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Hepatoxicty
Fact or Fiction
By Roy Harper
This article was originally featured in issue #8 of Mind and Muscle Magazine. Be sure to also check out avantlabs.com for the full Avant Labs product line of groundbreaking supplements.
We all know that the alpha alkylated steroids are hepatotoxic, right... But, is there actually any truth to this? We’ve been told for years that if you take 17 alpha-alkylated steroids, you will eventually run into Liver problems. Never combine 17 alpha-alkylated's, never go beyond 50mg day, never go longer than 4 weeks, etc. All of this is ! As I we walk you through some studies, today, you’ll see 17 alpha-alkylated steroids can be hepatotoxic but not to the degree you would think.
To make a steroid hepatotoxic, you need only a small change to a steroid molecule; A strong bond that cannot readily be down broken by enzymes in the Liver. This may be a bond at the 17th position, or even at the 1st position (as in methenolone or proviron). Because the Liver cannot easily break the steroid down before it is released in to the blood stream, this also results in the steroid to becoming more orally bio-available.
We can see that the Liver has to work harder to break down these steroids. Enzymes in the blood and tissue easily metabolize other steroids such as testosterone. Commonly, this increase in Liver activity has been viewed as a harmful process, but as you will see, this increase is, in and of itself, irrelevant. The Liver is THE filter of the human body -- it can figure out what to do with just about anything. The only real problem comes in when one keeps their Liver at full blast for long periods of time.
Let’s look at some studies showing the Hepatotoxicity of steroids. Here's one of my favorites, a study published in 1979[1]. Essentially, researches did a study of deaths caused by hepatic angiosarcoma (a malignant tumor of vascular tissue in the Liver) between 1964 and 1974. Researchers found 131 reported cases of death from hepatic angiosarcoma. Out of the 131 cases, 3.1% (4 cases) were reported to be at all related to the use of androgenic-anabolic steroids. Keep in mind that these 4 people could have Liver complications before any steroids were used, aka a genetic disposition. In fact there is no proof, in this study at least, that the anabolic-androgenic steroids even caused the hepatic angiosarcoma.
This is the classic case of associating a cause with an effect, without any evidence, aside from both existing. Furthermore, based on the above numbers, there are only 0.4 cases of hepatic angiosarcoma reported each year, by those using anabolic steroids. Now consider the number of people on steroids at this time. Now factor in all the people that don’t know their ass from a hole in the ground when it comes to using anabolic steroids, properly. Clearly, this is very week evidence. Lastly there has not been a real increase in hepatic angiosarcoma since the early seventies. Meanwhile, there has been a huge, almost exponential, increase in steroid use during this period.
Another study, that somewhat supports the previous Hepatotoxicity case, showed the possibilities of hepatic adenomas(cysts in the Liver) caused by androgenic-anabolic steroids[2]. In this study, a Japanese girl was found to have multiple Liver lesions after the use of the drug oxymetholone (aka anadrol). Most everyone “knows” that anadrol is linked with Liver problems, but a closer inspection into this study shows more.
Apparently, this girl, starting at the age of 14, was diagnosed with aplastic anemia. She was prescribed oxymetholone at 30mg per day. This continued for 6 years until the lesions first appeared. Assuming that the girl was most likely around 100 lbs., this was a pretty heavy dosage. If you extrapolated this data out to a 200 - 250lbs. male, that would be taking approximately 60 - 90mg of anadrol per day for 6 years. Ouch!
The researchers also stated that there were only 17 other cases of hepatic adenomas, found in English literature between 1975 and 1998. They failed to mention the causes of these 17 cases, but there is no reason to believe they were all using 17 alpha-alkylated androgens and 17 is certainly miniscule compared to the number of people who have used them. The authors’ finish off the study by saying the following: "This report may be helpful in identifying the potion who is at risk of developing hepatic sex hormone-related tumors." So remember, if you're a small 14-year-old girl taking 30mg of anadrol per day for 6 years, you may be at risk!
