Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

s in humans. DHEA is produced in the

adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...

s, the

gonad A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...

s, and the brain. It functions as a metabolic intermediate in the

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

of the

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

and

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

sex steroids both in the gonads and in various other tissues. However, DHEA also has a variety of potential biological effects in its own right, binding to an array of nuclear and cell surface receptors, and acting as a neurosteroid and modulator of neurotrophic factor receptors. In the United States, DHEA is sold as an over-the-counter supplement, and medication called prasterone.

Biological function

As an androgen

DHEA and other adrenal androgens such as androstenedione, although relatively weak androgens, are responsible for the androgenic effects of

adrenarche Adrenarche is an early stage in sexual maturation that happens in some higher primates (including humans), typically peaks at around 20 years of age, and is involved in the development of pubic hair, body odor, skin oiliness#Oily skin, skin oiline ...

, such as early pubic and axillary hair growth, adult-type

body odor Body odor or body odour (BO) is present in all animals and its intensity can be influenced by many factors (behavioral patterns, survival strategies). Body odor has a strong genetic basis, but can also be strongly influenced by various factors, ...

, increased oiliness of hair and skin, and mild

acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...

. DHEA is potentiated locally via conversion into

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

and dihydrotestosterone (DHT) in the skin and hair follicles. Women with complete androgen insensitivity syndrome (CAIS), who have a non-functional

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...

(AR) and are immune to the androgenic effects of DHEA and other androgens, have absent or only sparse/scanty pubic and axillary hair and body hair in general, demonstrating the role of DHEA and other androgens in body hair development at both adrenarche and

pubarche Pubarche () refers to the first appearance of pubic hair at puberty. It is one of the earliest physical changes of puberty and can occur independently of complete puberty. It is usually the second sign of puberty, after thelarche in females and gon ...

As an estrogen

DHEA is a weak

. In addition, it is transformed into potent estrogens such as estradiol in certain tissues such as the

vagina In mammals and other animals, the vagina (: vaginas or vaginae) is the elastic, muscular sex organ, reproductive organ of the female genital tract. In humans, it extends from the vulval vestibule to the cervix (neck of the uterus). The #Vag ...

, and thereby produces estrogenic effects in such tissues.

As a neurosteroid

As a neurosteroid and neurotrophin, DHEA has important effects in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

Biological activity

Hormonal activity

Androgen receptor

Although it functions as an endogenous precursor to more potent androgens such as testosterone and DHT, DHEA has been found to possess some degree of

ic activity in its own right, acting as a low affinity (K_i = 1 μM), weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the

(AR). However, its intrinsic activity at the receptor is quite weak, and on account of that, due to

competition Competition is a rivalry where two or more parties strive for a common goal which cannot be shared: where one's gain is the other's loss (an example of which is a zero-sum game). Competition can arise between entities such as organisms, indi ...

for binding with full agonists like testosterone, it can actually behave more like an antagonist depending on circulating testosterone and dihydrotestosterone (DHT) levels, and hence, like an antiandrogen. However, its affinity for the receptor is very low, and for that reason, is unlikely to be of much significance under normal circumstances.

Estrogen receptors

In addition to its affinity for the androgen receptor, DHEA has also been found to bind to (and activate) the ERα and

ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by t ...

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

s with K_i values of 1.1 μM and 0.5 μM, respectively, and EC₅₀ values of >1 μM and 200 nM, respectively. Though it was found to be a partial agonist of the ERα with a maximal efficacy of 30–70%, the concentrations required for this degree of activation make it unlikely that the activity of DHEA at this receptor is physiologically meaningful. Remarkably however, DHEA acts as a full agonist of the ERβ with a maximal response similar to or actually slightly greater than that of estradiol, and its levels in circulation and local tissues in the human body are high enough to activate the receptor to the same degree as that seen with circulating estradiol levels at somewhat higher than their maximal, non- ovulatory concentrations; indeed, when combined with estradiol with both at levels equivalent to those of their physiological concentrations, overall activation of the ERβ was doubled.

Other nuclear receptors

DHEA does not bind to or activate the progesterone,

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...

, or mineralocorticoid receptors. Other nuclear receptor targets of DHEA besides the androgen and estrogen receptors include the PPARα, PXR, and CAR. However, whereas DHEA is a

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

of the PPARα and PXR in rodents, it is not in humans. In addition to direct interactions, DHEA is thought to regulate a handful of other

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s via indirect, genomic mechanisms, including the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s CYP2C11 and 11β-HSD1 – the latter of which is essential for the biosynthesis of the

s such as cortisol and has been suggested to be involved in the antiglucocorticoid effects of DHEA – and the carrier protein IGFBP1.

