©ALL CONTENT OF THIS WEBSITE IS COPYRIGHTED AND CANNOT BE REPRODUCED WITHOUT THE ADMINISTRATORS CONSENT 2003-2020



Steroids & Cycles

K1

Blue-Eyed Devil...
Jun 25, 2006
5,046
1
38
STEROIDS and CYCLES
by: DatbTrue


Lets take a look at hormones

In tissue associated with reproduction (such as prostate and seminal vesicles), Testosterone acts as a prohormone and is irreversibly converted by the enzyme 5a-reductase to a more potent androgen 5a-dihydrotestosterone (DHT). 5a-dihydrotestosterone (DHT), is considered more potent because it binds with greater affinity to the androgen receptor (AR) and therefore is strongly androgenic.

In other tissues, such as adipose tissue and parts of the brain, Testosterone is converted by the aromatase enzyme to the hormone estrogen and estradiol which binds to the estrogen receptor.

In bone Testosterone exerts its effect by acting both directly and by aromatizing to estradiol.

In skeletal muscle there is no 5a-reductase activity. Intracellular DHT is very low in skeletal muscle, and its presence is further diminished because of the high activity of the enzyme 3a-hydroxysteroid-dehydrogenase in this tissue (and cardiac tissue as well). This enzyme converts DHT irreversibly to 3a-androstanediol. So in skeletal muscle tissue testosterone itself is primarily binding to the androgen receptor. However aromatase expression and activity is significant and the conversion of testosterone to estrogen is ongoing. It has not yet been determined to what extent if any estrogen plays in mediating some of muscle building effects of androgens but it appears to play a role. In skelelatol muscle it is present and active.

Testosterone and DHT can also be converted to weaker androgens, if the target tissue posses the necessary enzyme activity (i.e. 3a-hydroxysteroid dehydrogenase, 17b-hydroxysteroid dehydrogenase).


Modulators of androgens

The effects of androgens at the molecular level can vary. The events that are engendered by androgens when they bind to an Androgen Receptor can be increased or decreased depending on the distribution of what is known as androgen receptor coregulators. This distribution can vary throughout various tissues and change throughout time. These coregulators are simply proteins that affect the transcriptional activity of the androgen receptor. For example one category of coregulator stabilizes the ligand-bound receptor (i.e. the androgen molecule bound to its receptor) while others facilitate the translocation (or movement) of the ligand-bound receptor (i.e. the androgen molecule bound to its receptor) to the nucleus of the cell.

This field of study is still developing and gets rather complex when discussing those numerous coregulating factors that regulate at the nuclear level in enhancing transcriptional activity. Their importance in various tissue and their modulation of androgen action is not specifically known. However I believe this area accounts in part for the body's response to exogenously administered hormones in increasing or decreasing or adjusting the intracellular effects across time as a response mechanism.

Androgen/Anabolic Modification


We all understand that with structural modifications to testosterone, the anabolic effects of this androgen can be enhanced. But there is a hypothesis that this can occur natively at the cellular levels depending on the intracellular metabolism of the anabolic steroid in different tissues, with the activity of 5a-reductase being particularly important. As a result of the "altered by metabolism" the anabolic steroid may induce various specific conformational changes of the androgen receptor complex when it binds. This then affects subsequent interaction with various coregulators in different tissues and determine the extent of anabolism. How an anabolic steroid may affect androgen receptor conformation (shape change, strength of binding, degree of activation) and interaction with particular coregulators is not specifically known but may be a way the body determines or fine tunes how hormones will behave in different tissue.

For this to make sense though you need a mental picture of the process of an androgen binding to a receptors and then that complex turning inward into the cell and moving into the nucleus where transcription occurs.
 

K1

Blue-Eyed Devil...
Jun 25, 2006
5,046
1
38
Steroids and Binding affinities

Steroids and Binding affinities

Anabolic steroids bind to the androgen receptor with different affinities (i.e. strengths). The following study, Saartok T, Dahlberg E, Gustafsson JA (1984), Relative binding-affinity of anabolic–androgenic steroids—comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin, Endocrinology 114: 2100–2106 compared the relative binding affinity of the following anabolic steroids:
Ethylestrenol (Orabolin),
Fluoxymesterone (Halotestin),
Mesterolone (Proviron),
Methandienone (Methanabol),
Methenolone Acetate (Primobolan),
17a-methyltestosterone,
Nandrolone decanoate (Deca-Durabolin), and
Oxymetholone (Anadrol)
to that of tritiated methyltrienolone (trenbolone but with a 17a-alkyl substituent) to androgen receptors in cytoplasm taken from skeletal muscle and prostate gland of the rat and skeletal muscle of the rabbit.

The order of relative binding affinities in comparison with methyltrienolone, which had the strongest affinity, was:
Nandrolone decanoate (Deca-Durabolin),
Methenolone Acetate (Primobolan),
Testosterone,
Mesterolone (Proviron),

This group of steroids demonstrated a relatively high and similar affinity for the androgen receptor in all three tissues (rat muscle & prostate & rabbit muscle).

