Dehydroepiandrosterone
Encyclopedia
5-Dehydroepiandrosterone (5-DHEA) is a 19-carbon endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

 steroid hormone
Steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens...

. It is the major secretory steroidal product of the adrenal glands and is also produced by the gonads and the brain. DHEA is the most abundant circulating steroid in humans.

DHEA has been implicated in a broad range of biological effects in humans and other mammals. It acts on the androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...

 both directly and through its metabolites, which include androstenediol
Androstenediol
Androstenediol may refer to:* 4-Androstenediol, the steroid androgen that can be converted to testosterone* 5-Androstenediol, steroid* Methandriol, a synthetic androstenediol derivative...

 and androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...

, which can undergo further conversion to produce the androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...

 testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...

 and the estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...

s, including estrone
Estrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...

, estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...

, and estriol
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...

. DHEA is also a potent sigma-1
Sigma-1 receptor
The sigma-1 receptor is a chaperone protein at the endoplasmatic reticulum that modulates calcium signaling through the IP3 receptor. In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene....

 agonist. It is considered a neurosteroid.

Strength

Evidence is inconclusive with respect to if DHEA has an effect on strength in the elderly.

Memory

DHEA supplementation has been studied as a treatment for Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

, but was not found to be effective. Some small placebo-controlled
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

 randomized clinical trial studies have found long-term supplementation to improve mood and relieve depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...

 found that a 7-day course of DHEA (150 mg twice daily) improved episodic memory
Episodic memory
Episodic memory is the memory of autobiographical events that can be explicitly stated. Semantic and episodic memory together make up the category of declarative memory, which is one of the two major divisions in memory...

 in healthy young men. In this study, DHEA was also shown to improve subjective mood and decrease evening cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...

 concentration, which is known to be elevated in depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...

. The effect of DHEA on memory appeared to be related to an early activation of the anterior cingulate cortex (ACC) and this was suggested to be due to neuronal recruitment of the steroid-sensitive ACC that may be involved in prehippocampal memory processing.

Consistent with this hypothesis are DHEAS data from several studies of military special operations units. In these studies, warfighters who exhibited higher levels of DHEA and higher DHEA/cortisol ratios during extreme stress were those who also exhibited superior hippocampal and prefrontal dependent cognitive abilities during stress.

Physical performance

Some studies have shown that supplementation in ageing women (but not men) using high doses of DHEA led to induction of an anabolic growth factor, increased muscle strength and lean body mass, activated immune function, and enhanced quality of life. However, a randomized placebo-controlled trial found that DHEA supplementation in younger men had no statistically significant effect on lean body mass, strength, or testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...

 levels.

Female reproductive health

Since 2000, DHEA supplementation has been used in reproductive medicine in combination with gonadotropins as a way to treat female infertility. The hormone is believed to act on the chromosomal integrity of eggs, creating healthier embryos and increasing the chances of a successful pregnancy. A study released in 2010 from Tel Aviv University showed that women who took DHEA supplements prior to an infertility treatment were three times more likely to conceive than those who did not. Additionally, studies conducted by the Center for Human Reproduction in New York found that women with poor ovarian reserve
Poor ovarian reserve
Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment...

 who were supplemented with DHEA four to 12 weeks prior to an IVF cycle had a 22% reduction in number of chromosomally abnormal embryos and a 50-80% reduction in miscarriages.

Cardiovascular disease and risk of death

A 1986 study found that a higher level of endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

 DHEA, as determined by a single measurement, correlated with a lower risk of death or cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...

. 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
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

 in diabetic patients, reducing tissue levels of pentosidine
Pentosidine
Pentosidine is a biomarker for advanced glycation endproducts, or AGEs. It is a well characterized and easily detected member of this large class of compounds.-Background:...

—a biomarker for advanced glycation endproduct
Advanced glycation endproduct
An advanced glycation end-product is the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. An advanced glycation...

s.

Diabetes and carotid atherosclerosis

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."

Men over 65

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
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...

 (Cyclic guanosine monophosphate), and significant decreases in low-density lipoprotein (LDL). The authors say that the "findings...suggest that chronic DHEA supplementation would exert antiatherogenic effects, particularly in elderly subjects who display low circulating levels of this hormone."

