Dehydroepiandrosterone (DHEA), also known as androstenolone, is an

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wi ...

precursor. It is one of the most abundant circulating

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

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 cortex which ...

s, the

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

s, and the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

. It functions as a

metabolic intermediate Metabolic intermediates are molecules that are the precursors or metabolites of biologically significant molecules. Although these intermediates are of relatively minor direct importance to cellular function, they can play important roles in the a ...

in the

biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...

of the

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

and

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

sex steroid Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects are ...

s 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 Nuclear may refer to: Physics Relating to the nucleus of the atom: * Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics *Nuclear space *Nuclear ...

and

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

s, and acting as a neurosteroid and modulator of

neurotrophic factor receptor Neurotrophic factor receptors or neurotrophin receptors are a group of growth factor receptors which specifically bind to neurotrophins (neurotrophic factors). Two classes of neurotrophic factor receptors are the p75 and the "Trk" families of Tyr ...

s. In the United States, DHEA is sold as an

over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...

supplement, and

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

called

prasterone Prasterone, also known as dehydroepiandrosterone (DHEA) and sold under the brand names Intrarosa, Diandrone, and Gynodian Depot among others, is a medication as well as over-the-counter dietary supplement which is used to correct DHEA deficienc ...

Biological function

As an androgen

DHEA and other adrenal androgens such as

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepia ...

, 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 and in humans, typically peaks at around 20 years of age, and is involved in the development of pubic hair, body odor, skin oiliness, axillary hair, sexual ...

, such as early

pubic In vertebrates, the pubic region ( la, pubis) is the most forward-facing (ventral and anterior) of the three main regions making up the coxal bone. The left and right pubic regions are each made up of three sections, a superior ramus, inferior r ...

and

axillary hair Underarm hair, also known as axillary hair, is the hair in the underarm area (''axilla''). Development Underarm or axillary hair goes through four stages of development, driven by weak androgens produced by the adrenal in males and females du ...

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 diseases ...

, 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, black ...

. DHEA is potentiated locally via conversion into

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

and

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...

(DHT) in the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...

and

hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...

s. Women with

complete androgen insensitivity syndrome Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. As such, the insensitivity to androgens is only clinically significant when it occurs in individuals ...

(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 Body hair, or androgenic hair, is the terminal hair that develops on the human body during and after puberty. It is differentiated from the head hair and less visible vellus hair, which is much finer and lighter in color. The growth of androge ...

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. Pubarche is one of the physical changes of puberty and can occur independently of complete puberty. Pubarche usually results from rising levels of androgen and not estrogens in femal ...

As an estrogen

DHEA is a weak

. In addition, it is transformed into potent estrogens such as

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...

in certain tissues such as the

vagina In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hymen ...

, 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 and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

Biological activity

Hormonal activity

Androgen receptor

Although it functions as an endogenous

precursor Precursor or Precursors may refer to: * Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of u ...

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 Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

(K_i = 1 μM), weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic e ...

of the

(AR). However, its

intrinsic activity Intrinsic activity (IA) and efficacy refer to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its mol ...

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, indivi ...

for binding with

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

s like testosterone, it can actually behave more like an antagonist depending on circulating testosterone and

(DHT) levels, and hence, like an

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the ...

. 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 Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex ...

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 ...

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...

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

, 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 Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

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 vertebr ...

, or

mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...

s. Other

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

targets of DHEA besides the androgen and estrogen receptors include the

PPARα Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gen ...

, PXR, and

CAR A car or automobile is a motor vehicle with wheels. Most definitions of ''cars'' say that they run primarily on roads, seat one to eight people, have four wheels, and mainly transport people instead of goods. The year 1886 is regarded as ...

. However, whereas DHEA is a

ligand In coordination chemistry, a ligand is an ion or molecule (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 electr ...

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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s via indirect, genomic mechanisms, including the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

CYP2C11 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...

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

s such as

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

and has been suggested to be involved in the

antiglucocorticoid An antiglucocorticoid is a drug which reduces glucocorticoid activity in the body. They include direct glucocorticoid receptor antagonists such as mifepristone and synthesis inhibitors such as metyrapone, ketoconazole, and aminoglutethimide. ...

effects of DHEA – and the

carrier protein A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane ...

IGFBP1 Insulin-like growth factor-binding protein 1 (IBP-1) also known as placental protein 12 (PP12) is a protein that in humans is encoded by the ''IGFBP1'' gene. Function This gene is a member of the Insulin-like growth factor-binding protein (IGFB ...