The relative binding with Fluoxymesterone (Halotestin), Methandienone (Methanabol) and Stanozolol (Winstrol) was much weaker.

The binding affinity of Oxymetholone (Anadrol) and Ethylestrenol (Orabolin) was too low to be determined.


Binding Affinity alone does not determine the effectiveness for hypertrophy


There is a large discrepancy as to what is known about the in vivo activities of these steroids compared with their in vitro activity. This discrepency remains even when differences in bioavailability, clearance and affinity to sex hormone-binding globulin in the blood circulation are accounted for.

As an example Oxymetholone (Anadrol) and Stanozolol (Winstrol) have low relative binding affinity compared with 17a-methyltestosterone in the aforementioned in vitro study and yet these steroids have a relatively high myotrophic (muscle weight increasing) activity compared with the same steroid when administered in vivo to the castrated rat. See below taken from Potts GO, Arnold A, Beyler AL (1976), Dissociation of the androgenic and other hormonal activities from the protein anabolic effects of steroids. In: Kochakian CD (ed). Handbook of Experimental Pharmacology, vol. 43. Springer-Verlag: Berlin, pp 361–401.


Note: Steroid and (common name)

Chloromethyl Testosterone (Turinabol)
Methandrostenolone (Dianabol)
Methenolone Acetate (Primobolan)
Nandrolone decanoate (Deca-Durabolin)
Oxandrolone (Anavar)
Oxymetholone (Anadrol)
Stanozolol (Winstrol)
T (Testosterone)


In the study, Feldkoren BI, Andersson S (2005), Anabolic–androgenic steroid interaction with rat androgen receptor in vivo and in vitro: a comparative study, J Steroid Biochem Mol Biol 94: 481–487, they determined that Stanozolol (Winstrol) and Methandienone (Methanabol) have significantly lower binding affinities compared with testosterone but all three steroids were potent activators in a cell-based androgen receptor-dependent transactivation assay.


The degree of physical binding to the androgen receptor, as measured by in vitro ligand-binding assays, does not fully explain the biological activity of anabolic steroids.


In a very interesting study, Holterhus PM, Piefke S, Hiort O (2002), Anabolic steroids, testosterone-precursors and virilizing androgens induce distinct activation profiles of androgen responsive promoter constructs, J Steroid Biochem Mol Biol 82: 269–275, gene expression due to androgen receptor activation by structurally different androgens has also been reported.

The study examined three anabolic steroids Nandrolone decanoate (Deca-Durabolin), Oxymetholone (Anadrol) and Stanozolol (Winstrol), together with what the investigators term three "virilizing androgens" (testosterone, DHT and methyltrienolone) and two testosterone precursors (DHEA and androstenedione).

All the steroids proved to be potent activators of the androgen receptor, but the anabolic steroids and the testosterone precursors demonstrated "promoter activation profiles distinct from the virilizing androgens".

This takes us back to the hypothesis mentioned above in the section "Androgen/Anabolic Modification".

The authors of this study concluded that their results were due to specific ligand-induced conformation changes which determined how the hormone receptor complex can specifically interact with coregulators and neighbouring transcription factors. This meant that transactivation capability (extent of activation) depends on the structure of the response element (a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription). Understanding that a response element binds to this androgen receptor complex at least helps us visualize that different "shaped" receptor complexes may "fit" differently. Coregulators may attach along the way or behave differently and together this "blob" which looks different then another steroid induced "blob" may enter and interact in the nucleus distinctly.

Again this is a new area of understanding and how androgen receptors interact with its coregulators in different tissues is paramount to understanding how anabolic steroids exert their actions. It also clues us in to the possibility of emphasizing an anabolic action (as a totality of a steroid cocktail and timing) over the actions of an androgenic singular compound.


Example - amplified by 5a-reduction

A good bit of the discussion herein in derives from British Journal of Pharmacology (2008) 154 502–521 on Steroid Pharmacology so lets quote a highlighted possibility:

A possible basis for increasing the myotrophic-to-androgenic ratio may be by exploiting the fundamental difference between the 5a-reductase concentrations in skeletal muscle and androgenic tissue. One way of increasing the anabolic– androgenic dissociation is to administer a steroid that has a greater binding affinity for the androgen receptor but upon reduction to a 5a-metabolite has a lesser affinity. Among the anabolic steroids, 19-nortestosterone (nandrolone) was one of the first synthesized, the most used and probably the best studied. Although DHT has a greater binding affinity for the androgen receptor than its parent steroid testosterone, by contrast the 5a-reduced form of 19-nortestosterone, 5a- dihydro-19-nortestosterone, has a lesser binding affinity than its parent steroid 19-nortestosterone (Toth and Zakar, 1982).

Hence, in androgenic tissue (non-skeletal muscle), testosterone is converted to a more potent metabolite, whereas 19-nortestosterone is converted to a less potent one. As 5a-reduction occur readily in androgenic tissue (such as prostate) but is negligible in skeletal muscle, this explains why 19-nortestosterone has a greater myotrophic-to-androgenic ratio when compared with testosterone.