Neurosteroid activity

Neurotransmitter receptors

DHEA has been found to directly act on several neurotransmitter receptors, including acting as a positive allosteric modulator of the

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

, as a negative allosteric modulator of the GABA_A receptor, and as an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the σ₁ receptor.

Neurotrophin receptors

In 2011, the surprising discovery was made that DHEA, as well as its sulfate ester, DHEA-S, directly bind to and activate TrkA and p75^NTR, receptors of neurotrophins like nerve growth factor (NGF) and

brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the can ...

(BDNF), with high affinity. DHEA was subsequently also found to bind to

TrkB Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recept ...

and TrkC with high affinity, though it only activated TrkC not TrkB. DHEA and DHEA-S bound to these receptors with affinities in the low nanomolar range (around 5 nM), which were nonetheless approximately two orders of magnitude lower relative to highly potent polypeptide neurotrophins like NGF (0.01–0.1 nM). In any case, DHEA and DHEA-S both circulate at requisite concentrations to activate these receptors and were thus identified as important endogenous neurotrophic factors. They have since been labeled "steroidal microneurotrophins", due to their small-molecule and steroidal nature relative to their polypeptide neurotrophin counterparts. Subsequent research has suggested that DHEA and/or DHEA-S may in fact be phylogenetically ancient "ancestral" ligands of the neurotrophin receptors from early on in the

evolution Evolution is the change in the heritable Phenotypic trait, characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, re ...

of the

nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...

. The findings that DHEA binds to and potently activates neurotrophin receptors may explain the positive association between decreased circulating DHEA levels with age and age-related neurodegenerative diseases.

Microtubule-associated protein 2

Similarly to pregnenolone, its synthetic derivative 3β-methoxypregnenolone (MAP-4343), and progesterone, DHEA has been found to bind to microtubule-associated protein 2 (MAP2), specifically the MAP2C subtype (K_d = 27 μM). However, it is unclear whether DHEA increases binding of MAP2 to tubulin like pregnenolone.

ADHD

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

Other activity

G6PDH inhibitor

DHEA is an uncompetitive inhibitor of (K_i = 17 μM; IC₅₀ = 18.7 μM), and is able to lower levels and reduce NADPH-dependent free radical production. It is thought that this action may possibly be responsible for much of the antiinflammatory, antihyperplastic, chemopreventative, antihyperlipidemic, antidiabetic, and antiobesic, as well as certain immunomodulating activities of DHEA (with some experimental evidence to support this notion available). However, it has also been said that inhibition of G6PDH activity by DHEA '' in vivo'' has not been observed and that the concentrations required for DHEA to inhibit G6PDH ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' are very high, thus making the possible contribution of G6PDH inhibition to the effects of DHEA uncertain.

Cancer

DHEA supplements have been promoted in supplement form for its claimed cancer prevention properties; there is no scientific evidence to support these claims.

Miscellaneous

DHEA has been found to competitively inhibit TRPV1.

DHEA in regards to aging

DHEA levels peak in early adulthood and gradually decline with age. By supplementing with DHEA, some individuals aim to restore hormone levels, potentially improving energy levels, mood, and libido. DHEA can help improve bone density as it is related to androgens which is important for bone health. DHEA controls the production of osteoblasts and insulin like growth factor 1 (IGF-1) expression which strengthens bone growth through metabolites. This helps delay the risk of

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

in early adults.

Biochemistry

Biosynthesis

DHEA is produced in the zona reticularis of the adrenal cortex under the control of adrenocorticotropic hormone (ACTH) and by the

s under the control of

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and rele ...

(GnRH). It is also produced in the brain. DHEA is synthesized from

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

via the

s cholesterol side-chain cleavage enzyme (CYP11A1; P450scc) and 17α-hydroxylase/17,20-lyase (CYP17A1), with pregnenolone and 17α-hydroxypregnenolone as intermediates. It is derived mostly from the adrenal cortex, with only about 10% being secreted from the

s. Approximately 50 to 70% of circulating DHEA originates from desulfation of DHEA-S in peripheral tissues. DHEA-S itself originates almost exclusively from the adrenal cortex, with 95 to 100% being secreted from the adrenal cortex in women.

Increasing endogenous production

Regular exercise is known to increase DHEA production in the body.

Calorie restriction Calorie restriction (CR, also known as caloric restriction or energy restriction) is a dietary regimen that reduces the energy intake from foods and beverages without incurring malnutrition. The possible effect of calorie restriction on body w ...

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.

