Pharmaceuticals (i.e., drugs) play an integral role in the fight against human disease. In order to fight this battle more effectively, drugs are typically designed to enhance their disease-fighting properties while minimizing any adverse side effects associated with their use. A classic drug-design example, germane to bodybuilders and athletes, is the creation of the synthetic testosterone derivative, the anabolic steroid, which was done to enhance the muscle-building, anabolic effects of these compounds while reducing their negative androgenic side effects, such as increased prostate growth and an increased risk for cardiovascular disease. Although the design of the synthetic anabolic steroid improved the anabolic to androgenic profile relative to testosterone, the production of a purely anabolic steroid has eluded all drug-design attempts thus far.
The inability to produce an exclusively anabolic steroid generated interest in another class of molecules known as selective androgen receptor modulators (SARMs), which appear to be very good candidates for creating exclusively anabolic compounds. In addition to selective modulators for the androgen receptor, the insulin and estrogen receptors have more recently been targeted for the design of selective receptor modulators that also possess a tremendous potential to exclusively activate muscle-anabolism, with little to no adverse side effects.
SARMs Have Low Androgenic Properties With the Potential to Be Purely Anabolic
SARMs are a relatively new class of non-steroidal compounds that bind and activate the testosterone receptor in a considerably different manner than either testosterone or anabolic steroids. This different binding mode likely contributes to the unique capacity to preferentially trigger anabolism over androgenicity.
Although SARMs provide an opportunity for molecules that are purely anabolic, none so far only stimulate anabolic muscle growth without producing some androgenic effects. However, more recent SARMs have been developed with relatively greater levels of anabolism and less androgenic properties. In fact, several SARMs have shown a ratio of anabolic to androgenic effects greater than 3:1 relative to testosterone with a ratio of 1:1.[SUP]1,2[/SUP]
Furthermore, a recent investigation by Dalton et al.[SUP]3[/SUP] illustrated, in a double-blind placebo study with 120 men as subjects, that ingesting the SARM called GTx-024 showed a dose-dependent improvement in total lean body mass and physical strength with no increase in prostate size. The researchers concluded that GTx-024 is an orally bioavailable SARM with tissue-selective anabolic and androgenic pharmacologic activity. However, although GTx-024 has low androgenic properties it also, along with most other SARMs, has been shown to be inadequately anabolic.
In addition to the study by Dalton et al., other investigations have looked at many candidate SARMs in preclinical and clinical trial studies[SUP]4,5[/SUP] and concluded that many different SARMs induce modest gains in lean body mass in healthy volunteers, but they are nowhere near the much greater gains in skeletal muscle mass reported with high-level dosing of anabolic steroids. The modest gains of 1.0 to 1.5 kilograms in fat-free mass with these SARMs over four to six weeks should be contrasted with the five- to seven-kilogram gains in fat-free mass with 300- and 600-milligram doses of testosterone enanthate. Nevertheless, because SARMs have become increasingly more anabolic over time, there is still hope that future generation SARMs will have greater potency, ultimately reaching the goal of being completely anabolic.
Selective Insulin Receptor Modulators (SIRMs) Have the Greatest Anabolic Potential
Insulin achieves its remarkable muscle-building effect by binding to the insulin receptor, which activates muscle cell protein synthesis and muscle growth.[SUP]6,7[/SUP] However, just as testosterone has desired anabolic properties along with unwanted side effects, insulin also has a desired anabolic impact on muscle tissue, along with several other effects throughout the body that could have an adverse impact your health. In fact, one of insulin’s unwanted side effects is its ability to potentially cause the rapid uptake of too much glucose from the blood. Although glucose uptake could increase energy levels within the muscle cell, enhancing muscular performance and muscle growth, too much glucose uptake could dangerously lower blood sugar— causing hypoglycemia. What's more, insulin also stimulates cell division by activating another signaling pathway known as the mitogen-activating protein kinase (MAPK) pathway.[SUP]8[/SUP] Insulin activation of this pathway could cause excessive cell division, promoting the progression of certain types of cancers.
