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Title: 5α-reductase  
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Subject: Benign prostatic hyperplasia, Spironolactone, Finasteride, Polyestradiol phosphate, Androgenic hair, Allopregnanolone, Epiandrosterone
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3-oxo-5-alpha-steroid 4-dehydrogenase
EC number CAS number IntEnz BRENDA ExPASy KEGG MetaCyc metabolic pathway
PRIAM PDB structures PDBsum
Gene Ontology EGO
steroid-5-alpha-reductase, alpha polypeptide 1
Symbol SRD5A1
Entrez HUGO OMIM RefSeq UniProt EC number Locus p15
steroid-5-alpha-reductase, alpha polypeptide 2
Symbol SRD5A2
Entrez HUGO OMIM RefSeq UniProt EC number Locus p23

5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism, and prostate cancer. There are three isoenzymes of 5-alpha reductase, which vary in different tissues with age.

5α-reductases catalyze the following chemical reaction:

a 3-oxo-5α-steroid + acceptor \rightleftharpoons a 3-oxo-Δ4-steroid + reduced acceptor

Thus, the two substrates of these enzymes are a 3-oxo-5α-steroid and acceptor, whereas its two products are 3-oxo-Δ4-steroid and a reduced acceptor.

Production and activity

The enzyme is produced in many tissues in both males and females, especially in the reproductive tract, testes and ovaries,[1] skin, seminal vesicles, prostate, epididymis and many organs,[2] including the Nervous System.[3][4] There are three isoenzymes of 5-alpha reductase: steroid 5α-reductase 1, 2, and 3 (SRD5A1, SRD5A2 and SRD5A3).[2][5][6][7]

5α-reductases act on 3-oxo (3-keto), Δ4,5 C 19/C21 steroids as its substrates. “3-keto” refers to the double bond of the third carbon to oxygen. Carbons 4 and 5 also have a double bond, represented by 'Δ 4, 5'. The reaction involves a stereospecific and permanent break of the Δ 4, 5 with the help of NADPH as a cofactor. A hydride anion (H−) is also placed on the α face at the fifth carbon, and a proton on the β face at carbon 4.[8]

Distribution with age

5α-R1 is expressed in fetal scalp and nongenital skin of the back anywhere from 5 to 50 times less than in the adult. 5α-R2 is expressed in fetal prostates similar to adults. 5α-R1 is expressed mainly in the epithelium and 5α-R2 the stroma of the fetal prostate. Scientists looked for 5α-R2 expression in fetal liver, adrenal, testis, ovary, brain, scalp, chest, and genital skin, using immunoblotting, and were only able to find it in genital skin.[8]

After birth, the 5α-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5α-R2 is expressed in prostate, seminal vesicles, epididymis liver, and to a lesser extent the scalp and skin. Hepatic expression of both 5α-R1 and 2 is immediate, but disappears in the skin and scalp at month 18. Then, at puberty, only 5α-R1 is reexpressed in the skin and scalp.

5α-R1 and 5α-R2 appear to be expressed in the prostate in male fetuses and throughout postnatal life. In adulthood, 5α-R1-3 is ubiquitously expressed. 5α-R1 and 5α-R2 are also expressed, although to different degrees in liver, genital and nongenital skin, prostate, epididymis, seminal vesicle, testis, ovary, uterus, kidney, exocrine pancreas, and the brain.[8] [3]


Specific substrates include testosterone, progesterone, androstenedione, epi-testosterone, cortisol, aldosterone, and deoxycorticosterone. The entire physiologic effect of their reduction is unknown, but likely related to their excretion or is itself physiologic.[8] Beyond being a catalyst in the rate-limiting step in testosterone reduction, 5alpha-reductase enzyme isoforms I and II reduce progesterone to dihydroprogesterone (DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). In vitro and animal models suggest subsequent 3alpha-reduction of DHT, DHP and DHDOC lead to steroid metabolites with effect on cerebral function by enhancing gamma-aminobutyric acid GABAergic inhibition. These neuroactive steroid derivatives enhance GABA at GABA(A) receptors and have anticonvulsant, antidepressant and anxiolytic effects, and also alter sexual and alcohol related behavior.[9] 5α-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself.[10] Allopregnanolone and THDOC are neurosteroids, with the latter having effects on the susceptibility of animals to seizures. In socially isolated mice, 5α-R1 is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. This down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction.[3][4] 5α-dihydroaldosterone is a potent antinatriureticTemplate:Dn agent, although different from aldosterone. Its formation in the kidney is enhanced by restriction of dietary salt, suggesting it may help retain sodium as follows:[11]

Substrate + NADPH + H+ → 5α-substrate + NADP+

5α-DHP is a major hormone in circulation of normal cycling and pregnant women.[12]


5α-reductase is most known for converting testosterone, the male sex hormone, into the more potent dihydrotestosterone:

The major difference is the Δ4,5 double-bond on the A (leftmost) ring. The other differences between the diagrams are unrelated to structure.