Distribution

In the circulation, DHEA is mainly bound to albumin, with a small amount bound to sex hormone-binding globulin (SHBG). The small remainder of DHEA not associated with albumin or SHBG is unbound and free in the circulation. DHEA easily crosses the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

into the

Metabolism

DHEA is transformed into DHEA-S by sulfation at the C3β position via the sulfotransferase

s SULT2A1 and to a lesser extent SULT1E1. This occurs naturally in the adrenal cortex and during first-pass metabolism in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and intestines when exogenous DHEA is administered orally. Levels of DHEA-S in circulation are approximately 250 to 300 times those of DHEA. DHEA-S in turn can be converted back into DHEA in peripheral tissues via steroid sulfatase (STS). The terminal half-life of DHEA is short at only 15 to 30 minutes. In contrast, the terminal half-life of DHEA-S is far longer, at 7 to 10 hours. As DHEA-S can be converted back into DHEA, it serves as a circulating reservoir for DHEA, thereby extending the duration of DHEA. Metabolites of DHEA include DHEA-S, 7α-hydroxy-DHEA, 7β-hydroxy-DHEA, 7-keto-DHEA, 7α-hydroxyepiandrosterone, and 7β-hydroxyepiandrosterone, as well as androstenediol and androstenedione.

Pregnancy

During pregnancy, DHEA-S is metabolized into the sulfates of 16α-hydroxy-DHEA and 15α-hydroxy-DHEA in the fetal

as intermediates in the production of the estrogens estriol and estetrol, respectively.

Levels

Prior to

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...

in humans, DHEA and DHEA-S levels elevate upon differentiation of the zona reticularis of the adrenal cortex. Peak levels of DHEA and DHEA-S are observed around age 20, which is followed by an age-dependent decline throughout life eventually back to prepubertal concentrations. Plasma levels of DHEA in adult men are 10 to 25 nM, in premenopausal women are 5 to 30 nM, and in postmenopausal women are 2 to 20 nM. Conversely, DHEA-S levels are an order of magnitude higher at 1–10 μM. Levels of DHEA and DHEA-S decline to the lower nanomolar and micromolar ranges in men and women aged 60 to 80 years. DHEA levels are as follows: * Adult men: 180–1250 ng/dL * Adult women: 130–980 ng/dL * Pregnant women: 135–810 ng/dL * Prepubertal children (<1 year): 26–585 ng/dL * Prepubertal children (1–5 years): 9–68 ng/dL * Prepubertal children (6–12 years): 11–186 ng/dL * Adolescent boys (Tanner II–III): 25–300 ng/dL * Adolescent girls (Tanner II–III): 69–605 ng/dL * Adolescent boys (Tanner IV–V): 100–400 ng/dL * Adolescent girls (Tanner IV–V): 165–690 ng/dL

Measurement

As almost all DHEA is derived from the adrenal glands, blood measurements of DHEA-S/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 (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...

. Women with

polycystic ovary syndrome Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...

tend to have elevated levels of DHEA-S.

Chemistry

DHEA, also known as androst-5-en-3β-ol-17-one, is a

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...

androstane

and a 17-ketosteroid. It is closely related structurally to androstenediol (androst-5-ene-3β,17β-diol), androstenedione (androst-4-ene-3,17-dione), and

(androst-4-en-17β-ol-3-one). DHEA is the 5- dehydro analogue of epiandrosterone (5α-androstan-3β-ol-17-one) and is also known as 5-dehydroepiandrosterone or as δ⁵-epiandrosterone.

Isomers

The term "dehydroepiandrosterone" is ambiguous chemically because it does not include the specific positions within epiandrosterone at which hydrogen atoms are missing. DHEA itself is 5,6-didehydroepiandrosterone or 5-dehydroepiandrosterone. A number of naturally occurring isomers also exist and may have similar activities. Some isomers of DHEA are 1-dehydroepiandrosterone (1-androsterone) and 4-dehydroepiandrosterone. These isomers are also technically "DHEA", since they are dehydroepiandrosterones in which hydrogens are removed from the epiandrosterone skeleton. Dehydroandrosterone (DHA) is the 3α- epimer of DHEA and is also an endogenous androgen.

History

DHEA was first isolated from human

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

in 1934 by

Adolf Butenandt Adolf Friedrich Johann Butenandt (; 24 March 1903 – 18 January 1995) was a German biochemist. He was awarded the Nobel Prize in Chemistry in 1939 for his "work on sex hormones." He initially rejected the award in accordance with government pol ...

and Kurt Tscherning.

Biological function

As an androgen

As an estrogen

As a neurosteroid

Biological activity

Hormonal activity

Androgen receptor

Estrogen receptors

Other nuclear receptors

Neurosteroid activity

Neurotransmitter receptors

Neurotrophin receptors

Microtubule-associated protein 2

ADHD

Other activity

G6PDH inhibitor

Cancer

Miscellaneous

DHEA in regards to aging

Biochemistry

Biosynthesis

Increasing endogenous production

Distribution

Metabolism

Pregnancy

Levels

Measurement

Chemistry

Isomers

History

See also

References

Further reading