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Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is a natural steroid prohormone produced from cholesterol by the adrenal glands, the gonads, adipose tissue, brain and in the skin (by an autocrine mechanism). DHEA is the precursor of androstenedione, which can undergo further conversion to produce the androgen testosterone and the estrogens estrone and estradiol. DHEA is also a potent sigma-1 agonist.

Synonyms and brand names

Synonyms for Dehydroepiandrosterone are: Dehydroisoandrosterone; 3β-Hydroxy-5-androsten-17-one; 3β-Hydroxyandrost-5-en-17-one; Dehydroisoandrosterone; Hydroxyandrost-5-en-17-one; Prasterone; trans-Dehydroandrosterone.

Brand names for DHEA include Prastera, Fidelin and Fluasterone; supplement versions are manufactured from wild Mexican yam.

Dehydroepiandrosterone sulfate

Dehydroepiandrosterone sulfate (DHEAS) is the sulfated version of DHEA. This conversion is reversibly catalyzed by sulfotransferase (SULT2A1) primarily in the adrenals, the liver, and small intestine. In the blood, most DHEA is found as DHEAS with levels that are about 300 times higher than those of free DHEA. Orally-ingested DHEA is converted to its sulfate when passing through intestines and liver. Whereas DHEA levels naturally reach their peak in the early morning hours, DHEAS levels show no diurnal variation. From a practical point of view, measurement of DHEAS is preferable to DHEA, as levels are more stable.

Production

DHEA is produced from cholesterol through two cytochrome P450 enzymes. Cholesterol is converted to pregnenolone by the enzyme P450 scc (side chain cleavage); then another enzyme, CYP17A1, converts pregnenolone to 17α-Hydroxypregnenolone and then to DHEA. In humans, DHEA is the dominant steroid hormone and precursor of all sex steroids.

Role

DHEA can be understood as a prohormone for the sex steroids. DHEAS may be viewed as buffer and reservoir. As most DHEA is produced by the zona reticularis of the adrenal, it is argued that there is a role in the immune and stress response.

As almost all DHEA is derived from the adrenal glands, blood measurements of DHEAS/DHEA are useful to detect excess adrenal activity as seen in adrenal cancer or hyperplasia, including certain forms of congenital adrenal hyperplasia. Women with polycystic ovary syndrome tend to have elevated levels of DHEAS.

Effects and uses

Studies have shown that DHEA is useful in patients with systemic lupus erythematosus. An application of the evidence was discussed by the U.S. Food and Drug Administration in 2001 and is available online. This review also shows that cholesterol and other serum lipids decrease with the use of DHEA (mainly a decrease in HDL-C and triglycerides can be expected in women, p110).

DHEA supplementation has been studied as a treatment for Alzheimer's disease, but was found to be ineffective. Some small placebo-controlled randomized clinical trial studies have found long-term supplementation to improve mood and relieve depression or to decrease insulin resistance. However, a larger placebo-controlled randomized clinical trial reported in the New England Journal of Medicine in 2006 found that DHEA supplementation in elderly men and women had no beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life.

In contrast to the non-beneficial effects of DHEA on memory in the elderly, a randomised UK study found that a 7-day course of DHEA (150 mg twice daily) improved episodic memory in healthy young men. In this study, DHEA was also shown to improve subjective mood and decrease evening cortisol concentration, which is known to be elevated in depression. The effect of DHEA on memory appeared to be related to an early activation of the anterior cingulate cortex (ACC) and it was suggested this was due to neuronal recruitment of the steroid sensitive ACC that may be involved in pre-hippocampal memory processing.

DHEA supplements are sometimes used as muscle-building or performance-enhancing drugs by athletes. However, a randomized placebo-controlled trial found that DHEA supplementation had no effect on lean body mass, strength, or testosterone levels.

