- Jun 25, 2006
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Designer Steroid THG
Structure, Activity and Toxicity Analysis
If you don’t recognize the three letters THG, you must have been hiding in a cave somewhere for the past couple of months. I am, of course, referring to the new designer steroid tetrahydrogestrinone (THG), which was recently brought to light in what promises to be the biggest organized bust for steroid use in the history of competitive sports. At least these were the words of Terry Madden, Chief Executive Officer of the U.S. Anti-Doping Agency (USADA), when addressing a group of newspaper and television reporters in a recent press conference. His accompanying press release spoke of an anonymous Olympic coach who turned over a syringe containing this designer steroid and implicated Victor Conte of BALCO Labs in California as the source for the agent. Conte is credited with coaching many of the world’s top athletes. USADA is now deep into a media frenzy, with many big names speculated to be among those who will test positive for the substance, and government officials promising heavy criminal charges for Conte and others potentially involved. The political and social implications for this scandal could warrant a long article alone; the topics are being addressed to the point of total redundancy by just about every media outlet in the country. If you want to know who is getting nabbed and what was happening behind the scenes, I recommend following the subject in the mainstream press. I, however, am going to focus on a very different part of the THG saga. I am going to take an up- close look at the THG molecule itself, to try to give you some idea concerning the actual properties of this agent. I’m sure many of you are curious about THG, as I was when I first heard talk of a “new” designer steroid. Its name, tetrahydrogestrinone, is a little difficult to decipher at first glance, though. Madden will only say that it’s similar to both gestrinone and trenbolone, which doesn’t really tell us enough to even pinpoint its structure. We are going to have to unravel this one for ourselves if we want answers.
A Cousin of Gestrinone
The first agent of reference, gestrinone, is not actually an anabolic/androgenic steroid, although it may indeed have some androgenic activity.[1] It’s primarily an anti-gonadotropic agent, used medically in the treatment of endometriosis.[2] It is not available, nor is it considered a controlled substance, in this country. Its structural relationship to trenbolone should be obvious when looking at the diagrams provided. Its activity, however, is far removed from this strong anabolic steroid. The reason is obviously the 17-alpha ethynyl modification, a trait that seems to strongly interfere with binding to the androgen receptor. With oral anabolic steroids, we typically see methyl groups added to this position, or in some instances ethyl groups. Both will usually make a steroid orally active, while at the same time allowing it to retain an effective level of activity at the androgen receptor. No commercial anabolic steroid has ever carried an ethynyl modification. As it turns out, this is the sole place of alteration in the creation of our new designer steroid.
THG and Methyl-Trenbolone“Tetrahydro” informs us that four (tetra) hydrogen atoms have been added to the gestrinone molecule to create our new steroid. We must figure out for ourselves where they were added. Although we are given no clue as to exactly where they are, it becomes obvious when we examine the structure of gestrinone. If we want to turn this into a potent steroid, we definitely need to get rid of its 17alpha ethynyl modification, first and foremost. Although gestrinone does seem to have some weak activity in this regard, it’s certainly not going to be enough to warrant using it as a muscle-building agent. If we substitute its ethynyl modification for an ethyl group, however, we are left with a compound that closely resembles one of the most powerful steroids known to man, methyltrienolone (17alpha-methyl-trenbolone). We also have exactly four extra hydrogen atoms in the process. Although we could come up with a couple of other scenarios, any other way of trying to add four hydrogen atoms would have eliminated the relationship noted between THG, trenbolone and gestrinone. THG, therefore, absolutely must be a slightly tweaked (18-homologated) and ethylated form of methyltrienolone. The relationship Madden points out between trenbolone and THG is entirely cosmetic, not functional. For our purposes, he might have well been likening THG to testosterone or nandrolone. It would be far more accurate to look at methyltrienolone when attempting to discern its properties, which should be similar in almost every regard including preferred route of administration (oral), resistance to metabolism, unusually high milligram-for- milligram potency, and side effect potential. In terms of the basic questions asked of every steroid, we can be confident that THG converts neither estrogen nor a weaker dihydronandrolone derivative, which means both moderate to strong androgenic activity and no worries about water or fat retention (the latter two traits usually being tied to estrogen conversion). There is the probability that THG has some progestational activity, however this is just a point of speculation (slightly more so than my others) until we have evidence to prove it, and is