New findings in post-cycle therapy  

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Big Cat
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28/08/2018 1:15 am  

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):561-8.

(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.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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triguy
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28/08/2018 1:50 am  

GR = Glucocorticoid?

AR =androgen recptor or adrenocorticotropin?

......."likely the reason oxandrolone for instance tends to allow people to bounce back faster than for example stanozolol or Dbol"

..and the reason being it doesn't upregulate the Glucocorticoid expression?

Im doing my own research on how the Hpta & adrenal system work in concert to increase or decrease work capacity. I was noticing some athletes havind dedcreased work capacity & it having something to do with exogenous androgens suppressing or stimulating glucocorticoids to a point where it imbalances the adrenal system & in turn decrease work capacity. I was curious on maybe it was ex androgens suppressing cortisol's positive effects to a point where work capacity was being diminished. Strictly speaking in terms of sports performance not maximal hyptrophy as the goal.


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Big Cat
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28/08/2018 2:39 am  

GR = gluco receptor
AR = Androgen receptor

In terms of performance, the necessary amount of cortisol is beneficial, since it relocates energy stores to a place of easy access. Androgens are well known to off-set the effects of glucocorticoids, either by competitive inhibition of the GR, heterodimerization of AR with GR, supressive effects on the proliferation of adrenocortical cells, or another mechanism that has not yet been elucidated. Nandi copied, in his work on glucocorticoids and androgens, the theory of zhao et al about squelching in regards to that last mechanism, but that doesn't correlate with the optimal 1:1 ratio they found.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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Big Cat
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28/08/2018 3:22 am  
Posted by: triguy
......."likely the reason oxandrolone for instance tends to allow people to bounce back faster than for example stanozolol or Dbol"

..and the reason being it doesn't upregulate the Glucocorticoid expression?

no, the reason being that the oxandrolone/AR complexes dimerizes with and inhibits the cortisol/GR complexes. The result is lower glucocorticoid activity, which could possibly be one reason, if we follow the train of thought of Vreeburg et al, for the easier recovery from oxandrolone.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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triguy
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28/08/2018 4:03 am  

thanx for the responses but "dumb it down a little"

am i correct in saying dbol &winny upregulates GR expression, maybe that's the reason winny causes joint issues ( too much expression & it stops or lowers glucocoritcoid production, which in turn causes joint issues from uncontrolled inflammation?)

.....the athlete in ques was on dbol for the whole cycle when he experienced diminished work capacity. Im thinkin for the same reason above is why he felt the way he felt (overtrained) he wasnt having properadrenal functioning possibly due to adrenal burnout from constant GRexpression?

speaking hypothetically, if he took testosterone & Avar (inhibits Gr/cortisol complex) he may be able to not disrupt's the adrenals production of glucocorticoid and its positive effects on ATHLETIC recovery/ recovery in terms of increased work capacity not PCT.

but that normal prod of glucoroticoids may disrupt GnRH?

3 weeks androgens (test alone or test+halo)
1 week of GNRH stimulator or Lh stimulator (nolva, 6-oxo, formestane)

....that week off will allow the hpta to resume functioning again allow the adrenals to funtion properly to aid in recovery & increase work capacity

also during ths week of HPTA stims he measures blood cortisol to make sure its in the normal range for him as not to disrupt the GNRH???

all comments are welcome but remember the goals are athletic performance & increased work capacity NOT maixmal hypertrophy


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Big Cat
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28/08/2018 4:37 am  
Posted by: triguy
am i correct in saying dbol & winny upregulates GR expression,

Winny definitely, dbol probably.

quote:


maybe that's the reason winny causes joint issues ( too much expression & it stops or lowers glucocoritcoid production, which in turn causes joint issues from uncontrolled inflammation?)


I would imagine the increased GR concentration would have an anti-inflamattory effect. It does however bind the low affinity GR in the liver microsomes, which is an inhibitor of complement and in turn blocks it, which could be what is causing reduced anti-inflammatory effect.

quote:


.....the athlete in ques was on dbol for the whole cycle when he experienced diminished work capacity. Im thinkin for the same reason above is why he felt the way he felt (overtrained) he wasnt having properadrenal functioning possibly due to adrenal burnout from constant GRexpression?


Dbol is just one of those drugs known to reduce aerobic capacity, this is likely the cause of the perceived effect. This is probably due to its estrogenic nature and nothing more.

The solution would be to opt for a drug that is more suited to your goals of performance. Using boldenone as a base steroid, 800 a week or something, and combine that with a little Var, or a low dose androgen (little tren or something) should do the trick

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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Bigr
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28/08/2018 5:10 am  

Does this information in any way change advice we give people regarding certain steroids/cycles/PCT?


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acecombact1
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28/08/2018 5:58 am  

I dont think missing with the down stream G-protein coupled recptors signaling pathways (i.e RAS/RAF) is a good idea. There is alot of stuff that we dont know about from when a ligand binds to a recpetor to until it activates translation/transcription. Ma cancers are cause because one small subunite in the signaling cascade is not working like its supposed to.


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Big Cat
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28/08/2018 6:40 am  
Posted by: Big'r
Does this information in any way change advice we give people regarding certain steroids/cycles/PCT?

No, it rather augments our understanding of inhibition and perhaps teaches us some cortisol control may be wise.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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Duc
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28/08/2018 11:07 am  
Posted by: Big Cat
...and perhaps teaches us some cortisol control may be wise.

Personally I have never been in doubt that cortisol control, especially after and in the second half of a heavy cycle , is paramount.


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Seabiscuit Hogg
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28/08/2018 11:44 am  

Hmm... I've been wondering for some time why using SERMs concurrently with tren seemed to reduce testicular atrophy.(this is purely anectdotal of course)nolva does seem to be superior for this purpose.
Why is tren so suppressive to the HPTA if it also suppresses cortisol?

Seabiscuit Hogg is a fictious internet character. It is not recommended that you receive medical advice from fictious internet characters.

SBH :)


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Neuromancer
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28/08/2018 12:36 pm  

You say ideally a short estered potent drug should be taken at the end of a cycle, what would fall under potent? Tren A? Test P?

Just curious


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Big Cat
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28/08/2018 1:34 pm  

Those would be ideal. Mind you even longer estered test would be all that bad given the length of the PCT, but long estered tren would be another story.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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Big Cat
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28/08/2018 2:10 pm  
Posted by: Seabiscuit Hogg
Hmm... I've been wondering for some time why using SERMs concurrently with tren seemed to reduce testicular atrophy.(this is purely anectdotal of course) Nolva does seem to be superior for this purpose.
Why is tren so suppressive to the HPTA if it also suppresses cortisol?

Possibly the action of progesterone coupled with the high level of androgenic action. Also keep in mind that while trenbolone acts against cortisol in many ways, once the tren is gone, meaning in the post-cycle, your cortisol will peak.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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Duc
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28/08/2018 3:02 pm  
Posted by: Big Cat
. Also keep in mind that while trenbolone acts against cortisol in many ways, once the tren is gone, meaning in the post-cycle, your cortisol will peak.

It certainly will. We have seen great effects when applying 15mgr Remeron ED after the cycle, and I believe it is well established that Remeron in fact does reduce cortisol. Personally, I have had great effect from it when used for this purpose. There are some side effects, but when used for a short time, it is not a bad drug to control cortisol.


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