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5-alpha-reductase Inhibitor

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Title: 5-alpha-reductase Inhibitor  
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Subject: Dutasteride, Bexlosteride, Turosteride, Lapisteride, Izonsteride
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5-alpha-reductase Inhibitor

5α-reductase inhibitors (5-ARIs) are a class of drugs with antiandrogen effects, used primarily in the treatment of benign prostatic hyperplasia (BPH) and androgenic alopecia.

These agents inhibit the enzyme 5α-reductase, which is involved in the metabolic transformations of a variety of endogenous steroids. 5α-reductase inhibition is most known for preventing conversion of testosterone, the major androgen sex hormone, to the more potent dihydrotestosterone (DHT), in androgen-associated disorders.


  • Medical use 1
  • Adverse reactions 2
  • Pharmacology 3
    • Pharmaceuticals 3.1
    • Research 3.2
  • Herbs and other inhibitors 4
  • See also 5
  • References 6

Medical use

Propecia (finasteride) 1 mg tablets
Avodart (dutasteride) 500 µg capsules

5-ARIs are clinically used in the treatment of conditions that are exacerbated by DHT:[1]

They have also been explored in the treatment and prevention of prostate cancer. However, their use for this indication is controversial, as some authors have expressed concern that they may inadvertently lead to development of more aggressive tumor variants.

5-ARIs are also sometimes employed as supplementary antiandrogens in hormone replacement therapy for trans women.

Adverse reactions

In general, adverse drug reactions (ADRs) experienced with 5-ARIs are dose-dependent. Common ADRs include impotence, decreased libido, decreased ejaculate volume, depression, and anxiety. Rare ADRs include breast tenderness and enlargement (gynecomastia), and allergic reaction.[1][2]

The FDA has notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-ARI class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).[3]

Finasteride is associated with intraoperative floppy iris syndrome and cataract formation.[4][5]


The pharmacology of 5α-reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate. Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone. The entire physiologic effect of their reduction is unknown, but likely related to their excretion or is itself physiologic.[6] Beyond being a catalyst in the rate-limiting step in testosterone reduction, 5α-reductase isoforms I and II reduce progesterone to 5α-dihydroprogesterone (5α-DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). In vitro and animal models suggest subsequent 3α-reduction of DHT, 5α-DHP and DHDOC lead to neurosteroid metabolites with effect on cerebral function. These neurosteroids, which include allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 5α-androstanediol, act as potent positive allosteric modulators of GABAA receptors, and have anticonvulsant, antidepressant, anxiolytic, prosexual, and anticonvulsant effects.[7] 5α-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself.[8] 5α-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:[9]

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

5α-DHP is a major hormone in circulation of normal cycling and pregnant women.[10]

Inhibition of the enzyme can be classified into two categories: steroidal and nonsteroidal. The steroidal class has more inhibitors with examples including finasteride (MK-906), dutasteride (GG745), 4-MA, turosteride, MK-386, MK-434, and MK-963. Several 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 gamma-linolenic acid), zinc, and green tea.[6]

Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT by reducing the Δ4,5 double-bond. This, in turn, results in slight elevations in testosterone and estradiol levels. Gynecomastia, sexual dysfunction, and depression, are some possible side effects of 5α-reductase inhibition.

Other enzymes compensate to a degree for the absent conversion, specifically with local expression at the skin of reductive 17β-hydroxysteroid dehydrogenase, and oxidative 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase enzymes.[11]

In BPH, DHT acts as a potent cellular androgen and promotes prostate growth; therefore, it inhibits and alleviates symptoms of BPH. In alopecia, male and female-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces hair loss.


Finasteride (Proscar or Propecia) inhibits the function of two of the isoenzymes (type II and III), whereas dutasteride inhibits all three.[12] Finasteride potently inhibits 5α-R2 at a mean inhibitory concentration IC50 of 69 nM, but is less effective with 5α-R1 until an IC50 of 360 nM.[13] Finasteride decreases mean serum level of DHT by 71% after 6 months,[14] and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines.[15] Long term side effects can occur after discontinuation of the drug.[16]

Dutasteride (Avodart) has more complete suppression of all three 5α-reductase isoenzymes. It inhibits types 1 and 2 better than finasteride, leading to it causing further reduction in DHT at 6 months than the older drug (94.7% versus 70.8%).[17] It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 milligrams per day over three months.[18] A second study with 3.5 mg/d for 4 months decreased intraprostatic DHT even further by 99%.[19] It has also been shown to inhibit the 5α-R3 isoenzyme in vitro,[20] suggesting that dutasteride may be a triple 5α reductase inhibitor in vivo.[6]

Alfatradiol (Ell-Cranell Alpha, Pantostin) is a topical 5-ARI used for androgenic alopecia in men and women.[21] [22]


Some of the 5-ARIs in research are as follows:

Herbs and other inhibitors

Many plants, as well as their associated phytochemical constituents, have inhibitory effects on 5α-reductase.[31] In addition, many of these compounds are also phytoestrogens.[32]

These supplements have limited testing in human clinical trials, and their potential for the treatment of BPH, androgenic alopecia, and related conditions is unknown.

See also


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