probably not extremely important overall anyway. The results from a cycle of tetrahydrogestrinone are likely to be high quality; the steroid imparting pure lean muscle tissue and strength gains instead of the sheer mass we would expect from bulking agents like testosterone, Dianabol or Anadrol. It is much more like Winstrol or Anavar in terms of overall effect, which makes THG a steroid more ideally suited for athletes competing in speed sports (such as track and field events) where it is not desirable to carry around unnecessary water weight. THG is far more potent than these well-known anabolics, however. We can base this to some extent on the potency of methyltrienolone, which is known to be effective in humans at doses lower than one milligram per day. Its potency has been measured in animal assays to be anywhere from 30 to 120 times greater than that of methyltestosterone, with greater dissociation between anabolic and androgenic effects[3],[4] (both traits are very pronounced). Being so similar in structure to methyltrienolone, THG should also require only very small doses to impart strong benefits to its user. The suggested use, according to our anonymous Olympic coach, of only “a few drops under the tongue each day,” seems to validate this point. It’s interesting to note also that THG minus its delta-11 modification (a di-ene instead of a tri-ene) has been shown, in the one study I could find on this substance, to be an extremely potent anabolic compound, measured to be over 14 times more active than methyltest.[5] There is no reason to think the jump to full-blown THG would be anything but an improvement on this already powerful drug. Although I can’t give exact figures, I feel very comfortable stating that THG is far more potent than any other anabolic steroid commercially available, anywhere. Gestrinone (18a-homo-pregna-4,9,11-trien-20-yn-17b-ol-3-one) Trenbolone (17beta-Hydroxyestra-4,9,11-trien-3-one) Methyltrienolone (17a-methylestra-4,9,11-trien-17b-ol-3-one)
Tetrahydrogestrinone (18a-Homo-pregna-4,9,11-trien-17b-ol-3-one)
High Toxicity
Since THG is essentially a modified form of methyltrienolone, we should really look to the data on this steroid to evaluate its potential for liver toxicity. This seems most prudent, as THG logically is going to be similarly resistant to steroid breakdown (a trait that leaves methyltrienolone levels of potency and toxicity that are hard to match in a synthetic anabolic steroid). Studies published from the University of Bonn, Germany, back in 1966, make this very clear.[6] In fact, researchers had deemed this the most liver toxic steroid to ever be studied in humans, summing up their findings well when stating: “Methyltrienolone… which is orally active as an anabolic agent in a dose less than 1.0 mg per day in normal adults, has been tested with regard to its influence on liver function. As measured by multiple parameters (BSP retention; total bilirubin; activities of transaminases, alkaline phosphates and cholinesterase in serum; activity of proaccelerin in plasma) methyltrienolone turned out to be very active as to causing biochemical symptoms of intrahepatic cholestasis… thus methyltrienolone at present being the most “hepatotoxic” steroid.”High hepatotoxicity (liver toxicity) precludes methyltrienolone from being sold as a prescription agent at this time, in any part of the world. It’s used solely as a research chemical, a purpose for which it is well suited. Its sheer potency makes it an excellent in vitro receptor-biding standard to compare other agents to, and being so resistant to metabolism, active methyltrienolone metabolites are not going to greatly interfere with the results of most experiments. But it’s not an agent anyone should recommend for human use. It is one of the last steroids you’d want to take, actually. An 18-homologated/17-ethylated derivative (THG) should, by all logic, be little better. In my book, THG earns the distinction of being the most liver toxic anabolic steroid in use at this time. Knowing its relation to methyltrienolone, I am very surprised it was even developed.
A Steroid of Opportunity
So how was such an unusual designer steroid manufactured? Madden seemed to consider it the result of a highly sophisticated chemist doing highly sophisticated steroid synthesis. He states it with such fervor that you are left thinking the person responsible has surmounted the impossible in the creation of THG. To Madden, it seems to be a genius product from a genius mind, the likes of which are not soon to be repeated. The reality is much different, however. In looking at this compound, it seems clear to me that THG was a steroid of opportunity. What I mean is, I doubt it was designed from scratch, with its developer meticulously piecing together his or her version of the perfect undetectable steroid. Instead, I strongly suspect it was made because someone noticed an opportunity to easily modify another readily available substance (gestrinone) enough to make an effective anabolic agent out of it. In all honesty, there are many compounds I would have devised before this one, had I been cavalier enough to be in this business, especially given its expected high level of liver toxicity. An ethylated derivative of methyltrienolone is strong medicine, probably too strong to consider safe. Availability of a base manufacturing material must have been the leading factor. Otherwise, why push the envelope so far?