Let's move on to some more useful studies. Take for example a 1995 study that showed the toxic effects of anabolic-androgenic steroids in primary rat hepatic cell cultures[3]. In this study the researchers used the following drugs and dosages:
Steroid 1x10^-8M 1x10^-6M 1x10^-4M
19-nortestosterone 0.002744mg 0.2744mg 27.44mg
Fluoxymesterone 0.003365mg 0.3365mg 33.65mg
testosterone cypionate 0.004126mg 0.4126mg 41.26mg
Stanozolol 0.003285mg 0.3285mg 32.85mg
Danazol N/A N/A N/A
Oxymetholone 0.003325mg 0.3325mg 33.25mg
testosterone 0.002884mg 0.2884mg 28.84mg
Estradiol 0.0027424mg 0.2724mg 27.24mg
Methyltestosterone 0.003024mg 0.3024mg 30.24mg
As proof of the hepatoxicity they used Lactate dehydrogenase release, neutral red retention, and glutathione depletion to determine plasma membrane damage, cell viability, and possible oxidative injury, respectively.
What they showed was that the 17 alpha-alkylated steroids, methyltestosterone, stanozolol and oxymetholone, significantly increased Lactate dehydrogenase release and decreased neutral red retention at the 1x10^-4M dosage for 24h. Both methyltestosterone and oxymetholone also showed depleted glutathione at the 1x10^-4M dosage after 2h, 6h and 8h treatments. In other words they increased Liver activity. You may also note that the other, non-alkylated steroids showed no significant difference in any levels. All in all this not only shows that 17 alpha-alkylated steroids are directly “hepatotoxic”, but also non-alkylated steroids are note hepatotoxic at all. But is this a real measure of Hepatotoxicity? There is yet to be any correlation between the increase of the above-mentioned measurement and “Hepatotoxicity”. Obviously, high dosages of the 17 alpha-alkylated steroids are potentially dangerous, but upon closer inspection, the study reveals more.
Take a look, the researchers took cell cultures from the liversse of 60-day-old Sprague-Dawley rats. Not only are rat livers much smaller than human livers, but these were merely cultures. Furthermore, it was the 1x10^-4M concentrations that caused the most changes, but these are approximately 1 to a 1/3 of a full, daily human dosage -- at least for the 17 alpha-alkylated steroids. Even at the 1x10^-6M concentration, there were no significant changes observed. It's apparent that the levels of 17 alpha-alkylated steroids used were potentially toxic, but for a human to take the same amount would be insane. I'm guessing this could translate to maybe 4 grams every 24 hours or 28 grams a week if not more.
What is common so far is we can only prove that any steroid, that is believed to be hepatotoxic, only increases Liver activity. I’ll say it again, where is the correlation to Hepatotoxicity? We know that if the Liver is running at 100% for long periods this may cause complications, but this is akin to any other chemical, which is metabolized by the Liver. Ever noticed that Liver cancer due to alcoholism takes decades of constant alcohol abuse? It’s apparent that the possibility for Hepatotoxicity is there, but for the smart steroid user this is nearly an impossible task.
Another study done in 1999, attempted to show the acute and chronic effects of stanozolol on the Liver[4]. In acute treatments of stanozolol, dosages not mentioned, both cytochrome P456 and b5 (microsomal enzymes) levels dropped after 48 hours, and then at 72 hours, levels significant increased. On the other hand, with chronic treatments, time or dosage not mentioned, these microsomal enzymes showed a decrease in levels. Researchers showed that both acute and chronic treatments resulted in "slight to moderate inflammatory or degenerative lesions in centrilobular hepatocytes", but the authors did not note true Hepatotoxicity.
How about we look at the other side of the story, the good studies. For instance, in a 1999 study, which looked at the effects of an 8-week cycle of 17 alpha-alkylated steroids[5]. The researchers used fluoxymesterone, methylandrostanolone, or stanozolol on rats at 2mg/kg-body weight, five times a week for 8 weeks. That's 182mg per dosage, for a 200lb man, or 910mg per week. Half of the rats were sedentary and the other were trained on a treadmill.
