Androgen receptor

From Wikipedia, the free encyclopedia

 

AR
Available structures PDB Ortholog search: PDBe RCSB

List of PDB id codes
Identifiers
Aliases	AR, AIS, AR8, DHTR, HUMARA, HYSP1, KD, NR3C4, SBMA, SMAX1, TFM, androgen receptor
External IDs	OMIM: 313700 MGI: 88064 HomoloGene: 28 GeneCards: AR

RNA expression pattern

Orthologs
Species	Human	Mouse
Entrez	367	11835
Ensembl	n/a	ENSMUSG00000046532
UniProt	P10275	P19091
RefSeq (mRNA)	NM_001011645 NM_000044	NM_013476
RefSeq (protein)

NP_000035 NP_001011645 NP_001334990 NP_001334992 NP_001334993	NP_038504
Location (UCSC)	n/a	Chr X: 98.15 – 98.32 Mb
PubMed search

Androgen_recep
crystal structure of the human androgen receptor ligand binding domain bound with an androgen receptor nh2-terminal peptide, ar20-30, and r1881
Identifiers
Symbol	Androgen_recep
Pfam	PF02166
InterPro	IPR001103

Available protein structures:

Normal function of the androgen receptor. Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestone (DHT). Upon steroid binding, the androgen receptor (AR) undergoes a conformational change and releases heat-shock proteins (hsps). Phosphorylation (P) occurs before or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and translated into proteins.

 

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 the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.

The main function of the androgen receptor is as a DNA-binding transcription factor that regulates gene expression; however, the androgen receptor has other functions as well. Androgen regulated genes are critical for the development and maintenance of the male sexual phenotype.

Function

Effect on development

In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by 5-alpha-reductase to dihydrotestosterone, an even more potent agonist for androgen receptor activation. Testosterone appears to be the primary androgen receptor-activating hormone in the Wolffian duct, whereas dihydrotestosterone is the main androgenic hormone in the urogenital sinus, urogenital tubercle, and hair follicles. Testosterone is therefore responsible primarily for the development of male primary sexual characteristics, whilst dihydrotestosterone is responsible for secondary male characteristics. 

Androgens cause slow epiphysis, or maturation of the bones, but more of the potent epiphysis effect comes from the estrogen produced by aromatization of androgens. Steroid users of teen age may find that their growth had been stunted by androgen and/or estrogen excess. People with too little sex hormones can be short during puberty but end up taller as adults as in androgen insensitivity syndrome or estrogen insensitivity syndrome.

Also, AR knockout-mice studies have shown that AR is essential for normal female fertility, being required for development and full functionality of the ovarian follicles and ovulation, working through both intra-ovarian and neuroendocrine mechanisms.

Maintenance of male skeletal integrity

Via the androgen receptor, androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling can be attributed to both osteoblasts and osteocytes.

Mechanism of action

Genomic

The primary mechanism of action for androgen receptors is direct regulation of gene transcription. The binding of an androgen to the androgen receptor results in a conformational change in the receptor that, in turn, causes dissociation of heat shock proteins, transport from the cytosol into the cell nucleus, and dimerization. The androgen receptor dimer binds to a specific sequence of DNA known as a hormone response element. Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specific gene transcription. Up-regulation or activation of transcription results in increased synthesis of messenger RNA, which, in turn, is translated by ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is the insulin-like growth factor I receptor (IGF-1R). Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior.

One function of androgen receptor that is independent of direct binding to its target DNA sequence, is facilitated by recruitment via other DNA-binding proteins. One example is serum response factor, a protein that activates several genes that cause muscle growth.

Androgen receptor is modified by post translational modification through acetylation, which directly promotes AR mediated transactivation, apoptosis and contact independent growth of prostate cancer cells. AR acetylation is induced by androgens  and determines recruitment into chromatin. The AR acetylation site is a key target of NAD-dependent and TSA-dependent histone deacetylases  and long non coding RNA.

Non-genomic

More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other steroid hormone receptors such as estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA. Androgen receptors interact with certain signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in ion transport. Regulation of signal transduction pathways by cytoplasmic androgen receptors can indirectly lead to changes in gene transcription, for example, by leading to phosphorylation of other transcription factors.

