Decreased Testosterone from 11 Beta HSD Cortisol Inhibitors (Lean Xtreme,Retain2,etc)

[Bobaslaw]

I have become greatly concerned over the impending research studies that have determined 11 Beta Hydroxysteroid Dehydrogenase to be important to optimal testosterone production by Leydig Cells, and how inhibiting this enzyme leads to decreased spermatogenesis and testosterone production.
This is a very scary thought for anyone using a 11 Beta HSD mediated cortisol inhibitor, especially during a time when Testosterone production is so very important (PCT).
Basically we all are aware of the common staple of PCT has been a cortisol inhibitor containing some form of 7-OH or 7-OXO, such as is found in products like Designer Supplements Lean Xtreme or Anabolic Xtreme Retain 2. These products claim to reduce cortisol by a few methods including the inhibition of the 11 Beta HSD enzyme.
We have always heard about 11 Beta HSD being the primary enzyme that activates Glucocorticoids (GCs), and thus inhibiting this enzyme was a welcome prospect to reducing baseline cortisol level in the body. I believe this to be common knowledge until just recently.
The thing that people may not realize is the actual importance of adequate levels of 11Beta HSD in the testes (Leydig Cells). The reason for this importance is due to the fact that 11 Beta HSD is not just a reductive enzyme, it is also an oxidative one as well. Reductive activity of 11 Beta HSD is what we commonly know as “activating” glucocorticoids (GCs) from their inactive form (increasing cortisol). What most people are not aware of is that 11 Beta HSD workes in the reverse direction as well. This is where it exhibits its oxidative properties, deactivating GCs. Although 11 Beta HSD’s action in the body is mainly a reductive process which we try to inhibit, the opposite is true with respect to what is happening in the Leydig Cells.
In the testes, GC’s can bind to GC receptors and inhibit the Leydig Cell from producing testosterone. In the testes 11 Beta HSD has been shown to be a predominantly Oxidative role NOT a reductive role as in the majority of the body’s organs (Liver, etc). What this means is that low levels of 11 Beta Hsd in the Leydig cells causes a decrease in the oxidative reaction (converting active GCs to an inactive form), thus causing a higher level of active GCs in the testes to agonize the Leydig Cell receptors. This in turn leads to the underproduction of testosterone and decreased spermatogenesis.
I have an assortment of Pubmed studies showing this to be true in the rat model. The thing that I would like to see is actual human bloodwork with test levels from before and after use of 11 Beta HSD mediated cortisol inhibitors during off cycle so results can be proper. I would also love to get feedback form companies such as DS and AX on this issue.
Anyhow, here are links to the studies as well as exerpts that I will insert directly into this post. (below each respective study).
Feedback on this issue is greatly welcome.

Hormonal Regulation of Oxidative and Reductive Activities of 11{beta}-Hydroxysteroid Dehydrogenase in Rat Leydig Cells -- Gao et al. 138 (1): 156 -- Endocrinology

We have proposed that the 11ß-hydroxysteroid dehydrogenase (11ß-HSD) of Leydig cells protects against glucocorticoid-induced inhibition of testosterone (T) production. However, Leydig cells express type I 11ß-HSD, which has been shown to be reductive in liver parenchymal cells. Because reduction would have the opposite effect of activating glucocorticoid, the present study was designed to determine: 1) whether Leydig cell 11ß-HSD is primarily oxidative or reductive; and 2) whether oxidative and reductive activities are separately modified by known regulators of Leydig cell steroidogenic function.

This increase accentuated the predominance of oxidative activity in Leydig cells, with a ratio of oxidative to reductive activity of 4:1 after DEX treatment, compared with 2:1 in controls that were untreated. We conclude that 11ß-HSD activity in Leydig cells is primarily oxidative. Moreover, oxidation and reduction are regulated separately by hormones.

It has been shown that stress or disease-induced increases in plasma corticosterone result in diminished testosterone secretion from the testes. This article reviews investigations from our laboratories that explore the role of 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) in this process. It is proposed that the level of 11 beta-OHSD in Leydig cells dictates the level of intracellular glucocorticoid available to the glucocorticoid receptor and thus the potency of corticosteroid as an inhibitor of testosterone secretion.