Levels of NADH-cytochrome c reductase, succinate cytochrome c reductase, and cytochrome oxidase (showing Liver activity), increased in the steroid-administered rats, while citrate synthase showed no change. Comparatively, in vitro, the "cytochrome oxidase and citrate synthase activities were insensitive to the anabolic steroids, whereas NADH-cytochrome c reductase and succinate cytochrome c reductase activities were partly inhibited."
Furthermore, in vivo, each rat had Liver enzyme levels that were within normal range. From this, the researchers determined that the steroid-administered rats, trained or sedentary, did not show "...classical serum indicators of hepatic function". Extrapolating this, 910mg a week for 8 weeks could potentially have little to no effect on the Liver in humans.
As for human studies, in 1999 researchers tried to prove that the Hepatotoxicity of steroids is overstated[6]. In this study, 15 of the partints were bodybuilders using self-administered steroid dosages and 10 were non-steroid bodybuilders. Serum data was compared to 49 patients with viral hepatitis, and 592 exercising and non-exercising medical students. [
All of the bodybuilders showed increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK) while gamma-glutamyltranspeptidase (GGT) levels were in the normal range. In comparison, hepatitis patients showed increased ALT, AST, and GGT levels while the control exercising medical students showed increased CK levels. From this, the researchers suggested that it is the correlation between AST, ALT and GGT that shows true Liver dysfunction. Keep in mind, we can only guess that the 15 steroid users were using 17 alpha-alkylated steroids, and we do not know what the dosages that were used., but common sense tells us the results are likely relevant.
Last but not least, a simple study done in 1996, showed the long term benefits after taking a 3 month break from steroids[7]. 16 bodybuilders using steroids were compared to 12 bodybuilders that were not. After a three-month drug withdrawal, the researchers showed that levels of Liver enzymes, types not mentioned, returned to the same as the non users. Again the dosages are left to the reader’s imagination and we can only guess that the 16 steroid users were using 17 alpha-alkylated steroids.
So what can we conclude from all of this? First off, 17 alpha-alkylated steroids are hepatotoxic in high dosages taken for a long time. On the other hand, short cycles and small dosages appear to be perfectly safe. I suggest that maximum dosages should be 500mg to 900mg per day. They should be cycled for perhaps 8 weeks at a time, and if needed a 3-month break from them should be used. Using the above-mentioned techniques, your Liver can be healthy for a long time. Simply put, the hysteria surrounding “Hepatoxic” steroids, is based mainly on folk lore.
References:
[1] Lancet 1979 Nov 24;2(8152):1120-3, Hepatic angiosarcoma associated with androgenic-anabolic steroids. Falk H, Thomas LB, Popper H, Ishak KG.
[2] J Gastroenterol 2000;35(7):557-62, Multiple hepatic adenomas caused by long-term administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis. Nakao A, Sakagami K, Nakata Y, Komazawa K, Amimoto T, Nakashima K, Isozaki H, Takakura N, Tanaka N.
[3] J Pharmacol Toxicol Methods 1995 Aug;33(4):187-95, Toxic effects of anabolic-androgenic steroids in primary rat hepatic cell cultures. Welder AA, Robertson JW, Melchert RB.
[4] Arch Toxicol 1999 Nov;73(8-9):465-72, Evaluation of acute and chronic hepatotoxic effects exerted by anabolic-androgenic steroid stanozolol in adult male rats. Boada LD, Zumbado M, Torres S, Lopez A, Diaz-Chico BN, Cabrera JJ, Luzardo OP.
[5] Med Sci Sports Exerc. 1999 Feb;31(2):243-50, Rat Liver lysosomal and mitochondrial activities are modified by anabolic-androgenic steroids. Molano F, Saborido A, Delgado J, Moran M, Megias A.
[6] Clin J Sport Med 1999 Jan;9(1):34-9, Anabolic steroid-induced Hepatotoxicity: is it overstated? erman RD, Pertusi RM, Zachariah NY, Dufour DR, McConathy WJ.
[7] Int J Sports Med 1996 Aug;17(6):429-33, Body composition, cardiovascular risk factors and Liver function in long-term androgenic-anabolic steroids using bodybuilders three months after drug withdrawal. Hartgens F, Kuipers H, Wijnen JA, Keizer HA.