A 1986 study found that a higher level of endogenous DHEA, as determined by a single measurement, correlated with a lower risk of death or cardiovascular disease. However, a more recent 2006 study found no correlation between DHEA levels and risk of cardiovascular disease or death in men. A 2007 study found the DHEA restored oxidative balance in diabetic patients, reducing tissue levels of pentosidine—a biomarker for advanced glycation endproducts.

Some in vitro studies have found DHEA to have an anti-proliferative or apoptotic effect on cancer cell lines. The clinical significance of these findings, if any, is unknown. Higher levels of DHEA, in fact, have been correlated with an increased risk of developing breast cancer in both pre- and postmenopausal women.

An anonymous 2002 review, in the French journal Prescrire, concluded: DHEA plasma levels are so low in most animals that they are difficult to measure, hindering studies on DHEA and aging. DHEA had not yet, at the time of writing, been linked to any specific health disorder. Side effects are liked to its androgenic effects, unfavorable lipid metabolism effects, and "possible growth-stimulating effect" on hormone dependent malignancies. "In practice, there is currently no scientific reason to prescribe DHEA for any purpose whatsoever.

A 2005 study, measured serum DHEA in 206 men with type-2 diabetes, and found an inverse relationship between serum DHEA and carotid atherosclerosis in men. The authors say the study "supports the notion that DHEA, which is sold in increasing amount as a food supplement, is atheroprotective in humans, and that androgen replacement therapy should be considered for men with hypogonadism.

A 2006 study supplemented DHEA to men of average 65 years of age, and found that the men experienced significant increases in testosterone and cGMP (Cyclic guanosine monophosphate), and significant decreases in low-density liprotein (LDL). The authors say that the "findings...suggest that chronic DHEA supplementation would exert antiatherogenic effects, particularly in elderly subjects who display low ciriculating levels of this hormone.

A 2008 study in the Journal of the American Geriatrics Society, June 2008, measured serum DHEA in 940 men and women ranging from age 21 to 88, following them from 1978 until 2005. The researches found that low levels of DHEA-s showed a significant association with shorter lifespan and that higher DHEA-s levels are a "strong predictor" of longevity in men, even after adjusting for age, blood pressure, and plasma glucose. No relationship was found between serum DHEA and longevity for women during the study period. The study did not find a signigicant difference in longevity until the 15-year follow-up point, which the researchers note may explain why some past research that followed men for less duration found no relationship.

Disputed effects

In the United States, DHEA or DHEAS have been advertised with claims that they may be beneficial for a wide variety of ailments. DHEA and DHEAS are readily available in the United States, where they are marketed as over-the-counter dietary supplements. A 2004 review in the American Journal of Sports Medicine concluded that "The marketing of this supplement's effectiveness far exceeds its science. Because DHEA is converted to androstenedione and then testosterone, it has two chances to aromatize into estrogen- estrone from androstenedione, and estradiol from testosterone. As such, it is possible for increases in estrogen levels more than testosterone in men.

Increasing endogenous production

Regular exercise is known to increase DHEA production in the body. Caloric restriction has also been shown to increase DHEA in primates. Some theorize that the increase in endogenous DHEA brought about by caloric restriction is partially responsible for the longer life expectancy known to be associated with caloric restriction.

Legality

United States

A bill has been introduced, in March 2007, in the U.S. Senate (S. 762) that attempts to classify DHEA as a controlled substance under the category of anabolic steroids. The sponsor is Charles Grassley (R-IA). The cosponsors are Richard Durbin (D-IL), and John McCain (R-AZ). This bill was referred to the Senate Judiciary Committee. Then in December 2007, Charles Grassley introduced the "S. 2470: Dehydroepiandrosterone Abuse Reduction Act of 2007," in an attempt to amend the Controlled Substances Act to make "unlawful for any person to knowingly selling, causing another to sell, or conspiring to sell a product containing dehydroepiandrosterone to an individual under the age of 18 years, including any such sale using the Internet," without a prescription. The bill was read twice and referred to the Senate Judiciary Committee.