Thus, 11 beta-OHSD oxidizes corticosterone to the inactive metabolite 11-dehydrocorticosterone, relieving steroid-dependent inhibition of Leydig cell function. Lowered enzyme activity increases glucocorticoid dependent inhibition of testosterone production. We conclude that the evidence supports a role of 11 beta-OHSD in testosterone secretion by the testes.

The paper from M. P. Hardy’s laboratory in this issue of Endocrinology addresses the ontogeny of 11-HSD oxidase and reductase activity and modulation of glucocorticoid action upon testosterone synthesis in Leydig cells (12). Elevations in circulating levels of glucocorticoids depress testosterone production by mature Leydig cells, resulting in decreased serum testosterone levels (13) and the elimination of endogenous corticosterone levels in vivo increases the steroidogenic capacity of purified Leydig cells in vitro. The demonstration of 11-HSD-1 messenger RNA and protein in Leydig cells led to the hypothesis that this isozyme regulates steroidogenesis in the testes by inactivating glucocorticoids within the cell, allowing normal testosterone synthesis (14).
Adult Leydig cells have both oxidative and reductive 11-HSD activity with oxidation prevailing over reduction.

Sharp reductions in immunocytochemical staining intensity were observed in the treated animals for a Leydig cell marker, 11ß-hydroxysteroid dehydrogenase, which occurred concurrently with decreased serum T levels. This was consistent with the hypothesis that CORT-mediated induction of apoptosis leads to declines in Leydig cell numbers, thereby affecting T production. These results suggest that excessive exposure to CORT initiates apoptosis in rat Leydig cells, potentially contributing to suppression of circulating T levels during stress and other conditions in which glucocorticoid concentrations are elevated.

 

[Mulletsoldier]

Good point, however, many of the formulas using 11B inhibitors are selective tissue inhibitors. Not 'suicide inhibitors' which would lead to 11B's decreased oxidative role in the testes.

 

[Bobaslaw]

Good point, however, many of the formulas using 11B inhibitors are selective tissue inhibitors. Not 'suicide inhibitors' which would lead to 11B's decreased oxidative role in the testes.

Interesting, however, is there proof of this? I mean is there anything to document this? I have not seen anything supporting what you are saying (yet). Unless I can see some kind of study to show that 7-oxo or 7-oh is not selective for 11Beta HSD in the Leydig Cells I must remain somewhat skeptical. Hopefully DS or AX would be able to shed more light on this.

Thanks for the information!

 

[Mulletsoldier]

Interesting, however, is there proof of this? I mean is there anything to document this? I have not seen anything supporting what you are saying (yet). Unless I can see some kind of study to show that 7-oxo or 7-oh is not selective for 11Beta HSD in the Leydig Cells I must remain somewhat skeptical. Hopefully DS or AX would be able to shed more light on this.

Thanks for the information!

Who says I am talking about either of those compounds?

 

[Bobaslaw]

Who says I am talking about either of those compounds?

Ahh. I see.

It was just that the manner of your response that made me feel that was being implied (since those are the main 2 compounds that are being questioned here). Sorry for jumping the gun.

 

[comacho]

i had a thread about this already,

then i had a poll and asked if they suffered any sides from anti cort supps

many people said no to any low test like symptoms...mostly joint aches

so, in vitro studies that you read and i read as well do not support the in vivo effect

no worries, take them and see for yourself

because nobody will do a study like that anyways. I trust other people's replies and i believe there are no test related sides. if there were any it should have been reported by people taking them during PCT a long time ago.

 

[Bobaslaw]

Well, after further research I have found significant info in Pubmed that shows 7-oxo and metabolites actually lead to a decrese in Testosterone even when LH levels are high. Also Possible this applies to 7-OH since interconversion between the metabolites does occur.
This seems to uphold that 11BetaHSD could be affected in the leydig cells. Either way, even if there is a different pathway responsible, I am not happy with this information.

