Long-term studies are needed to elucidate the role of DHEA in altering the risk of CVD in menopausal women.

Insulin resistance. Some clinical data support the contention that DHEA supplementation improves lean body mass and glucose tolerance. In 112 elderly men and women with relative DHEA deficiency, two years of DHEA replacement did not improve insulin secretion or action, nor did it improve the pattern of postprandial glucose metabolism.34

DHEA use in postmenopausal women. In postmenopausal women, evidence to support the use of DHEA to improve libido and well-being is sparse and inconclusive, with a dearth of safety data.

DHEA in postmenopausal women may be useful in the prevention and treatment of osteoporosis and osteopenia. In women 60-70 years of age, DHEA administered percutaneously (to avoid hepatic first-pass effect) for 12 months resulted in an increase in bone mineral density (BMD) at the hip and lumbar spine, with a favorable impact on urinary and serum bone markers.35

In a recent review of randomized controlled trials of DHEA and DHEA-S use for decreased libido and well-being in postmenopausal women, the authors concluded that data are limited by inadequate sample size and short duration of treatment.36

Some CAM clinicians recommend a daily oral intake of 5-20 mg of DHEA to postmenopausal women with a loss of vitality and/or low libido. It is believed that at this level DHEA is converted to more potent androgens, including testosterone. At pharmacologic levels of 1,600 mg daily, DHEA will be converted to estrone and estradiol. Few adverse effects have been reported at lower doses, although in some women, androgenic side effects (e.g., facial hair growth and acne) can occur with low doses. Clinical trials are needed to support these efficacy and safety observations.

Oral DHEA given to 60 symptomatic perimenopausal women in the dose of 50 mg daily for six months resulted in little improvement of perimenopausal symptoms or well-being when compared to placebo.37 Improvement of behavioral symptoms in postmenopausal women is believed to be mediated by neuroendocrine effects of DHEA-S or its active metabolites on pituitary beta-endorphin secretion.38 DHEA supplementation in early and late postmenopausal women is also associated with an increase in GH and IGF-1 levels.39 Increases in hip BMD was noted in a small group (n = 14) of women aged 60-70 years who used topical 10% DHEA cream,35 but the results could not be replicated in a six-month trial of 100 mg DHEA daily.40

Topical application of DHEA for two weeks to postmenopausal women resulted in a significant increase in serum testosterone levels with little change in estradiol and estrone levels.41 Interestingly, oral administration of DHEA to postmenopausal women was associated with an increase in estradiol and estrone levels in addition to an increase in testosterone levels, likely due to the hepatic first pass effect.42

Anti-aging therapy. In a two-year randomized placebo-controlled double-blind trial of individuals age 60 years of age and older with low androgen levels, neither DHEA nor testosterone replacement was effective in treating age-related changes. Likewise, there was no effect of DHEA on either muscle size or strength.43

DHEA was reported to improve insulin sensitivity in one small trail,44 but a larger, long-term study did not report the same effect.43

Cognition and dementia. The Baltimore Longitudinal Study of Aging did not detect any relationship between cognitive status and DHEA levels. Existing data do not support any improvement in memory or other aspects of cognitive function following DHEA treatment in healthy older people.45

In patients with Alzheimer's disease, DHEA replacement for six months did not result in cognitive improvement or influence the severity of disease.46

Safety

Lower doses of DHEA (25-50 mg/d) appear to be efficacious, well tolerated, and safe in the elderly population.47,48 Some women experience androgenic side effects such as oily skin, acne, excess facial hair, and hirsutism, but these are less common with lower doses. Long-term metabolic consequences of increased serum androgens in women are a concern, since DHEA is converted to androgens in vivo.

With high doses of DHEA, side effects reported by women include jaundice, elevated liver function tests, virilization, adverse effect on lipids and the breast, depressed mood, and, possibly, hepatocarcinogenicity. Nausea, vomiting, seborrheic dermatitis, and jaundice have been noted with low-dose chronic use.49

DHEA is contraindicated in women of reproductive age, especially if they are at any risk of pregnancy, because of possible masculinization of a female fetus. DHEA is also contraindicated in women who have hormone-responsive tumors.

The consistency of the amounts of DHEA in available formulations is questionable. An analysis of 16 DHEA-containing dietary supplements revealed that only seven contained DHEA within 90%-110% of the specifications on the product label.50

Conclusion

It is a popular notion that DHEA is beneficial, more so in older individuals and the elderly; however, the available clinical data do not support this idea. This is likely due to the wide variation in formulations, doses, and duration of therapy studied and the different standards used to assess efficacy. The ease of obtaining DHEA over the counter and the lack of regulation and quality control in the United States are major causes for concern and have been heavily criticized. Ongoing research is crucial and may serve to elucidate the potential benefits and risks of DHEA for both women and men as they age.

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