These potentially harmful side effects associated with insulin use, along with insulin’s powerful anabolic capabilities, has driven a great deal of drug-design research into the controlled activation of the insulin receptor that would only activate the beneficial muscle-building actions of insulin without the adverse effects. Consequently, a unique class of drugs known as selective insulin receptor modulators (SIRMs) is being developed that will hopefully promote only muscle anabolism and not the aforementioned side effects.[SUP]9[/SUP]
SIRMs Selectively Activate Muscle Protein Synthesis and Tolerable Glucose Uptake
In the search for compounds that selectively activate the desired response from insulin signaling, a recent study by Bhaskar et al.[SUP]10[/SUP] discovered an antibody molecule that has SIRM-like activity. While rapidly probing several thousand potential binding partners for the insulin receptor, the authors identified an antibody molecule they called XMetA. This newly discovered antibody tightly binds the insulin receptor but specifically activates protein synthesis and glucose uptake in the cell, although not as powerfully as insulin. More specifically, XMetA selectively triggers the AKT/mTOR pathway with a maximal effect that is 40 percent that of insulin but, in contrast to insulin, does not induce the MAPK pathway to drive cell division.
In a second study looking at potential SIRM candidates, Jensen et al.[SUP]11[/SUP] explored thousands of potential small molecules for SIRM-like activity and discovered the synthetic insulin mimetic peptide S597 that selectively initiates a different signaling response relative to insulin. In this study, the researchers show that S597 activates the insulin receptor but not as strongly as insulin does. As a result of this lower insulin receptor activity by S597, only the AKT/mTOR signaling pathway is fully turned on, while the MAPK pathway is only partially stimulated.
SERMs Boost Testosterone and Muscle Growth
Selective estrogen receptor modulators (SERMs) are another group of selective receptor modulators that bind to the estrogen receptor, preventing interaction with its natural ligand estrogen. Unlike estrogen, which only activates the estrogen receptor, SERMs can either activate or inactivate the estrogen receptor in a tissue-dependent manner. In tissues where the SERM-estrogen receptor interaction inactivates the receptor, SERMS have an anti-estrogen influence. Originally, athletes and bodybuilders began using SERMs, such as Nolvadex or Clomid, for their anti-estrogenic ability to inactivate the estrogen receptor— particularly during and after a cycle of anabolic steroids, that may trigger abnormally high estrogen levels produced from the conversion of certain anabolic steroids into estrogen by a process known as aromatization. In order to mitigate the influence of too much estrogen, which can lead to unpleasant side effects such as gynecomastia, SERMs were used to prevent estrogen activation of the estrogen receptor. After many years using SERMs for their potent anti-estrogenic qualities, it became clear that SERMs, by way of their anti-estrogenic impact, not only inhibit the unwanted consequences of too much estrogen but also increase the amount of endogenous testosterone.
SERMs Increase Testosterone Production, But Only in Men
Exactly how the anti-estrogenic SERM effect increases testosterone levels was not well characterized until a group of scientists uncovered some of the biochemical details. In this study, Mazzarino et al.[SUP]12[/SUP] investigated the impact of three different SERMs— Nolvadex, Clomid and toremifene— on hormone and testosterone levels in four male and female subjects. All eight subjects were given two doses of one of the three previously mentioned SERMs, at 80 milligrams and 100 milligrams 24 hours apart, and their hormone levels were measured. In all four male subjects, testosterone levels increased significantly while all four female subjects showed no increase in testosterone production. Furthermore, the male subjects also showed an increase in luteinizing hormone (LH), which is a hormone produced in the anterior pituitary gland that stimulates the testicles to produce testosterone. More importantly, LH production is typically decreased by negative feedback when there is an ample amount of testosterone available. Because testosterone can be aromatized into estrogen, LH can also be inhibited by estrogen. Therefore, SERM interaction with the estrogen receptor in the brain prevents estrogen from binding, which removes the negative feedback from estrogen on LH production, thus stimulating an increase in testosterone production.
In conclusion, the design of next-generation selective receptor modulators for the testosterone, insulin and estrogen receptors will likely provide the first exclusively anabolic compound in the near future, despite the complex nature of the task. Once this extraordinary compound is created, one can’t help but wonder how much of an impact it will have on bodybuilding and sport. While it will bolster the size and strength of the modern-day bodybuilder or athlete as never before, no drug, however well designed, can foster the necessary drive and passion to be a champion— no matter how perfectly anabolic that compound might be.
