Dihydrotestosterone

Source: Wikipedia, the free encyclopedia.
This article is about dihydrotestosterone as a hormone. For its use as a medication, see Androstanolone.
This article is about 5α-dihydrotestosterone, an androgen. For the inactive 5β isomer, see 5β-Dihydrotestosterone.

Dihydrotestosterone
The chemical structure of dihydrotestosterone.
A ball-and-stick model of dihydrotestosterone.
Names
IUPAC name
17β-Hydroxy-5α-androstan-3-one
Systematic IUPAC name
(1S,3aS,3bR,5aS,9aS,9bS,11aS)-1-Hydroxy-9a,11a-dimethylhexadecahydro-7H-cyclopenta[a]phenanthren-7-one
Other names
DHT; 5α-Dihydrotestosterone; 5α-DHT; Androstanolone; Stanolone; 5α-Androstan-17β-ol-3-one
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.007.554 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C19H30O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h12,14-17,21H,3-11H2,1-2H3/t12-,14-,15-,16-,17-,18-,19-/m0/s1 checkY
    Key: NVKAWKQGWWIWPM-ABEVXSGRSA-N checkY
  • O=C4C[C@@H]3CC[C@@H]2[C@H](CC[C@]1(C)[C@@H](O)CC[C@H]12)[C@@]3(C)CC4
Properties
C19H30O2
Molar mass 290.447 g·mol−1
Pharmacology
A14AA01 (WHO)
Transdermal (gel), in the cheek, under the tongue, intramuscular injection (as esters)
Pharmacokinetics:
Oral: very low (due to extensive first pass metabolism)[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an

sebum and body hair
composition.

The

17α-hydroxyprogesterone via the androgen backdoor pathway in the absence 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

5α-reductase in select tissues, and is the primary androgen in the genitals, prostate gland, seminal vesicles, skin, and hair follicles.[2]

DHT signals act mainly in an

anabolic agent when administered exogenously as a medication.[10]

Selective biological functions of testosterone versus DHT in male puberty[11][12]
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

prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer.[2] 5α-Reductase inhibitors, which prevent DHT synthesis, are effective in the prevention and treatment of these conditions.[13][14][15][16] Androgen deprivation is a therapeutic approach to prostate cancer that can be implemented by castration to eliminate gonadal testosterone as a precursor to DHT, but metastatic tumors may then develop into castration-resistant prostate cancer (CRPC). Although castration results in 90-95% decrease of serum testosterone, DHT in the prostate is only decreased by 50%, supporting the notion that the prostate expresses necessary enzymes (including 5α-reductase) to produce DHT without testicular testosterone,[17] that outline the importance of 5α-reductase inhibitors.[14]

DHT may play a function in skeletal muscle amino acid transporter recruitment and function.[18]

anti-stress, and pro-cognitive effects.[19][20]

5α-Reductase 2 deficiency

See also: 5α-Reductase 2 deficiency

Much of the biological role of DHT has been elucidated in studies of individuals with

better source needed] and the ratio of circulating testosterone to DHT is greatly elevated (at about 3.5 to 5 times higher than normal).[13]

Genetic males (46,XY) with 5α-reductase type 2 deficiency are born with

spontaneous erections develop,[23] they usually show a sexual preference for females, and almost all develop a male gender identity.[13][24]

Nonetheless, males with 5α-reductase type 2 deficiency exhibit signs of continued undervirilization in a number of domains.

sebum secretion and acne incidence.[12]

In genetic males with 5α-reductase type 2 deficiency, the

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.[23][25]

Unlike males, genetic females with 5α-reductase type 2 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.

sebum production is normal.[26][27] This is in accordance with the fact that sebum secretion appears to be entirely under the control of 5α-reductase type 1.[27]

5α-Reductase inhibitors

See also: 5α-Reductase inhibitor, Finasteride, Dutasteride, and MK-386

5α-Reductase inhibitors like finasteride and dutasteride inhibit 5α-reductase type 2 and/or other isoforms and are able to decrease circulating DHT levels by 65 to 98% depending on the 5α-reductase inhibitor in question.[28][29][30][22] As such, similarly to the case of 5α-reductase type 2 deficiency, they provide useful insights in the elucidation of the biological functions of DHT.[31] 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.[14][32] 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.[15] In addition to prostate diseases, 5α-reductase inhibitors have subsequently been developed and introduced for the treatment of pattern hair loss in men.[33] 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.[13] 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.[34] 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.[35][16]