Genetics

Gene

In humans, the androgen receptor is encoded by the AR gene located on the X chromosome at Xq11-12.

AR deficiencies

The androgen insensitivity syndrome, formerly known as testicular feminization, is caused by a mutation of the androgen receptor gene located on the X chromosome (locus:Xq11-Xq12). The androgen receptor seems to affect neuron physiology and is defective in Kennedy's disease. In addition, point mutations and trinucleotide repeat polymorphisms has been linked to a number of additional disorders.

CAG repeats

The AR gene contains CAG repeats which affect receptor function, where fewer repeats leads to increased receptor sensitivity to circulating androgens and more repeats leads to decreased receptor sensitivity. Studies have shown that racial variation in CAG repeats exists, with African-Americans having fewer repeats than non-Hispanic white Americans. The racial trends in CAG repeats parallels the incidence and mortality of prostate cancer in these groups.

Structure

Structural domains of the two isoforms (AR-A and AR-B) of the human androgen receptor. Numbers above the bars refer to the amino acid residues that separate the domains starting from the N-terminus (left) to C-terminus (right). NTD = N-terminal domain, DBD = DNA binding domain. LBD = ligand binding domain. AF = activation function.

Isoforms

Two isoforms of the androgen receptor (A and B) have been identified:

• AR-A - 87 kDa - N-terminus truncated (lacks the first 187 amino acids), which results from in vitro proteolysis.
• AR-B - 110 kDa - full length

Domains

Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functional domains labeled A through F:

• A/B) - N-terminal regulatory domain contains:
  • activation function 1 (AF-1) between residues 101 and 370 required for full ligand activated transcriptional activity
  • activation function 5 (AF-5) between residues 360-485 is responsible for the constitutive activity (activity without bound ligand)
  • dimerization surface involving residues 1-36 (containing the FXXLF motif where F = phenylalanine, L = leucine, and X = any amino acid residue) and 370-494, both of which interact with the LBD in an intramolecular head-to-tail interaction
• C) - DNA binding domain (DBD)
• D) - Hinge region - flexible region that connects the DBD with the LBD; along with the DBD, contains a ligand dependent nuclear localization signal
• E) - Ligand binding domain (LBD) containing
  • activation function 2 (AF-2), responsible for agonist induced activity (activity in the presence of bound agonist)
  • AF-2 binds either the N-terminal FXXFL motif intramolecularly or coactivator proteins (containing the LXXLL or preferably FXXFL motifs)
  • A ligand dependent nuclear export signal
• F) - C-terminal domain

Splice variants

AR-V7 is an androgen receptor splice variant that can be detected in circulating tumor cells of metastatic prostate cancer patients. and is predictive of resistance to some drugs.

Ligands

Affinities of selected androgen receptor ligands

Compound	AR RBA (%)
Metribolone	100
Dihydrotestosterone	85
Cyproterone acetate	7.8
Bicalutamide	1.4
Nilutamide	0.9
Hydroxyflutamide	0.57
Flutamide	<0 .0057="" span="">
Notes: Human prostate tissue used for the assays. Sources: See template.

Agonists

• Endogenous androgens (e.g., testosterone, dihydrotestosterone, androstenedione, androstenediol, dehydroepiandrosterone)
• Synthetic androgens (e.g., methyltestosterone, metandienone, nandrolone, trenbolone, oxandrolone, stanozolol)

Mixed

• Selective androgen receptor modulators (e.g., andarine, enobosarm)

Antagonists

• Steroidal antiandrogens (e.g., cyproterone acetate, chlormadinone acetate, spironolactone, oxendolone)
• Nonsteroidal antiandrogens (e.g., flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide)
• N-Terminal domain antiandrogens (e.g., bisphenol A, EPI-001, ralaniten, JN compounds)

As a drug target

The AR is an important therapeutic target in prostate cancer. Thus many different antiandrogens have been developed, primarily targeting the ligand binding domain of the protein. AR ligands can either be classified based on their structure (steroidal or nonsteroidal) or based on their ability to activate or inhibit transcription (agonists or antagonists). Inhibitors that target alternative functional domains (N-terminal domain, DNA binding domain) of the protein are still under development.