\

Effects of transdermal application of 7-oxo-DHEA on the levels of steroid hormones, gonadotropins and lipids in healthy men.

Sulcová J, Hill M, Masek Z, Ceska R, Novácek A, Hampl R, Stárka L.

Institute of Endocrinology, Prague, Czech Republic. [email protected]

The aim of this study was to investigate the effect of 7-oxo-DHEA (dehydroepiandrosterone) on the serum levels of steroid sexual hormones, gonadotropins, lipids and lipoproteins in men. 7-oxo-DHEA was applied onto the skin as a gel to 10 volunteers aged 27 to 72 years for 5 consecutive days. The single dose contained 25 mg 7-oxo-DHEA. Serum concentrations of testosterone, estradiol, cortisol, androstenedione, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin (SHBG), total cholesterol, HDL- and LDL-cholesterol, triglycerides, apolipoprotein A-I and B and lipoprotein(a) were measured before the beginning and shortly after the end of the steroid application. After the treatment, we noted the following significant changes: a decline of testosterone and estradiol levels, increase of LH, HDL-cholesterol and apolipoprotein A-I levels. The decrease of total cholesterol levels was of the borderline significance. A slight but significant increase was found in apolipoprotein B and lipoprotein(a). The most expressive was the fall of the atherogenic index. We suggest that the gel containing 7-oxo-DHEA might be a suitable drug for improving the composition of the steroid and lipid parameters in elderly men.

\

Delayed effects of short-term transdermal application of 7-oxo-dehydroepiandrosterone on its metabolites, some hormonal steroids and relevant proteohormones in healthy male volunteers.

Sulcová J, Hampl R, Hill M, Stárka L, Novácek A.

Institute of Endocrinology, Prague, Czech Republic. [email protected]

Twenty-one healthy male volunteers aged 20-70 years were given transdermally 25 mg of 7-oxo-dehydroepiandrosterone daily in the form of an emulgel for 8 consecutive days. Morning blood was collected as follows: before application, and after the first, fourth and eighth doses (days 0, 2, 5 and 9), and then at different time intervals after termination of the treatment (days 16, 23, 37, 51, 72 and 100). Cortisol, testosterone, epitestosterone, estradiol, dehydroepiandrosterone and its sulfate, 7alpha- and 7beta-hydroxy-dehydroepiandrosterone, luteinizing hormone, follicle-stimulating hormone and sex hormone-binding globulin were measured in blood sera. In the course of treatment 7beta-hydroxy-dehydroepiandrosterone was significantly increased; testosterone and gonadotropins were lowered, but only after the first dose. All other significant changes were observed during the period after termination of the application:7beta-hydroxy-dehydroepiandrosterone remained increased for 28 days, 7alpha-hydroxy-dehydroepiandrosterone, testosterone, estradiol and sex hormone-binding globulin were decreased as late as day 63 and 91, respectively. On the other hand, epitestosterone was significantly increased between days 23 and 100. The levels of all other parameters studied were not significantly changed. The study points to an immediate as well as delayed effect of the short-term transdermal application of 7-oxo-dehydroepiandrosterone on relevant hormonal parameters.

 

[comacho]

Good point, however, many of the formulas using 11B inhibitors are selective tissue inhibitors. Not 'suicide inhibitors' which would lead to 11B's decreased oxidative role in the testes.

selective in that some of these inhibitors will go after 11bHSD1 and not 2

but since most of these products are in caps, they will be systemic and all organs will be exposed to it.

so what about topical spray? i have found Czech study using topical 7-keto-dhea that lowered all cholesterol (test, estro etc) and boosted LH.

however users here, including me and so on are not complaining about low test issue, which i found very interesting. which is fine because anti-cort supps help.

 

[Mulletsoldier]

selective in that some of these inhibitors will go after 11bHSD1 and not 2

but since most of these products are in caps, they will be systemic and all organs will be exposed to it.

so what about topical spray? i have found Czech study using topical 7-keto-dhea that lowered all cholesterol (test, estro etc) and boosted LH.

however users here, including me and so on are not complaining about low test issue, which i found very interesting. which is fine because anti-cort supps help.

