Dihydrotestosterone (DHT,5α-dihydrotestosterone,5α-DHT,androstanolone orstanolone) is anendogenousandrogensex steroid andhormone primarily involved in the growth and repair of theprostate and thepenis, as well as the production ofsebum andbody hair composition.
DHT signals act mainly in anintracrine andparacrine manner in the tissues in which it is produced, playing only a minor role, if any, as a circulatingendocrine hormone.[3][4][5] Circulating levels of DHT are one-tenth and one-twentieth those of testosterone in terms of total and free concentrations, respectively,[6] 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.[7] In addition, unlike testosterone, DHT is inactivated by3α-hydroxysteroid dehydrogenase (3α-HSD) into the very weak androgen3α-androstanediol in varioustissues such asmuscle,adipose, andliver among others,[5][8][9] and in relation to this, DHT has been reported to be a very pooranabolic 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 ofandrogen-dependent conditions including hair conditions likehirsutism (excessive facial/body hair growth) andpattern hair loss (androgenic alopecia or pattern baldness) andprostate diseases such asbenign prostatic hyperplasia (BPH) andprostate 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]
Much of the biological role of DHT has been elucidated in studies of individuals withcongenital5α-reductase type 2 deficiency, anintersex condition caused by aloss-of-function mutation in thegene encoding5α-reductase type 2, the major enzyme responsible for the production of DHT in the body.[13][21][2] It is characterized by a defective and non-functional 5α-reductase type 2 enzyme and a partial but majority loss of DHT production in the body.[13][21] In the condition, circulating testosterone levels are within or slightly above the normal male range, but DHT levels are low (around 30% of normal),[22][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]
Nonetheless, males with 5α-reductase type 2 deficiency exhibit signs of continued undervirilization in a number of domains.Facial hair was absent or sparse in a relatively large group ofDominican males with the condition, known as theGüevedoces. 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 ofandrogenic hairgrowth, withterminal hair largely restricted to theaxillae and lowerpubic triangle, is observed in males with the condition. No temporal recession of the hairline orandrogenic alopecia (pattern hair loss or baldness) has been observed in any of the cases of 5α-reductase type 2 deficiency that have been reported, whereas this is normally seen to some degree in almost all Caucasian males in their teenage years.[13] Individuals with 5α-reductase type 2 deficiency were initially reported to have no incidence ofacne,[8][2] but subsequent research indicated normalsebumsecretion and acne incidence.[12]
In genetic males with 5α-reductase type 2 deficiency, theprostate gland is rudimentary or absent, and if present, remains small, underdeveloped, and unpalpable throughout life.[8][4] In addition, neither BPH nor prostate cancer have been reported in these individuals.[14] Genetic males with the condition generally showoligozoospermia due to undescended testes, butspermatogenesis 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][26]
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.[27][23] On the other hand,sebum production is normal.[27][28] This is in accordance with the fact that sebum secretion appears to be entirely under the control of 5α-reductase type 1.[28]
5α-Reductase inhibitors likefinasteride anddutasteride 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.[29][30][31][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.[32] 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][33] 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 ofpattern hair loss in men.[34] 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.[35] 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.[36][16]
5α-Reductase inhibitors are overallwell tolerated and show a low incidence ofadverse effects.[37]Sexual dysfunction, includingerectile dysfunction,loss of libido, andreduced ejaculate volume, may occur in 3.4 to 15.8% of men treated with finasteride or dutasteride.[37][38] A small increase in the risk ofaffective symptoms includingdepression,anxiety, andself-harm may be seen.[39][40][41] However risk within the affected group can vary very strongly with some patients vividly reporting very strong persistent effects. Both the sexual dysfunction and affective symptoms may be due partially or fully to prevention of the synthesis ofneurosteroids likeallopregnanolone rather necessarily than due to inhibition of DHT production.[39] A small risk ofgynecomastia has been associated with 5α-reductase inhibitors (1.2–3.5%).[37][42] 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 causebirth defects such as ambiguous genitalia in the malefetuses ofpregnant women. As such, they are not used in women during pregnancy.[37]
MK-386 is a selective 5α-reductase type 1 inhibitor which was never marketed.[43] Whereas 5α-reductase type 2 inhibitors achieve much higher reductions in circulating DHT production, MK-386 decreases circulating DHT levels by 20 to 30%.[44] Conversely, it was found to decrease sebum DHT levels by 55% in men versus a modest reduction of only 15% for finasteride.[45][46] However, MK-386 failed to show significant effectiveness in a subsequent clinical study for the treatment of acne.[47]
DHT is apotentagonist of theandrogen receptor (AR), and is the AR's most potent knownendogenousligand. It has anaffinity (Kd) of 0.25 to 0.5 nM for the human AR, which is about 2- to 3-fold higher than that oftestosterone (Kd = 0.4 to 1.0 nM)[48] and 15–30 times higher than that ofadrenal androgens.[49] In addition, thedissociation rate of DHT from the AR is 5-fold slower than that of testosterone.[50] TheEC50 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).[51] Inbioassays, DHT has been found to be 2.5- to 10-fold more potent than testosterone.[48]
Theelimination 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.[52] A study of transdermal (patches) DHT and testosterone treatment reported terminal half-lives of 2.83 hours and 1.29 hours, respectively.[53]
Unlike other androgens such as testosterone, DHT cannot be converted by the enzymearomatase into anestrogen likeestradiol. 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.[54] 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]