5α-Reductase inhibitors are overall

affective symptoms including depression, anxiety, and self-harm may be seen.[38][39][40] 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.[38] A small risk of gynecomastia has been associated with 5α-reductase inhibitors (1.2–3.5%).[36][41] Based on reports of 5α-reductase type 2 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.[13][16] There are far fewer 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.[36]

MK-386 is a selective 5α-reductase type 1 inhibitor which was never marketed.[42] Whereas 5α-reductase type 2 inhibitors achieve much higher reductions in circulating DHT production, MK-386 decreases circulating DHT levels by 20 to 30%.[43] Conversely, it was found to decrease sebum DHT levels by 55% in men versus a modest reduction of only 15% for finasteride.[44][45] However, MK-386 failed to show significant effectiveness in a subsequent clinical study for the treatment of acne.[46]

Biological activity

DHT is a

adrenal androgens.[48] In addition, the dissociation rate of DHT from the AR is 5-fold slower than that of testosterone.[49] 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).[50] In bioassays, DHT has been found to be 2.5- to 10-fold more potent than testosterone.[47]

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.[51] A study of transdermal (patches) DHT and testosterone treatment reported terminal half-lives of 2.83 hours and 1.29 hours, respectively.[52]

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.[53] 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.[19]

Biochemistry

steroidogenesis, showing DHT around the bottom middle among the androgens[54]

Biosynthesis

DHT is synthesized

prostate gland, skin, hair follicles, liver, and brain.[8] Around 5 to 7% of testosterone undergoes 5α-reduction into DHT,[56][57] 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.[8]

There are two major

scalp hair follicles,[60] although SRD5A2 predominates in these cells.[59] The SRD5A2 subtype is the almost exclusive isoform expressed in the prostate gland.[61][22]

Backdoor pathway

The androgen backdoor pathway (red arrows) roundabout testosterone embedded in within conventional androgen synthesis that lead to 5α-dihydrotestosterone through testosterone.[17][62][63]
Main article: Androgen backdoor pathway

DHT under certain normal and pathological conditions can additionally be produced via a route that does not involve testosterone as an intermediate but instead goes through other intermediates.[17] This route is called the "backdoor pathway".[64]

The pathway can start from

17α-hydroxyprogesterone or from progesterone
and can be outlined as follows (depending on the initial substrate):

This pathway is not always considered in the clinical evaluation of patients with

21α-hydroxylase deficiency. Ignoring this pathway in such instances may lead to diagnostic pitfalls and confusion,[66] when the conventional androgen biosynthetic pathway cannot fully explain the observed consequences.[64]

As with the conventional pathway of DHT synthesis, the backdoor pathway similarly requires

5α-reductase.[63] Whereas 5α-reduction is the last transformation in the classical androgen pathway, it is the first step in the backdoor pathway.[17]

Distribution

The

affinity for SHBG than does testosterone, estradiol, or any other steroid hormone.[69][68]

Plasma protein binding of testosterone and dihydrotestosterone
Compound Group Level (nM) Free (%) SHBGTooltip Sex hormone-binding globulin (%)
CBG
Tooltip Corticosteroid-binding globulin (%)		 Albumin (%)
Testosterone Adult men 23.0 2.23 44.3 3.56 49.9
Adult women
  Follicular phase 1.3 1.36 66.0 2.26 30.4
  Luteal phase 1.3 1.37 65.7 2.20 30.7
  Pregnancy 4.7 0.23 95.4 0.82 3.6
Dihydrotestosterone Adult men 1.70 0.88 49.7 0.22 39.2
Adult women
  Follicular phase 0.65 0.47 78.4 0.12 21.0
  Luteal phase 0.65 0.48 78.1 0.12 21.3
  Pregnancy 0.93 0.07 97.8 0.04 21.2
Sources: See template.

