Chemistry and Forms

Dehydroepiandrosterone; dehydroepiandrosterone sulfate.

Physiology and Function

Dehydroepiandrosterone (DHEA) and its sulfate ester metabolite (DHEA-S) are among the most abundant steroids in the human body, yet their physiological roles remain largely unknown. DHEA is a naturally occurring steroid synthesized in the adrenal cortex, gonads, central nervous system (CNS), skin, and gastrointestinal (GI) tract and is a precursor for the synthesis of more than 50 hormones, including androgenic and estrogenic steroids.

Adrenal production and serum concentrations of DHEA are known to peak between ages 25 and 30 years and thereafter decrease with age, severe illness, and chronic stress. The main characteristic of DHEA is that its concentration in plasma varies throughout life, being low during early childhood and after age 60. Aging in humans is accompanied by a progressive decline in the secretion of DHEA and DHEA sulfate (DHEA-S), paralleling that of the growth hormone–insulin-like growth factor-I (GH-IGF-I) axis. Although the functional relationship of the decline of the GH-IGF-I system and catabolism is recognized, the biological role of DHEA in human aging remains undefined. DHEA has different effects in men, premenopausal women, and postmenopausal women, with associations often reversed for older men and women. DHEA and DHEA-S are metabolized by the hepatic cytochrome P450 (CYP450) enzyme system or via a cutaneous pathway, where it is metabolized by the skin and other tissues sensitive to sex steroids.

Known or Potential Therapeutic Uses

Low endogenous levels of DHEA and DHEA-S have consistently been associated with the aging process and diseases such as systemic lupus erythematosus (SLE), diabetes, and cancer. Consequently, DHEA administration has primarily been suggested to prevent or reverse such conditions. For example, by modulating endocrine parameters and synthesis of neuroactive steroids, low-dose DHEA (25 mg/day) administration increases adrenal hormone plasma levels in early and late menopause. ¹ Likewise, DHEA monotherapy can be effective for midlife-onset major and minor depression. ² However, Nair et al. ³ found that administration of DHEA in elderly subjects does not demonstrate “physiologically relevant beneficial effects” on markers for antiaging, such as body composition, physical performance, insulin sensitivity, or quality of life, although they did observe an increase in plasma levels of sulfated DHEA. The role of DHEA within hormone replacement therapy (HRT) and as an antiaging substance remains controversial and research preliminary.

Historical/Ethnomedicine Precedent

Antiaging and longevity tonic medications have been sought-after, proposed, and used throughout history worldwide in almost all civilizations. Such medications have often been associated with human reproductive function, hormones, and fluids. Needham discussed the use of crystallized medications derived from the collected urine of adolescents in ancient China. Early in the twentieth century, the adrenal glands came into focus with the research work of experimental physiologist Walter Cannon at the University of Chicago and his pioneering study of homeostasis and the autonomic nervous system. Clinical application of these concepts began with the work of Henry Harrower, Royal Lee, and others with the use of glandular preparations in therapeutic nutrition.

Possible Uses

Addison’s disease, adrenal insufficiency, allergic disorders, Alzheimer’s disease, andropause, anorexia nervosa, atherosclerosis, athletic performance enhancement, autoimmune diseases, cancer prevention, chronic fatigue syndrome, dementia, depression, diabetes mellitus (type 2), endothelial function, erectile dysfunction, fatigue, human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) support, hypercholesterolemia, hypogonadism, immune modulation, insulin sensitivity, longevity, menopause, multi-infarct dementia, multiple sclerosis, obesity, osteoporosis, Parkinson’s disease, rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus (SLE), testosterone deficiency.

Dietary Sources

Animal proteins are the richest dietary sources of DHEA.

Nutrient Preparations Available

A semisynthetic form of DHEA is available as a nutraceutical. Some product surveys have found variable potency and quality in commercially available DHEA preparations.

Dosage Forms Available

Capsule, liquid, tablet, and sublingual form.

Source Materials for Nutrient Preparations

Soy or wild yams are used for extraction of a steroid precursor molecule, which is then chemically synthesized into DHEA (and a wide variety of other sex hormones).

Dosage Range

Adult

Dietary:

• Average American daily intake: DHEA per se is not a normal dietary component.
• Recommended dietary allowance (RDA): No RDA has been established.

  Supplemental/Maintenance: Usually not necessary. Optimal levels of intake have not been established. Individuals who have not been diagnosed as having a hormonal deficiency pattern, preferably through laboratory tests, should usually not take DHEA.

