glucocorticoid issues with orals

[MFT81]

I read alex-69 mention this on another thread, can we shed a bit more light and explain what and why this is a factor with oral only cycles.

Just trying to get more light on why oral only is a bad idea since there are alot of threads on this today.

[GauchB]

IMO bad for a couple of reasons.

1. Gains for me not as good.
2. Harder on the Kidneys/Liver
3. Again for me seems to take longer to get that Kick.

But everyone is different, and if you do well with just orals get no sides and are happy with results then it dosen't matter what anyone says.

[MFT81]

Yeah I agree with all that but I want to know what are glucocorticoid issues?

I understand the basics of orals and why they tend to be frowned upon but this is something I've never read about.

[brass-man]

You can make it really simple if you choose to. Alpha alkylated steroids are more liver/kidney toxic on a mg to mg basis than those that are not. Most orals are alpha alkylated. Most injectables are not.

In this spirit, you can just plain use more injectables with less toxicity. More gear, more gains.

There's also complex issues that deal with the pharmokinetics of these compounds, but if you want to take the core of the issue, it's above.

[dogfight]

I read alex-69 mention this on another thread, can we shed a bit more light and explain what and why this is a factor with oral only cycles.

Just trying to get more light on why oral only is a bad idea since there are alot of threads on this today.

bumb for a answer to his question

[brass-man]

Yeah I agree with all that but I want to know what are glucocorticoid issues?

I understand the basics of orals and why they tend to be frowned upon but this is something I've never read about.

This is something new to me. As far as i knew, one of the ways that anabolic steroids work is through androgen receptor mediated inhibition of glucocorticoid binding. This is not something unique to orals. I'm going to take a gander at pubmed.

[MFT81]

Here is the thread that sparked my interest.
People that do short cycles

In it Alex-69 talks about how oral only is a bad idea because of Glucocorticoid issues, So far from what Ive gathered is that glucocorticoid is a hormone that is anti-anabolic and that steroids (Maybe all Maybe some I dont know?) help keep this hormone from binding.

How do orals come into play with this?

How far off am I?

What is a horseshoe? are there any horse-socks? is anybody listening to me?

[brass-man]

Okay. I found the studies that i think they're referring to. I've got some issues with it. The study states that alpha alkylated steroids will increase the concentration of glucocorticoid receptors in the rat liver via negative allosteric interference with these receptors themselves, while testosterone does not.

Endocrinology. 1994 Mar;134(3):1401-8.
Pharmacol Toxicol. 1995 Oct;77(4):264-9.

Here are my issues with the study, how it relates to the post, and the subject in general.

He stated "glucocorticoid" instead of "cortisol". This is important. In humans, cortisol accounts for the vast majority of corticosteroid activity. In this study, a synthetic corticosteroid was used to measure approximate binding affinities and receptor concentrations. It was also done in rats. The steroids investigated were methyl-testosterone, danazol, stanozolol , and testosterone propionate . Last I checked, Methyl-test and danazol aren't really compounds we use much. So, we're left with a comparison between a natural hormone- testosterone, and a very different synthetic hormone- stanozolol aka winny, as far as how this study applies to us. Until they take a look at more of the alpha alkylated steroids as well as the non alkylated steroids, you can't make sweeping conclusions about either class.

As a result, the list of conclusions can be substantially narrowed. But that doesn't mean we can't take anything from this study.

It is safe to say that the three orals investigated may increase cortisol receptor concentrations. Depending on how long this effects last, it may become an issue post cycle when the allosteric inhibition that these compounds also provide is taken out of the picture. This would be even easier to swallow if the study was repeated, and cortisol was used with human hepatocytes.

However, you definitely can't make the conclusion that "All orals do this, and no injectables do." That's bad science.

[BITTAPART2]

they are hormones pretty much, related to cortisol. It is stimulated the most in the liver :gluconeogeneses" if one ingests a lot of orals or maybe a regular amount i dont know the studies he is refering to but anyway, the liver will start to concentrate these gluco's an it binds to cortisol receptors, so this in itself is undesirable.

[BITTAPART2]

also let it be known that these glucocorticoids lessen the bodies ablility to use calcium and can cause infections of the liver if too many. I think what he means is that the stress they cause on your liver(when compared to injectables on a mg for mg basis) will result in all of these negative outcomes ie, fat gain, poor liver function, calcium absorbtion bloat etc.,.

[Dude-Man]

Ps. Brass-Man is me.

[AleX-69]

Brass-Man is on the right track..

I will copy and paste an Article from Big Cat as it sums up the topic:
Since the topic of PCT remains hot, a repost of a post I made at CEM some time ago. Feel free to throw in both personal findings and scientific evidence for other things you feel need to be included in PCT besides Clomid, Nolva and HCG .

THe role of glucocorticoids

The GnRH gene contains a glucocorticoid response element (1), which suggest that glucocorticoids have a direct regulatory function on GnRH expression in the hypothalamus. Chandran et al (2) demonstrated that dexamethasone had a direct supressive effect in GnRH release.

