Linolenic Acid, Alpha Linolenic Acid, and Linoleic Acid
In the following studies, Gamma Linolenic Acid (GLA), Alpha Linolenic
Acid (ALA), and Linoleic Acid were shown to be the most potent
known inhibitors of type 1 and 2 forms of 5-alpha reductase and
highly effective in decreasing the levels of dihydrotestosterone
(DHT), when applied topically. More importantly this is accomplished
without affecting any systemic effects. The study further suggests
that these fatty acids can be useful in the treatment of disorders
related to dihydrotestosterone including male pattern baldness,
acne, and excessive female body hair (hirsuitism).
STUDY: Growth suppression of hamster flank organs by
topical application of gamma-linolenic and other fatty acid
inhibitors of 5 alpha-reductase.
Liang T; Liao S
Journal of Investigational Dermatology: 1997 Aug; 109 (2): 152-7
Certain unsaturated aliphatic fatty acids, such as gamma-linolenic
acid, inhibit 5alpha-reductase activity in vitro and in vivo.
Hamster flank organ growth, as measured by the increase in the
area of pigmented macule, is dependent on androgen. When one
of the paired flank organs of a castrated hamster was treated
topically with testosterone, the treated organ, but not the
contralateral flank organ, became larger and darker. Topical
application of gamma-linolenic acid to the testosterone-treated
flank organ suppressed this testosterone effect. Other fatty
acids that were not inhibitors of 5alpha-reductases were not
active. Topical treatment of hamster flank organs with 5alpha-dihydrotestosterone
also stimulated the growth of the organ. This 5alpha-dihydrotestosterone-dependent
activity, however, was not significantly affected by gamma-linolenic
acid, suggesting that flank organ growth was dependent on 5alpha-dihydrotestosterone
and that gamma-linolenic acid acted by inhibiting 5alpha-reductase.
With intact male hamsters, the endogenous androgen-dependent
growth of flank organs is also suppressed by topical treatment
with gamma-linolenic acid. The effect of gamma-linolenic acid
is localized at the site of its application; topical application
of gamma-linolenic acid did not affect the androgen-dependent
growth of other organs such as testis, epididymis, seminal vesicle,
and prostate. gamma-Linolenic acid, with low toxicity and absence
of systemic effect, therefore may be potentially useful for
treatment of androgen-dependent skin disorders.
STUDY: Inhibition of steroid 5 alpha-reductase by specific
aliphatic unsaturated fatty acids.
Liang T; Liao S
Journal of Biochemistry, 1992 Jul 15, 285 ( Pt 2):, 557-62
Human or rat microsomal 5 alpha-reductase activity, as measured
by enzymatic conversion of testosterone into 5 alpha-dihydrotestosterone
or by binding of a competitive inhibitor, [3H]17 beta-NN-diethulcarbamoyl-4-methyl-4-aza-5
alpha-androstan-3-one ([3H]4-MA) to the reductase, is inhibited
by low concentrations (less than 10 microM) of certain polyunsaturated
fatty acids. The relative inhibitory potencies of unsaturated
fatty acids are, in decreasing order: gamma-linolenic acid greater
than cis-4,7,10,13,16,19-docosahexaenoic acid = cis-6,9,12,15-octatetraenoic
acid = arachidonic acid = alpha-linolenic acid greater than
linoleic acid greater than palmitoleic acid greater than oleic
acid greater than myristoleic acid. Other unsaturated fatty
acids such as undecylenic acid, erucic acid and nervonic acid,
are inactive. The methyl esters and alcohol analogues of these
compounds, glycerols, phospholipids, saturated fatty acids,
retinoids and carotenes were inactive even at 0.2 mM. The results
of the binding assay and the enzymatic assay correlated well
except for elaidic acid and linolelaidic acid, the trans isomers
of oleic acid and linoleic acid respectively, which were much
less active than their cis isomers in the binding assay but
were as potent in the enzymatic assay. gamma-Linolenic acid
had no effect on the activities of two other rat liver microsomal
enzymes: NADH:menadione reductase and glucuronosyl transferase.
gamma-Linolenic acid, the most potent inhibitor tested, decreased
the Vmax. and increased Km values of substrates, NADPH and testosterone,
and promoted dissociation of [3H]4-MA from the microsomal reductase.
gamma-Linolenic acid, but not the corresponding saturated fatty
acid (stearic acid), inhibited the 5 alpha-reductase activity,
but not the 17 beta-dehydrogenase activity, of human prostate
cancer cells in culture. These results suggest that unsaturated
fatty acids may play an important role in regulating androgen
action in target cells.