No, selective insofar as tissue, not 11B isomers. Once again, I'm not speaking about 7-OXO/OH, or other DHEA metabolites. There are other 11B inhibitors.

 

[Bobaslaw]

selective in that some of these inhibitors will go after 11bHSD1 and not 2

but since most of these products are in caps, they will be systemic and all organs will be exposed to it.

so what about topical spray? i have found Czech study using topical 7-keto-dhea that lowered all cholesterol (test, estro etc) and boosted LH.

however users here, including me and so on are not complaining about low test issue, which i found very interesting. which is fine because anti-cort supps help.

Comacho, the point here is that 11BetaHSD-1 is predominant as dehydrogenase in the testes (Leydig Cells). HSD-2 exists in very insignificant amounts as studies primarily reveal HSD1 mRNA in the Leydig Cells.
The point is the predominant role of HSD-1 as dehydrogenase (oxidative) is crippled in the testes by 11BetaHSD-1 inhibition (in the testicular tissue). Remember that 11BetaHSD-1 is bi directional enzyme, it acts both as a reductase and as an dehydrogenase. HSD2 acts only as a dehydrogenase and is unidirectional.
This is why HSD1 is so important in the testes, since unlike other tissues in the body, it is mostly responsible for converting cortislol back to an inactive form. In the liver, for example, 11BetaHSD-1 is primarily a reductase, so lowering it there works to reduce cortisol activation.
The Chech Pubmed study supports exactly what symptoms we would see if 11BetaHSD-1 were inhibited in the testes. Leydig Cells would be suppresed by elevated testicular corticosterone agonism. LH would actually increase in this scenario, as the testes would be in a suppressed testosterone producing state so the Pituitary would try to counter this by releasing more LH.

As far as users reporting anything. Well, depending on how much of a drop in test compared to their basline especially if someone is not in PCT. Some may not "feel" anyting as we all know that libido is not difinitive in assessing test levels. But if someone is in PCT and shutdown it makes a heck of a difference in how quick production of Test will go up. Using the "feeling" judgement there is pointless as well to assess anything scientifically. If you are shutdown you will have low libido and low test so you cannot directly assess how much "more" suppressed a testicular 11BetaHSD-1 inhibitor would make you "feel"

 

[comacho]

i read studies on 11bHSD1 and 2

1 like you said can make cortisone to cortisol and back and forth

2 makes cortisol to cortisone (inactivating it), period, but liek you said very low amount of this enzyme around HOWEVER affinity for cortisol is HIGHER than HSD1.

so 1 is the 'bad' guy we need to tackle and 2 should be left alone.

i understand the rise in LH part due to lowered steroidogenesis thanks to inhibiting HSD1.

all i can say is interesting LOL until we hear more feedbacks from someone that actaully experiences lowered test sides from these supps.

 

[Bobaslaw]

so 1 is the 'bad' guy we need to tackle and 2 should be left alone.

HSD1 is only "bad" in tissues where it is predominantely a reductase (liver, adipose, etc). Just saying it is "bad" does not make light of this critical missing piece of information.
Thus HSD1 is "good" in the testes, and you DO NOT want it inhibited there.

Take Care.

 

[comacho]

from the old thread i asked someone to do some blood work after his PCT which will include anti-cort of some sort (DHEA metabolites), so hopefully he will post it once he does.

anybody else?

 

[mattikus]

Negative effects on test is one of the many reasons that I prefer phosphatidylserine for cort control, especially in PCT. May even help testicular function. I have been using PS for a while and love it. Never used any of the aforementioned products, and probably never will.

 

[Bobaslaw]

from the old thread i asked someone to do some blood work after his PCT which will include anti-cort of some sort (DHEA metabolites), so hopefully he will post it once he does.

anybody else?