Testosterone and DHT are known to inhibit HPTA by slowing GnRH pulse in the hypothalamus. In a rat study (3) castrated and adrenolectomized rats saw a huge increase in LH and FSH secretion. Simply adding testosterone however did not stop the rise in gonadotrophins. only when corticosterone was added did testosterone resume its inhibitory functions. However testosterone had no effect on glucocorticoid mediated GnRH supression (4), which suggest that corticosteroids are inhibitory at the pituitary level as well, quite possibly by reducing pituitary sensitivity to GnRH.

This was confirmed by Kubajak and Kamel (5) who found that corticosterone had no effect with maximal concentrations of testosterone, but augmented the inhibitory effect on LH release in the presence of lower levels of testosterone . This would also warn those against jumping to conclusions that testosterone might not be supressive if no glucocorticoids are present, since maximal levels of T supressed LH maximally as well.

This all taken together suggest the need for glucocorticoid control in the PCT if we want to achieve maximal recovery. In the first place we can do this by avoiding the use of 17AA steroids near the end of a cycle. It has been shown that several 17AA steroids including stanozolol , danazol and methyltestosterone , but not fluoxymesterone or metribolone, can upregulate GR expression (6). Potent short-acting androgens however may be the best way to finish a cycle. Short-acting, to avoid lingering supression from androgens that won't clear the body fast enough, and potent because it has been demonstrated that AR activation in the adrenocortical cells inhibits their growth and steroidogenisis. (7). Lastly I may have finally found a reason to use those pesky arginine supplements the market was swarmed with just a short while ago, (8,9), since there is evidence that nitric oxide can inhibit glucocorticoid action by reducing binding to the GR. This may actually be a wiser choice than searching for a competitive GR inhibitor, since such inhibitors invariably show some affinity for androgen and progesterone receptors as well.

The conclusion is that some form of glucocorticoid control is necessary during PCT, and that there is some evidence that even Glucocorticoid managemen on-cycle can reduce problems post-cycle, likely the reason oxandrolone for instance tends to allow people to bounce back faster than for example stanozolol or Dbol .

The role of IGF-1

More evidence seems to suggest that there is plausible evidence for cycling between androgens and GH/IGF-1. At Least one study (10) demonstrates that IGF-1 plays a key role in regulating GnRH release via a Ras/Raf-1/Mapk induced pathway and an increase in the c-fos factor.

This makes a great case for starting IGF-1 after finishing androgens, both in aiding recovery, as well as keeping gains going. I'm not a big fan of IGF-1 due to the high cost and low returns, but no one can deny its use for athletes that need to maintain mass and keep gaining it while continuous steroid use is not an option.

The role of progesterone

Calogero et al (4) also found a modulating effect of progesterone on corticosterone-related GnRH-inhibition. Though the results of studies cited show differing roles for progesterone, on the one hand protective, on the other hand inhibitory. It was even suggested that progesterone may inhibit corticosterone-related inhibition, but not when higher doses of corticosterone were used. This suggests that we may be able to take the edge off of some really supressive estrogenic drugs, nandrolone and more notably MENT and trenbolone , by reducing glucocorticoid action even a little, as suggested above.

Although it was also suggested that this could be mediated by a progesterone metabolite (progesterone is the base for many neurologically important steroids), which would of course not be plausible with androgenic progestins. So this remains PURE speculation until futher elucidation of the mechanism of progesterone in this regard becomes available, and should not be carried into conversation as saying "hey Big Cat said that progesterone is good for you post-cycle if you lower cortisol".

Role of estrogen

Another study (11) suggests that, at least at the hypothalamic level, estrogen may actually stimulate the HPTA. This data may be consistent with some reports that suggest tamoxifen is estrogenic and not anti-estrogenic at this level. This data does not suggest any different approach, merely explains how it could be possible that nolvadex seems to work better than Clomid, since it acts as an estrogen at the hypothalamus and as an anti-estrogen at the pituitary.


References


(1) Radovick S, Wondisford FE, Nakayama Y, Yamada M, Cutler GB Jr, Weintraub BD.Isolation and characterization of the human gonadotropin-releasing hormone gene in the hypothalamus and placenta.Mol Endocrinol. 1990 Mar;4(3):476-80.

(2)Chandran UR, Attardi B, Friedman R, Zheng Z, Roberts JL, DeFranco DB.Glucocorticoid repression of the mouse gonadotropin-releasing hormone gene is mediated by promoter elements that are recognized by heteromeric complexes containing glucocorticoid receptor.J Biol Chem. 1996 Aug 23;271(34):20412-20.

(3) Vreeburg JT, de Greef WJ, Ooms MP, van Wouw P, Weber RF.
Effects of adrenocorticotropin and corticosterone on the negative feedback action of testosterone in the adult male rat.Endocrinology. 1984 Sep;115(3):977-83.

