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 and the penis, as well as the production of sebum and body hair composition.
This article is about dihydrotestosterone as a hormone. For its use as a medication, see Androstanolone.
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. 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 activity[edit]
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 (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]
Performance enhancement[edit]
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[edit]
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[edit]
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 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]
