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ANABOLIC STEROIDS: THE NEXT GENERATION Selective Androgen Receptor Modulators
by Dan Gwartney, MD
PQ: Nearly all of the SARM drugs moving forward into clinical trials are non-steroidal, meaning they are not based upon testosterone, but instead are modified receptor.
A parent picking up his child at an elementary school might look into the chaotic crowd of kids, moving with the randomness that defines Brownian motion at a noise forms of other chemicals that are known to interact with and stimulate the androgen level that would make O’Hare airport seem like a library, hoping to glimpse a distinctive T-shirt to identify his progeny. Not only is it near impossible to discern little Johnny from his best friend Jimmy; he may look a lot like Janey, the tomboy. Fortunately, puberty makes gender distinction much easier.
Many of the changes that occur during puberty are due to the effects of sex hormones; in men, this refers mainly to testosterone. However, it has been argued that testosterone is in many ways a prohormone, as it is converted in the body (male and female) into estradiol (a potent estrogen or female sex hormone) or dihydrotestosterone (a more potent androgen called DHT) in certain tissues. During puberty, many teens experience tenderness under the nipple or even breast growth due to an excess of estrogen called gynecomastia.1 Later in life, many men experience hair loss or problems urinating due to an enlarged prostate caused by an excess in DHT.2 Of course, testosterone is also an active and powerful hormone in its own right, stimulating the development of muscle mass and strength. The effects seen from testosterone or its metabolites, estradiol or DHT, are dependent (for the most part) on the interaction of the steroid with its respective receptor (testosterone, estradiol and DHT are all steroids). Obviously, the effects of the estrogen (estradiol) are much different from the androgens (testosterone and DHT), even though their chemical structures are similar. This is because estradiol does not interact strongly with the androgen receptor and the androgens do not interact strongly with the estrogen receptors. Looking specifically at the androgens, the effects are often divided into two classes, androgenic versus anabolic. Androgenic effects include those relating to reproductive glands or features that are gender-specific, such as penile length, deepening of the voice or hair growth/loss patterns. Many women who have used anabolic steroids experienced androgenic side effects, such as sounding more like a man or clitoral enlargement (the clitoris contains erectile tissue, similar to the penis but is normally smaller than a pencil eraser).3 Anabolic effects include growth and increased density of skeletal muscle and bone, which is the primary purpose for the use of anabolic steroids by athletes. Since the earliest days of androgen research, scientists have sought to separate the anabolic properties from androgenic and vice versa. The quest to develop drugs that are purely anabolic has been as fruitless as the quests of King Arthur’s knights as they sought out the Holy Grail. However, many interesting drugs were developed over the course of time that provided a greater ratio of anabolic to androgenic effects. In fact, many of the anabolic steroids developed were found to be highly anabolic, with relatively little androgenic burden as measured in labs. Of course, as the examples of many female athletes have shown, in women and children, even the “cleanest” anabolic steroid can cause androgenic effects when used in high enough doses. An additional problem is that most anabolic steroids interfere with the natural production of testosterone (and sperm), because the body reacts as it would if testosterone production was too high; it turns off the “on signal” from the brain, which effectively shuts down the testicles.4 Given the lack of federal support for research into anabolic steroids, bias against the steroid drug class due to sports doping and adolescent abuse, lack of patent protection (and thus profitability) and desire for an androgen-free anabolic (this would increase the consumer base to include women, children and men with androgen-sensitive tumors), pharmaceutical companies have returned to that grail-like quest of the “pure” anabolic. Though the properties vary somewhat depending on the specific use intended for a drug (bone-building to treat osteoporosis in the elderly; muscle-building to treat people with cancer or other wasting diseases; increase red blood cell production in cases of anemia; suppress testicular function for male contraception; increase libido for men and women, etc.), nearly every example of such drugs looks to provide the anabolic benefits without virilizing women or increasing prostate growth in men.5-14 As the benefits and side-effects are all outcomes from activating the same androgen receptor, the drugs have to be proven to be selective (stimulate anabolic effects without promoting androgenic effects). Hence, the emergence of the drug class known as SARM. Selective androgen receptor modulators (SARM) are drugs that activate the androgen receptor normally occupied by testosterone or its more androgenic metabolite, DHT. [There are some SARM that inhibit androgen receptor function, called anti-androgens, but this article will focus on the anabolic SARM.] The clinical effects of a SARM must provide the anabolic effects without producing any androgenic side effects at the same dose. A number of such drugs have