Acid, Vitamin B6 and Zinc Sulfate
This article published in British Journal of Dermatology demonstrated
that when Azelaic acid, Zinc Sulfate and Vitamin B6 where combined
at very low concentrations, a 90% inhibition of 5-Alpha Reductase
Inhibition of 5alpha-reductase activity in human skin by zinc
and Azelaic acid.
Stamatiadis, D; Bulteau-Portois, MC; Mowszowicz, I.
British Journal of Dermatology, 1988 Nov, 119(5):627-32.
The effects of zinc sulfate and azelaic acid on 5 alpha-reductase
activity in human skin were studied using an in vitro assay with
1,2[3H]-testosterone as substrate. When added at concentrations
of 3 or 9 mmol/l, zinc was a potent inhibitor of 5-alpha-reductase
activity. At high concentrations, zinc could completely inhibit
the enzyme activity. Azelaic acid was also a potent inhibitor
of 5 alpha-reductase; inhibition was detectable at concentrations
as low as 0.2 mmol/l and was complete at 3 mmol/l. An additive
effect of the two inhibitors was observed. Vitamin B6 potentiated
the inhibitory effect of zinc, but not of azelaic acid, suggesting
that two different mechanisms are involved. When the three substances
were added together at very low concentrations which had shown
to be ineffective alone, 90% inhibition of 5 alpha-reductase activity
was obtained. If this inhibition is confirmed in vivo, zinc sulfate
combined with azelaic acid could be an effective agent in the
treatment of androgen related pathology of human skin.
Palmetto In the following studies Saw Palmetto extract was shown
to inhibit both type 1 and 2 forms of 5 alpha-reductase (Finasteride
or Propecia® only inhibits type 2), was more potent than Finasteride
and was able to effectively reduce binding of Testosterone and
DHT to their receptors on various tissues. In the following studies
Saw Palmetto Extract is referred to as Permixon or lipido-sterol
extract of Serenoa repens (LSESr)
Study: Human prostatic steroid 5 alpha-reductase isoforms--a
comparative study of selective inhibitors.
This study suggests that Fenistride (active ingredient of Propecia)
only inhibited the Type 2 form of 5 alpha reductase where Saw
Palmetto extract inhibited both type 1 and 2 forms of 5 alpha-reductase
and was more potent than Fenistride.
Iehlé C; Délos S; Guirou O; Tate R; Raynaud JP; Martin PM
J Steroid Biochem Mol Biol, 54: 5-6, 1995 Sep, 273-9
The present study describes the independent expression of the
type 1 and 2 isoforms of human 5 alpha-reductase in the baculovirus-directed
insect cell expression system and the selectivity of their inhibition.
The catalytic properties and kinetic parameters of the recombinant
isozymes were consistent with published data. The type 1 isoform
displayed a neutral (range 6-8) pH optimum and the type 2 isoform
an acidic (5-6) pH optimum. The type 2 isoform had higher affinity
for testosterone than did the type 1 isoform (Km = 0.5 and 2.9
microM, respectively). Finasteride and turosteride were selective
inhibitors of the type 2 isoform (Ki (type 2) = 7.3 and 21.7 nM
compared to Ki (type 1) = 108 and 330 nM, respectively). 4-MA
and the lipido-sterol extract of Serenoa repens (LSESr) markedly
inhibited both isozymes (Ki (type 1) = 8.4 nM and 7.2 micrograms/ml,
respectively; Ki (type 2) = 7.4 nM and 4.9 micrograms/ml, respectively).
The three azasteroids were competitive inhibitors vs substrate,
whereas LSESr displayed non-competitive inhibition of the type
1 isozyme and uncompetitive inhibition of the type 2 isozyme.
These observations suggest that the lipid component of LSESr might
be responsible for its inhibitory effect by modulating the membrane
environment of 5 alpha-reductase. Partially purified recombinant
5 alpha-reductase type 1 activity was preserved by the presence
of lipids indicating that lipids can exert either stimulatory
or inhibitory effects on human 5 alpha-reductase.
Study: The effect of Permixon on androgen receptors.
This study shows that Saw Palmetto extract was able to effectively
reduce Binding of Testostrone and DHT to their receptors on
el-Sheikh MM; Dakkak MR; Saddique A
Acta Obstet Gynecol Scand, 67: 5, 1988, 397-9
Permixon, the liposterolic extract of the plant Serenoa Repens
is a recently introduced drug for the treatment of benign prostatic
hyperplasia. The effect of Permixon on dihydrotestosterone and
testosterone binding by eleven different tissue specimens was
tested. The drug reduced the mean uptake of both hormones by
40.9% and 41.9% respectively in all tissue specimens. Since
hirsutism and virilism are among other gynecological problems
caused either by excessive androgen stimulation or excess endorgan
response, we suggest that Permixon could be a useful treatment
in such conditions and recommend further investigations of the
possible therapeutic values of the drug in gynecological practice.