Neurosteroid activity

Neurotransmitter receptors

DHEA has been found to directly act on several

neurotransmitter receptor A neurotransmitter receptor (also known as a neuroreceptor) is a membrane receptor protein that is activated by a neurotransmitter. Chemicals on the outside of the cell, such as a neurotransmitter, can bump into the cell's membrane, in which the ...

s, including acting as a

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...

of the

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

, as a

negative allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds t ...

of the GABA_A receptor, and as an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the σ₁ receptor.

Neurotrophin receptors

In 2011, the surprising discovery was made that DHEA, as well as its sulfate ester,

DHEA-S Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroep ...

, directly bind to and activate

TrkA Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the ''NTRK1'' gen ...

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 cano ...

(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 recepto ...

and

TrkC Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the ''NTRK3'' gene. TrkC is the high affinity catalyt ...

with high affinity, though it only activated TrkC not TrkB. DHEA and DHEA-S bound to these receptors with affinities in the low

nanomolar Molar concentration (also called molarity, amount concentration or substance concentration) is a measure of the concentration of a chemical species, in particular of a solute in a solution, in terms of amount of substance per unit volume of solut ...

range (around 5 nM), which were nonetheless approximately two orders of magnitude lower relative to highly potent

polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

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 factor Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and cell differentiation, differentiation of both developing and mature neurons. Most ...

s. They have since been labeled "steroidal microneurotrophins", due to their

small-molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...

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 change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...

of the

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes 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 disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

Microtubule-associated protein 2

Similarly to

pregnenolone Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/ metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...

, its synthetic derivative

3β-methoxypregnenolone 3β-Methoxypregnenolone (developmental code name MAP-4343), or pregnenolone 3β-methyl ether, also known as 3β-methoxypregn-5-en-20-one, is a synthetic neuroactive steroid and derivative of pregnenolone. It interacts with microtubule-associate ...

(MAP-4343), and

, DHEA has been found to bind to

microtubule-associated protein 2 Microtubule-associated protein 2 is a protein in humans that is encoded by the ''MAP2'' gene. Function This gene encodes a protein that belongs to the microtubule-associated protein family. The proteins of this family were originally isolated s ...

(MAP2), specifically the MAP2C subtype (K_d = 27 μM). However, it is unclear whether DHEA increases binding of MAP2 to

tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...

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 Uncompetitive inhibition, also known as anti-competitive inhibition, takes place when an enzyme inhibitor binds only to the complex formed between the enzyme and the substrate (the E-S complex). Uncompetitive inhibition typically occurs in react ...

of (K_i = 17 μM; IC₅₀ = 18.7 μM), and is able to lower levels and reduce NADPH-dependent

free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...

production. It is thought that this action may possibly be responsible for much of the

antiinflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as ...

, antihyperplastic, chemopreventative,

antihyperlipidemic Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholester ...

antidiabetic Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists (liraglutide, exenatide, and others), and pramlintide, all are administered orally and are thus ...

, 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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' 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'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

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

Cancer

DHEA supplements have been promoted as chemopreventative, for their claimed cancer prevention properties. There is scientific evidence to support these claims.

Miscellaneous

DHEA has been found to competitively inhibit

TRPV1 The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the ''TRPV1'' gene. It was the first isolated member of th ...

Biochemistry

Biosynthesis

DHEA is produced in the

zona reticularis The zona reticularis (sometimes, reticulate zone) 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 ...

of the

adrenal cortex The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...

under the control of

adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...

(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 released ...

(GnRH). It is also produced in the

. DHEA is synthesized from

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

via the

cholesterol side-chain cleavage enzyme Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where "scc" is an acronym for side-chain cleavage. P450scc is a mitochondrial enzyme that catalyzes conversion of cholesterol to pregnenolone. This is the first reactio ...

(CYP11A1; P450scc) and 17α-hydroxylase/17,20-lyase (CYP17A1), with

and 17α-hydroxypregnenolone as intermediates. It is derived mostly from the

, 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 Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...

is known to increase DHEA production in the body.

Calorie restriction Calorie restriction (caloric restriction or energy restriction) is a dietary regimen that reduces intake of energy from caloric foods & beverages without incurring malnutrition. "Reduce" can be defined relative to the subject's previous intake be ...

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 Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

, with a small amount bound to

sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen ...

(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 prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

into the

Metabolism

DHEA is transformed into DHEA-S by

sulfation Sulfation is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected less directly. Regardless of the mechanism, the ...

at the C3β position via the

sulfotransferase Sulfotransferases (SULTs) are transferase enzymes that catalyze the transfer of a sulfo group from a donor molecule to an acceptor alcohol or amine. The most common sulfo group donor is 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In the case o ...

SULT2A1 Bile salt sulfotransferase also known as hydroxysteroid sulfotransferase (HST) or sulfotransferase 2A1 (ST2A1) is an enzyme that in humans is encoded by the ''SULT2A1'' gene. Function Sulfotransferase enzymes catalyze the sulfate conjugation ...

and to a lesser extent

SULT1E1 Estrogen sulfotransferase is an enzyme that in humans is encoded by the ''SULT1E1'' gene. Sulfotransferase enzymes catalyze the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. These cytosolic enzymes are ...