In Closing
I’ve spoken about designer steroids in my column before, specifically the detection of norbolethone (a research steroid never commercially sold) in the urine of Olympic cyclist Tammy Thomas. This scandal first brought public attention to designer steroids, and the fundamental fact that not all steroids are detectable. Although to some, the outing of both THG and norbolethone may illustrate successes for steroid testing, they should underline a more troubling fact for testing officials at USADA— designer steroids are definitely out there, and sports organizations have discovered only a couple, so far. In our current case, the compound would likely have remained undetectable were it not for an inside “snitch” handing over a sample to officials. Although Madden may not acknowledge it when gloating about his recent victorious battle, I suspect he knows he is losing the war, disastrously, when it comes to fighting drug use in sports. The THG saga should raise some concern for athletes using underground designer steroids, as well, beyond the possibility of eventually getting caught for using these drugs. The lack of FDA approval on these agents could potentially put the user at risk. In this case, many individuals were using a steroid they probably would have immediately passed on had they known its true properties. I sincerely doubt each vial was wrapped with a warning label, “Potential Liver Toxic Monstrosity – Buyer Beware.” Either way, I still doubt we will see the last of drugs like THG.
References:
[1] Tissue and endocrine responses to gestrinone and danazol in the treatment of endometriosis. Forbes KL, Thomas FJ. Reprod Fertil Dev, 1993;5(1):103-9.
[2] Hormonal therapy of endometriosis. Metzger DA, Luciano AA. Obstet Gynecol Clin North Am, 1989 Mar;16(1):105-22.
[3] Liver toxicity of a new anabolic agent: methyltrienolone (17-alpha-methyl-4,9,11-estratriene-17 beta-ol-3-one). Kruskemper, Noell. Steroids,1966 Jul;8(1):13-24.
[4] T. Feyel-Cabanes, Compt Rend Soc Biol, 157, 1428 (1963)
[5] Edgren, Peterson, Jones, et al. Recent Progr. Hormone Res, 22, 305 (1966)
[6] Liver toxicity of a new anabolic agent: methyltrienolone (17-alpha-methyl-4,9,11-estratriene-17 beta-ol-3-one). Kruskemper, Noell. Steroids, 1966 Jul;8(1):13-24.
Structure, Activity and Toxicity Analysis
If you don’t recognize the three letters THG, you must have been hiding in a cave somewhere for the past couple of months. I am, of course, referring to the new designer steroid tetrahydrogestrinone (THG), which was recently brought to light in what promises to be the biggest organized bust for steroid use in the history of competitive sports. At least these were the words of Terry Madden, Chief Executive Officer of the U.S. Anti-Doping Agency (USADA), when addressing a group of newspaper and television reporters in a recent press conference. His accompanying press release spoke of an anonymous Olympic coach who turned over a syringe containing this designer steroid and implicated Victor Conte of BALCO Labs in California as the source for the agent. Conte is credited with coaching many of the world’s top athletes. USADA is now deep into a media frenzy, with many big names speculated to be among those who will test positive for the substance, and government officials promising heavy criminal charges for Conte and others potentially involved. The political and social implications for this scandal could warrant a long article alone; the topics are being addressed to the point of total redundancy by just about every media outlet in the country. If you want to know who is getting nabbed and what was happening behind the scenes, I recommend following the subject in the mainstream press. I, however, am going to focus on a very different part of the THG saga. I am going to take an up- close look at the THG molecule itself, to try to give you some idea concerning the actual properties of this agent. I’m sure many of you are curious about THG, as I was when I first heard talk of a “new” designer steroid. Its name, tetrahydrogestrinone, is a little difficult to decipher at first glance, though. Madden will only say that it’s similar to both gestrinone and trenbolone, which doesn’t really tell us enough to even pinpoint its structure. We are going to have to unravel this one for ourselves if we want answers.
A Cousin of Gestrinone
The first agent of reference, gestrinone, is not actually an anabolic/androgenic steroid, although it may indeed have some androgenic activity.[1] It’s primarily an anti-gonadotropic agent, used medically in the treatment of endometriosis.[2] It is not available, nor is it considered a controlled substance, in this country. Its structural relationship to trenbolone should be obvious when looking at the diagrams provided. Its activity, however, is far removed from this strong anabolic steroid. The reason is obviously the 17-alpha ethynyl modification, a trait that seems to strongly interfere with binding to the androgen receptor. With oral anabolic steroids, we typically see methyl groups added to this position, or in some instances ethyl groups. Both will usually make a steroid orally active, while at the same time allowing it to retain an effective level of activity at the androgen receptor. No commercial anabolic steroid has ever carried an ethynyl modification. As it turns out, this is the sole place of alteration in the creation of our new designer steroid.