Fact or Fiction
By Roy Harper
This article was originally featured in issue #8 of Mind and Muscle Magazine. Be sure to also check out avantlabs.com for the full Avant Labs product line of groundbreaking supplements.
We all know that the alpha alkylated steroids are hepatotoxic, right... But, is there actually any truth to this? We’ve been told for years that if you take 17 alpha-alkylated steroids, you will eventually run into Liver problems. Never combine 17 alpha-alkylated's, never go beyond 50mg day, never go longer than 4 weeks, etc. All of this is ! As I we walk you through some studies, today, you’ll see 17 alpha-alkylated steroids can be hepatotoxic but not to the degree you would think.
To make a steroid hepatotoxic, you need only a small change to a steroid molecule; A strong bond that cannot readily be down broken by enzymes in the Liver. This may be a bond at the 17th position, or even at the 1st position (as in methenolone or proviron). Because the Liver cannot easily break the steroid down before it is released in to the blood stream, this also results in the steroid to becoming more orally bio-available.
We can see that the Liver has to work harder to break down these steroids. Enzymes in the blood and tissue easily metabolize other steroids such as testosterone. Commonly, this increase in Liver activity has been viewed as a harmful process, but as you will see, this increase is, in and of itself, irrelevant. The Liver is THE filter of the human body -- it can figure out what to do with just about anything. The only real problem comes in when one keeps their Liver at full blast for long periods of time.
Let’s look at some studies showing the Hepatotoxicity of steroids. Here's one of my favorites, a study published in 1979[1]. Essentially, researches did a study of deaths caused by hepatic angiosarcoma (a malignant tumor of vascular tissue in the Liver) between 1964 and 1974. Researchers found 131 reported cases of death from hepatic angiosarcoma. Out of the 131 cases, 3.1% (4 cases) were reported to be at all related to the use of androgenic-anabolic steroids. Keep in mind that these 4 people could have Liver complications before any steroids were used, aka a genetic disposition. In fact there is no proof, in this study at least, that the anabolic-androgenic steroids even caused the hepatic angiosarcoma.
This is the classic case of associating a cause with an effect, without any evidence, aside from both existing. Furthermore, based on the above numbers, there are only 0.4 cases of hepatic angiosarcoma reported each year, by those using anabolic steroids. Now consider the number of people on steroids at this time. Now factor in all the people that don’t know their ass from a hole in the ground when it comes to using anabolic steroids, properly. Clearly, this is very week evidence. Lastly there has not been a real increase in hepatic angiosarcoma since the early seventies. Meanwhile, there has been a huge, almost exponential, increase in steroid use during this period.
Another study, that somewhat supports the previous Hepatotoxicity case, showed the possibilities of hepatic adenomas(cysts in the Liver) caused by androgenic-anabolic steroids[2]. In this study, a Japanese girl was found to have multiple Liver lesions after the use of the drug oxymetholone (aka anadrol). Most everyone “knows” that anadrol is linked with Liver problems, but a closer inspection into this study shows more.
Apparently, this girl, starting at the age of 14, was diagnosed with aplastic anemia. She was prescribed oxymetholone at 30mg per day. This continued for 6 years until the lesions first appeared. Assuming that the girl was most likely around 100 lbs., this was a pretty heavy dosage. If you extrapolated this data out to a 200 - 250lbs. male, that would be taking approximately 60 - 90mg of anadrol per day for 6 years. Ouch!
The researchers also stated that there were only 17 other cases of hepatic adenomas, found in English literature between 1975 and 1998. They failed to mention the causes of these 17 cases, but there is no reason to believe they were all using 17 alpha-alkylated androgens and 17 is certainly miniscule compared to the number of people who have used them. The authors’ finish off the study by saying the following: "This report may be helpful in identifying the potion who is at risk of developing hepatic sex hormone-related tumors." So remember, if you're a small 14-year-old girl taking 30mg of anadrol per day for 6 years, you may be at risk!
