At the risk of getting flamed for asking to be spoonfed, I wanted to know the main ideas about the DHT derivatives if anyone has firsthand experience they’d like to share. That info would supplement my own research quite well
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Dihydrotestosterone
Article Talk
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 (
DHT,
5α-dihydrotestosterone,
5α-DHT,
androstanolone or
stanolone) is an
endogenous androgen sex steroid and
hormone primarily involved in the growth and repair of the
prostate, the production of
sebum, and
body hair composition.
Dihydrotestosterone
Pharmacology | |
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Properties | |
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Identifiers | |
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Names | |
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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 | |
CAS Number | |
3D model (JSmol) | |
ChEBI | |
ChEMBL | |
ChemSpider | |
DrugBank | |
ECHA InfoCard | 100.007.554 |
KEGG | |
PubChem CID | |
UNII | |
CompTox Dashboard(EPA) | |
InChI
- 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
Key: NVKAWKQGWWIWPM-ABEVXSGRSA-N
| |
SMILES
- 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
| |
Chemical formula | C19H30O2 |
Molar mass | 290.447 g·mol−1 |
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)[1] |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
verify (what is ?)
Infobox references | |
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 bondof testosterone. DHT may also be synthesized from
progesterone and
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 functionedit
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.
[2]
DHT signals act 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.
[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 by
3α-hydroxysteroid dehydrogenase (3α-HSD) into the very weak androgen
3α-androstanediol in various
tissues such as
muscle,
adipose, and
liver among others,
[5][8][9] and in relation to this, DHT has been reported to be a very poor
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
androgen-dependent conditions including hair conditions like
hirsutism (excessive facial/body hair growth) and
pattern hair loss (androgenic alopecia or pattern baldness) and
prostate diseasessuch 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]
Metabolites of DHT have been found to act as
neurosteroids with their own AR-independent biological activity.
[19] 3α-Androstanediol is a potent
positive allosteric modulator of the
GABAA receptor, while
3β-androstanediol is a potent and
selectiveagonist of the
estrogen receptor (ER) subtype
ERβ.
[19] 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.
[19][20]
5α-Reductase 2 deficiencyedit
See also:
5α-Reductase 2 deficiency
Much of the biological role of DHT has been elucidated in studies of individuals with
congenital 5α-reductase type 2 deficiency, an
intersex condition caused by a
loss-of-function mutation in the
gene encoding
5α-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]
Genetic males (46,XY) with 5α-reductase type 2 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.
[13] Due to their lack of conspicuous
male genitalia, genetic males with the condition are typically raised as girls.
[21] 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,
[12] and no
menstruation,
breast development, or other signs of
feminizationthat occur during female puberty.
[13][21][2] In addition, normal
libido and
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.
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
axillaeand 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 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 of
acne,
[8][2]but subsequent research indicated normal
sebum secretion and acne incidence.
[12]
In genetic males with 5α-reductase type 2 deficiency, the
prostate 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 show
oligozoospermiadue 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.
[26][23] On the other hand,
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 inhibitorsedit
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
well tolerated and show a low incidence of
adverse effects.
[36] 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.
[36][37] A small increase in the risk of
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
gynecomastiahas 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 defectssuch 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 activityedit
DHT is a
potent agonist of the AR, and is in fact the most potent known
endogenousligand of the receptor. It 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)
[47] and 15–30 times higher than that of
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]
Biochemistryedit
Comprehensive overview of
steroidogenesis, showing DHT around the bottom middle among the androgens
[54]
Biosynthesisedit
DHT is synthesized
irreversibly from testosterone by the enzyme
5α-reductase.
[8][13] This occurs in various
tissues including the
genitals (
penis,
scrotum,
clitoris,
labia majora),
[55] 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
isoforms of 5α-reductase,
SRD5A1 (type 1) and
SRD5A2(type 2), with the latter being the most biologically important isoenzyme.
[8] There is also third 5α-reductase:
SRD5A3.
[46]SRD5A2 is most highly expressed in the genitals,
prostate gland,
epididymides,
seminal vesicles,
genital skin,
facial and
chest hair follicles,
[58][59] and
liver, while lower expression is observed in certain
brainareas, 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.
[8] In the skin, 5α-reductase is expressed in
sebaceous glands,
sweat glands,
epidermal cells, and hair follicles.
[58][59] Both isoenzymes are expressed in
scalp hairfollicles,
[60] although SRD5A2 predominates in these cells.
[59] The SRD5A2 subtype is the almost exclusive isoform expressed in the prostate gland.
[61][22]
Backdoor pathwayedit
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
progesteroneand can be outlined as follows (depending on the initial substrate):
This pathway is not always considered in the clinical evaluation of patients with
hyperandrogenism, for instance due to rare
disorders of sex development like
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]
Distributionedit
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.
[67][68] DHT has higher
affinityfor 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(%) | CBGTooltip 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. | | | | | | |
Metabolismedit
See also:
Testosterone § 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.
[8][70] 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.
[8]
Unlike testosterone, DHT cannot be
aromatized into an
estrogen like estradiol, and for this reason, has no propensity for estrogenic effects.
[71]
Excretionedit
DHT is
excreted in the
urine as
metabolites, such as
conjugates of
3α-androstanedioland
androsterone.
[72][8]
Ranges for circulating total DHT levels tested with
HPLC–MS/MS and reported by
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 dialysisand 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
LC–MS/MS have reported ranges of 11–95 ng/dL (0.38–3.27 nmol/L) in adult men, 14–77 ng/dL (0.47–2.65 nmol/L) for healthy adult men (age 18–59 years), 23–102 ng/dL (0.8–3.5 nmol/L) for community-dwelling adult men (age <65 years), and 14–92 ng/dL (0.49–3.2 nmol/L) for healthy older men (age 71–87 years).
[5] In the case of women, mean circulating DHT levels have been found to be about 9 ng/dL (0.3 nmol/L) in
premenopausal women and 3 ng/dL (0.1 nmol/L) in
postmenopausal women.
[5]There was no variation in DHT levels across the
menstrual cycle in premenopausal women, which is in contrast to testosterone (which shows a peak at
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 (
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 expressed
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 useedit
Main article:
Androstanolone
DHT is available in
pharmaceuticalformulations for
medical use as an
androgenor
anabolic–androgenic steroid (AAS).
[76] It is used mainly in the treatment of male
hypogonadism.
[77] When used as a medication, dihydrotestosterone is referred to as
androstanolone (
INNTooltip International Nonproprietary Name) or as
stanolone(
BANTooltip British Approved Name),
[76][78][79] and is sold under brand names such as
Andractim among others.
[76][78][79][77][80] The availability of pharmaceutical DHT is limited; it is not available in the
United States or
Canada,
[81][82] but is available in certain
European countries.
[79][77] The available formulations of DHT include
buccal or
sublingual tablets,
topical gels, and, as
esters in
oil,
injectables like
androstanolone propionate and
androstanolone valerate.
[76][77][80]
Performance enhancementedit
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]
Chemistryedit
DHT, also known as 5α-androstan-17β-ol-3-one, is a
naturally occurring androstanesteroid 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.
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
Trends in Endocrinology and Metabolism coined the term "backdoor pathway" as a
metabolic route to DHT that: 1) bypasses conventional intermediates
androstenedione and testosterone; 2) involves
5α-reduction of 21-carbon (C21)
pregnanes to 19-carbon (C19)
androstanes; and 3) involves the 3α-oxidation of
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.
[97] demonstrated that yet another metabolic pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC). This pathway can be outlined as
androstenedione →
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]
Referencesedit
- This article incorporates textavailable under the CC BY 4.0 license.
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