Longevity

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 significant 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.

"No reason to prescribe"

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 linked 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."

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 supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...

s. 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 must first be converted to androstenedione and then to testosterone in men, it has two chances to aromatize into estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...

 - estrone from androstenedione, and estradiol from testosterone. As such, it is possible that supplementation with DHEA could increase estrogen levels more than testosterone levels in men.

Adverse effects

As a hormone precursor, there has been a smattering of reports of side effects possibly caused by the hormone metabolites of DHEA. Some of these include possibly serious cardiovascular effects such as heart palpitations.

Dehydroepiandrosterone sulfate

Dehydroepiandrosterone sulfate (DHEAS) is the sulfated version of DHEA. This conversion is reversibly catalyzed by sulfotransferase
Sulfotransferase
Sulfotransferases are transferase enzymes that catalyze the transfer of a sulfate group from a donor molecule to an acceptor alcohol or amine. The most common sulfate donor is 3'-phosphoadenosine-5'-phosphosulfate...

 (SULT2A1
SULT2A1
Alcohol sulfotransferase is an enzyme that catalyzes the sulfate conjugation of primary and secondary alcohols including many hormones, neurotransmitters, drugs, and xenobiotic compounds.- Family members :...

) primarily in the adrenals, the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, and small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

. 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
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...

 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
Pregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...

 by the enzyme P450 scc
P450 scc
Cytochrome P450, family 11, subfamily A, polypeptide 1 , often referred to as P450scc , is a mitochondrial enzyme associated with the conversion of cholesterol to pregnenolone. The gene name is CYP11A1...

 (side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...

 cleavage); then another enzyme, CYP17A1, converts pregnenolone
Pregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...

 to 17α-Hydroxypregnenolone and then to DHEA.

Mechanism of action

DHEA can be understood as a prohormone
Prohormone
A prohormone is a substance that is a precursor to a hormone, usually having minimal hormonal effect by itself. The term has been used in medical science since the middle of the 20th century. The primary function of a prohormone is to enhance the strength of the hormone that already occurs in the...

 for the sex steroid
Sex steroid
Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and...

s. DHEAS may be viewed as buffer
Buffer solution
A buffer solution is an aqueous solution consisting of a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid. It has the property that the pH of the solution changes very little when a small amount of strong acid or base is added to it. Buffer solutions are used as a...

 and reservoir
Reservoir
A reservoir , artificial lake or dam is used to store water.Reservoirs may be created in river valleys by the construction of a dam or may be built by excavation in the ground or by conventional construction techniques such as brickwork or cast concrete.The term reservoir may also be used to...

. As most DHEA is produced by the zona reticularis
Zona reticularis
The zona reticularis is the innermost layer of the adrenal cortex, lying deep to the zona fasciculata and superficial to the adrenal medulla. The cells are arranged cords that project in different directions giving a net-like appearance The zona reticularis is the innermost layer of the adrenal...

 of the adrenal cortex, 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
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....

. Women with polycystic ovary syndrome
Polycystic ovary syndrome
Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....

 tend to have elevated levels of DHEAS.

Increasing endogenous production

Regular exercise is known to increase DHEA production in the body. Calorie restriction
Calorie restriction
Caloric restriction , or calorie restriction, is a dietary regimen that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects...

 has also been shown to increase DHEA in primates. 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.

Isomers

The term "dehydroepiandrosterone" is ambiguous chemically because it does not include the specific positions within epiandrosterone at which hydrogen atoms are missing. DHEA has a number of naturally occurring isomers that may have similar pharmacological effects. Some isomers of DHEA are 1-dehydroepiandrosterone and 4-dehydroepiandrosterone
4-Dehydroepiandrosterone
4-Dehydroepiandrosterone is an adrenal steroid that is an isomer of 5-dehydroepiandrosterone. 4-DHEA is a natural metabolite of androstenedione that occurs in tissues of rabbits, sheep and rats.-Synonyms :...