For most of Michael Rudolph’s career he has been engrossed in the exercise world as either an athlete (he played college football at Hofstra University), personal trainer or as a Research Scientist (he earned a B.Sc. in Exercise Science at Hofstra University and a Ph.D. in Biochemistry and Molecular Biology from Stony Brook University). After earning his Ph.D., Michael investigated the molecular biology of exercise as a fellow at Harvard Medical School and Columbia University for over eight years. That research contributed seminally to understanding the function of the incredibly important cellular energy sensor AMPK— leading to numerous publications in peer-reviewed journals including the journal Nature. Michael is currently a scientist working at the New York Structural Biology Center doing contract work for the Department of Defense on a project involving national security.
References:
1. Yin D, Gao W, et al. Pharmacodynamics of selective androgen receptor modulators. J Pharmacol Exp Ther 2003;304, 1334-1340.
2. Hanada K, Furuya K, et al. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol Pharm Bull 2003;26, 1563-1569.
3. Dalton JT, Barnette KG, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle 2011;2, 153-161.
4. Narayanan R, Coss CC, et al. Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways. Mol Endocrinol 2008;22, 2448-2465.
5. Edwards JP, West SJ, et al. New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone. Bioorg Med Chem Lett 1998;8, 745-750.
6. Biolo G, Declan Fleming RY and Wolfe RR. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest 1995;95, 811-819.
7. Guillet C, Prod'homme M, et al. Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans. Faseb J 2004;18, 1586-1587.
8. Kayali AG, Austin DA and Webster NJ. Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes. Diabetes 2000;49, 1783-1793.
9. Vigneri R, Squatrito S and Frittitta L. Selective Insulin Receptor Modulators (SIRM): A New Class of Antidiabetes Drugs? Diabetes 2012;61, 984-985.
10. Bhaskar V, Goldfine ID, et al. A fully human, allosteric monoclonal antibody that activates the insulin receptor and improves glycemic control. Diabetes 2012;61, 1263-1271.
11. Jensen M, Palsgaard J, et al. Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts. Biochem J 2008;412, 435-445.
12. Mazzarino M, Bragano MC, et al. Relevance of the selective oestrogen receptor modulators tamoxifen, toremifene and clomiphene in doping field: endogenous steroids urinary profile after multiple oral doses. Steroids 2011;76, 1400-1406.
The inability to produce an exclusively anabolic steroid generated interest in another class of molecules known as selective androgen receptor modulators (SARMs), which appear to be very good candidates for creating exclusively anabolic compounds. In addition to selective modulators for the androgen receptor, the insulin and estrogen receptors have more recently been targeted for the design of selective receptor modulators that also possess a tremendous potential to exclusively activate muscle-anabolism, with little to no adverse side effects.
SARMs Have Low Androgenic Properties With the Potential to Be Purely Anabolic
SARMs are a relatively new class of non-steroidal compounds that bind and activate the testosterone receptor in a considerably different manner than either testosterone or anabolic steroids. This different binding mode likely contributes to the unique capacity to preferentially trigger anabolism over androgenicity.
Although SARMs provide an opportunity for molecules that are purely anabolic, none so far only stimulate anabolic muscle growth without producing some androgenic effects. However, more recent SARMs have been developed with relatively greater levels of anabolism and less androgenic properties. In fact, several SARMs have shown a ratio of anabolic to androgenic effects greater than 3:1 relative to testosterone with a ratio of 1:1.[SUP]1,2[/SUP]
Furthermore, a recent investigation by Dalton et al.[SUP]3[/SUP] illustrated, in a double-blind placebo study with 120 men as subjects, that ingesting the SARM called GTx-024 showed a dose-dependent improvement in total lean body mass and physical strength with no increase in prostate size. The researchers concluded that GTx-024 is an orally bioavailable SARM with tissue-selective anabolic and androgenic pharmacologic activity. However, although GTx-024 has low androgenic properties it also, along with most other SARMs, has been shown to be inadequately anabolic.
