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Studies
Gamma 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).

Study1

STUDY: Growth suppression of hamster flank organs by topical application of gamma-linolenic and other fatty acid inhibitors of 5 alpha-reductase.

AUTHOR
Liang T; Liao S

JOURNAL
Journal of Investigational Dermatology: 1997 Aug; 109 (2): 152-7

ABSTRACT
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.



Study2

STUDY: Inhibition of steroid 5 alpha-reductase by specific aliphatic unsaturated fatty acids.

AUTHOR
Liang T; Liao S

JOURNAL
Journal of Biochemistry, 1992 Jul 15, 285 ( Pt 2):, 557-62

ABSTRACT
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.

Azelaic 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 was achieved.

Study1

Inhibition of 5alpha-reductase activity in human skin by zinc and Azelaic acid.

AUTHOR
Stamatiadis, D; Bulteau-Portois, MC; Mowszowicz, I.

JOURNAL
British Journal of Dermatology, 1988 Nov, 119(5):627-32.

ABSTRACT
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.

Saw 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)
Study1

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.

AUTHOR
Iehlé C; Délos S; Guirou O; Tate R; Raynaud JP; Martin PM

JOURNAL
J Steroid Biochem Mol Biol, 54: 5-6, 1995 Sep, 273-9

ABSTRACT
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.


Study2

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 various tissues.

AUTHOR
el-Sheikh MM; Dakkak MR; Saddique A

JOURNAL
Acta Obstet Gynecol Scand, 67: 5, 1988, 397-9

ABSTRACT
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.

 

 

 

 
   
 
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