Comacho, although opting to have testing done is the only way to get hard results, you have to do this in an optimal circumstance to properly evaluate the action of said compound.
PCT is not the best time to do this because your test levels are under the effect of shudown/restart and will be all over the place regardless of 7-oxo/OH/etc. You could not even begin to guestimate what effect 7-oxo/OH,etc (on its own) has on the results in this circumstance.
Blood testing needs to be done at a time when your testosterone/LH would normally be stable, so you could judge exactly the effects of the compond without being tainted by "after cycle shutdown"...

Hope this makes sense.

Take Care.

 

[comacho]

right on,



you got insurance? LOL

my doc wont let me i am sure, i had to beg for a last check up, he was so confused why i wanted to know,,,i was just curious.

so asking for another test will be impossible for me.

one day someone will test it out i hope.

 

[jmh80]

Hmmmm.

I'll keep this in mind. I have Lean Xtreme v2, X-lean, and Retain 2.

If I can get off these stacks - I may try one of these by themselves with before and after blood work - if my doc. will work with me.

 

[thesinner]

As per my understanding 7-keto is a 11-hsd inhibitor, as it occupies the enzyme while converting into 7-hydroxy and vice versa. And yes, 11-HSD oxidative and reductive; otherwise, 7-OH wouldn't have any barring on cortisol.

Here's my thoughts. Not saying they're right, just what they are. I'll show this thread to Matt, and see what he says.

If we decrease 11-HSD, we will in turn decrease the amount of cortisol and corticosterone circulating. This will be a product favored equilibrium because there's a constant flow of substrates from which to form them; therefore, by lowering the limiting reactant (i.e. inhibiting the enzyme) to the proper concentration, it'll be a pseudo first order reaction, totally maintained by the concentration of free enzyme. All in all, there will be significantly less active cort to have to be converted into its inactive form.

 

[Bobaslaw]

As per my understanding 7-keto is a 11-hsd inhibitor, as it occupies the enzyme while converting into 7-hydroxy and vice versa. And yes, 11-HSD oxidative and reductive; otherwise, 7-OH wouldn't have any barring on cortisol.

Here's my thoughts. Not saying they're right, just what they are. I'll show this thread to Matt, and see what he says.

If we decrease 11-HSD, we will in turn decrease the amount of cortisol and corticosterone circulating. This will be a product favored equilibrium because there's a constant flow of substrates from which to form them; therefore, by lowering the limiting reactant (i.e. inhibiting the enzyme) to the proper concentration, it'll be a pseudo first order reaction, totally maintained by the concentration of free enzyme. All in all, there will be significantly less active cort to have to be converted into its inactive form.

Yes, 7OH/OXO are a substrate for the 11B-HSD1 enzyme exactly as you say. The metabolites occupy the enzyme and interconvert between the 2 different metabolites. Basically, denying a significant amount of 11Beta-HSD1 from converting cort from inactive to active (reductive) as well as active to inactive (oxidative).
I understand your point about the idea that if baseline cortisol is decreased by occupying the reductive isomer then it may not matter if 11B-HSD1 (oxidative) is decreased, since less cortisol is present to "need" to be inactivated by the trestes. The only thing I can say is that it is probably not enough of a baseline decrese, due to the ratio differences of the enzyme. The testes 11B-HSD (oxidative) is predominant over the reductase at a ratio of 2:1 (studies support this). This testicular ratio is much higher than the reverse ratio in the liver since practically all 11Beta-HSD there is reductive, thus testicular cort will probably be at a far lower level (under normal conditions) than if equal amounts of enzyme were inhibited in both locations.
Hope this makes sense.... I look forward to your thoughts on that.

Now, this all would hold true only if significant amounts of 7oh/oxo would even make it to the testes. Information I received from the DS pres. on BB.com shows some significant information regarding oral 7oxo as opposed to the transdermal used in the studies I posted earlier.
Basically, I was told that transdermally the DHEA metabolites bypass the liver, as opposed to an oral first run. This delivery method would affect other tissues at a greater concentration than the oral route. (thus the treandermal study results) Orally, I was told that 7OH would be acted upon fully at the Liver and not bypass into the rest of the body. I question this theory as far as dose dependancy because I'm sure if you get into a high enough oral dose, it will start clearing past the liver. I guess that is what the dosage directions are for on supps


Take Care.

