5α-reductase inhibitors are a group of medications with antiandrogenic activity, used in benign prostatic hyperplasia, prostate cancer, male pattern baldness, and hormone replacement therapy (male to female) for transgender women.
These drugs decrease the levels of available 5α-reductase, thus reducing the products of its enzymatic reaction. Specific substrates that it enzymatically converts include testosterone, progesterone, androstenedione, epi-testosterone, cortisol, aldosterone, and deoxycorticosterone. 5α-reductase inhibition is most known for preventing conversion of testosterone, the male sex hormone, to the more potent dihydrotestosterone in androgenic disorders.
- mild-to-moderate benign prostatic hyperplasia and lower urinary tract symptoms
- androgenic (or androgenetic) alopecia.
- prostate cancer
Note that the use of 5-α reductase inhibition is controversial in prostate cancer, as some authors have expressed concern that it may inadvertently lead to development of more aggressive neoplastic variants.
In general, adverse drug reactions (ADRs) experienced with 5α-reductase inhibitors 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.
The FDA has notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (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).
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, 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. 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. 5α-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. 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:
- Substrate + NADPH + H+ → 5α-substrate + NADP+
5α-DHP is a major hormone in circulation of normal cycling and pregnant women.
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.
Inhibition of 5α-reductase results in decreased conversion of testosterone to dihydrotestosterone (DHT) by reducing the Δ4,5 double-bond. This, in turn increases levels of testosterone and estradiol. Gynecomastia, erectile 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 17b-hydroxysteroid dehydrogenase, oxidative 3a-hydroxysteroid dehydrogenase, and 3b-hydroxysteroid dehydrogenase enzymes.
In benign prostatic hyperplasia (BPH), DHT acts as a potent cellular androgen and promotes prostate growth; therefore, it inhibits and alleviates symptoms of BPH. In alopecia, male-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces alopecia.
Finasteride (Proscar or Propecia) inhibits the function of two of the isoenzymes (type II and III), whereas dutasteride inhibits all three. 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. Finasteride decreases mean serum level of DHT by 71% after 6 months, and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines. Long term side effects can occur after discontinuation of the drug.
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%). It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 milligrams per day over three months. A second study with 3.5 mg/d for 4 months decreased intraprostatic DHT even further by 99%. It has also been shown to inhibit the 5α-R3 isoenzyme in vitro, suggesting that dutasteride may be a triple 5α reductase inhibitor in vivo.
Some of the 5 alpha reductase inhibitors in research are as follows:
Herbs and other inhibitors
Zinc, riboflavin (vitamin B2), azelaic acid, β-sitosterol, certain unsaturated aliphatic fatty acids such as gamma-linolenic acid, alpha-linolenic acid, linoleic acid, myristoleic acid, and oleic acid, and a variety of polyphenols have been found to inhibit 5α-reductase activity to varying degrees. Other inhibitors include alizarin, curcumin, and green tea catechins, including (-)-epicatechin-3-gallate, and (-)-epigallo-catechin-3-gallate (EGCG). A chemical found in the Reishi mushroom Ganoderma lucidum also is inhibitory. Ganoderic acid or organoderol B are thought to be the compounds in the mushroom that are specifically active.
Valoneic acid dilactone and gallagyldilactone are two hydrolysable tannin polyphenols isolated from the heartwood of Shorea laeviforia and oaks species such as the North American white oak (Quercus alba) and European red oak (Quercus robur) are inhibitory. Certain pesticides are able to disturb the sex steroid hormone system and to act as antiandrogens.
Other herbs include:
- Angelica koreana 
- Garden Balsam or Rose Balsam (Impatiens balsamina)
- Pollen of Turnip, turnip rape, fast plants, field mustard, or turnip mustard (Brassica rapa)
- Dodder (Cuscuta reflexa)
- Euphorbia jolkinii
- Lingzhi mushroom or Reishi mushroom (Ganoderma lucidum)
- Chinese Knotweed (Polygonum multiflorum)
- Black Pepper leaf extract (Piper nigrum) 
- Red Stinkwood (Pygeum africanum)
- Saw Palmetto (Serenoa repens, active substance possibly lauric acid)
- Pine (Pinus sp. resin, active substance abietic acid)
- Ku Shen or Bitter root (Sophora flavescens)
- Japanese hedge parsley (Torilis japonica)
- Eastern Arborvitae, Northern Whitecedar (Thuja occidentalis)
- Spore of Japanese climbing fern (Lygodium japonicum)
These supplements have limited testing in human clinical trials, and their potential for the treatment of BPH, androgenic hair loss, and related conditions is unknown.
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