been developed, with nearly every major pharmaceutical company reporting work in the area. This is surprising, as none of the companies are putting research and development money behind uses for testosterone, nandrolone or any of the other known anabolic steroids that have been in use for decades. Many of the challenges to using testosterone have been addressed. Clinicians noted that oral anabolic steroids were toxic to the liver, injectable esters produced noticeable highs and lows and topical preparations had a high rate of skin reactions.15,16 However, the latest generation of topical testosterone gels are well-tolerated and a long-acting ester that need only be injected once every three months, testosterone undecanoate, has been used for years in many other countries with favorable reviews.17 Therapies that do not exceed the physiologic range are being used safely with no significant increase in any adverse effects. In fact, many favorable responses are being noted with testosterone therapy. An insightful editorial on SARM drugs offered one suggestion as to why SARM drugs are selective.18 While acknowledging the probability that SARM drugs reach some tissues in higher concentration compared to testosterone, some lower; activate the androgen receptor in different ways; interact with the genes targeted by androgen-androgen receptor complexes; or are metabolized differently— a noted researcher in the field believes much of the specificity of SARM drugs may be due to the fact that they do not react with the enzyme 5-alpha-reductase. 5-alpha-reductase is the enzyme that converts testosterone to the more androgenic hormone, DHT.2 In the tissues that demonstrate an anabolic effect (muscle and bone for example), 5-alpha-reductase activity is much lower than in tissues that have an androgenic response (prostate and skin). This opinion coincides well with the observation that the anabolic steroid nandrolone (19-nortestosterone, Deca Durabolin) promotes muscle gains without affecting or even reducing the size of the prostate.19 Nandrolone does react with 5-alpha-reductase, but rather than converting to a more androgenic metabolite, it is converted to a less androgenic steroid.20 Unfortunately, using nandrolone without the additional support of an androgenic anabolic steroid may lead to problems with erectile dysfunction or libido loss, as nandrolone can suppress natural testosterone production. Undaunted, SARM research advances. Nearly all of the SARM drugs moving forward into clinical trials are non-steroidal, meaning they are not based upon testosterone, but instead are modified forms of other chemicals that are known to interact with and stimulate the androgen receptor. Certainly, there are some steroidal SARM drugs being studied, but they represent a distinct minority.12 Again, this may relate to the fact that the explosion in steroid research of the 1950s and 1960s resulted in the loss of patentability of most of the suitable steroidal SARM drug candidates. Research has been reported on SARM drugs that support bone density, increase/maintain the libido (sex drive) in female rats, inhibit sperm and testosterone production and reduce body fat.5-11 And…of course there has been research into the effect of SARM drugs on muscle.12-14 Remember, most all research revolves around rodents or tissue growing in sterile dishes in the lab. However, the results of a phase II study in the use of one SARM were reported that looked at the lean mass and physical performance benefits in a group of elderly men and women.21 Ostarine, the SARM most advanced through the development phase, was provided to 120 elderly people (60 men averaging 66 years of age; 60 women averaging 63 years of age) who were healthy. The subjects were divided into four groups based upon the ostarine dose provided; 0.1mg, 0.3mg, 1mg or 3mg per day. Tests were performed prior to therapy and after three months. The researchers discovered that ostarine provided a dose-dependent increase in lean mass and stair-climbing power, without increasing PSA (in men), sebum production (oily skin) or suppressing LH concentration (the “on signal” for natural testosterone production from the brain that is shut down by anabolic steroids). The study concluded that ostarine increased lean mass and strength without evidencing any androgenic side effects. Further ostarine research into its use in treating the wasting related to cancer is scheduled. This finding seems rather exciting; after all, it offers the benefits of anabolic steroids without the side effects. However, it remains unclear as to what value ostarine, or other SARM drugs may hold in the potential field of anabolic therapy for early andropause or strength and physique enhancement. The subjects in this study were all elderly, meaning they likely all were experiencing the age-related decline in anabolic hormones (testosterone, DHEA, growth hormone, etc). Also, the degree of gain in lean mass was only 1.4kg after three months of therapy for the highest dose group. The increase in speed (+15 percent) and power (+25 percent) measured during the stair-climbing was impressive though, suggesting the gain in lean mass was mostly muscle. It would have been helpful if changes in body composition were described as well.21 Two findings from the study were interesting from the perspective of possible use for enhancement therapies. The first was that the effects were dose-dependent, meaning the higher the dose, the greater the effects (within the range studied). This relationship between drug concentration and effect