Dihydrotestosterone

From Wikipedia, the free encyclopedia

Dihydrotestosterone

Names
IUPAC name (5S,8R,9S,10S,13S,14S,17S)-17-Hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one
Other names DHT; 5α-Dihydrotestosterone; 5α-DHT; Androstanolone; Stanolone; 5α-Androstan-17β-ol-3-one
Identifiers
CAS Number	521-18-6
3D model (JSmol)	Interactive image
ChEBI	CHEBI:16330
ChEMBL	ChEMBL27769
ChemSpider	10189
DrugBank	DB02901
ECHA InfoCard	100.007.554
KEGG	C03917
PubChem CID	10635
UNII	08J2K08A3Y
CompTox Dashboard (EPA)	DTXSID9022364
InChI[show]
SMILES[show]
Properties
Chemical formula	C19H30O2
Molar mass	290.447 g·mol−1
Pharmacology
ATC code	A14AA01 (WHO)
Routes of administration	Transdermal (gel), in the cheek, under the tongue, intramuscular injection (as esters)
Pharmacokinetics:
Bioavailability	Oral: very low (due to extensive first pass metabolism)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

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 including the prostate gland, seminal vesicles, epididymides, skin, hair follicles, liver, and brain. This enzyme mediates reduction of the C4-5 double bond of testosterone. Relative to testosterone, DHT is considerably more potent as an agonist of the androgen receptor (AR).

In addition to its role as a natural hormone, DHT has been used as a medication, for instance in the treatment of low testosterone levels in men; for information on DHT as a medication, see the androstanolone article.

Biological function

DHT is biologically important for sexual differentiation of the male genitalia during embryogenesis, maturation of the penis and scrotum at puberty, growth of facial, body, and pubic hair, and development and maintenance of the prostate gland and seminal vesicles. It is produced from the less potent testosterone by the enzyme 5α-reductase in select tissues, and is the primary androgen in the genitals, prostate gland, seminal vesicles, skin, and hair follicles.

DHT signals mainly in an intracrine and paracrine manner in the tissues in which it is produced, playing only a minor role, if any, as a circulating endocrine hormone. Circulating levels of DHT are 1/10th and 1/20th those of testosterone in terms of total and free concentrations, respectively, whereas local DHT levels may be up to 10 times those of testosterone in tissues with high 5α-reductase expression such as the prostate gland. In addition, unlike testosterone, DHT is inactivated by 3α-hydroxysteroid dehydrogenase (3α-HSD) into the very weak androgen 3α-androstanediol in various tissues such as muscle, adipose, and liver among others, and in relation to this, DHT has been reported to be a very poor anabolic agent when administered exogenously as a medication.

Selective biological functions of testosterone versus DHT in male puberty

Testosterone	DHT
Spermatogenesis and fertility	Prostate enlargement and prostate cancer risk
Male musculoskeletal development	Facial, axillary, pubic, and body hair growth
Voice deepening	Scalp temporal recession and pattern hair loss
Increased sebum production and acne
Increased sex drive and erections

In addition to normal biological functions, DHT also plays an important causative role in a number of androgen-dependent conditions including hair conditions like hirsutism (excessive facial/body hair growth) and pattern hair loss (androgenic alopecia or pattern baldness) and prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer. 5α-Reductase inhibitors, which prevent DHT synthesis, are effective in the prevention and treatment of these conditions.

Metabolites of DHT have been found to act as neurosteroids with their own AR-independent biological activity. 3α-Androstanediol is a potent positive allosteric modulator of the GABA_A receptor, while 3β-androstanediol is a potent and selective agonist of the estrogen receptor (ER) subtype ERβ. These metabolites may play important roles in the central effects of DHT and by extension testosterone, including their antidepressant, anxiolytic, rewarding/hedonic, anti-stress, and pro-cognitive effects.