THG and Methyl-Trenbolone“Tetrahydro” informs us that four (tetra) hydrogen atoms have been added to the gestrinone molecule to create our new steroid. We must figure out for ourselves where they were added. Although we are given no clue as to exactly where they are, it becomes obvious when we examine the structure of gestrinone. If we want to turn this into a potent steroid, we definitely need to get rid of its 17alpha ethynyl modification, first and foremost. Although gestrinone does seem to have some weak activity in this regard, it’s certainly not going to be enough to warrant using it as a muscle-building agent. If we substitute its ethynyl modification for an ethyl group, however, we are left with a compound that closely resembles one of the most powerful steroids known to man, methyltrienolone (17alpha-methyl-trenbolone). We also have exactly four extra hydrogen atoms in the process. Although we could come up with a couple of other scenarios, any other way of trying to add four hydrogen atoms would have eliminated the relationship noted between THG, trenbolone and gestrinone. THG, therefore, absolutely must be a slightly tweaked (18-homologated) and ethylated form of methyltrienolone. The relationship Madden points out between trenbolone and THG is entirely cosmetic, not functional. For our purposes, he might have well been likening THG to testosterone or nandrolone. It would be far more accurate to look at methyltrienolone when attempting to discern its properties, which should be similar in almost every regard including preferred route of administration (oral), resistance to metabolism, unusually high milligram-for- milligram potency, and side effect potential. In terms of the basic questions asked of every steroid, we can be confident that THG converts neither estrogen nor a weaker dihydronandrolone derivative, which means both moderate to strong androgenic activity and no worries about water or fat retention (the latter two traits usually being tied to estrogen conversion). There is the probability that THG has some progestational activity, however this is just a point of speculation (slightly more so than my others) until we have evidence to prove it, and is probably not extremely important overall anyway. The results from a cycle of tetrahydrogestrinone are likely to be high quality; the steroid imparting pure lean muscle tissue and strength gains instead of the sheer mass we would expect from bulking agents like testosterone, Dianabol or Anadrol. It is much more like Winstrol or Anavar in terms of overall effect, which makes THG a steroid more ideally suited for athletes competing in speed sports (such as track and field events) where it is not desirable to carry around unnecessary water weight. THG is far more potent than these well-known anabolics, however. We can base this to some extent on the potency of methyltrienolone, which is known to be effective in humans at doses lower than one milligram per day. Its potency has been measured in animal assays to be anywhere from 30 to 120 times greater than that of methyltestosterone, with greater dissociation between anabolic and androgenic effects[3],[4] (both traits are very pronounced). Being so similar in structure to methyltrienolone, THG should also require only very small doses to impart strong benefits to its user. The suggested use, according to our anonymous Olympic coach, of only “a few drops under the tongue each day,” seems to validate this point. It’s interesting to note also that THG minus its delta-11 modification (a di-ene instead of a tri-ene) has been shown, in the one study I could find on this substance, to be an extremely potent anabolic compound, measured to be over 14 times more active than methyltest.[5] There is no reason to think the jump to full-blown THG would be anything but an improvement on this already powerful drug. Although I can’t give exact figures, I feel very comfortable stating that THG is far more potent than any other anabolic steroid commercially available, anywhere. Gestrinone (18a-homo-pregna-4,9,11-trien-20-yn-17b-ol-3-one) Trenbolone (17beta-Hydroxyestra-4,9,11-trien-3-one) Methyltrienolone (17a-methylestra-4,9,11-trien-17b-ol-3-one)
Tetrahydrogestrinone (18a-Homo-pregna-4,9,11-trien-17b-ol-3-one)
High Toxicity
Since THG is essentially a modified form of methyltrienolone, we should really look to the data on this steroid to evaluate its potential for liver toxicity. This seems most prudent, as THG logically is going to be similarly resistant to steroid breakdown (a trait that leaves methyltrienolone levels of potency and toxicity that are hard to match in a synthetic anabolic steroid). Studies published from the University of Bonn, Germany, back in 1966, make this very clear.[6] In fact, researchers had deemed this the most liver toxic steroid to ever be studied in humans, summing up their findings well when stating: “Methyltrienolone… which is orally active as an anabolic agent in a dose less than 1.0 mg per day in normal adults, has been tested with regard to its influence on liver function. As measured by multiple parameters (BSP retention; total bilirubin; activities of transaminases, alkaline phosphates and cholinesterase in serum; activity of proaccelerin in plasma) methyltrienolone turned out to be very active as to causing biochemical symptoms of intrahepatic cholestasis… thus methyltrienolone at present being the most “hepatotoxic” steroid.”High hepatotoxicity (liver toxicity) precludes methyltrienolone from being sold as a prescription agent at this time, in any part of the world. It’s used solely as a research chemical, a purpose for which it is well suited. Its sheer potency makes it an excellent in vitro receptor-biding standard to compare other agents to, and being so resistant to metabolism, active methyltrienolone metabolites are not going to greatly interfere with the results of most experiments. But it’s not an agent anyone should recommend for human use. It is one of the last steroids you’d want to take, actually. An 18-homologated/17-ethylated derivative (THG) should, by all logic, be little better. In my book, THG earns the distinction of being the most liver toxic anabolic steroid in use at this time. Knowing its relation to methyltrienolone, I am very surprised it was even developed.
