Please Scroll Down to See Forums Below 
goku_kakarot77
New member
Steroid catabolism: implications for cycling
Many of us lose sight of what happens to these compounds once either secreted (endogenous) or injected/ingested (exogenous). Below is a brief summary of these processes. A lot of people yammer on about steroid recptor shut down yadda yadda yadda. In fact, in skeletal muscle increased androgens actually increase AR concentration. So, this idea of AR down regulation is most likely incorrect. More likely, that halt of gains or decreased effectiveness of androgens with time is more likely due to increased catabolic activities of the processes described below.
Let us view some common practices in light of this strong possibility:
Increasing dosage as gains wain:
It is likely that at approximately week 8, when most experience plateau, AAS catabolic processes have increased from pre-cycle levels. Increasing dosages will likely only lead to further increase of these catabolic activities, leading to more organ stress (most inactivation occurs in the liver and kidneys) and more difficult recovery.
High dose cycling
It is reasonable to conclude that high dosages will only hasten an increase in these activities, leading to high levels of AAS catabolism, increased organ stress and 'programing' of the body toward a dramatic increase in AAS catabolic activities upon future use of any AAS.
A more rational approach
Maybe we should all think a little bit before jumping up the dosage. A more reasonable approach would be to:
1. use more reasonable dose and limit cycles to durations of 12 weeks or less.
2. It may also be advisable to keep total dosages to less than 1.2 grams total. I've pulled that number out of my hat and is probably high.
3. Switch drugs at approximately 8 weeks. This might confuse the physiologic response by presenting different compounds.
Steroid inactivation and catabolism
General principles
Inactivation refers to the metabolic conversion of a biologically active compound into an inactive one. Inactivation can occur at various stages of hormone action. Peripheral inactivation (e.g. by liver enzymes) is required to ensure steady-state levels of plasma hormones as steroids are more or less continuously secreted into the bloodstream. Moreover, if a hormone is to act as a " chemical signal ", its half-life in the circulation must be limited, so that any change in secretion rate is immediately reflected by a change in its plasma concentration (particularly when secretion rates are decreased). But hormone inactivation can also occur in target tissues, notably after the hormone has triggered the relevant biological effects in order to ensure termination of hormone action.
The main site of peripheral steroid inactivation and catabolism is the liver, but some catabolic activity also occurs in the kidneys. Inactive hormones are mainly eliminated as urinary (mostly conjugated) metabolites. Usually, steroids are eliminated once they have been inactivated (i.e., they are not " recycled "). This elimination (e.g. as a urinary excretion products) requires conversion to hydrophilic compounds in order to ensure their solubility in biological fluids at rather high concentrations. Depending on the structure of the starting steroid, the following reactions may be involved (4):
1. Reduction of a double bond at C-4 and reduction of an oxo(keto) group at C-3 to a secondary alcoholic group.
2. Reduction of an oxo group at C-20 to a secondary alcoholic group.
Oxidation of a 17?-hydroxyl group.
3. Further hydroxylations at various positions of the steroid nucleus (e.g. 7-hydroxylation of 5a-reduced androgens).
4. Conjugation (sulphate and/or glucuronide derivatives).
Some related information. More to come.
1: Drug Metab Dispos. 2003 Sep;31(9):1117-24. Links
Glucuronidation of anabolic androgenic steroids by recombinant human UDP-glucuronosyltransferases.Kuuranne T, Kurkela M, Thevis M, Sch?nzer W, Finel M, Kostiainen R.
Division of Pharmaceutical Chemistry, University of Helsinki, Finland.
A multidimensional study on the glucuronidation of anabolic androgenic steroids and their phase I metabolites by 11 recombinant human UDP-glucuronosyltransferases (UGTs) was carried out using liquid chromatographic-tandem mass spectrometric analyses. Large differences between the enzymes with respect to the conjugation profiles of the 11 tested aglycones were detected. Two UGTs, 1A6 and 1A7, did not exhibit measurable activity toward any of the aglycones that were examined in this study. Regioselectivity was demonstrated by UGTs 1A8, 1A9, and 2B15 that preferentially catalyzed hydroxyl glucuronidation at the 17beta-position. Most of the other enzymes glucuronidated hydroxyl groups at both the 3alpha- and the 17beta-positions. Clear stereoselectivity was observed in glucuronidation of diastereomeric nandrolone metabolites (5alpha-estran-3alpha-ol-17-one and 5beta-estran-3alpha-ol-17-one), whereas such specificity was not seen when analogous methyltestosterone metabolites were assayed. UGTs 1A1, 1A3, 1A4, 1A8, 1A9, 1A10, 2B4, 2B7, and 2B15 readily glucuronidated 5alpha-androstane-3alpha,17beta-diol, but none of them exhibited methyltestosterone glucuronidation activity. In agreement with the latter observations, we found that the methyltestosterone glucuronidation activity of human liver microsomes is extremely low, whereas in induced rat liver microsomes it was significantly higher. The homology among UGTs 1A7 to 1A10 at the level of amino acid sequence is very high, and it was thus surprising to find large differences in their activity toward this set of aglycones. Furthermore, the high activity of UGT1A8 and 1A10 toward some of the substrates indicates that extrahepatic enzymes might play a role in the metabolism of anabolic androgenic steroids.