Let's move on to some more useful studies. Take for example a 1995 study that showed the toxic effects of anabolic-androgenic steroids in primary rat hepatic cell cultures[3]. In this study the researchers used the following drugs and dosages:
Steroid 1x10^-8M 1x10^-6M 1x10^-4M
19-nortestosterone 0.002744mg 0.2744mg 27.44mg
Fluoxymesterone 0.003365mg 0.3365mg 33.65mg
testosterone cypionate 0.004126mg 0.4126mg 41.26mg
Stanozolol 0.003285mg 0.3285mg 32.85mg
Danazol N/A N/A N/A
Oxymetholone 0.003325mg 0.3325mg 33.25mg
testosterone 0.002884mg 0.2884mg 28.84mg
Estradiol 0.0027424mg 0.2724mg 27.24mg
Methyltestosterone 0.003024mg 0.3024mg 30.24mg
As proof of the hepatoxicity they used Lactate dehydrogenase release, neutral red retention, and glutathione depletion to determine plasma membrane damage, cell viability, and possible oxidative injury, respectively.
What they showed was that the 17 alpha-alkylated steroids, methyltestosterone, stanozolol and oxymetholone, significantly increased Lactate dehydrogenase release and decreased neutral red retention at the 1x10^-4M dosage for 24h. Both methyltestosterone and oxymetholone also showed depleted glutathione at the 1x10^-4M dosage after 2h, 6h and 8h treatments. In other words they increased Liver activity. You may also note that the other, non-alkylated steroids showed no significant difference in any levels. All in all this not only shows that 17 alpha-alkylated steroids are directly “hepatotoxic”, but also non-alkylated steroids are note hepatotoxic at all. But is this a real measure of Hepatotoxicity? There is yet to be any correlation between the increase of the above-mentioned measurement and “Hepatotoxicity”. Obviously, high dosages of the 17 alpha-alkylated steroids are potentially dangerous, but upon closer inspection, the study reveals more.
Take a look, the researchers took cell cultures from the liversse of 60-day-old Sprague-Dawley rats. Not only are rat livers much smaller than human livers, but these were merely cultures. Furthermore, it was the 1x10^-4M concentrations that caused the most changes, but these are approximately 1 to a 1/3 of a full, daily human dosage -- at least for the 17 alpha-alkylated steroids. Even at the 1x10^-6M concentration, there were no significant changes observed. It's apparent that the levels of 17 alpha-alkylated steroids used were potentially toxic, but for a human to take the same amount would be insane. I'm guessing this could translate to maybe 4 grams every 24 hours or 28 grams a week if not more.
What is common so far is we can only prove that any steroid, that is believed to be hepatotoxic, only increases Liver activity. I’ll say it again, where is the correlation to Hepatotoxicity? We know that if the Liver is running at 100% for long periods this may cause complications, but this is akin to any other chemical, which is metabolized by the Liver. Ever noticed that Liver cancer due to alcoholism takes decades of constant alcohol abuse? It’s apparent that the possibility for Hepatotoxicity is there, but for the smart steroid user this is nearly an impossible task.
Another study done in 1999, attempted to show the acute and chronic effects of stanozolol on the Liver[4]. In acute treatments of stanozolol, dosages not mentioned, both cytochrome P456 and b5 (microsomal enzymes) levels dropped after 48 hours, and then at 72 hours, levels significant increased. On the other hand, with chronic treatments, time or dosage not mentioned, these microsomal enzymes showed a decrease in levels. Researchers showed that both acute and chronic treatments resulted in "slight to moderate inflammatory or degenerative lesions in centrilobular hepatocytes", but the authors did not note true Hepatotoxicity.
How about we look at the other side of the story, the good studies. For instance, in a 1999 study, which looked at the effects of an 8-week cycle of 17 alpha-alkylated steroids[5]. The researchers used fluoxymesterone, methylandrostanolone, or stanozolol on rats at 2mg/kg-body weight, five times a week for 8 weeks. That's 182mg per dosage, for a 200lb man, or 910mg per week. Half of the rats were sedentary and the other were trained on a treadmill.