was also noted for testosterone enanthate in studies performed by noted researcher Shalender Bhasin.22,23 As no adverse side effects were noted, it would have been valuable to expand the drug range further to establish an upper limit for safety and efficacy. Secondly, ostarine had no effect on LH levels, meaning it did not suppress natural testosterone production. If natural testosterone concentrations are unaffected (this was not reported, so that would be an assumption), then the ostarine would be supplementing the anabolic effect of a person’s natural testosterone levels, in essence giving them the equivalent of a 125-200mg/week testosterone ester head start. It is difficult to say at this time where ostarine could best be used, but it is highly improbable that it will be approved for use in healthy, young adults or even people entering the beginning phases of andropause/menopause given the bias against physique or performance enhancement. Yet, as a drug that may offer a safe method of increasing one’s anabolic drive and support the effects of a healthy lifestyle of diet and exercise, ostarine is intriguing. The pharmaceutical companies are already cautioning against the entry of SARM drugs into a doping athlete’s regimen, but one can understand the appeal to such a crowd. The reported properties of ostarine suggest it could be a safe oral anabolic that could be taken alone by men and women alike, or stacked with injectable anabolic steroids to allow a greater anabolic response with less androgenic exposure. It is also possible that ostarine could be used as a bridge during post-cycle therapy, as it does not appear to suppress LH production (or recovery in the case of anabolic steroid use). Of course, SARM drugs may turn out to be no more effective than anabolic steroids combined with partial 5-alpha-reductase blockade and they may lack some of the physiologic effects such as diversion of mesenchymal stem cells toward muscle cell development and away from fat cell development or the upregulation of androgen receptors.24,25 It is much too early to tell.
The same ethical arguments against anabolic steroid use will surely be measured against SARM use, whether it is muscle-building by bodybuilders, strength gains by football players, fracture prevention by gymnasts or hematocrit (red blood cell) increases by cyclists and marathoners. Sadly, the ethics of sports doping will likely delay the essential research that is necessary to understand the potential value future SARM drugs may have for treating the aging-related decline in anabolic metabolism or quality-of-life enhancement for responsible adults. Hopefully, research into these fields will commence to increase the understanding of SARM drugs’ roles in assisting in the battle against the societal epidemic of obesity and promotion of fitness-based lifestyles.
by Dan Gwartney, MD
PQ: Nearly all of the SARM drugs moving forward into clinical trials are non-steroidal, meaning they are not based upon testosterone, but instead are modified receptor.
A parent picking up his child at an elementary school might look into the chaotic crowd of kids, moving with the randomness that defines Brownian motion at a noise forms of other chemicals that are known to interact with and stimulate the androgen level that would make O’Hare airport seem like a library, hoping to glimpse a distinctive T-shirt to identify his progeny. Not only is it near impossible to discern little Johnny from his best friend Jimmy; he may look a lot like Janey, the tomboy. Fortunately, puberty makes gender distinction much easier.
Many of the changes that occur during puberty are due to the effects of sex hormones; in men, this refers mainly to testosterone. However, it has been argued that testosterone is in many ways a prohormone, as it is converted in the body (male and female) into estradiol (a potent estrogen or female sex hormone) or dihydrotestosterone (a more potent androgen called DHT) in certain tissues. During puberty, many teens experience tenderness under the nipple or even breast growth due to an excess of estrogen called gynecomastia.1 Later in life, many men experience hair loss or problems urinating due to an enlarged prostate caused by an excess in DHT.2 Of course, testosterone is also an active and powerful hormone in its own right, stimulating the development of muscle mass and strength. The effects seen from testosterone or its metabolites, estradiol or DHT, are dependent (for the most part) on the interaction of the steroid with its respective receptor (testosterone, estradiol and DHT are all steroids). Obviously, the effects of the estrogen (estradiol) are much different from the androgens (testosterone and DHT), even though their chemical structures are similar. This is because estradiol does not interact strongly with the androgen receptor and the androgens do not interact strongly with the estrogen receptors. Looking specifically at the androgens, the effects are often divided into two classes, androgenic versus anabolic. Androgenic effects include those relating to reproductive glands or features that are gender-specific, such as penile length, deepening of the voice or hair growth/loss patterns. Many women who have used anabolic steroids experienced androgenic side effects, such as sounding more like a man or clitoral enlargement (the clitoris contains erectile tissue, similar to the penis but is normally smaller than a pencil eraser).3 Anabolic effects include growth and increased density of skeletal muscle and bone, which is the primary purpose for the