. These isomers are also technically DHEA, since they are dehydroepiandrosterones in which hydrogens are removed from the epiandrosterone
Epiandrosterone
Epiandrosterone is a steroid hormone with weak androgenic activity. It is a natural metabolite of dehydroepiandrosterone via the 5-alpha reductase enzyme. It was first isolated in 1931, by Adolf Friedrich Johann Butenandt and Kurt Tscherning...

 skeleton.

United States

A bill has been introduced, in March 2009, in the U.S. Senate (S. 641) that attempts to classify DHEA as a controlled substance under the category of anabolic steroids. The sponsor is Charles Grassley (R
Republican Party (United States)
The Republican Party is one of the two major contemporary political parties in the United States, along with the Democratic Party. Founded by anti-slavery expansion activists in 1854, it is often called the GOP . The party's platform generally reflects American conservatism in the U.S...

-IA
Iowa
Iowa is a state located in the Midwestern United States, an area often referred to as the "American Heartland". It derives its name from the Ioway people, one of the many American Indian tribes that occupied the state at the time of European exploration. Iowa was a part of the French colony of New...

). The cosponsors are Richard Durbin (D
Democratic Party (United States)
The Democratic Party is one of two major contemporary political parties in the United States, along with the Republican Party. The party's socially liberal and progressive platform is largely considered center-left in the U.S. political spectrum. The party has the lengthiest record of continuous...

-IL
Illinois
Illinois is the fifth-most populous state of the United States of America, and is often noted for being a microcosm of the entire country. With Chicago in the northeast, small industrial cities and great agricultural productivity in central and northern Illinois, and natural resources like coal,...

), and John McCain
John McCain
John Sidney McCain III is the senior United States Senator from Arizona. He was the Republican nominee for president in the 2008 United States election....

 (R
Republican Party (United States)
The Republican Party is one of the two major contemporary political parties in the United States, along with the Democratic Party. Founded by anti-slavery expansion activists in 1854, it is often called the GOP . The party's platform generally reflects American conservatism in the U.S...

-AZ
Arizona
Arizona ; is a state located in the southwestern region of the United States. It is also part of the western United States and the mountain west. The capital and largest city is Phoenix...

). This bill was referred to the Senate Judiciary Committee. 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. Only civil (noncriminal) penalties are provided. The bill was read twice and referred to the Senate Judiciary Committee, where it died.

Sports and athletics

DHEA is a prohibited substance under the World Anti-Doping Code of the World Anti-Doping Agency, which manages drug testing for Olympics and other sports. In January 2011, NBA
National Basketball Association
The National Basketball Association is the pre-eminent men's professional basketball league in North America. It consists of thirty franchised member clubs, of which twenty-nine are located in the United States and one in Canada...

 player O.J. Mayo was given a 10-game suspension after testing positive for DHEA. Mayo termed his use of DHEA as "an honest mistake". Mayo is the seventh player to test positive for performance-enhancing drugs since the league began testing in 1999. Rashard Lewis, then with the Orlando Magic, tested positive for DHEA and was suspended 10 games before the start of the 2009-10 season.

Synonyms and brand names

Synonyms for dehydroepiandrosterone:

The International Nonproprietary Name
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...

 is "prasterone". Systematic names include 3-beta-hydroxy-5-androsten-17-one, 3-beta-hydroxyandrost-5-en-17-one, 3beta-hydroxy-5-androsten-17-one, 3beta-hydroxy-androst-5-en-17-one, 3beta-hydroxy-D5-androsten-17-one, 3beta-hydroxyandrost-5-en-17-one, 3beta-hydroxyandrost-5-ene-17-one, 3-beta-hydroxy-etioallocholan-5-ene-17-one, and 5-androsten-3beta-ol-17-one. Fidelin is Paladin's trade name for DHEA.

Fluasterone is a synthetic derivative of DHEA.

Cancer

Some in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

studies have found DHEA to have both antiproliferative and yet also apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 effect on cancer cell lines. The clinical significance of these findings, if any, is unknown. Higher levels of DHEA and other endogenous sex hormones are strongly associated with an increased risk of developing breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

 in both pre- and postmenopausal
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...

 women.

External links

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