5α-Reductase deficiency

Much of the biological role of DHT has been elucidated in studies of individuals with congenital 5α-reductase type II deficiency, an intersex condition caused by a loss-of-function mutation in the gene encoding 5α-reductase type II, the major enzyme responsible for the production of DHT in the body. It is characterized by a defective and non-functional 5α-reductase type II enzyme and a partial but majority loss of DHT production in the body. In the condition, circulating testosterone levels are within or slightly above the normal male range, but DHT levels are low (around 30% of normal), and the ratio of circulating testosterone to DHT is greatly elevated (at about 3.5 to 5 times higher than normal).

Genetic males (46,XY) with 5α-reductase type II deficiency are born with undervirilization including pseudohermaphroditism (ambiguous genitalia), pseudovaginal perineoscrotal hypospadias, and usually undescended testes. Their external genitalia are female-like, with micropenis (a small, clitoris-like phallus), a partially unfused, labia-like scrotum, and a blind-ending, shallow vaginal pouch. Due to their lack of conspicuous male genitalia, genetic males with the condition are typically raised as girls. At the time of puberty however, they develop striking phenotypically masculine secondary sexual characteristics including partial virilization of the genitals (enlargement of the phallus into a near-functional penis and descent of the testes), voice deepening, typical male musculoskeletal development, and no menstruation, breast development, or other signs of feminization that occur during female puberty. In addition, normal libido and spontaneous erections develop, they usually show a sexual preference for females, and almost all develop a male gender identity.

Nonetheless, males with 5α-reductase type II deficiency exhibit signs of continued undervirilization in a number of domains. Facial hair was absent or sparse in a relatively large group of Dominican males with the condition, known as the Güevedoces. However, more facial hair has been observed in patients with the disorder from other parts of the world, although facial hair was still reduced relative to that of other men in the same communities. The divergent findings may reflect racial differences in androgen-dependent hair growth. A female pattern of androgenic hair growth, with terminal hair largely restricted to the axillae and lower pubic triangle, is observed in males with the condition. No temporal recession of the hairline or androgenic alopecia (pattern hair loss or baldness) has been observed in any of the cases of 5α-reductase type II deficiency that have been reported, whereas this is normally seen to some degree in almost all Caucasian males. Individuals with 5α-reductase type II deficiency were initially reported to have no incidence of acne, but subsequent research indicated normal sebum secretion and acne incidence.

In genetic males with 5α-reductase type II deficiency, the prostate gland is rudimentary or absent, and if present, remains small, underdeveloped, and unpalpable throughout life. In addition, neither BPH nor prostate cancer have been reported in these individuals. Genetic males with the condition generally show oligozoospermia due to undescended testes, but spermatogenesis is reported to be normal in those with testes that have descended, and there are case instances of men with the condition successfully fathering children.

Unlike males, genetic females with 5α-reductase type II deficiency are phenotypically normal. However, similarly to genetic males with the condition, they show reduced body hair growth, including an absence of hair on the arms and legs, slightly decreased axillary hair, and moderately decreased pubic hair. On the other hand, sebum production is normal. This is in accordance with the fact that sebum secretion appears to be entirely under the control of 5α-reductase type I.

5α-Reductase inhibitors

5α-Reductase inhibitors like finasteride and dutasteride inhibit 5α-reductase type II and/or other isoforms and are able to decrease circulating DHT levels by 65 to 98% depending on the 5α-reductase inhibitor in question. As such, similarly to the case of 5α-reductase type II deficiency, they provide useful insights in the elucidation of the biological functions of DHT. 5α-Reductase inhibitors were developed and are used primarily for the treatment of BPH. The drugs are able to significantly reduce the size of the prostate gland and to alleviate symptoms of the condition. Long-term treatment with 5α-reductase inhibitors is also able to significantly reduce the overall risk of prostate cancer, although a simultaneous small increase in the risk of certain high-grade tumors has been observed. In addition to prostate diseases, 5α-reductase inhibitors have subsequently been developed and introduced for the treatment of pattern hair loss in men. They are able to prevent further progression of hair loss in most men with the condition and to produce some recovery of hair in about two-thirds of men. 5α-Reductase inhibitors seem to be less effective for pattern hair loss in women on the other hand, although they do still show some effectiveness. Aside from pattern hair loss, the drugs are also useful in the treatment of hirsutism and can greatly reduce facial and body hair growth in women with the condition.

