[Bobaslaw]

Originally Posted by Sir Savage

Yes, you are correct. Peak blood concentrations of whatever you are delivering would occur two hours after administration, and the research suggests that our carriers would have a max peak of 1/3 that of oral.

Sure, some of the actives go systemic. That can't be completely avoided and we've never claimed that. But it's only 1/3 of that of oral, which is a very significant difference. Think of it this way- 100% vs. 33.33%. That is an enormouse difference, hence the terms systematic vs. local.

Now, in the following study on GA in a topical solution-



you'll notice that no changes were found in blood pressure, plasma renin activity, plasma aldosterone or cortisol, all of which indicate that very little of the GA went systemic, since GA (or licorice in general) is well known to exert these effects when taken systemically.

And when you add in the fact that I don't think the authors of the study used many of the ingredients in our carrier, the concern over GA (or any other ingredient) going systemic in significant amounts really seems to become a non-issue.

Thanks for the info

Can you indulge me a bit more and let me know how much GA is in a serving of Napalm? It's one question that no one here has answered and I have not found this answer in my searches so far.

[Sir Savage]

Don't think we're quite ready to release that yet, my man. Apologies.

[Bobaslaw]

Originally Posted by Sir Savage

Don't think we're quite ready to release that yet, my man. Apologies.

Really!?! Thats a bit strange since it's only a dosage amount.
Unfortunately then, it does not enable me to determine how much of the GA is actually going systemic and see whether it is anywhere near a significant enough dose.
Yes, I know you keep telling me about the insignificant amount and all, but in this game, I have come to realize I can only trust what I know for a fact from studies and plain math.
Unfortunately, in your previous post on the Topical GA study, it does not take have Test levels as a parameter. I can not just "assume" there is no change, just because other hormone levels seem unaltered. That is just not a scientific way to detemin such things.
So, If you cannot say how much GA is in Napalm, nor show any studies/trials that show what test levels are before and after Napalm use, I have to assume (unfortunately)the possibility that enough GA is making it systemically to affect testicular steroidogenesis.
This is truly unfortuante, as knowing the GA dosage could also clear this up.

Take Care.

[Sir Savage]

Well, the problem from our perspective is that if we release information on specifics of our formula, it's going to accelerate the copy cats.

In the past, we've been copied repeatedly. SesaThin, Lipoderm-Ultra, etc. Hell, this very board was started as a place to discuss the copying of our old androgen products. There are essentially no intellectual property rights in the supplement industry, so we have to do what we can to protect our products from copycats. Sometimes, that means developing proprietary formulas.

However, a few notes about your concerns-

1) You CAN use plasma cortisol levels and the other criteria measured in the study as a proxy for systemic distribution and ultimately, the impact on testosterone levels. The reason is that if it's not getting into other areas of the body in any significant amount, then there's no reason to think it would accumulate in the hypothalamus, pituitary, or testes and impact testosterone. It's not perfect, no, but science doesn't promise us perfection- only evidence.

In your case, say you calculated the amount of GA that goes systemic. Then what? Is that strong evidence that it reduced your testosterone? Of course not. It's not a controlled experiment with a large enough sample size to determine anything.

2) There is some evidence that licorice can cause a reduction in testosterone, but there's no direct evidence that's GA that causes it. There are many other compounds in licorice that could be responsible.

[Bobaslaw]

Originally Posted by Sir Savage

Well, the problem from our perspective is that if we release information on specifics of our formula, it's going to accelerate the copy cats.

In the past, we've been copied repeatedly. SesaThin, Lipoderm-Ultra, etc. Hell, this very board was started as a place to discuss the copying of our old androgen products. There are essentially no intellectual property rights in the supplement industry, so we have to do what we can to protect our products from copycats. Sometimes, that means developing proprietary formulas.

However, a few notes about your concerns-

1) You CAN use plasma cortisol levels and the other criteria measured in the study as a proxy for systemic distribution and ultimately, the impact on testosterone levels. The reason is that if it's not getting into other areas of the body in any significant amount, then there's no reason to think it would accumulate in the hypothalamus, pituitary, or testes and impact testosterone. It's not perfect, no, but science doesn't promise us perfection- only evidence.

In your case, say you calculated the amount of GA that goes systemic. Then what? Is that strong evidence that it reduced your testosterone? Of course not. It's not a controlled experiment with a large enough sample size to determine anything.

I can use the amount to figure out the equivelent oral dosage and compare with studies on GA/decresed testosterone where the oral dosages used are presented. I would have to take into account that oral doses would partially be taken up in the liver(targeting given HSD enzymes there) before the rest making it systemic, as opposed to the transdermal route which would have a higher percentage of the given dose making it to target tissues systemically (since the liver would not take it up first).
Still, it is something to work off of... Not perfect in the least.
A test study for transdermal doses using your transporter would be the best concrete documentation, however.

