5-alpha-reductase inhibitor

5-reductase inhibitors (5-ARIs) are a class of drugs

with antiandrogen eects, used primarily in the treatment
of benign prostatic hyperplasia (BPH) and androgenic
alopecia.
These agents inhibit the enzyme 5-reductase, which
is involved in the metabolic transformations of a variety of endogenous steroids. 5-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

Avodart (dutasteride) 500 g capsules

2 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 notied healthcare professionals that the
Warnings and Precautions section of the labels for the 5ARI class of drugs has been revised to include new safety
information about the increased risk of being diagnosed
Propecia (nasteride) 1 mg tablets
with a more serious form of prostate cancer (high-grade
5-ARIs are clinically used in the treatment of conditions prostate cancer).[3]
that are exacerbated by DHT:[1]
Finasteride is associated with intraoperative oppy iris
syndrome and cataract formation.[4][5]

Mild-to-moderate benign prostatic hyperplasia and

lower urinary tract symptoms

3 Pharmacology

Androgenic alopecia in both men and women

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.

The pharmacology of 5-reductase inhibition is

complex, but involves the binding of NADPH
to the enzyme followed by the substrate.
Specic substrates include testosterone, progesterone,
androstenedione, epitestosterone, cortisol, aldosterone,
5-ARIs are also sometimes employed as supplementary and deoxycorticosterone. The entire physiologic efantiandrogens in hormone replacement therapy for trans fect of their reduction is unknown, but likely related
women.
to their excretion or is itself physiologic.[6] Beyond
1

3 PHARMACOLOGY

being a catalyst in the rate-limiting step in testosterone

reduction, 5-reductase isoforms I and II reduce progesterone to 5-dihydroprogesterone (5-DHP) and
deoxycorticosterone to dihydrodeoxycorticosterone
(DHDOC). In vitro and animal models suggest subsequent 3-reduction of DHT, 5-DHP and DHDOC
lead to neurosteroid metabolites with eect on cerebral function. These neurosteroids, which include
allopregnanolone,
tetrahydrodeoxycorticosterone
(THDOC), and 5-androstanediol, act as potent positive
allosteric modulators of GABAA receptors, and have
anticonvulsant, antidepressant, anxiolytic, prosexual, and
anticonvulsant eects.[7] 5-dihydrocortisol is present
in the aqueous humor of the eye, is synthesized in the
lens, and might help make the aqueous humor itself.[8]
5-dihydroaldosterone is a potent antinatriuretic agent,
although dierent 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+
5-substrate + NADP+

3.1 Pharmaceuticals
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 5-R2 at a mean inhibitory concentration IC50 of
69 nM, but is less eective with 5-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 5-R3 at a similar potency to 5-R2 in transfected cell lines.[15] Long term side eects can occur after
discontinuation of the drug.[16]
Dutasteride (Avodart) has more complete suppression of
all three 5-reductase isoenzymes. It inhibits types 1
and 2 better than nasteride, 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 5-R3
isoenzyme in vitro,[20] suggesting that dutasteride may be
a triple 5 reductase inhibitor in vivo.[6]
Alfatradiol (Ell-Cranell Alpha, Pantostin) is a topical 5ARI used for androgenic alopecia in men and women.[21]
[22]

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

3.2 Research

Inhibition of the enzyme can be classied into two categories: steroidal and nonsteroidal. The steroidal class has Some of the 5-ARIs in research are as follows:
more inhibitors with examples including nasteride (MK906), dutasteride (GG745), 4-MA, turosteride, MK-386,
Bexlosteride (LY-191,704)
MK-434, and MK-963. Several have pursued synthesis
of nonsteroidals to inhibit 5-reductase due to the unde Izonsteride (LY-320,236)
sired side eects of steroidals. The most potent and se LY-266111
lective inhibitors of 5-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoid
Epristeride (SKF-105,657, ONO-9302)
acid derivatives, and more recognizably, polyunsaturated
fatty acids (especially gamma-linolenic acid), zinc, and
(ONO-3805)
green tea.[6]
Lapisteride (CS-891)
Inhibition of 5-reductase results in decreased conversion of testosterone to DHT by reducing the 4,5 double Turosteride (FCE-26,073)
bond. This, in turn, results in slight elevations in testos FCE 28260
terone and estradiol levels. Gynecomastia, sexual dysfunction, and depression, are some possible side eects
AS 97004
of 5-reductase inhibition.
EM-402
Other enzymes compensate to a degree for the absent conversion, specically with local expression at
the skin of reductive 17-hydroxysteroid dehydrogenase,
and oxidative 3-hydroxysteroid dehydrogenase and 3hydroxysteroid dehydrogenase enzymes.[11]

Z-350[26]

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 eect of androgenic receptor activation, so
reducing levels of DHT also reduces hair loss.

4-MA (Dual inhibitor of both I & II isozymes (IC50

= 8.5 nM), but also 3--HSD inhibitor, investigated
extensively but said to be hepatotoxic).[27]

L-751788
16-((4-chlorophenyl)oxy)4,7dimethyl-4-azaandronstan-3-one

PNU-175706

3
MK-386 (L-733692),

Alizarin,

MK-434 (17 beta-benzoyl-4-aza-5 alpha-androst-1ene-3-one).[28]

Curcumin, the principal curcuminoid of turmeric.