5α-Reductase inhibitors are overall well-tolerated and show a low incidence of adverse effects. Sexual dysfunction, including erectile dysfunction, loss of libido, and reduced ejaculate volume, may occur in 3.4 to 15.8% of men treated with finasteride or dutasteride. A small increase in the risk of affective symptoms including depression, anxiety, and self-harm may be seen. Both the sexual dysfunction and affective symptoms may be due partially or fully to prevention of the synthesis of neurosteroids like allopregnanolone rather necessarily than due to inhibition of DHT production. A very small risk of gynecomastia has been associated with 5α-reductase inhibitors (1.2 to 3.5%). Based on reports of 5α-reductase type II deficiency in males and the effectiveness of 5α-reductase inhibitors for hirsutism in women, reduced body and/or facial hair growth is a likely potential side effect of these drugs in men. There are very few studies evaluating the side effects of 5α-reductase inhibitors in women. However, due to the known role of DHT in male sexual differentiation, 5α-reductase inhibitors may cause birth defects such as ambiguous genitalia in the male fetuses of pregnant women. As such, they are not used in women during pregnancy.

MK-386 is a selective 5α-reductase type I inhibitor which was never marketed. Whereas 5α-reductase type II inhibitors achieve much higher reductions in circulating DHT production, MK-386 decreases circulating DHT levels by 20 to 30%. Conversely, it was found to decrease sebum DHT levels by 55% in men versus a modest reduction of only 15% for finasteride. However, MK-386 failed to show significant effectiveness in a subsequent clinical study for the treatment of acne.

Biological activity

DHT is a potent agonist of the AR, and is in fact the most potent known endogenous ligand of the receptor. It has an affinity (K_d) of 0.25 to 0.5 nM for the human AR, which is about 2- to 3-fold higher than that of testosterone (K_d = 0.4 to 1.0 nM) and 15–30 times higher than that of adrenal androgens. In addition, the dissociation rate of DHT from the AR is 5-fold slower than that of testosterone. The EC₅₀ of DHT for activation of the AR is 0.13 nM, which is about 5-fold stronger than that of testosterone (EC₅₀ = 0.66 nM). In bioassays, DHT has been found to be 2.5- to 10-fold more potent than testosterone.

The elimination half-life of DHT in the body (53 minutes) is longer than that of testosterone (34 minutes), and this may account for some of the difference in their potency. A study of transdermal DHT and testosterone treatment reported terminal half-lives of 2.83 hours and 1.29 hours, respectively.

Unlike other androgens such as testosterone, DHT cannot be converted by the enzyme aromatase into an estrogen like estradiol. Therefore, it is frequently used in research settings to distinguish between the effects of testosterone caused by binding to the AR and those caused by testosterone's conversion to estradiol and subsequent binding to and activation of ERs. Although DHT cannot be aromatized, it is still transformed into metabolites with significant ER affinity and activity. These are 3α-androstanediol and 3β-androstanediol, which are predominant agonists of the ERβ.

Biochemistry

Comprehensive overview of steroidogenesis, showing DHT around the bottom middle among the androgens.

Biosynthesis

DHT is synthesized irreversibly from testosterone by the enzyme 5α-reductase. This occurs in various tissues including the genitals (penis, scrotum, clitoris, labia majora), prostate gland, skin, hair follicles, liver, and brain. Around 5 to 7% of testosterone undergoes 5α-reduction into DHT, and approximately 200 to 300 μg of DHT is synthesized in the body per day. Most DHT is produced in peripheral tissues like the skin and liver, whereas most circulating DHT originates specifically from the liver. The testes and prostate gland contribute relatively little to concentrations of DHT in circulation.

