5-Reductase
5-reductases, also known as 3-oxo-5-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism.  There are three isoenzymes of 5-reductase, SRD5A1, SRD5A2, and SRD5A3, which vary in different tissues with age.
5-Reductases catalyze the following chemical reaction:
Thus, the two substrates of these enzymes are a 3-oxo-5-steroid and acceptor, whereas its two products are 3-oxo-4-steroid and a reduced acceptor.
For example:

# Production and activity
The enzyme is produced in many tissues in both males and females, in the reproductive tract, testes and ovaries, skin, seminal vesicles, prostate, epididymis and many organs, including the Nervous System. There are three isoenzymes of 5-reductase: steroid 5-reductase 1, 2, and 3 (SRD5A1, SRD5A2 and SRD5A3).
5-Reductases act on 3-oxo (3-keto), 4,5 C19/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 '4,5'. The reaction involves a stereospecific and permanent break of the 4,5 with the help of NADPH as a cofactor. A hydride anion (H) is also placed on the  face at the fifth carbon, and a proton on the  face at carbon 4.

# Distribution with age
5-R1 is expressed in fetal scalp and nongenital skin of the back, anywhere from 5 to 50 times less than in the adult. 5-R2 is expressed in fetal prostates similar to adults. 5-R1 is expressed mainly in the epithelium and 5-R2 the stroma of the fetal prostate. Scientists looked for 5-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.
After birth, the 5-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5-R2 is expressed in prostate, seminal vesicles, epididymis, liver, and to a lesser extent the scalp and skin. Hepatic expression of both 5-R1 and 2 is immediate, but disappears in the skin and scalp at month 18. Then, at puberty, only  5-R1 is reexpressed in the skin and scalp.
5-R1 and 5-R2 appear to be expressed in the prostate in male fetuses and throughout postnatal life. In adulthood, 5-R1-3 is ubiquitously expressed. 5-R1 and 5-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.

# Substrates
Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone. Outside of dihydrotestosterone, much of the physiological role of 5-reduced steroids is unknown. Beyond reducing testosterone to dihydrotestosterone, 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 effects on cerebral function achieved by enhancing GABAergic inhibition. These neuroactive steroid derivatives enhance GABA via allosteric modulation at GABA(A) receptors and have anticonvulsant, antidepressant and anxiolytic effects, and also alter sexual and alcohol related behavior. 5-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself. Allopregnanolone and THDOC are neurosteroids, with the latter having effects on the susceptibility of animals to seizures. In socially isolated mice, 5-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. 5-dihydroaldosterone is a potent antinatriuretic 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:
5-DHP is a major hormone in circulation of normal cycling and pregnant women.

## Testosterone
5-Reductase is most known for converting testosterone, the male sex hormone, into the more potent dihydrotestosterone:
- Testosterone.
Testosterone.
- Dihydrotestosterone
The major difference is the 4,5 double-bond on the A (leftmost) ring. The other differences between the diagrams are unrelated to structure.

## List of conversions
The following reactions are known to be catalyzed by 5-reductase:
- Cholestenone  5-Cholestanone
- Progesterone  5-Dihydroprogesterone
- 3-Dihydroprogesterone  Allopregnanolone
- 3-Dihydroprogesterone  Isopregnanolone
- Deoxycorticosterone  5-Dihydrodeoxycorticosterone
- Corticosterone  5-Dihydrocorticosterone
- Cortisol  5-Dihydrocortisol
- Aldosterone  5-Dihydroaldosterone
- Androstenedione  5-Androstanedione
- Testosterone  5-Dihydrotestosterone

# Inhibition
The mechanism of 5 reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate. 5-reductase inhibitor drugs are used in benign prostatic hyperplasia, prostate cancer, pattern hair loss (androgenetic alopecia), and hormone replacement therapy for transgender 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 5-reductase due to the undesired side effects of steroidals. The most potent and selective inhibitors of 5-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. Riboflavin was also identified as a 5-reductase inhibitor .
Additionally, it has been claimed that alfatradiol works through this mechanism of activity (5-reductase), as well as the Ganoderic acids in lingzhi mushroom, and the Saw Palmetto.
Inhibition of 5-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, specifically with local expression at the skin of reductive 17-hydroxysteroid dehydrogenase, oxidative 3-hydroxysteroid dehydrogenase, and 3-hydroxysteroid dehydrogenase enzymes.
Gynecomastia, erectile dysfunction, impaired cognitive function,  fatigue, hypoglycemia, impaired liver function, constipation, and depression, are only a few of the possible side-effects of 5-reductase inhibition. Long term side effects, that continued even after discontinuation of the drug have been reported.

## Finasteride
Finasteride inhibits two 5-reductase isoenzymes (II and III), while dutasteride inhibits all three. Finasteride potently inhibits 5-R2 at a mean inhibitory concentration IC50 of 69 nM, but is less effective with 5-R1 till an IC50 of 360 nM. Finasteride decreases mean serum level of DHT by 71% after 6 months, and was shown in vitro to inhibit 5-R3 at a similar potency to 5-R2 in transfected cell lines.

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

# Congenital deficiencies

## 5-Reductase 1
5-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 5-reductase type 1 expression in bone and muscle. In 5 alpha reductase type 2 deficient males, the type 1 isoenzyme is thought to be responsible for their virilization at puberty.

## 5-Reductase 2
The second isoenzyme of 5 reductase is deficient in the classic intersex condition (pseudovaginal perineoscrotal hypospadias), or 5-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." There is a range of external appearance that has been described of external genitalia at birth, with varying degrees of virilization.

## 5-Reductase 3
When small interfering RNA is used to knock down the expression of 5-R3 isozyme in cell lines, there is decreased cell growth, viability, and a decrease in DHT/T ratios. It has also shown the ability to reduce testosterone, androstenedione, and progesterone in androgen stimulated prostate cell lines by adenovirus vectors.
Congenital deficiency of 5-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.

# Nomenclature
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-5-steroid:acceptor 4-oxidoreductase. Other names in common use include:
- 5-Reductase
- 3-Oxosteroid 4-dehydrogenase
- 3-Oxo-5-steroid 4-dehydrogenase
- Steroid 4-5-reductase
- 4-3-Keto steroid 5-reductase
- 4-3-Oxo steroid reductase
- 4-3-Ketosteroid-5-oxidoreductase
- 4-3-Oxosteroid-5-reductase
- 3-Keto-4-steroid-5-reductase
- Testosterone 5-reductase
- 4-Ene-3-ketosteroid-5-oxidoreductase
- 4-5-Dehydrogenase
- 3-Oxo-5-steroid:(acceptor) 4-oxidoreductase