If the model is correct, such a diminished androgenic activity should not be confined to the accessory reproductive tissues in the human such as the prostate, but also in non-genital target tissues where clear roles for the metabolism to DHT have been defined such as the male patterns of facial and body hair growth, thus allowing more muscle per whisker.

Other things to keep in mind (Snippets)

In the study, Antonio J, Wilson JD, George FW (1999), Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles, J Appl Physiol 87: 2016–2019, the authors speculate that upregulation may occur with the administration of pharmacological amounts of androgens, converting muscles that normally have a minor, or no response, to muscles with enhanced androgen responsiveness.

Anabolic steroids may act as glucocorticoid receptor antagonists. However most binding studies indicate that anabolic steroids have very low binding affinity for the glucocorticoid receptor An alternative hypothesis, therefore, is that anabolic steroids may interfere with glucocorticoid receptor expression at the gene level.
 

K1

Blue-Eyed Devil...
Jun 25, 2006
5,046
1
38
Continued

Fatloss

Expensive in a fatloss scenario would be loss of too much muscle to gain one unit of fatloss. Before the body was losing no muscle but losing units of fat. When this comes to a halt EXTREME measures are taken to continue the diet. Often all that is required is to toggle the other way for a short time. If you have just lost 10lbs (or units) of weight toggling back the other way and regaining 3lbs (units) is advantageous. When you resume the fatloss by toggling back into that protocol you will begin to lose fat again. The body needs to see the scarcity of food as something new rather then something prolonged. So toggling attempts to bring back some of that "newness" and take away some of that "emergency management" of the body's response.

Muscle Gain

Expensive in the muscle gain scenario would be gain of too much fat to gain one unit of muscle. Before the body was gaining very little fat but gaining units of muscle. When this comes to a halt EXTREME measures are taken to continue the anabolism. Often all that is required is to toggle the other way for a short time. If you have just gained 10lbs (units) of muscle toggling back the other way and losing 3lbs (units) of fat is advantageous. When you resume the anabolism by toggling back into that protocol you will begin to gain muscle again.

Now in the context of steroid use, you have another anabolic variable besides food - hormones. The body needs to see a decline in elevated hormonal levels and a reduction of the imbalance so it can restore itself or ready itself for a new anabolic challenge. Too much intracellular signaling of the growth message means the body will turn down the volume of that message.

A Prime in the middle of a cycle

Because the body's response is often lagging the change for hormonal elevations a toggle the other way needs to be about 4 weeks to be successful.

So If you are on a steroid cycle consider that 4 weeks of the cycle will be a prime. That prime will consist of a caloric restriction and a protocol for fatloss. The steroid usage will be drastically decreased but maintained. This basic level will allow you to hold the muscle you gained (as measured by strength) while you lose fat for 4 weeks. (this would be a time when use of catabolic compounds such as T3 would be of benefit... clenbuterol as well)

As an example of a 20 week cycle, you may choose to go 8 weeks of anabolism - 4 weeks of prime (diet and steroid reduction) - 8 weeks of anabolism.

Now because that 4 week prime will still consist of a pharmacological level of androgen in the body you will not completely restore sensitivity. So you will not repeat in the final 8 weeks the mix of steroids you used in the first 8 weeks. The 2nd 8 weeks is the time to use heavier androgens such as trenbolone.

It is harder to recover from heavy androgen use close to PCT. This can be helped by doing a course of IGF-1 LR3 over the final 4 weeks of the cycle OR if you are using insulin it has some restorative effect. Low dose Clomid actually has value if used as well... but since you will be using it in PCT it may be better to use sparingly. You can low dose Clomid for months but higher doses need to be limited.

A couple weeks into PCT you will use IGF-1 LR3 again for 4 weeks to help recover from the androgen use.

So that is how/where I would choose to use a 4 week prime.
 

K1

Blue-Eyed Devil...
Jun 25, 2006
5,046
1
38
Continued

Post

Myocyte Androgen Receptors Increase Metabolic Rate and Improve Body Composition by Reducing Fat Mass, Shannon M. Fernando, Pengcheng Rao, Lee Niel, Diptendu Chatterjee, Marijana Stagljar and D. Ashley Monks, Endocrinology Vol. 151, No. 7 3125-3132 2010


Testosterone and other androgens are thought to increase lean body mass and reduce fat body mass in men by activating the androgen receptor. However, the clinical potential of androgens for improving body composition is hampered by our limited understanding of the tissues and cells that promote such changes. Here we show that selective overexpression of androgen receptor in muscle cells (myocytes) of transgenic male rats both increases lean mass percentage and reduces fat mass. Similar changes in body composition are observed in human skeletal actin promoter driving expression of androgen receptor (HSA-AR) transgenic mice and result from acute testosterone treatment of transgenic female HSA-AR rats. These shifts in body composition in HSA-AR transgenic male rats are associated with hypertrophy of type IIb myofibers and decreased size of adipocytes. Metabolic analyses of transgenic males show higher activity of mitochondrial enzymes in skeletal muscle and increased O2 consumption by the rats. These results indicate that androgen signaling in myocytes not only increases muscle mass but also reduces fat body mass, likely via increases in oxidative metabolism.