There are two major isoforms of 5α-reductase, SRD5A1 (type I) and SRD5A2 (type II), with the latter being the most biologically important isoenzyme. There is also third 5α-reductase: SRD5A3. SRD5A2 is most highly expressed in the genitals, prostate gland, epididymides, seminal vesicles, genital skin, facial and chest hair follicles, and liver, while lower expression is observed in certain brain areas, non-genital skin/hair follicles, testes, and kidneys. SRD5A1 is most highly expressed in non-genital skin/hair follicles, the liver, and certain brain areas, while lower levels are present in the prostate, epididymides, seminal vesicles, genital skin, testes, adrenal glands, and kidneys. In the skin, 5α-reductase is expressed in sebaceous glands, sweat glands, epidermal cells, and hair follicles. Both isoenzymes are expressed in scalp hair follicles, although SRD5A2 predominates in these cells. The SRD5A2 subtype is the almost exclusive isoform expressed in the prostate gland.

Distribution

The plasma protein binding of DHT is more than 99%. In men, approximately 0.88% of DHT is unbound and hence free, while in premenopausal women, about 0.47–0.48% is unbound. In men, DHT is bound 49.7% to sex hormone-binding globulin (SHBG), 39.2% to albumin, and 0.22% to corticosteroid-binding globulin (CBG), while in premenopausal women, DHT is bound 78.1–78.4% to SHBG, 21.0–21.3% to albumin, and 0.12% to CBG. In late pregnancy, only 0.07% of DHT is unbound in women; 97.8% is bound to SHBG while 2.15% is bound to albumin and 0.04% is bound to CBG. DHT has higher affinity for SHBG than does testosterone, estradiol, or any other steroid hormone.

Metabolism

DHT is inactivated in the liver and extrahepatic tissues like the skin into 3α-androstanediol and 3β-androstanediol by the enzymes 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase, respectively. These metabolites are in turn converted, respectively, into androsterone and epiandrosterone, then conjugated (via glucuronidation and/or sulfation), released into circulation, and excreted in urine.

Unlike testosterone, DHT cannot be aromatized into an estrogen like estradiol, and for this reason, has no propensity for estrogenic effects.

Excretion

DHT is excreted in the urine as metabolites, such as conjugates of 3α-androstanediol and androsterone.

Levels

Serum DHT levels are about 10% of those of testosterone, but levels in the prostate gland are 5- to 10-fold higher than those of testosterone due to a more than 90% conversion of testosterone into DHT by locally expressed 5α-reductase. For this reason, and in addition to the fact that DHT is much more potent as an AR agonist than is testosterone,^[45] DHT is considered to be the major androgen of the prostate gland.

Medical use

DHT is available in pharmaceutical formulations for medical use as an androgen or anabolic–androgenic steroid (AAS). It is used mainly in the treatment of male hypogonadism. When used as a medication, dihydrotestosterone is referred to as androstanolone (INN) or as stanolone (BAN), and is sold under brand names such as Andractim among others. The availability of pharmaceutical DHT is limited; it is not available in the United States or Canada, but is available in certain European countries. The available formulations of DHT include buccal or sublingual tablets, topical gels, and, as esters in oil, injectables like androstanolone propionate and androstanolone valerate.

Chemistry

DHT, also known as 5α-androstan-17β-ol-3-one, is a naturally occurring androstane steroid with a ketone group at the C3 position and a hydroxyl group at the C17β position. It is the derivative of testosterone in which the double bond between the C4 and C5 positions has been reduced or hydrogenated.

History

DHT was first synthesized by Adolf Butenandt and his colleagues in 1935. It was prepared via hydrogenation of testosterone, which had been discovered earlier that year. DHT was introduced for medical use as an AAS in 1953, and was noted to be more potent than testosterone but with reduced androgenicity. It was not elucidated to be an endogenous substance until 1956, when it was shown to be formed from testosterone in rat liver homogenates. In addition, the biological importance of DHT was not realized until the early 1960s, when it was found to be produced by 5α-reductase from circulating testosterone in target tissues like the prostate gland and seminal vesicles and was found to be more potent than testosterone in bioassays. The biological functions of DHT in humans became much more clearly defined upon the discovery and characterization of 5α-reductase type II deficiency in 1974. DHT was the last major sex hormone, the others being testosterone, estradiol, and progesterone, to be discovered, and is unique in that it is the only major sex hormone that functions principally as an intracrine and paracrine hormone rather than as an endocrine hormone.