Metabolism

See also: Testosterone § Metabolism
Testosterone structures
The image above contains clickable links
This diagram illustrates the
hydroxyl (–OH) groups
.

DHT is inactivated in the liver and extrahepatic tissues like the skin into

conjugated (via glucuronidation and/or sulfation), released into circulation, and excreted in urine.[8]

Unlike testosterone, DHT cannot be

aromatized into an estrogen like estradiol, and for this reason, has no propensity for estrogenic effects.[71]

Excretion

DHT is

3α-androstanediol and androsterone.[72][8]

Levels

Ranges for circulating total DHT levels tested with

LabCorp are as follows:[73]

  • Men: 30–85 ng/dL
  • Women: 4–22 ng/dL
  • Prepubertal children: <3 ng/dL
  • Pubertal boys: 3–65 ng/dL (mean at
    Tanner stage 5
    : 43 ng/dL)
  • Pubertal girls: 3–19 ng/dL (mean at Tanner stage 5: 9 ng/dL)

Ranges for circulating free DHT levels tested with HPLC–MS/MS and

equilibrium dialysis and reported by LabCorp are as follows:[73]

  • <18 years of age: not established
  • Adult males: 2.30–11.60 pg/mL (0.54–2.58% free)
  • Adult females: 0.09–1.02 pg/mL (<1.27% free)

Other studies and labs assessing circulating total DHT levels with

mid-cycle).[5] With immunoassay-based techniques, testosterone levels in premenopausal women have been found to be about 40 ng/dL (1.4 nmol/L) and DHT levels about 10 ng/dL (0.34 nmol/L).[5][74] With radioimmunoassays, the ranges for testosterone and DHT levels in women have been found to be 20 to 70 ng/dL and 5 to 30 ng/dL, respectively.[74]

Levels of total testosterone, free testosterone, and free DHT, but not total DHT, all measured with

LC–MS/MS, are higher in women with polycystic ovary syndrome (PCOS) than in women without this condition.[5][75]

Circulating DHT levels in eugonadal men are about 7- to 10-fold lower than those of testosterone, and plasma levels of testosterone and DHT are highly correlated (

5α-reductase.[7] Because of this, and because DHT is much more potent as an androgen receptor agonist than testosterone,[47] DHT is the major androgen in the prostate gland.[7]

Medical use

Main article: Androstanolone

DHT is available in

injectables like androstanolone propionate and androstanolone valerate.[76][77][80]

Performance enhancement

DHT has been used as a

performance enhancing drug, specifically as an alternative to testosterone, as it was once known to be capable of falsifying drug tests.[83]

Chemistry

DHT, also known as 5α-androstan-17β-ol-3-one, is a

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.[84][85] It was prepared via hydrogenation of testosterone,[85] which had been discovered earlier that year.[86] DHT was introduced for medical use as an AAS in 1953, and was noted to be more potent than testosterone but with reduced androgenicity.[87][88][89] It was not elucidated to be an endogenous substance until 1956, when it was shown to be formed from testosterone in rat liver homogenates.[85][90] 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.[91][92][93][94] The biological functions of DHT in humans became much more clearly defined upon the discovery and characterization of 5α-reductase type 2 deficiency in 1974.[14] 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.[95]

DHT was[when?] one of the original "underground" methods used to falsify drug testing in sport, as DHT does not alter the ratio of testosterone to epistestosterone in an athlete's urinary steroid profile, a measurement that was once the basis of drug tests used to detect steroid use. However, DHT use can still be detected by other means which are now universal in athletic drug tests, such as metabolite analysis.[96]

In 2004, Richard Auchus, in a review published in

5α-androstane-3α,17β-diol to DHT. This newly discovered pathway explained how DHT is produced under certain normal and pathological conditions in humans when the classical androgen pathway (via testosterone) cannot fully explain the observed consequences.[64] This review was based on earlier works (published in 2000–2004) by Shaw et al., Wilson et al., and Mahendroo et al., who studied DHT biosynthesis in tammar wallaby pouch young and mice.[17]

In 2011, Chang et al.

5α-androstane-3,17-dione → DHT. While this pathway was described as the "5α-dione pathway" in a 2012 review,[98] the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.[99][17]

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