Dihydrotestosterone

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Dihydrotestosterone
Androstanolone.svg
Dihydrotestosterone-3D-balls.png
Systematic (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
Clinical data
Pregnancy
category
  • X
Routes of
administration		 Intramuscular, transdermal
Pharmacokinetic data
Bioavailability Oral: 0–2%[citation needed]
Metabolism Hepatic
Excretion Renal
Identifiers
CAS Number 521-18-6 YesY
ATC code A14AA01 (WHO)
PubChem CID 10635
IUPHAR/BPS 2856
DrugBank DB02901 YesY
ChemSpider 10189 YesY
UNII 08J2K08A3Y YesY
ChEBI CHEBI:16330 YesY
ChEMBL CHEMBL27769 N
Chemical data
Formula C19H30O2
Molar mass 290.442 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)
This article is about the 5α-reduced potent androgen metabolite of testosterone. For the inactive 5β-reduced metabolite of testosterone, see 5β-Dihydrotestosterone.

Dihydrotestosterone (DHT), or 5α-dihydrotestosterone (5α-DHT), also known as 5α-androstan-17β-ol-3-one, 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).

DHT is also known as androstanolone (INN) and stanolone (BAN), and is used medically under brand names including Anabolex, Anaprotin, Andractim, Androlone, Gelovit, Neoprol, Pesomax, and Stanaprol as an anabolic-androgenic steroid (AAS).[1][2] Unlike testosterone and various other AAS, DHT cannot be aromatized, and for this reason, has no risk of estrogenic side effects such as gynecomastia.[3]

Biological activity[edit]

DHT has an affinity (Kd) of 0.25 to 0.5 nM for the human AR, which is about 2- to 3-fold higher than that of testosterone (Kd = 0.4 to 1.0 nM)[4] and 15–30 times higher than that of adrenal androgens.[5] The dissociation rate of DHT from the AR is 5-fold slower than that of testosterone.[6] The EC50 of DHT for activation of the AR is 0.13 nM, which is about 5-fold higher than that of testosterone (EC50 = 0.66 nM).[7] In bioassays, DHT has been found to be 2.5- to 10-fold more potent than testosterone.[4]

The terminal 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.[8] A study of transdermal DHT and testosterone treatment reported terminal half-lives of 2.83 hours and 1.29 hours, respectively.[9]

Biological function[edit]

Sexual development[edit]

During embryogenesis DHT has an essential role in the formation of the male external genitalia, while in the adult DHT acts as the primary androgen in the prostate and in hair follicles.[10]

An example illustrating the significance of DHT for the development of secondary sex characteristics is congenital 5α-reductase deficiency. This genetic mutation can result in pseudohermaphroditism.[11] This condition typically presents with underdeveloped male genitalia and prostate. These individuals are often raised as girls due to their lack of conspicuous male genitalia.[11] In the onset of puberty, although their DHT levels remain very low, their testosterone levels elevate normally. Their musculature develops like that of other male adults. After puberty, men with this condition have a large deficiency of pubic and body hair, and no incidence of androgenic alopecia (pattern hair loss).[12] They also have no incidence of prostate cancer.[13]

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 estrogen receptors.[14]

Pathology[edit]

DHT produced locally at the site of hair follicles by 5α-reductase, and not systemic DHT, is the primary causal factor in male androgenic alopecia, although the pathology regarding this phenomenon is poorly understood.[15][16] In the case of female androgenic alopecia, on the other hand, the situation is more complex, and DHT is only one of several possible causes.[17] Women with increased levels of DHT may develop symptoms of hyperandrogenism such as certain androgynous masculine secondary sex characteristics, including a deepened voice and facial hair. In men, prostate growth and differentiation are highly dependent on androgens, especially DHT, and DHT is involved in the pathogenesis of benign prostatic hyperplasia (BPH) and prostate cancer.[18]

Medical treatment[edit]

See also: Management of baldness

5α-Reductase inhibitors like finasteride and dutasteride, which inactivate the 5α-reductase enzyme and block the formation of DHT, are commonly used for the treatment of two DHT-related conditions, androgenic alopecia and BPH. Both finasteride and dutasteride are approved for the treatment of BPH and androgenic alopecia. Dutasteride is three times more potent than finasteride in inhibiting the type II enzyme and 100 times more potent than finasteride in inhibiting the type I form of the DHT-producing enzyme. Both finasteride and dutasteride are potent inhibitors of the third isotype of the enzyme.[19]

Acne, hirsutism, and seborrhea are also DHT-related conditions, and 5α-reductase inhibitors may be used to treat these conditions as well.[20] In addition, antiandrogens like cyproterone acetate, spironolactone, and bicalutamide as well as estrogens like ethinyl estradiol (which are functional antiandrogens) may also be used to treat these conditions.[20][21]

Biochemistry[edit]

Biosynthesis[edit]

DHT is synthesized from testosterone by the enzyme 5α-reductase.[22] In males, approximately 5% of testosterone undergoes 5α-reduction into DHT.[citation needed]

Metabolism[edit]

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.[23] 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, and for this reason, has no propensity for estrogenic effects.[24]

Levels[edit]

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.[25] For this reason, in addition to the fact that DHT is much more potent as an AR agonist than is testosterone,[4] DHT is considered to be the major androgen of the prostate gland.[25]

Chemistry[edit]

Chemical structure of testosterone. Compared with DHT, there is a double bond in the A ring between the C4 and C5 positions.

DHT is a 5α-androstane (C19) 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.

Derivatives[edit]

See also: Androgen ester § List of dihydrotestosterone esters, and List of androgens/anabolic steroids

Several C17β ester prodrugs of DHT, including androstanolone benzoate, androstanolone enanthate, androstanolone propionate, and androstanolone valerate, have been developed and introduced for medical use as AAS.[1][26]

Synthetic derivatives of DHT used as AAS include mesterolone (1α-methyl-DHT), drostanolone (2α-methyl-DHT), metenolone (1β-methyl-δ1-DHT), stenbolone (2-methyl-δ1-DHT), epitiostanol (2α,3α-epithio-3-deketo-DHT), mepitiostane (a 17-ether prodrug of epitiostanol), 1-testosterone (dihydroboldenone; Δ1-DHT), mesabolone (a 17-ether prodrug of Δ1-DHT), prostanozol (a 17-ether prodrug of the non-17α-methylated analogue of stanozolol), and bolazine (an azine dimer prodrug of a drostanolone-like AAS), as well as the 17α-alkylated derivatives mestanolone (17α-methyl-DHT), methasterone (2α,17α-dimethyl-DHT), oxandrolone (2-oxa-17α-methyl-DHT), oxymetholone (2-hydroxymethylene-17α-methyl-DHT), stanozolol (a 2,3-pyrazole A ring-fused derivative of 17α-methyl-DHT), furazabol (a 2,3-furan A ring-fused derivative of 17α-methyl-DHT), androisoxazole (a 2,3-isoxazole A ring-fused derivative of 17α-methyl-DHT), methylstenbolone (2,17α-dimethyl-δ1-DHT), methyl-1-testosterone (methyldihydroboldenone; 17α-methyl-δ1-DHT), methylepitiostanol (2α,3α-epithio-3-deketo-17α-methyl-DHT), desoxymethyltestosterone (3-deketo-17α-methyl-δ2-DHT), and mebolazine (an azine dimer prodrug of a methasterone-like AAS).[27]

References[edit]

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  15. ^ Nordqvist C (2012-02-23). "What Is DHT (Dihydrotestosterone)? What Is DHT's Role In Baldness?". Medical News Today. 
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