A New Understanding of Steroid Action
Anabolics and Gene Transcription
Steroids have two very distinct sides to the way they work in the human body. On the one hand, they have anabolic activities, a term that relates to the lean tissue building effects of these agents. This, of course, is the main goal of steroid use in the vast majority of cases. On the other hand, they also have androgenic properties, which refers to their “masculinizing” effects. This includes such male traits as secondary hair growth, deepening of the voice during puberty, maturation and function of the male reproductive system, oil production in the skin, and aggression. For the bodybuilder, this dichotomy of activity typically (although crudely) is looked at as the balance between results and side effects. For any given purpose, we are constantly trying to maximize the level of muscle growth we can achieve, while simultaneously trying to minimize the level of unnecessary side effects we must endure to get there. Science has long searched for the “pure” anabolic agent; an agent entirely devoid of androgenic activity. Such an agent could be an ideal treatment option when lean tissue building is solely desired. Unfortunately, science has never delivered on the pure anabolic promise. All available anabolic/androgenic agents exhibit both properties to some degree.
Accounting for the Differences
It is well understood that different steroids have different anabolic and androgenic effects in the body. Stanozolol, methenolone and oxandrolone for example, tend to exhibit strong tissue building effects with only weak to moderate (compared to other agents) androgenic activity. Drugs like testosterone, oxymetholone, methandrostenolone and mesterolone, on the other hand, seem to be much more strongly androgenic. This leads to the ultimate and very important question: Why does this occur? Understanding what accounts for the differences in affect between different agents is the first step in developing a pure anabolic, or at the very least, an understanding of why it’s not feasible to do so. But to get to this point, we need to fully understand how steroids work in the body, on a cellular level. For researchers, this has been one of the most diverse and controversial areas of research. Over the years, there have been many different opinions and theories postulated as to how these agents work and why some offer different benefits or drawbacks compared to others.
Receptor Activation
Steroids largely work through a mechanism known as gene transcription. The process starts when the steroid attaches to, and activates, a receptor floating around various “androgen responsive” cells of the body. This receptor is specific for anabolic/androgenic steroids (called the androgen receptor), as it is not activated by other hormones. The steroid and receptor bond with each other, forming what’s known as the “androgen-receptor complex.” This complex is then translocated as a whole to the cell nucleus, where it will attach to a specific hormone-responsive element on the cell’s DNA. This will ultimately cause the transcription of genes inside the cell that control specific functions. Of course, the most notable effect of this includes an increase in protein synthesis in skeletal muscle tissue (muscle growth). But the process of gene transcription itself has been poorly understood when it comes to anabolic steroids, leading to a great deal of speculation concerning exactly how these agents are able to exert their activities inside the cell, as well as to what genes are being transcribed.
Metabolism vs. Transcription
Anabolic steroid researchers have been specifically debating for a long time as to whether or not two different anabolic steroids, attached to androgen receptors in the same tissue, could cause two separate gene-transcribing activities. Some have argued that the same gene is transcribed in all cases, while others insist the different effects of various anabolic/androgenic agents can only be accounted for by different gene transcriptions. This question is an important one, as divergent transcribing effects could help better explain many of the differences we notice in terms of growth, side effects and other benefits and activities with different anabolic/androgenic steroids. Otherwise, differences between agents will be manifest largely through the way they are metabolized in cells and the ability of the original agent (or its active metabolites) to make it to the androgen receptor intact[1]. For example, nandrolone is largely converted to dihydronandrolone, a very weak androgenic agent, in tissues where 5-alpha reductase is abundant. This is the same enzyme that converts testosterone to the much stronger agent dihydrotestosterone, mitigating much of the androgenic activity associated with this hormone. This means that in tissues where testosterone’s androgenic potency is normally increased, nandrolone’s activity is actually measurably weakened. It’s a weaker steroid that is essentially hitting the androgen receptor here; these cells are dealing more with DHN than nandrolone. We can also take into account peripheral interaction with other (non-androgen) receptors,[2] an activity also known to affect a steroid’s anabolic potency. But are these the only main factors to consider, or may there also be other things at work at the level of gene transcription that account for the different effects of steroids?