use of anabolic steroids by athletes. Since the earliest days of androgen research, scientists have sought to separate the anabolic properties from androgenic and vice versa. The quest to develop drugs that are purely anabolic has been as fruitless as the quests of King Arthur’s knights as they sought out the Holy Grail. However, many interesting drugs were developed over the course of time that provided a greater ratio of anabolic to androgenic effects. In fact, many of the anabolic steroids developed were found to be highly anabolic, with relatively little androgenic burden as measured in labs. Of course, as the examples of many female athletes have shown, in women and children, even the “cleanest” anabolic steroid can cause androgenic effects when used in high enough doses. An additional problem is that most anabolic steroids interfere with the natural production of testosterone (and sperm), because the body reacts as it would if testosterone production was too high; it turns off the “on signal” from the brain, which effectively shuts down the testicles.4 Given the lack of federal support for research into anabolic steroids, bias against the steroid drug class due to sports doping and adolescent abuse, lack of patent protection (and thus profitability) and desire for an androgen-free anabolic (this would increase the consumer base to include women, children and men with androgen-sensitive tumors), pharmaceutical companies have returned to that grail-like quest of the “pure” anabolic. Though the properties vary somewhat depending on the specific use intended for a drug (bone-building to treat osteoporosis in the elderly; muscle-building to treat people with cancer or other wasting diseases; increase red blood cell production in cases of anemia; suppress testicular function for male contraception; increase libido for men and women, etc.), nearly every example of such drugs looks to provide the anabolic benefits without virilizing women or increasing prostate growth in men.5-14 As the benefits and side-effects are all outcomes from activating the same androgen receptor, the drugs have to be proven to be selective (stimulate anabolic effects without promoting androgenic effects). Hence, the emergence of the drug class known as SARM. Selective androgen receptor modulators (SARM) are drugs that activate the androgen receptor normally occupied by testosterone or its more androgenic metabolite, DHT. [There are some SARM that inhibit androgen receptor function, called anti-androgens, but this article will focus on the anabolic SARM.] The clinical effects of a SARM must provide the anabolic effects without producing any androgenic side effects at the same dose. A number of such drugs have been developed, with nearly every major pharmaceutical company reporting work in the area. This is surprising, as none of the companies are putting research and development money behind uses for testosterone, nandrolone or any of the other known anabolic steroids that have been in use for decades. Many of the challenges to using testosterone have been addressed. Clinicians noted that oral anabolic steroids were toxic to the liver, injectable esters produced noticeable highs and lows and topical preparations had a high rate of skin reactions.15,16 However, the latest generation of topical testosterone gels are well-tolerated and a long-acting ester that need only be injected once every three months, testosterone undecanoate, has been used for years in many other countries with favorable reviews.17 Therapies that do not exceed the physiologic range are being used safely with no significant increase in any adverse effects. In fact, many favorable responses are being noted with testosterone therapy. An insightful editorial on SARM drugs offered one suggestion as to why SARM drugs are selective.18 While acknowledging the probability that SARM drugs reach some tissues in higher concentration compared to testosterone, some lower; activate the androgen receptor in different ways; interact with the genes targeted by androgen-androgen receptor complexes; or are metabolized differently— a noted researcher in the field believes much of the specificity of SARM drugs may be due to the fact that they do not react with the enzyme 5-alpha-reductase. 5-alpha-reductase is the enzyme that converts testosterone to the more androgenic hormone, DHT.2 In the tissues that demonstrate an anabolic effect (muscle and bone for example), 5-alpha-reductase activity is much lower than in tissues that have an androgenic response (prostate and skin). This opinion coincides well with the observation that the anabolic steroid nandrolone (19-nortestosterone, Deca Durabolin) promotes muscle gains without affecting or even reducing the size of the prostate.19 Nandrolone does react with 5-alpha-reductase, but rather than converting to a more androgenic metabolite, it is converted to a less androgenic steroid.20 Unfortunately, using nandrolone without the additional support of an androgenic anabolic steroid may lead to problems with erectile dysfunction or libido loss, as nandrolone can suppress natural testosterone production. Undaunted, SARM research advances. Nearly all of the SARM drugs moving forward into clinical trials are non-steroidal, meaning they are not based upon testosterone, but instead are modified forms of other chemicals that are known to interact with and stimulate the androgen receptor. Certainly, there are some steroidal SARM drugs being studied, but they represent a distinct minority.12 Again, this may relate to the fact that the