  Pharmacological/Therapeutic: There is no consensus among practitioners who prescribe DHEA as to an optimal dose. Some practitioners are routinely prescribing 10 to 30 mg per day for healthy men and 5 to 15 mg per day for healthy women, whereas others often prescribe 50 to 100 mg per day. Dosage is usually split into morning and late-afternoon doses. Much larger doses have been administered under close observation to patients with cancer, acquired immunodeficiency syndrome (AIDS), SLE, and other serious conditions. The metabolic fate of exogenous DHEA is variable and unpredictable because it can become one of many other hormones. Orally administered DHEA can also be metabolized by enzymes in the small intestine, causing biotransformation even before it has been absorbed. Even when using laboratory testing to evaluate appropriateness of and response to DHEA, no data yet exist on what constitutes a physiologic dose or an optimum serum level. Consequently, the judicious practice would be to err on the side of caution by using initial low doses of DHEA, following a conservative schedule for any dosage increase, and observing discrimination and vigilance in the use of supraphysiologic doses.

  Beyond those who prescribe DHEA, its use is a controversial, but generally unexplored, issue. Opinions vary widely as to the benefits and risks of using hormones such as DHEA as nutraceutical therapies. Any such application should be monitored by a health care professional trained and experienced in nutritional therapeutics and is best undertaken after initially testing DHEA levels.

  Toxic: No toxic dose has been established.

Pediatric (<18 years)

DHEA is generally not considered therapeutically appropriate in children or adolescents, in the absence of conditions such as Addison’s disease, and has not been well studied in such populations.

Overview

The long-term safety of DHEA administration has not been established through well-done clinical studies involving human subjects from a variety of populations. The inherent tendency of DHEA to increase or otherwise alter healthy physiologic levels of a wide range of hormones suggests that unintended effects are highly probable and potentially adverse for some individuals in the absence of experienced clinical management.

Nutrient Adverse Effects

General Adverse Effects

Adults

Masculinization in women; altered secondary sexual characteristics in either gender.

Mutagenicity

Preliminary evidence and extrapolated hypotheses have been presented on both increased and decreased risk of angiogenesis and cancer in relation to endogenous and exogenous DHEA.

Adverse Effects Among Specific Populations

DHEA is often prescribed for biological aging, functional symptoms of aging, and prevention of functional degeneration hypothesized to derive from age-related depletion in hormonal levels. Given that the use of prescription medications increases with age, issues of potential interactions, adverse or beneficial, deserve special attention among the elderly population.

Pregnancy and Nursing

The safety of DHEA use during pregnancy and lactation has not been established, and such application is contraindicated because of potential impact on hormonal levels, regulatory systems, and fetal development.

Infants and Children

DHEA administration is generally contraindicated in children and adolescents because theoretically it may interfere with normal hormonal regulatory systems and developmental processes.

Contraindications

Given DHEA’s potential effect on testosterone and estrogen levels, its use by individuals with personal or family history of prostate or breast cancer, or other hormonally mediated cancer, is contraindicated. Such recommendation is based more on caution and plausibility than on a consistent or well-developed body of evidence. The 7-keto variant of DHEA was developed to circumvent the metabolic pathways associated with such hormonally mediated adverse effects.

Testing

Serum or saliva. Monitoring free and sulfate levels is considered the most accurate method of tracking DHEA levels, but exogenous DHEA can become many other hormones. Orally administered DHEA can also be metabolized by enzymes in the small intestine, causing biotransformation even before it has been absorbed.

Strategic Considerations

DHEA is often prescribed for biological aging, functional symptoms of aging, and prevention of functional degeneration hypothesized to derive from age-related depletion in hormonal levels. Because use of prescription drugs increases with age, issues of potential interactions, adverse or beneficial, deserve special attention in elderly individuals.

The status of endogenous DHEA and DHEA-S constitutes a significant aspect of many health conditions, especially those associated with aging. A wide range of medications may significantly increase or decrease circulating concentrations of DHEA and DHEA-S by various mechanisms. Some drugs may affect the hypothalamic-pituitary axis by inhibiting adrenocorticotropic hormone (ACTH) and therefore lower DHEA and DHEA-S levels. Other medications induce CYP450 enzymes, hasten metabolism of DHEA and DHEA-S, and decrease circulating concentrations of the hormones. The ratio of DHEA and DHEA-S can also be altered by agents that affect sulfatase activity. Whether a disease state is associated with lower levels of endogenous DHEA and DHEA-S or a medication alters such concentrations, minimal clinical evidence exists to indicate whether oral administration is safe or effective, or problematic and contraindicated, in specific patient populations.

Whenever DHEA is being prescribed for primary therapeutic effect or to counter a potential endogenous deficiency or drug-induced depletion, close supervision and regular monitoring are important, as is coordination of pharmacological interventions within an integrative perspective.

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