2) There is some evidence that licorice can cause a reduction in testosterone, but there's no direct evidence that's GA that causes it. There are many other compounds in licorice that could be responsible.

There numerous studies on GA itself and its effects on leydig cell function and steroidogenesis.


Thanks for the info and PM. I appreciate it

[Sir Savage]

Link?

There's new research out that shows administration of GA + corticosterone reduced testosterone in rats, but not GA alone that I'm aware of.

[Bobaslaw]

Originally Posted by Sir Savage

Link?

There's new research out that shows administration of GA + corticosterone reduced testosterone in rats, but not GA alone that I'm aware of.

Yes that study (below) is pertinent and yes GA and Cort simulate the natural environment of the testes in this circumstance.
Cortisol alone does not affect steroidogenesis because Leydig Cell 11B-HSD1 dehydrogenase is able to inactivete it. 11BHSD1 dehydrogenase is predominant in the testes over the reductase. Anyhow GA alone does not affect steroidogenesis either, as in this example there is no endogenous cort being accounted for since this is an in vivo experiment. Remember, in vitro we would have a level of cort in the testes that would affect steroidogenesis if 11B-HSD1 dehydrogenase is inhibited by GA.
Thus adding Cort and GA simulates fully the in vitro eqivelent action of GA on 11B-HSD1 while in the presence of native levels of cortisol in the testes.

Inhibition of 11beta-hydroxysteroid dehydrogenase ...[J Androl. 2008 May-Jun] - PubMed Result

Inhibition of 11beta-hydroxysteroid dehydrogenase enzymatic activities by glycyrrhetinic acid in vivo supports direct glucocorticoid-mediated suppression of steroidogenesis in Leydig cells.

Hu GX, Lin H, Sottas CM, Morris DJ, Hardy MP, Ge RS.
Institute of Molecular Toxicology and Pharmacology, School of Pharmacy, 2nd Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, People's Republic of China.

Previous studies have suggested that glucocorticoid (GC) can directly affect testicular testosterone (T) biosynthesis by Leydig cells through a receptor-mediated mechanism. Interconversion of corticosterone (CORT), the active form in rodents, and 11-dehydroCORT, the biologically inert 11-keto form, is catalyzed by 11betaHSD1. This enzyme thus controls the intracellular concentration of active GC. We have postulated that elevated CORT levels resulting from stress exceed the Leydig cell's capacity for metabolic inactivation of CORT, resulting in suppressed T production. The present study tested whether inhibition of 11betaHSD1 in vivo, by the administration of glycyrrhetinic acid (GA), increases intracellular active GC concentration and thereby affects serum T concentration and Leydig cell T production. Adult Sprague-Dawley rats were treated with vehicle (corn oil), CORT, GA, or GA + CORT. Serum luteinizing hormone (LH), CORT, and T levels were measured, as were the steroidogenic capacities of purified Leydig cells. Twofold elevations of CORT were achieved by the administration of either CORT or GA alone, but in both cases there was no effect on serum T levels. However, when CORT and GA were administered in combination, serum CORT levels increased 3.5-fold (to 420 +/- 34 ng/mL) and serum T levels were reduced significantly (to 0.72 +/- 0.07 ng/mL; control, 2.12 +/- 0.23 ng/mL). Serum levels of LH were not affected by CORT, GA, or GA + CORT. Consistent with the reduced serum T levels following GA + CORT, steroidogenic enzyme expression and capacities were significantly reduced compared to control. These data support a role for 11betaHSD1 in modulating intracellular CORT concentrations and, in turn, for a direct effect of GC on Leydig cells in response to stress.

Inhibitory effect of glycyrrhetinic acid on testos...[Endocrinol Jpn. 1988] - PubMed Result

Inhibitory effect of glycyrrhetinic acid on testosterone production in rat gonads

Sakamoto K, Wakabayashi K.
Tsumura Research Institute for Pharmacology, Ibaraki, Japan.

We studied the effects of shakuyaku-kanzo-toh (a Chinese herbal medicine) and its components on testosterone production by rat gonads. We used paeoniflorin as a main component of shakuyaku (paeoniae radix), glycyrrhizin as a main component of kanzo (glycyrrhizae radix) and glycyrrhetinic acid as a main metabolite of glycyrrhizin. Oral administration of shakuyaku-kanzo-toh, glycyrrhizin, and glycyrrhetinic acid decreased in vitro basal testosterone production in Leydig cells by LH stimulation. Glycyrrhizin and glycyrrhetinic acid caused a significant decrease in testosterone production with an accumulation of 17 alpha-hydroxyprogesterone when incubated with isolated Leydig cells, while paeoniflorin showed no such effect. The inhibitory effect of glycyrrhetinic acid was far more potent than that of glycyrrhizin, causing about 90% inhibition at 10 micrograms/ml. Glycyrrhizin and glycyrrhetinic acid did not change the cyclic AMP or progesterone level in the Leydig cells. When 14C-labeled androstenedione was incubated with microsomal fraction of testicular or ovarian tissue, glycyrrhizin and glycyrrhetinic acid inhibited the conversion of androstenedione to testosterone, indicating that these compounds inhibit the activity of 17 beta-hydroxysteroid dehydrogenase (EC. 1.1.1.64). The ED50 of glycyrrhetinic acid was about 4 microM

Another reference to GA and 17B-HSD:

Identification of novel functional inhibitors of 1...[Prostate. 2005] - PubMed Result

Identification of novel functional inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3).