The New Research
Researchers at the University of Libeck in Germany have recently made substantial progress in answering this question.[3] Investigators tested the effects of various steroids, including testosterone, dihydrotestosterone, nandrolone, oxandrolone, methyltrienolone and stanozolol, on a model androgen-responsive cell with three distinct artificial androgen-responsive genes. Researchers wanted to see if the different agents might cause different transcribing effects, or if in all cases the same activity occurred. The result was probably contrary to the expectations of many “single receptor, single gene” theorists. The experiment showed, quite clearly, that different transcribing effects could be seen with the same receptor type, in the same cell, with different anabolic/androgenic agents. The investigators summed up the results of their research well in stating, “… our model provides first experimental evidence for the existence of distinct target gene expression profiles due to AR-activation by structurally different androgenic steroid hormones. In fact, we showed that the AR transduces a ligand-specific signal down to the target gene level… This will add significantly to a comprehensive understanding of the diversity of biological actions of androgens and consequently, to new concepts on their role in physiology and pathophysiologically and their potential value as medication in the treatment of clinical conditions.”
In Conclusion
So what does this all mean? There are no real practical applications for this information at this time, other than to understand that much more is at work than steroid metabolism or binding to other receptor-types when it comes to the differences in androgenic and anabolic effect between the various agents. This study only touches on a very new area of research, but at the same time opens wide the door for future exploration. Further work here might one day help us determine the most effective drug combinations for exploiting the full anabolic potential of steroid administration (both medically and athletically), or aid us in planning steroid cycles that will provide the absolutely greatest balance of rewards versus risk. It might also one day lead science to the development of the holy grail of steroids; the pure anabolic agent so desired by medicine and athlete alike. Until then, at the very least, it should change the way we view the activities of steroids, and usher in a completely new level of understanding about how these drugs work in the body. The “single receptor, single gene” model is out. It has been replaced with a whole new, and much more diverse, set of possibilities.
References
[1] Relative binding activities of testosterone, 19-nortestosterone and their 5-alpha reduced derivatives to the androgen receptor and other androgen-binding proteins: a suggested role of 5-alpha reductive steroid metabolism in the dissociation of “myotropic” and “androgenic” activities of 19-nortestosterone. M. Toth, T. Zakar. J Steroid Biochem, 17 (6) (1982) 653-60
[2] Interaction of anabolic steroids with glucocorticoid receptor sites in rat muscel cytosol. M. Mayer, F. Rosen. Am J Physiol, 229 (5) (1975) 1381-86
[3] Anabolic steroids, testosterone-precursors and virilizing androgenic induce distinct activation profiles of androgen responsive promoter constructs. P.M. Holterhus, S. Piefke, O. Hiort. J Steroid Biochem & Molecular Biology, 82 (2002) 269-75
Anabolics and Gene Transcription
Steroids have two very distinct sides to the way they work in the human body. On the one hand, they have anabolic activities, a term that relates to the lean tissue building effects of these agents. This, of course, is the main goal of steroid use in the vast majority of cases. On the other hand, they also have androgenic properties, which refers to their “masculinizing” effects. This includes such male traits as secondary hair growth, deepening of the voice during puberty, maturation and function of the male reproductive system, oil production in the skin, and aggression. For the bodybuilder, this dichotomy of activity typically (although crudely) is looked at as the balance between results and side effects. For any given purpose, we are constantly trying to maximize the level of muscle growth we can achieve, while simultaneously trying to minimize the level of unnecessary side effects we must endure to get there. Science has long searched for the “pure” anabolic agent; an agent entirely devoid of androgenic activity. Such an agent could be an ideal treatment option when lean tissue building is solely desired. Unfortunately, science has never delivered on the pure anabolic promise. All available anabolic/androgenic agents exhibit both properties to some degree.
Accounting for the Differences
It is well understood that different steroids have different anabolic and androgenic effects in the body. Stanozolol, methenolone and oxandrolone for example, tend to exhibit strong tissue building effects with only weak to moderate (compared to other agents) androgenic activity. Drugs like testosterone, oxymetholone, methandrostenolone and mesterolone, on the other hand, seem to be much more strongly androgenic. This leads to the ultimate and very important question: Why does this occur? Understanding what accounts for the differences in affect between different agents is the first step in developing a pure anabolic, or at the very least, an understanding of why it’s not feasible to do so. But to get to this point, we need to fully understand how steroids work in the body, on a cellular level. For researchers, this has been one of the most diverse and controversial areas of research. Over the years, there have been many different opinions and theories postulated as to how these agents work and why some offer different benefits or drawbacks compared to others.
Receptor Activation
Steroids largely work through a mechanism known as gene transcription. The process starts when the steroid attaches to, and activates, a receptor floating around various “androgen responsive” cells of the body. This receptor is specific for anabolic/androgenic steroids (called the androgen receptor), as it is not activated by other hormones. The steroid and receptor bond with each other, forming what’s known as the “androgen-receptor complex.” This complex is then translocated as a whole to the cell nucleus, where it will attach to a specific hormone-responsive element on the cell’s DNA. This will ultimately cause the transcription of genes inside the cell that control specific functions. Of course, the most notable effect of this includes an increase in protein synthesis in skeletal muscle tissue (muscle growth). But the process of gene transcription itself has been poorly understood when it comes to anabolic steroids, leading to a great deal of speculation concerning exactly how these agents are able to exert their activities inside the cell, as well as to what genes are being transcribed.