explosion in steroid research of the 1950s and 1960s resulted in the loss of patentability of most of the suitable steroidal SARM drug candidates. Research has been reported on SARM drugs that support bone density, increase/maintain the libido (sex drive) in female rats, inhibit sperm and testosterone production and reduce body fat.5-11 And…of course there has been research into the effect of SARM drugs on muscle.12-14 Remember, most all research revolves around rodents or tissue growing in sterile dishes in the lab. However, the results of a phase II study in the use of one SARM were reported that looked at the lean mass and physical performance benefits in a group of elderly men and women.21 Ostarine, the SARM most advanced through the development phase, was provided to 120 elderly people (60 men averaging 66 years of age; 60 women averaging 63 years of age) who were healthy. The subjects were divided into four groups based upon the ostarine dose provided; 0.1mg, 0.3mg, 1mg or 3mg per day. Tests were performed prior to therapy and after three months. The researchers discovered that ostarine provided a dose-dependent increase in lean mass and stair-climbing power, without increasing PSA (in men), sebum production (oily skin) or suppressing LH concentration (the “on signal” for natural testosterone production from the brain that is shut down by anabolic steroids). The study concluded that ostarine increased lean mass and strength without evidencing any androgenic side effects. Further ostarine research into its use in treating the wasting related to cancer is scheduled. This finding seems rather exciting; after all, it offers the benefits of anabolic steroids without the side effects. However, it remains unclear as to what value ostarine, or other SARM drugs may hold in the potential field of anabolic therapy for early andropause or strength and physique enhancement. The subjects in this study were all elderly, meaning they likely all were experiencing the age-related decline in anabolic hormones (testosterone, DHEA, growth hormone, etc). Also, the degree of gain in lean mass was only 1.4kg after three months of therapy for the highest dose group. The increase in speed (+15 percent) and power (+25 percent) measured during the stair-climbing was impressive though, suggesting the gain in lean mass was mostly muscle. It would have been helpful if changes in body composition were described as well.21 Two findings from the study were interesting from the perspective of possible use for enhancement therapies. The first was that the effects were dose-dependent, meaning the higher the dose, the greater the effects (within the range studied). This relationship between drug concentration and effect was also noted for testosterone enanthate in studies performed by noted researcher Shalender Bhasin.22,23 As no adverse side effects were noted, it would have been valuable to expand the drug range further to establish an upper limit for safety and efficacy. Secondly, ostarine had no effect on LH levels, meaning it did not suppress natural testosterone production. If natural testosterone concentrations are unaffected (this was not reported, so that would be an assumption), then the ostarine would be supplementing the anabolic effect of a person’s natural testosterone levels, in essence giving them the equivalent of a 125-200mg/week testosterone ester head start. It is difficult to say at this time where ostarine could best be used, but it is highly improbable that it will be approved for use in healthy, young adults or even people entering the beginning phases of andropause/menopause given the bias against physique or performance enhancement. Yet, as a drug that may offer a safe method of increasing one’s anabolic drive and support the effects of a healthy lifestyle of diet and exercise, ostarine is intriguing. The pharmaceutical companies are already cautioning against the entry of SARM drugs into a doping athlete’s regimen, but one can understand the appeal to such a crowd. The reported properties of ostarine suggest it could be a safe oral anabolic that could be taken alone by men and women alike, or stacked with injectable anabolic steroids to allow a greater anabolic response with less androgenic exposure. It is also possible that ostarine could be used as a bridge during post-cycle therapy, as it does not appear to suppress LH production (or recovery in the case of anabolic steroid use). Of course, SARM drugs may turn out to be no more effective than anabolic steroids combined with partial 5-alpha-reductase blockade and they may lack some of the physiologic effects such as diversion of mesenchymal stem cells toward muscle cell development and away from fat cell development or the upregulation of androgen receptors.24,25 It is much too early to tell.
The same ethical arguments against anabolic steroid use will surely be measured against SARM use, whether it is muscle-building by bodybuilders, strength gains by football players, fracture prevention by gymnasts or hematocrit (red blood cell) increases by cyclists and marathoners. Sadly, the ethics of sports doping will likely delay the essential research that is necessary to understand the potential value future SARM drugs may have for treating the aging-related decline in anabolic metabolism or quality-of-life enhancement for responsible adults. Hopefully, research into these fields will commence to increase the understanding of SARM drugs’ roles in assisting in the battle against the societal epidemic of obesity and promotion of fitness-based lifestyles.