The mechanism of 5α reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate. 5α-reductase inhibitor drugs are used in benign prostatic hyperplasia, prostate cancer, male pattern baldness, and hormone replacement therapy (male to female) for transgendered women.

Inhibition of the enzyme can be classified into two categories: steroidal, which are irreversible, and nonsteroidal. There are more steroidal inhibitors, with examples including finasteride (MK-906), dutasteride (GG745), 4-MA, turosteride, MK-386, MK-434, and MK-963. Researchers have pursued synthesis of nonsteroidals to inhibit 5α-reductase due to the undesired side effects of steroidals. The most potent and selective inhibitors of 5α-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoid acid derivatives, and more recognizably, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea.[8] Riboflavin was also identified as a 5α-reductase inhibitor .[13]

Additionally, it has been claimed that Alfatradiol works through this mechanism of activity (5-alpha reductase), as well as the Ganoderic acids in Reishi, and the Saw Palmetto.

Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT, leading to increased testosterone and estradiol. Other enzymes compensate to a degree for the absent conversion, spec voifically with local expression at the skin of reductive 17b-hydroxysteroid dehydrogenase, oxidative 3a-hydroxysteroid dehydrogenase, and 3b-hydroxysteroid dehydrogenase enzymes.[14]

Gynecomastia, erectile dysfunction and depression, are only a few of the possible side-effects of 5α-reductase inhibition. Long term side effects, that continued even after discontinuation of the drug, are called "Post-Finasteride Syndrome".[15]


Finasteride inhibits two 5-alpha reductase isoenzymes (II and III), while dutasteride inhibits all three.[2] Finasteride potently inhibits 5α-R2 at a mean inhibitory concentration IC50 of 69 nM, but is less effective with 5α-R1 till an IC50 of 360 nM.[16] Finasteride decreases mean serum level of DHT by 71% after 6 months,[17] and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines.[2] Long term side effects can occur after discontinuation of the drug with Post-Finasteride Syndrome.[15]


Dutasteride inhibits 5α isoenzymes type 1 and 2 better than finasteride, leading to a more complete reduction in DHT at 24 weeks (94.7% versus 70.8%).[18] It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 milligrams per day over three months.[19] A second study with 3.5 mg/d for 4 months decreased intraprostatic DHT even further by 99%.[20] The suppression of DHT in vivo, and the report that dutasteride inhibits 5α-R3 in vitro[21] suggest that dutasteride may be a triple 5α reductase inhibitor.[8]

Congenital deficiencies

5-α reductase 1

5α-reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength, which has been proposed to be due to lack of 5α-reductase type 1 expression in bone and muscle.[22] In 5 alpha reductase type 2 deficient males, the type 1 isoenzyme is thought to be responsible for their virilization at puberty.[6]

5-α reductase 2

The second isoenzyme of 5-α reductase is deficient in the classic intersexualism pseudovaginal perineoscrotal hypospadia, or 5α-reductase deficiency. It was first discovered in indigenous cultures of Papua, New Guinea, where children were born with feminine genitalia in the absence of endogenous DHT during pregnancy, but with the surge of testosterone during adolescence, changed to males at puberty. Because of this change at puberty, the condition is also sometimes called "guevedoche."[23] There is a range of external appearance that has been described of external genitalia at birth, with varying degrees of virilization.

5-α-reductase 3

When small interfering RNA is used to knock down the expression of 5α-R3 isozyme in cell lines, there is decreased cell growth, viability, and a decrease in DHT/T ratios.[24] It has also shown the ability to reduce testosterone, androstenedione, and progesterone in androgen stimulated prostate cell lines by adenovirus vectors.[8]

Congenital deficiency of 5α-R3 at the gene SRD53A has been linked to a rare, autosomal recessive condition in which patients are born with severe intellectual dysfunction and cerebellar and ocular defects. The presumed deficiency is reduction of the terminal bond of polyprenol to dolichol, an important step in N-glycosylation of proteins, which in turn is important for proper folding of asparagine residues on nascent protein in the endoplasmic reticulum.[25]


This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-CH group of donor with other acceptors. The systematic name of this enzyme class is 3-oxo-5α-steroid:acceptor Delta4-oxidoreductase. Other names in common use include steroid

  • 5α-reductase
  • 3-oxosteroid Δ4-dehydrogenase
  • 3-oxo-5α-steroid Δ4-dehydrogenase
  • steroid Δ4-5α-reductase
  • Δ4-3-keto steroid 5α-reductase
  • Δ4-3-oxo steroid reductase
  • Δ4-3-ketosteroid-5α-oxidoreductase
  • Δ4-3-oxosteroid-5α-reductase
  • 3-keto-Δ4-steroid-5α-reductase
  • testosterone 5α-reductase
  • 4-ene-3-ketosteroid-5α-oxidoreductase
  • Δ4-5α-dehydrogenase
  • 3-oxo-5α-steroid:(acceptor) Δ4-oxidoreductase.

See also


Further reading


  • Medical Subject Headings (MeSH)


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