Metabolism vs. Transcription
Anabolic steroid researchers have been specifically debating for a long time as to whether or not two different anabolic steroids, attached to androgen receptors in the same tissue, could cause two separate gene-transcribing activities. Some have argued that the same gene is transcribed in all cases, while others insist the different effects of various anabolic/androgenic agents can only be accounted for by different gene transcriptions. This question is an important one, as divergent transcribing effects could help better explain many of the differences we notice in terms of growth, side effects and other benefits and activities with different anabolic/androgenic steroids. Otherwise, differences between agents will be manifest largely through the way they are metabolized in cells and the ability of the original agent (or its active metabolites) to make it to the androgen receptor intact[1]. For example, nandrolone is largely converted to dihydronandrolone, a very weak androgenic agent, in tissues where 5-alpha reductase is abundant. This is the same enzyme that converts testosterone to the much stronger agent dihydrotestosterone, mitigating much of the androgenic activity associated with this hormone. This means that in tissues where testosterone’s androgenic potency is normally increased, nandrolone’s activity is actually measurably weakened. It’s a weaker steroid that is essentially hitting the androgen receptor here; these cells are dealing more with DHN than nandrolone. We can also take into account peripheral interaction with other (non-androgen) receptors,[2] an activity also known to affect a steroid’s anabolic potency. But are these the only main factors to consider, or may there also be other things at work at the level of gene transcription that account for the different effects of steroids?
The New Research
Researchers at the University of Libeck in Germany have recently made substantial progress in answering this question.[3] Investigators tested the effects of various steroids, including testosterone, dihydrotestosterone, nandrolone, oxandrolone, methyltrienolone and stanozolol, on a model androgen-responsive cell with three distinct artificial androgen-responsive genes. Researchers wanted to see if the different agents might cause different transcribing effects, or if in all cases the same activity occurred. The result was probably contrary to the expectations of many “single receptor, single gene” theorists. The experiment showed, quite clearly, that different transcribing effects could be seen with the same receptor type, in the same cell, with different anabolic/androgenic agents. The investigators summed up the results of their research well in stating, “… our model provides first experimental evidence for the existence of distinct target gene expression profiles due to AR-activation by structurally different androgenic steroid hormones. In fact, we showed that the AR transduces a ligand-specific signal down to the target gene level… This will add significantly to a comprehensive understanding of the diversity of biological actions of androgens and consequently, to new concepts on their role in physiology and pathophysiologically and their potential value as medication in the treatment of clinical conditions.”
In Conclusion
So what does this all mean? There are no real practical applications for this information at this time, other than to understand that much more is at work than steroid metabolism or binding to other receptor-types when it comes to the differences in androgenic and anabolic effect between the various agents. This study only touches on a very new area of research, but at the same time opens wide the door for future exploration. Further work here might one day help us determine the most effective drug combinations for exploiting the full anabolic potential of steroid administration (both medically and athletically), or aid us in planning steroid cycles that will provide the absolutely greatest balance of rewards versus risk. It might also one day lead science to the development of the holy grail of steroids; the pure anabolic agent so desired by medicine and athlete alike. Until then, at the very least, it should change the way we view the activities of steroids, and usher in a completely new level of understanding about how these drugs work in the body. The “single receptor, single gene” model is out. It has been replaced with a whole new, and much more diverse, set of possibilities.
References
[1] Relative binding activities of testosterone, 19-nortestosterone and their 5-alpha reduced derivatives to the androgen receptor and other androgen-binding proteins: a suggested role of 5-alpha reductive steroid metabolism in the dissociation of “myotropic” and “androgenic” activities of 19-nortestosterone. M. Toth, T. Zakar. J Steroid Biochem, 17 (6) (1982) 653-60
[2] Interaction of anabolic steroids with glucocorticoid receptor sites in rat muscel cytosol. M. Mayer, F. Rosen. Am J Physiol, 229 (5) (1975) 1381-86
[3] Anabolic steroids, testosterone-precursors and virilizing androgenic induce distinct activation profiles of androgen responsive promoter constructs. P.M. Holterhus, S. Piefke, O. Hiort. J Steroid Biochem & Molecular Biology, 82 (2002) 269-75