A Steroid of Opportunity
So how was such an unusual designer steroid manufactured? Madden seemed to consider it the result of a highly sophisticated chemist doing highly sophisticated steroid synthesis. He states it with such fervor that you are left thinking the person responsible has surmounted the impossible in the creation of THG. To Madden, it seems to be a genius product from a genius mind, the likes of which are not soon to be repeated. The reality is much different, however. In looking at this compound, it seems clear to me that THG was a steroid of opportunity. What I mean is, I doubt it was designed from scratch, with its developer meticulously piecing together his or her version of the perfect undetectable steroid. Instead, I strongly suspect it was made because someone noticed an opportunity to easily modify another readily available substance (gestrinone) enough to make an effective anabolic agent out of it. In all honesty, there are many compounds I would have devised before this one, had I been cavalier enough to be in this business, especially given its expected high level of liver toxicity. An ethylated derivative of methyltrienolone is strong medicine, probably too strong to consider safe. Availability of a base manufacturing material must have been the leading factor. Otherwise, why push the envelope so far?
In Closing
I’ve spoken about designer steroids in my column before, specifically the detection of norbolethone (a research steroid never commercially sold) in the urine of Olympic cyclist Tammy Thomas. This scandal first brought public attention to designer steroids, and the fundamental fact that not all steroids are detectable. Although to some, the outing of both THG and norbolethone may illustrate successes for steroid testing, they should underline a more troubling fact for testing officials at USADA— designer steroids are definitely out there, and sports organizations have discovered only a couple, so far. In our current case, the compound would likely have remained undetectable were it not for an inside “snitch” handing over a sample to officials. Although Madden may not acknowledge it when gloating about his recent victorious battle, I suspect he knows he is losing the war, disastrously, when it comes to fighting drug use in sports. The THG saga should raise some concern for athletes using underground designer steroids, as well, beyond the possibility of eventually getting caught for using these drugs. The lack of FDA approval on these agents could potentially put the user at risk. In this case, many individuals were using a steroid they probably would have immediately passed on had they known its true properties. I sincerely doubt each vial was wrapped with a warning label, “Potential Liver Toxic Monstrosity – Buyer Beware.” Either way, I still doubt we will see the last of drugs like THG.
References:
[1] Tissue and endocrine responses to gestrinone and danazol in the treatment of endometriosis. Forbes KL, Thomas FJ. Reprod Fertil Dev, 1993;5(1):103-9.
[2] Hormonal therapy of endometriosis. Metzger DA, Luciano AA. Obstet Gynecol Clin North Am, 1989 Mar;16(1):105-22.
[3] Liver toxicity of a new anabolic agent: methyltrienolone (17-alpha-methyl-4,9,11-estratriene-17 beta-ol-3-one). Kruskemper, Noell. Steroids,1966 Jul;8(1):13-24.
[4] T. Feyel-Cabanes, Compt Rend Soc Biol, 157, 1428 (1963)
[5] Edgren, Peterson, Jones, et al. Recent Progr. Hormone Res, 22, 305 (1966)
[6] Liver toxicity of a new anabolic agent: methyltrienolone (17-alpha-methyl-4,9,11-estratriene-17 beta-ol-3-one). Kruskemper, Noell. Steroids, 1966 Jul;8(1):13-24.