DHT is synthesizedirreversibly fromtestosterone by the enzyme5α-reductase.[8][13] This occurs in varioustissues including thegenitals (penis,scrotum,clitoris,labia majora),[56]prostate gland,skin,hair follicles,liver, andbrain.[8] Around 5 to 7% of testosterone undergoes 5α-reduction into DHT,[57][58] 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 mostcirculating DHT originates specifically from the liver. The testes and prostate gland contribute relatively little to concentrations of DHT in circulation.[8]
There are two majorisoforms of 5α-reductase,SRD5A1 (type 1) andSRD5A2 (type 2), with the latter being the most biologically important isoenzyme.[8] There is also third 5α-reductase:SRD5A3.[47] SRD5A2 is most highly expressed in the genitals,prostate gland,epididymides,seminal vesicles,genital skin,facial andchest hair follicles,[59][60] andliver, while lower expression is observed in certainbrain areas, non-genital skin/hair follicles,testes, andkidneys. 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.[8] In the skin, 5α-reductase is expressed insebaceous glands,sweat glands,epidermal cells, and hair follicles.[59][60] Both isoenzymes are expressed inscalp hair follicles,[61] although SRD5A2 predominates in these cells.[60] The SRD5A2 subtype is the almost exclusive isoform expressed in the prostate gland.[62][22]
The androgen backdoor pathway (red arrows) roundabout testosterone embedded in within conventional androgen synthesis that lead to 5α-dihydrotestosterone through testosterone[17][63][64]
DHT under certain normal and pathological conditions can additionally be produced via a route that does not involve testosterone as anintermediate but instead goes through other intermediates.[17] This route is called the "backdoor pathway".[65]
This pathway is not always considered in the clinical evaluation of patients withhyperandrogenism, for instance due to raredisorders of sex development like21α-hydroxylase deficiency. Ignoring this pathway in such instances may lead to diagnostic pitfalls and confusion,[67] when the conventional androgen biosynthetic pathway cannot fully explain the observed consequences.[65]
As with the conventional pathway of DHT synthesis, the backdoor pathway similarly requires5α-reductase.[64] Whereas 5α-reduction is the last transformation in the classical androgen pathway, it is the first step in the backdoor pathway.[17]
Theplasma 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% tosex hormone-binding globulin (SHBG), 39.2% toalbumin, and 0.22% tocorticosteroid-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.[68][69] DHT has higheraffinity for SHBG than does testosterone, estradiol, or any other steroid hormone.[70][69]
Pubertal girls: 3–19ng/dL (mean at Tanner stage 5: 9ng/dL)
Ranges for circulating free DHT levels tested with HPLC–MS/MS andequilibrium dialysis and reported by LabCorp are as follows:[74]
<18 years of age: not established
Adult males: 2.30–11.60pg/mL (0.54–2.58% free)
Adult females: 0.09–1.02pg/mL (<1.27% free)
Other studies and labs assessing circulating total DHT levels withLC–MS/MS have reported ranges of 11–95ng/dL (0.38–3.27nmol/L) in adult men, 14–77ng/dL (0.47–2.65nmol/L) for healthy adult men (age 18–59years), 23–102 ng/dL (0.8–3.5 nmol/L) for community-dwelling adult men (age <65years), and 14–92ng/dL (0.49–3.2nmol/L) for healthy older men (age 71–87years).[5] In the case of women, mean circulating DHT levels have been found to be about 9ng/dL (0.3nmol/L) inpremenopausal women and 3ng/dL (0.1nmol/L) inpostmenopausal women.[5] There was no variation in DHT levels across themenstrual cycle in premenopausal women, which is in contrast to testosterone (which shows a peak atmid-cycle).[5] Withimmunoassay-based techniques, testosterone levels in premenopausal women have been found to be about 40ng/dL (1.4nmol/L) and DHT levels about 10ng/dL (0.34nmol/L).[5][75] Withradioimmunoassays, the ranges for testosterone and DHT levels in women have been found to be 20 to 70ng/dL and 5 to 30ng/dL, respectively.[75]
Levels of total testosterone, free testosterone, and free DHT, but not total DHT, all measured withLC–MS/MS, are higher in women withpolycystic ovary syndrome (PCOS) than in women without this condition.[5][76]
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 (correlation coefficient of 0.7).[5][7] In contrast to the circulation however, levels of DHT in the prostate gland are approximately 5- to 10-fold higher than those of testosterone.[7] This is due to a more than 90% conversion of testosterone into DHT in the prostate via locally expressed5α-reductase.[7] Because of this, and because DHT is much more potent as an androgen receptor agonist than testosterone,[48] DHT is the major androgen in the prostate gland.[7]
DHT was firstsynthesized byAdolf Butenandt and his colleagues in 1935.[85][86] It was prepared viahydrogenation of testosterone,[86] which had been discovered earlier that year.[87] DHT was introduced for medical use as an AAS in 1953, and was noted to be more potent than testosterone but with reduced androgenicity.[88][89][90] It was not elucidated to be an endogenous substance until 1956, when it was shown to be formed from testosterone in rat liver homogenates.[86][91] 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.[92][93][94][95] 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, andprogesterone, 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.[96]
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 toepistestosterone 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.[97]
In 2004, Richard Auchus, in a review published inTrends in Endocrinology and Metabolism coined the term "backdoor pathway" as ametabolic route to DHT that: 1) bypasses conventional intermediatesandrostenedione and testosterone; 2) involves5α-reduction of 21-carbon (C21)pregnanes to 19-carbon (C19)androstanes; and 3) involves the 3α-oxidation of5α-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.[65] 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.[98] demonstrated that yet another metabolic pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC). This pathway can be outlined asandrostenedione →5α-androstane-3,17-dione → DHT. While this pathway was described as the "5α-dione pathway" in a 2012 review,[99] the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.[100][17]
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