MK-963 (L-654066),[29]
FR146687 and FK143 (Fujisawa Pharmaceutical)
{Indolizine- and Indol-Butanoic Acids}
17-carboxy-4-androsten-3-one {

[30]

in

[31]

Steroidal Oxime.[32]
Please read attached online resource for even more
information on the subject.[33]
For example, making the caproate ester of
DHEA (#121) seems to work well as an inhibitor of 5-R (IC50 = 0.049nM).[34]

3.3

R1

Valoneic acid dilactone and gallagyldilactone are

two hydrolysable tannin polyphenols isolated from
the heartwood of Shorea laeviforia[44] and oaks
species such as the North American white oak
(Quercus alba) and European red oak (Quercus
robur) are inhibitory.[45]
Angelica koreana [46][47]
Garden Balsam or Rose Balsam (Impatiens balsamina)[48]
Pollen of Turnip, turnip rape, fast plants, eld mustard, or turnip mustard (Brassica rapa)[49]

Basic structure of Azasteroids

R1

Green tea catechins, including (-)-epicatechin3-gallate,

and
(-)-epigallo-catechin-3-gallate
(EGCG).[43]

Dodder (Cuscuta reexa)[50]

Euphorbia jolkinii[51][52]

N
O

Lingzhi mushroom or Reishi

(Ganoderma lucidum)[53][54][55][56]

O
R

R2

(A) 4-Azasteroid

(B) 6-Azasteroid

(C) 10-Azasteroid

Ganoderic acid,[57] or Ganoderol B are thought

to be the compounds in the mushroom that are
specically active.[58]

Basic structure of Azasteroids.

Note: the possibility for cyclopropane ring juncture

between carbon 1 and 2 on ring A also exist in structure B.
Can also functionalize carbon 4 in this structure either with methyl or halogen, etc.
Some of the 6-azasteroids may prove to be useful drugs,
but have yet to reach the pharmaceutical market.[35][36]

Herbs and other inhibitors

Many plants, as well as their associated phytochemical

constituents, have inhibitory eects on 5-reductase.[37]
In addition, many of these compounds are also
phytoestrogens.[38]
Zinc.[39]
Riboavin (vitamin B2).[40]
Azelaic acid,[39] (sometimes
minoxidil hair solution).

mushroom

combined

with

Chinese Knotweed (Polygonum multiorum),[59]

contains resveratrol-like Stilbenoids.
Black Pepper leaf extract (Piper nigrum) [60]
Red Stinkwood (Pygeum africanum)[61]
Saw Palmetto (Serenoa repens, active substance possibly lauric acid[62] )[63][64]
The berries of saw palmetto (Serenoa repens),
a small palm native to the south east United
States, possess a dual 5a-reductase inhibition
activity, due to their high content of phytosterols: -sitosterol, stigmasterol, lupeol,
lupenone, and cycloartenol. Permixon was
launched in Europe in 1984 but has no FDA
approval. The lipido-sterol extract markedly
inhibits both the human isoenzymes. Type
1 isoenzyme is noncompetitively (Ki = 7.2
g/mL) and type 2 isoenzyme uncompetitively
(Ki = 4.9 g/mL) inhibited[65]
Pine (Pinus sp.
acid)[66]

resin, active substance abietic

-sitosterol,[41] is just one of the many phytosterols.

Ku Shen or Bitter root (Sophora avescens)[67]

Polyphenols[42]

Japanese hedge parsley (Torilis japonica)[68]

5
Eastern Arborvitae, Northern Whitecedar (Thuja
occidentalis)[69]
Spore of Japanese climbing fern (Lygodium japonicum)[70]
Further dual phytotherapeutic 5a-reductase inhibitors include, among other extracts of Pygeum
africanum, Artocarpus altilis (breadfruit), Thuja
orientalis, Laminaria saccharina, Arnica montana, Cinchona succirubra, Eugenia caryophyllata
(cloves), Humulus lupulus (hops), Hypericum perforatum (St Johns wort), Mentha piperita (peppermint), Rosmarinus ocinalis, Salvia ocinalis
(sage) and Thymus ocinalis; furthermore, diterpens, avins, and isoavonoids such as genistein and
daidzein, lignans, resveratrol, curcumin, and certain
polyunsaturated fatty acids.
The relative inhibitory potencies of unsaturated fatty
acids are, in decreasing order: GLA, alpha-linolenic
acid, linoleic acid, palmitoleic acid, oleic acid, and
myristoleic acid.[71]
Medium chain fatty acids such as those found
in coconut and the kernel of many palm
fruits have also been found to inhibit 5reductase.[72]
Certain pesticides are able to disturb the sex steroid
hormone system and to act as antiandrogens.[73]

These supplements have limited testing in human clinical

trials, and their potential for the treatment of BPH, androgenic alopecia, and related conditions is unknown.

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6 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

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6.1

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5-alpha-reductase inhibitor Source: https://en.wikipedia.org/wiki/5-alpha-reductase_inhibitor?oldid=661301300 Contributors: Techelf,

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