KKKKK
Many of us lose sight of what happens to these compounds once either secreted (endogenous) or injected/ingested (exogenous). Below is a brief summary of these processes. A lot of people yammer on about steroid recptor shut down yadda yadda yadda. In fact, in skeletal muscle increased androgens actually increase AR concentration. So, this idea of AR down regulation is most likely incorrect. More likely, that halt of gains or decreased effectiveness of androgens with time is more likely due to increased catabolic activities of the processes described below.
Let us view some common practices in light of this strong possibility:
Increasing dosage as gains wain:
It is likely that at approximately week 8, when most experience plateau, AAS catabolic processes have increased from pre-cycle levels. Increasing dosages will likely only lead to further increase of these catabolic activities, leading to more organ stress (most inactivation occurs in the liver and kidneys) and more difficult recovery.
High dose cycling
It is reasonable to conclude that high dosages will only hasten an increase in these activities, leading to high levels of AAS catabolism, increased organ stress and 'programing' of the body toward a dramatic increase in AAS catabolic activities upon future use of any AAS.
A more rational approach
Maybe we should all think a little bit before jumping up the dosage. A more reasonable approach would be to:
1. use more reasonable dose and limit cycles to durations of 12 weeks or less.
2. It may also be advisable to keep total dosages to less than 1.2 grams total. I've pulled that number out of my hat and is probably high.
3. Switch drugs at approximately 8 weeks. This might confuse the physiologic response by presenting different compounds.
Steroid inactivation and catabolism
General principles
Inactivation refers to the metabolic conversion of a biologically active compound into an inactive one. Inactivation can occur at various stages of hormone action. Peripheral inactivation (e.g. by liver enzymes) is required to ensure steady-state levels of plasma hormones as steroids are more or less continuously secreted into the bloodstream. Moreover, if a hormone is to act as a " chemical signal ", its half-life in the circulation must be limited, so that any change in secretion rate is immediately reflected by a change in its plasma concentration (particularly when secretion rates are decreased). But hormone inactivation can also occur in target tissues, notably after the hormone has triggered the relevant biological effects in order to ensure termination of hormone action.
The main site of peripheral steroid inactivation and catabolism is the liver, but some catabolic activity also occurs in the kidneys. Inactive hormones are mainly eliminated as urinary (mostly conjugated) metabolites. Usually, steroids are eliminated once they have been inactivated (i.e., they are not " recycled "). This elimination (e.g. as a urinary excretion products) requires conversion to hydrophilic compounds in order to ensure their solubility in biological fluids at rather high concentrations. Depending on the structure of the starting steroid, the following reactions may be involved (4):
1. Reduction of a double bond at C-4 and reduction of an oxo(keto) group at C-3 to a secondary alcoholic group.
2. Reduction of an oxo group at C-20 to a secondary alcoholic group.
Oxidation of a 17?-hydroxyl group.
3. Further hydroxylations at various positions of the steroid nucleus (e.g. 7-hydroxylation of 5a-reduced androgens).
4. Conjugation (sulphate and/or glucuronide derivatives).
Some related information. More to come.
1: Drug Metab Dispos. 2003 Sep;31(9):1117-24. Links
Glucuronidation of anabolic androgenic steroids by recombinant human UDP-glucuronosyltransferases.Kuuranne T, Kurkela M, Thevis M, Sch?nzer W, Finel M, Kostiainen R.
Division of Pharmaceutical Chemistry, University of Helsinki, Finland.
A multidimensional study on the glucuronidation of anabolic androgenic steroids and their phase I metabolites by 11 recombinant human UDP-glucuronosyltransferases (UGTs) was carried out using liquid chromatographic-tandem mass spectrometric analyses. Large differences between the enzymes with respect to the conjugation profiles of the 11 tested aglycones were detected. Two UGTs, 1A6 and 1A7, did not exhibit measurable activity toward any of the aglycones that were examined in this study. Regioselectivity was demonstrated by UGTs 1A8, 1A9, and 2B15 that preferentially catalyzed hydroxyl glucuronidation at the 17beta-position. Most of the other enzymes glucuronidated hydroxyl groups at both the 3alpha- and the 17beta-positions. Clear stereoselectivity was observed in glucuronidation of diastereomeric nandrolone metabolites (5alpha-estran-3alpha-ol-17-one and 5beta-estran-3alpha-ol-17-one), whereas such specificity was not seen when analogous methyltestosterone metabolites were assayed. UGTs 1A1, 1A3, 1A4, 1A8, 1A9, 1A10, 2B4, 2B7, and 2B15 readily glucuronidated 5alpha-androstane-3alpha,17beta-diol, but none of them exhibited methyltestosterone glucuronidation activity. In agreement with the latter observations, we found that the methyltestosterone glucuronidation activity of human liver microsomes is extremely low, whereas in induced rat liver microsomes it was significantly higher. The homology among UGTs 1A7 to 1A10 at the level of amino acid sequence is very high, and it was thus surprising to find large differences in their activity toward this set of aglycones. Furthermore, the high activity of UGT1A8 and 1A10 toward some of the substrates indicates that extrahepatic enzymes might play a role in the metabolism of anabolic androgenic steroids.
KKKKK