In addition to the study by Dalton et al., other investigations have looked at many candidate SARMs in preclinical and clinical trial studies[SUP]4,5[/SUP] and concluded that many different SARMs induce modest gains in lean body mass in healthy volunteers, but they are nowhere near the much greater gains in skeletal muscle mass reported with high-level dosing of anabolic steroids. The modest gains of 1.0 to 1.5 kilograms in fat-free mass with these SARMs over four to six weeks should be contrasted with the five- to seven-kilogram gains in fat-free mass with 300- and 600-milligram doses of testosterone enanthate. Nevertheless, because SARMs have become increasingly more anabolic over time, there is still hope that future generation SARMs will have greater potency, ultimately reaching the goal of being completely anabolic.
Selective Insulin Receptor Modulators (SIRMs) Have the Greatest Anabolic Potential
Insulin achieves its remarkable muscle-building effect by binding to the insulin receptor, which activates muscle cell protein synthesis and muscle growth.[SUP]6,7[/SUP] However, just as testosterone has desired anabolic properties along with unwanted side effects, insulin also has a desired anabolic impact on muscle tissue, along with several other effects throughout the body that could have an adverse impact your health. In fact, one of insulin’s unwanted side effects is its ability to potentially cause the rapid uptake of too much glucose from the blood. Although glucose uptake could increase energy levels within the muscle cell, enhancing muscular performance and muscle growth, too much glucose uptake could dangerously lower blood sugar— causing hypoglycemia. What's more, insulin also stimulates cell division by activating another signaling pathway known as the mitogen-activating protein kinase (MAPK) pathway.[SUP]8[/SUP] Insulin activation of this pathway could cause excessive cell division, promoting the progression of certain types of cancers.
These potentially harmful side effects associated with insulin use, along with insulin’s powerful anabolic capabilities, has driven a great deal of drug-design research into the controlled activation of the insulin receptor that would only activate the beneficial muscle-building actions of insulin without the adverse effects. Consequently, a unique class of drugs known as selective insulin receptor modulators (SIRMs) is being developed that will hopefully promote only muscle anabolism and not the aforementioned side effects.[SUP]9[/SUP]
SIRMs Selectively Activate Muscle Protein Synthesis and Tolerable Glucose Uptake
In the search for compounds that selectively activate the desired response from insulin signaling, a recent study by Bhaskar et al.[SUP]10[/SUP] discovered an antibody molecule that has SIRM-like activity. While rapidly probing several thousand potential binding partners for the insulin receptor, the authors identified an antibody molecule they called XMetA. This newly discovered antibody tightly binds the insulin receptor but specifically activates protein synthesis and glucose uptake in the cell, although not as powerfully as insulin. More specifically, XMetA selectively triggers the AKT/mTOR pathway with a maximal effect that is 40 percent that of insulin but, in contrast to insulin, does not induce the MAPK pathway to drive cell division.
In a second study looking at potential SIRM candidates, Jensen et al.[SUP]11[/SUP] explored thousands of potential small molecules for SIRM-like activity and discovered the synthetic insulin mimetic peptide S597 that selectively initiates a different signaling response relative to insulin. In this study, the researchers show that S597 activates the insulin receptor but not as strongly as insulin does. As a result of this lower insulin receptor activity by S597, only the AKT/mTOR signaling pathway is fully turned on, while the MAPK pathway is only partially stimulated.
SERMs Boost Testosterone and Muscle Growth
Selective estrogen receptor modulators (SERMs) are another group of selective receptor modulators that bind to the estrogen receptor, preventing interaction with its natural ligand estrogen. Unlike estrogen, which only activates the estrogen receptor, SERMs can either activate or inactivate the estrogen receptor in a tissue-dependent manner. In tissues where the SERM-estrogen receptor interaction inactivates the receptor, SERMS have an anti-estrogen influence. Originally, athletes and bodybuilders began using SERMs, such as Nolvadex or Clomid, for their anti-estrogenic ability to inactivate the estrogen receptor— particularly during and after a cycle of anabolic steroids, that may trigger abnormally high estrogen levels produced from the conversion of certain anabolic steroids into estrogen by a process known as aromatization. In order to mitigate the influence of too much estrogen, which can lead to unpleasant side effects such as gynecomastia, SERMs were used to prevent estrogen activation of the estrogen receptor. After many years using SERMs for their potent anti-estrogenic qualities, it became clear that SERMs, by way of their anti-estrogenic impact, not only inhibit the unwanted consequences of too much estrogen but also increase the amount of endogenous testosterone.