Levels of NADH-cytochrome c reductase, succinate cytochrome c reductase, and cytochrome oxidase (showing Liver activity), increased in the steroid-administered rats, while citrate synthase showed no change. Comparatively, in vitro, the "cytochrome oxidase and citrate synthase activities were insensitive to the anabolic steroids, whereas NADH-cytochrome c reductase and succinate cytochrome c reductase activities were partly inhibited."
Furthermore, in vivo, each rat had Liver enzyme levels that were within normal range. From this, the researchers determined that the steroid-administered rats, trained or sedentary, did not show "...classical serum indicators of hepatic function". Extrapolating this, 910mg a week for 8 weeks could potentially have little to no effect on the Liver in humans.
As for human studies, in 1999 researchers tried to prove that the Hepatotoxicity of steroids is overstated[6]. In this study, 15 of the partints were bodybuilders using self-administered steroid dosages and 10 were non-steroid bodybuilders. Serum data was compared to 49 patients with viral hepatitis, and 592 exercising and non-exercising medical students. [
All of the bodybuilders showed increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK) while gamma-glutamyltranspeptidase (GGT) levels were in the normal range. In comparison, hepatitis patients showed increased ALT, AST, and GGT levels while the control exercising medical students showed increased CK levels. From this, the researchers suggested that it is the correlation between AST, ALT and GGT that shows true Liver dysfunction. Keep in mind, we can only guess that the 15 steroid users were using 17 alpha-alkylated steroids, and we do not know what the dosages that were used., but common sense tells us the results are likely relevant.
Last but not least, a simple study done in 1996, showed the long term benefits after taking a 3 month break from steroids[7]. 16 bodybuilders using steroids were compared to 12 bodybuilders that were not. After a three-month drug withdrawal, the researchers showed that levels of Liver enzymes, types not mentioned, returned to the same as the non users. Again the dosages are left to the reader’s imagination and we can only guess that the 16 steroid users were using 17 alpha-alkylated steroids.
So what can we conclude from all of this? First off, 17 alpha-alkylated steroids are hepatotoxic in high dosages taken for a long time. On the other hand, short cycles and small dosages appear to be perfectly safe. I suggest that maximum dosages should be 500mg to 900mg per day. They should be cycled for perhaps 8 weeks at a time, and if needed a 3-month break from them should be used. Using the above-mentioned techniques, your Liver can be healthy for a long time. Simply put, the hysteria surrounding “Hepatoxic” steroids, is based mainly on folk lore.
References:
[1] Lancet 1979 Nov 24;2(8152):1120-3, Hepatic angiosarcoma associated with androgenic-anabolic steroids. Falk H, Thomas LB, Popper H, Ishak KG.
[2] J Gastroenterol 2000;35(7):557-62, Multiple hepatic adenomas caused by long-term administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis. Nakao A, Sakagami K, Nakata Y, Komazawa K, Amimoto T, Nakashima K, Isozaki H, Takakura N, Tanaka N.
[3] J Pharmacol Toxicol Methods 1995 Aug;33(4):187-95, Toxic effects of anabolic-androgenic steroids in primary rat hepatic cell cultures. Welder AA, Robertson JW, Melchert RB.
[4] Arch Toxicol 1999 Nov;73(8-9):465-72, Evaluation of acute and chronic hepatotoxic effects exerted by anabolic-androgenic steroid stanozolol in adult male rats. Boada LD, Zumbado M, Torres S, Lopez A, Diaz-Chico BN, Cabrera JJ, Luzardo OP.
[5] Med Sci Sports Exerc. 1999 Feb;31(2):243-50, Rat Liver lysosomal and mitochondrial activities are modified by anabolic-androgenic steroids. Molano F, Saborido A, Delgado J, Moran M, Megias A.
[6] Clin J Sport Med 1999 Jan;9(1):34-9, Anabolic steroid-induced Hepatotoxicity: is it overstated? erman RD, Pertusi RM, Zachariah NY, Dufour DR, McConathy WJ.
[7] Int J Sports Med 1996 Aug;17(6):429-33, Body composition, cardiovascular risk factors and Liver function in long-term androgenic-anabolic steroids using bodybuilders three months after drug withdrawal. Hartgens F, Kuipers H, Wijnen JA, Keizer HA.