 

[Sldge]

I know we already went over all of this at BB but just in case anyone missed it.

Delivery method is definitely relavant when you understand how these metabolites work and where they work. 7OH does its work in the liver. 7oxo is used in a transdermal to skip the liver. If you read the following study (1) youll see that oral use of 7oxo showed no changes in hormonal concentrations.

What you need to understand is that the use of transdermal 7oxo is not the same as oral use of 7oxo or 7oh. Based on the studies we have you should not use transdermal 7OXO during PCT. Beyond that I dont know what else you are looking for.

(1)Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers.

Davidson M, Marwah A, Sawchuk RJ, Maki K, Marwah P, Weeks C, Lardy H.

Chicago Center for Clinical Research, Ill, USA.

OBJECTIVES: To evaluate the safety and pharmacokinetics of 3-acetyl-7-oxo-DHEA (3beta-acetoxyandrost-5-ene-7,17-dione) given orally. DESIGN: A randomized, double blind, placebo-controlled, escalating dose study. SETTING: The Chicago Center for Clinical Research. PARTICIPANTS: Twenty-two healthy men. STUDY METHOD: The participants received placebo (n = 6) or 3-acetyl-7-oxo-DHEA (n = 16) at 50 mg/d for 7 days followed by a 7-day washout; 100 mg/d for 7 days followed by a 7-day washout; and 200 mg/d for 28 days. OUTCOME MEASURES: Safety parameters, evaluated at each dose level, included measurement of total testosterone, free testosterone, dihydrotestosterone, estradiol, cortisol, thyroxin and insulin levels. Analyses for 7-oxo-DHEA-3beta-sulfate (DHEA-S), the only detectable metabolic product of the administered steroid, were conducted on plasma drawn from all subjects at 0.25, 0.5, 1, 2, 4, 6 and 12 hours after the final 100 mg dose of 3beta-acetyl-7-oxo-DHEA. RESULTS: There were no differences in the clinical laboratory values or in reported minor adverse experiences, between treatment and placebo groups. In general, blood hormone concentrations were unaffected by the treatment with 3beta-acetyl-7-oxo-DHEA and remained within the normal range. No changes in vital signs, blood chemistry or urinalysis occurred during treatment with 3beta-acetyl-7-oxo-DHEA compared to placebo. The administered steroid was not detected in the blood but was rapidly converted to 7-oxo-DHEA-S, the concentrations of which were proportional to dose. This steroid sulfate did not accumulate; plasma concentrations 12 hours after the 3beta-acetyl-7-oxo-DHEA dose at 7 and 28 days on the 200 mg/d dose were 15.8 and 16.3 microg/L respectively. The mean time to peak plasma level of 7-oxo-DHEA-S was 2.2 hours; the mean half life was 2.17 hours. The apparent clearance averaged 172 L/h, and the apparent mean volume of distribution was 540 L. CONCLUSION: These results indicate that 3beta-acetyl-7-oxo-DHEA is safe and well tolerated in normal healthy men at doses up to 200 mg/d for 4 weeks.
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Our research indicates it is not complete inhibition, but more competitive inhibition of 11betaHSD1 -- 7-alpha OH uses it to convert to 7-keto, and 7-keto uses it to convert back to 7-alpha OH (and 7-beta OH). Since cortisone uses the enzyme to convert to cortisol, the net result is lowered concentrations of cortisol.

While on the subject of those pondering the drop in testosterone, there was another study performed, seemingly to establish whether there was any toxicity issues () that show an estradiol reduction of 8%, cortisol reduction 7.7%, and (surprisingly) free testosterone INCREASE of around 15%.

And there is another study that was mentioned in an article by David Tolson saying that there was no change in testosterone or estradiol levels and only T3 was increased (J Ex Physiology online. 1999 2(4). Double-Blind Study Evaluating the Effects of Exercise Plus 3-Acetyl-7-oxo-dehydroepiandrosterone on Body Composition and Endocrine System in Overweight Adults. Colker CM, Torina GC, Swain MA, Kalman DS.)
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