. This occurs naturally in the adrenal cortex and during

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...

in the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

and

intestines The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...

when

exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system. Economics In an economic model, an exogeno ...

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 Steroid sulfatase (STS), or steryl-sulfatase (EC 3.1.6.2), formerly known as arylsulfatase C, is a sulfatase enzyme involved in the metabolism of steroids. It is encoded by the ''STS'' gene. Reactions This enzyme catalysis, catalyses the follow ...

(STS). The

terminal half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

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 Duration may refer to: * The amount of time elapsed between two events * Duration (music) – an amount of time or a particular time interval, often cited as one of the fundamental aspects of music * Duration (philosophy) – a theory of time and ...

of DHEA.

Metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s of DHEA include DHEA-S,

7α-hydroxy-DHEA 7α-Hydroxydehydroepiandrosterone (7α-hydroxy-DHEA; 7α-OH-DHEA), also known as 3β,7α-dihydroxyandrost-5-ene-17-one, is an endogenous, naturally occurring steroid and a major metabolite of dehydroepiandrosterone (DHEA) that is formed by CYP7B1 ...

7β-hydroxy-DHEA 7β-Hydroxydehydroepiandrosterone (7β-hydroxy-DHEA; 7β-OH-DHEA), also known as 3β,7β-dihydroxyandrost-5-ene-17-one, is an endogenous, naturally occurring steroid and a metabolite of dehydroepiandrosterone (DHEA). The major metabolic pathway o ...

, 7-keto-DHEA,

7α-hydroxyepiandrosterone 7α-Hydroxyepiandrosterone (7α-OH-EPIA), also known as 3β,7α-dihydroxy-5α-androstan-17-one, is an endogenous, naturally occurring metabolite of epiandrosterone and dehydroepiandrosterone (DHEA) that is formed by the enzyme CYP7B1 in tissues ...

, and

7β-hydroxyepiandrosterone 7β-Hydroxyepiandrosterone (7β-OH-EPIA), also known as 5α-androstan-3β,7β-diol-17-one, is an endogenous androgen, estrogen, and neurosteroid that is produced from dehydroepiandrosterone and epiandrosterone. It has neuroprotective effects and, ...

, as well as

androstenediol Androstenediol, or 5-androstenediol (abbreviated as A5 or Δ5-diol), also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepia ...

and

Pregnancy

During

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

, DHEA-S is

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

into the sulfates of 16α-hydroxy-DHEA and 15α-hydroxy-DHEA in the

fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...

as intermediates in the production of the estrogens

estriol Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost ...

and

estetrol Estetrol (E4), or oestetrol, is one of the four natural estrogenic steroid hormones found in humans, along with estrone (E1), estradiol (E2), and estriol (E3), estetrol is a major estrogen in the body. In contrast to estrone and estradiol, estet ...

, 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 girl, the testes in a boy. ...

, DHEA and DHEA-S levels elevate upon differentiation of the

of the

. 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:https://www.questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/DHEA.pdf * 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 autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. ...

. Women with

polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...

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 sy ...

androstane Androstane is a C19 steroidal hydrocarbon with a gonane core. Androstane can exist as either of two isomers, known as 5α-androstane and 5β-androstane. File:androstane.png, 5α-Androstane File:androstane 5beta.png, 5β-Androstane Pharmacology ...

and a 17-ketosteroid. It is closely related structurally to

(androst-5-ene-3β,17β-diol),

(androst-4-ene-3,17-dione), and

(androst-4-en-17β-ol-3-one). DHEA is the 5- dehydro analogue of

epiandrosterone Epiandrosterone, or isoandrosterone, also known as 3β-androsterone, 3β-hydroxy-5α-androstan-17-one, or 5α-androstan-3β-ol-17-one, is a steroid hormone with weak androgenic activity. It is a metabolite of testosterone and dihydrotestosterone ...

(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

skeleton.

Dehydroandrosterone Dehydroandrosterone (DHA), or 5-dehydroandrosterone (5-DHA), also known as isoandrostenolone, as well as androst-5-en-3α-ol-17-one, is an endogenous androgen steroid hormone. It is the 3α-epimer of dehydroepiandrosterone (DHEA; androst-5-en-3� ...

(DHA) is the 3α-

epimer In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is ...

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 in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

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 po ...

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

Biochemistry

Biosynthesis

Increasing endogenous production

Distribution

Metabolism

Pregnancy

Levels

Measurement

Chemistry

Isomers

History

See also

References

Further reading