Spires TE, Fink BE, Kick EK, You D, Rizzo CA, Takenaka I, Lawrence RM, Ruan Z, Salvati ME, Vite GD, Weinmann R, Attar RM, Gottardis MM, Lorenzi MV.
Oncology Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ 08543, USA.

BACKGROUND: Endocrine therapy of prostate cancer (PCa) relies on agents which disrupt the biosynthesis of testosterone in the testis and/or by direct antagonism of active hormone on the androgen receptor (AR) in non-gonadal target tissues of hormone action such as the prostate. METHODS: In an effort to evaluate new therapies which could inhibit gonadal or non-gonadal testosterone biosynthesis, we developed high throughput biochemical and cellular screening assays to identify inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3), the enzyme catalyzing the conversion of androstenedione (AdT) to testosterone. RESULTS: Initial screening efforts identified a natural product, 18beta-glycyrrhetinic acid, and a novel derivative of AdT, 3-O-benzylandrosterone, as potent inhibitors of the enzyme. Further efforts led to the identification of several classes of non-steroidal, low molecular weight compounds that potently inhibited 17beta-HSD3 enzymatic activity. One of the most potent classes of 17beta-HSD3 inhibitors was a series of anthranilamide small molecules identified from a collection of compounds related to non-steroidal modulators of nuclear hormone receptors. The anthranilamide based 17beta-HSD3 inhibitors were exemplified by BMS-856, a compound displaying low nanomolar inhibition of 17beta-HSD3 enzymatic activity. In addition, this series of compounds displayed potent inhibition of 17beta-HSD3-mediated cellular conversion of AdT to testosterone and inhibited the 17beta-HSD3-mediated conversion of testosterone necessary to promote AR-dependent transcription. CONCLUSIONS: The identification of non-steroidal functional inhibitors of 17beta-HSD3 may be a useful complementary approach for the disruption of testosterone biosynthesis in the treatment of PCa. Copyright 2005 Wiley-Liss, Inc.

[Sir Savage]

I do not agree that GA + CORT simulate the natural environment of the testes. The only way that would make sense would be in a hyper stressed state, where CORT levels would be greatly elevated. The important thing was that GA by itself (which would mimic the natural environment of the testes in normal individuals) didn't cause a decrease in testosterone.

And this seems to pan out in the most recent research in humans-

1: Horm Res. 2006;65(2):106-10. Epub 2006 Feb 3. Links
Liquorice in moderate doses does not affect sex steroid hormones of biological importance although the effect differs between the genders.Sigurjonsdottir HA, Axelson M, Johannsson G, Manhem K, Nystrom E, Wallerstedt S.
Department of Endocrinology, Sahlgrenska University Hospital/Sahlgrenska, Göteborg, Sweden. helga.sigurjonsdottir@medic.gu.se

BACKGROUND/AIM: Liquorice is commonly consumed, at least in the western world, and we have earlier shown that even moderate doses of liquorice have significant effects on the cortisol metabolism by inhibiting 11beta-hydroxysteroid dehydrogenase type 2. The suggestion that liquorice decreases the testosterone levels in men makes it vital to study the effect of moderate doses of liquorice on sex steroid hormones. METHODS: Fifteen women and 21 men (healthy volunteers and subjects with essential hypertension) consumed 100 g of liquorice (150 mg glycyrrhetinic acid) daily in a 9-week, open-treatment trial. Blood and 24-hour urine samples were collected for hormone analysis before and after 4 weeks of liquorice consumption and 4 weeks after cessation of liquorice intake. RESULTS: The liquorice induced a moderate decrease in the serum concentrations of dehydroepiandrostenedione sulphate in men (p = 0.002). The relative change in serum levels of dehydroepiandrosterone sulphate differed between the genders (p = 0.03). No significant changes were observed in the serum testosterone levels after 4 weeks of liquorice consumption, and the urine excretion of androgens (etiocholanolone and androstenedione) did not change. CONCLUSIONS: Liquorice in moderate doses primarily affects the cortisol metabolism and only marginally the androgen hormones. Gender may influence the action of liquorice. Copyright 2006 S. Karger AG, Basel

PMID: 16462145 [PubMed - indexed for MEDLINE]

And that's systemically. If the licorice/GA were administered locally, the effect would be expected to be roughly 1/3 of whatever reduction was seen.

[CryingEmo]

IMO i'd hire bobaslaw as a rep or something. *wink*