(4) Calogero AE, Burrello N, Bosboom AM, Garofalo MR, Weber RF, D'Agata R.Glucocorticoids inhibit gonadotropin-releasing hormone by acting directly at the hypothalamic level.J Endocrinol Invest. 1999 Oct;22(9):666-70.

(5)Kamel F, Kubajak CL.Modulation of gonadotropin secretion by corticosterone: interaction with gonadal steroids and mechanism of action.Endocrinology. 1987 Aug;121(2):***-8.

(6)Fernandez L, Boada LD, Luzardo OP, Zumbado M, Lopez A, Diaz-Chico BN, Chirino R.[3H]dexamethasone binding activity in liver microsomes is modulated differently by 17 alpha-alkylated androgens and testosterone in vivo.Pharmacol Toxicol. 1995 Oct;77(4):264-9.

(7)Rossi R, Zatelli MC, Valentini A, Cavazzini P, Fallo F, del Senno L, degli Uberti EC.Evidence for androgen receptor gene expression and growth inhibitory effect of dihydrotestosterone on human adrenocortical cells.J Endocrinol. 1998 Dec;159(3):373-80.

(8) Duma D, Silva-Santos JE, Assreuy J.Inhibition of glucocorticoid receptor binding by nitric oxide in endotoxemic rats.Crit Care Med. 2004 Nov;32(11):2304-10.

(9)Pennisi P, D'Alcamo MA, Leonetti C, Clementi A, Cutuli VM, Riccobene S, Parisi N, Fiore CE.Supplementation of L-arginine prevents glucocorticoid-induced reduction of bone growth and bone turnover abnormalities in a growing rat model.J Bone Miner Metab. 2005;23(2):134-9.

(10)Zhen S, Zakaria M, Wolfe A, Radovick S.Regulation of gonadotropin-releasing hormone (GnRH) gene expression by insulin -like growth factor I in a cultured GnRH-expressing neuronal cell line.Mol Endocrinol. 1997 Jul;11(8):1145-55.

(11)Radovick S, Ticknor CM, Nakayama Y, Notides AC, Rahman A, Weintraub BD, Cutler GB Jr, Wondisford FE.Evidence for direct estrogen regulation of the human gonadotropin-releasing hormone gene.J Clin Invest. 1991 Nov;88(5):1649-55.

[Dude-Man]

Alright. So here's the thing.

Upregulating cortisol receptors in the liver has little to do with Gnrh expression in the hypothalamus. That logic would only follow if you could prove that upregulation of receptors in the liver increases systemic cortisol levels, and that's something that hasn't been done.

Let me just preface this by saying that I don't advocate oral only cycles. I think that they're a really bad idea in principle, and they usually turn out to be a bad idea in experience.

I am only pointing out issues with the studies involved with this particular discussion and train of thought, as i feel that many studies are overvalued and misinterpreted.

Upregulation of cortisol receptors in the liver will probably result in issues post cycle, but more to do with loss of gains than lack of proper HPTA recovery, due to increased proteolysis and gluconeogenesis.

And, that of course rests on a bigtime caveat, that being that this research is correct.

[AleX-69]

Upregulation of cortisol receptors in the liver will probably result in issues post cycle, but more to do with loss of gains than ...

That was exactly what i was pointing at.

I think cortisol control in general is a factor which mostly forgotten during PCT. During my last PCT i was using a product containing MbAET which is supposed to be an 11b-HSD1 blocker. 11b-HSD1 is found in high concentrations within liver an certain fat tissue and converts cortisone to Cortisol.

I think this product made my PCT easier and i will continue to use it during future PCTs..

[Dude-Man]

That was exactly what i was pointing at.

I think cortisol control in general is a factor which mostly forgotten during PCT. During my last PCT i was using a product containing MbAET which is supposed to be an 11b-HSD1 blocker. 11b-HSD1 is found in high concentrations within liver an certain fat tissue and converts cortisone to Cortisol.

I think this product made my PCT easier and i will continue to use it during future PCTs..

It's important not to overlook the fact that these issues are totally dependent on how long receptors in the liver stay upregulated after removal of the competitive inhibitor (in the study, winny), and have little to do with the HPTA. More investigation needs to be done before any concrete conclusions can be drawn.

I'd be careful using 17a-methyl-b-androstenetriol. Looks like that could have some metabolites (maybe even active metabolites, a nono in PCT) that could produce a positive steroid test.

[AleX-69]

Thanks for the info.. but luckly i am not a tested athlete.

[MFT81]

wow, Really found out some great stuff since the last time I posted. Thanks Alex and Brass/D. Man for some great reviews.

Really goes to show some detailed reasons why the oral only is a bad idea.

Thanxs!

[AleX-69]

I'd be careful using 17a-methyl-b-androstenetriol. Looks like that could have some metabolites (maybe even active metabolites, a nono in PCT) that could produce a positive steroid test.

Do you - or someone else - have any input on the metabolites which MbAET could have? I would be very interested.

Moreover the substance seems to be liver toxic to some degree due to the methly group attached. Do you have any data on this topic?