SERMs Increase Testosterone Production, But Only in Men
Exactly how the anti-estrogenic SERM effect increases testosterone levels was not well characterized until a group of scientists uncovered some of the biochemical details. In this study, Mazzarino et al.[SUP]12[/SUP] investigated the impact of three different SERMs— Nolvadex, Clomid and toremifene— on hormone and testosterone levels in four male and female subjects. All eight subjects were given two doses of one of the three previously mentioned SERMs, at 80 milligrams and 100 milligrams 24 hours apart, and their hormone levels were measured. In all four male subjects, testosterone levels increased significantly while all four female subjects showed no increase in testosterone production. Furthermore, the male subjects also showed an increase in luteinizing hormone (LH), which is a hormone produced in the anterior pituitary gland that stimulates the testicles to produce testosterone. More importantly, LH production is typically decreased by negative feedback when there is an ample amount of testosterone available. Because testosterone can be aromatized into estrogen, LH can also be inhibited by estrogen. Therefore, SERM interaction with the estrogen receptor in the brain prevents estrogen from binding, which removes the negative feedback from estrogen on LH production, thus stimulating an increase in testosterone production.
In conclusion, the design of next-generation selective receptor modulators for the testosterone, insulin and estrogen receptors will likely provide the first exclusively anabolic compound in the near future, despite the complex nature of the task. Once this extraordinary compound is created, one can’t help but wonder how much of an impact it will have on bodybuilding and sport. While it will bolster the size and strength of the modern-day bodybuilder or athlete as never before, no drug, however well designed, can foster the necessary drive and passion to be a champion— no matter how perfectly anabolic that compound might be.
For most of Michael Rudolph’s career he has been engrossed in the exercise world as either an athlete (he played college football at Hofstra University), personal trainer or as a Research Scientist (he earned a B.Sc. in Exercise Science at Hofstra University and a Ph.D. in Biochemistry and Molecular Biology from Stony Brook University). After earning his Ph.D., Michael investigated the molecular biology of exercise as a fellow at Harvard Medical School and Columbia University for over eight years. That research contributed seminally to understanding the function of the incredibly important cellular energy sensor AMPK— leading to numerous publications in peer-reviewed journals including the journal Nature. Michael is currently a scientist working at the New York Structural Biology Center doing contract work for the Department of Defense on a project involving national security.
References:
1. Yin D, Gao W, et al. Pharmacodynamics of selective androgen receptor modulators. J Pharmacol Exp Ther 2003;304, 1334-1340.
2. Hanada K, Furuya K, et al. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol Pharm Bull 2003;26, 1563-1569.
3. Dalton JT, Barnette KG, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle 2011;2, 153-161.
4. Narayanan R, Coss CC, et al. Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways. Mol Endocrinol 2008;22, 2448-2465.
5. Edwards JP, West SJ, et al. New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone. Bioorg Med Chem Lett 1998;8, 745-750.
6. Biolo G, Declan Fleming RY and Wolfe RR. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest 1995;95, 811-819.
7. Guillet C, Prod'homme M, et al. Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans. Faseb J 2004;18, 1586-1587.
8. Kayali AG, Austin DA and Webster NJ. Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes. Diabetes 2000;49, 1783-1793.
9. Vigneri R, Squatrito S and Frittitta L. Selective Insulin Receptor Modulators (SIRM): A New Class of Antidiabetes Drugs? Diabetes 2012;61, 984-985.
10. Bhaskar V, Goldfine ID, et al. A fully human, allosteric monoclonal antibody that activates the insulin receptor and improves glycemic control. Diabetes 2012;61, 1263-1271.
11. Jensen M, Palsgaard J, et al. Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts. Biochem J 2008;412, 435-445.
12. Mazzarino M, Bragano MC, et al. Relevance of the selective oestrogen receptor modulators tamoxifen, toremifene and clomiphene in doping field: endogenous steroids urinary profile after multiple oral doses. Steroids 2011;76, 1400-1406.
