MESO-Rx: Why did you start studying how steroids work?
Dharkam: Well, this was because of several factors such as drug testing, increasing prices, reduced availability,…. Before that we did not care about how it worked. More was always better. In case of trouble we used more, period.
MESO-Rx: I guess you had to find ways to get better results with lesser drug amounts.
Dharkam: Exactly, this is the issue we faced at this time. I started searching to understand how drugs like steroids worked in order to elaborate new strategies to get the most out the least amount. Strange as it may seem, natural bodybuilders can probably benefit most from what I am going to say about steroid users. The natural bodybuilders should keep in mind they produce testosterone, too. They just have less than drug users. So it is even more important for them to get the most out of this modest amount. Of course, it won’t do any harm to steroids users to better understand what they are doing.
MESO-Rx: Let’s start with we beginning. What is going on in our muscles after training?
Dharkam: This is not an easy question since we still missing some crucial points. But as you can imagine there is a positive side and a negative side. In other words, training will induce an anabolic drive but will also have some negative catabolic effects on the trained muscles. Another big problem is that the link between the positive and the negative impacts of training is not always very clear.
MESO-Rx: What do you mean? Anabolism builds up muscles, catabolism destroys it.
Dharkam: If only it were so simple! But some of the catabolic effects of training will be essential to induce an anabolic drive.
MESO-Rx: In other words: no catabolism, no anabolism. We train to induce some form of damages on our muscles. Then, to avoid future problems when this kind of stress is re-imposed on the muscles, they grow bigger and stronger. But are you sure we must induce damage to induce hypertrophy?
Dharkam: The fastest way to get bigger muscles does involved inducing damage. This assumes you can recover quickly and completely. But there are some other ways to build up muscles without having to induce too much muscle damage. The best strategy being to combine the two techniques.
MESO-Rx: When I think about it, isn’t it stupid to induce damage and then rebuild the muscle? It is like having to go bankrupt to get rich. And bankrupt again to get richer…
Dharkam: I would not go so far. But to earn money you first have to invest. So you spend money before getting a return on that money spent. But investing into a project does not guarantee that you will get a fair return. This is the same with training. Causing damage is not a sure way of inducing hypertrophy. Just as your investment must be wise and not excessive, you do not want too much damage in order to produce what I call “positive catabolism.” It means when one wants to induce damage, it should be a damage which will trigger anabolism.
MESO-Rx: As in any investment, there will be some productive investment: what you call positive catabolism and some invests will be a complete waste given zero return. This is what you call negative catabolism.
MESO-Rx: So not every catabolism will trigger anabolism. Just like many infectious diseases will induce muscle wasting but no anabolism at all.
Dharkam: This is correct. This is the idea behind positive and negative catabolism.
MESO-Rx: OK, but I am not convinced that catabolism is essential for muscle growth. For example, anabolic steroids are said to be both anabolic and anti-catabolic at the same time. This indicates that catabolism is not required for muscle growth.
Dharkam: Anabolic steroids are the perfect example of my point. Do you have any evidence that they are anti-catabolic in humans?
MESO-Rx: This is the theory that is the most popular in the US. I guess this is based on extrapolation from animal studies. And there has been this assumption that steroids stop working on the muscle steroid receptors after a few weeks, so one of the theories is that steroids must be working on, or interfering with cortisol.
Dharkam: Well, get ready for a shock. I certainly do not pretend to know everything about how steroids work, but one thing that has been shown both in vitro and in vivo is that anabolic steroids are catabolic for the muscles.
MESO-Rx: Are we talking about the same drugs?
Dharkam: Yes, I am talking of stuff like nandrolone, stanazolol, testosterone, oxymetholone,… If you read the human studies you will see that those drugs increase creatine kinase level. One more time, this has been proven both in test tube and in real life. Other studies point out that anabolics increase the rate of appearance of leucine which is a marker for proteolysis.
[Editor: For our readers — creatine kinase is an enzyme released from the skeletal muscles. It is used to measure muscle damage.]
MESO-Rx: So you mean steroids increase muscle damage as seen with elevated levels of creatine kinase and muscle proteolysis. Is training required to see this effect?
Dharkam: No, remember this is taking place even in test tube when steroids are applied directly on muscle cells. However, anabolics potentiate training-induced muscle damage.
MESO-Rx: You mean that steroids plus training will induce more muscle damage than the same training alone? This is very controversial. Is an elevated creatine kinase level always correlative to trauma and catabolism? Would there be another explanation for this? Like simply longer, less traumatic training sessions? And from your rationale, Accutane should be an anabolic, because it also increases creatine kinase in the blood.
Dharkam: Steroids will make the muscle more vulnerable to the damaging effects of training. This has a direct implication: steroid users will not have to train as hard as a natural bodybuilder to induce damage. Don’t get me wrong — I am not saying that all the steroid users are not training hard. I am just saying that they can get away with easy, light training and still give their muscles the proper stimulation to induce growth.
As far as creatine kinase is concerned, it has to be understood that it is a rough marker of muscle damage. With the right kind of steroids, you can experience a huge CK increase. Smaller variations have far less significance than big increases. Inducing muscle damage is only one way of forcing muscle growth, not the only way. Reducing muscle damage while the not altering the protein synthesis rate will also increase muscle mass.
As far as all drugs that increase CK level being anabolic, this is not true. CK is just a marker of catabolism. It does not say whether it is a positive or a negative catabolism. By the way, clenbuterol increases CK level at proper dosage. Another sign that steroids or clen induce muscle damage is the more pronounced muscle soreness sensation following a training session with the proper drug choice (steroids that do not aromatize — but this is another story).
MESO-Rx: Do you play with creatine kinase and leucine rate of appearance to determine training volume and frequency?
Dharkam: First of all we use only creatine kinase (CK) level to adjust training. Leucine rate of appearance is both too complicated and way too expensive. On the other hand, creatine kinase level is only a rough measure. It sure could be more accurate. But it is useful at suggesting a trend. My goal in bodybuilders is to shoot for a very high CK level.
MESO-Rx: This is not for natural bodybuilders, is it?
Dharkam: No, of course not. This is for bodybuilders who take injectable drugs to properly recover. I want a moderately high level for steroid-free bodybuilders. Natural weight lifters should be careful not to go overboard with their CK level. There might be a role for anticatabolic supplements here. Of course, CK level fluctuates a lot among individuals. For example, African American CK level is far higher after training than for Caucasians. So CK level should be measured before the training period and during the training phase. I look at the increase rather than the absolute value.
MESO-Rx: If steroids induce catabolism how do they build bigger muscles? Where do they act to produce their effects?
Dharkam: Steroids are both catabolic and anabolic at the same time. There are just more anabolic than catabolic. Their effects are mediated by the androgen receptors.
MESO-Rx: Some studies show that taking androgen will greatly reduce the number of androgen receptors located in the muscles. This is said to be one of the major reasons why the average guy will not grow significant amounts of muscles while on steroids.
Dharkam: This is correct, when too much androgen is present in the blood, androgen receptor levels will decrease. But we have many studies showing that training a muscle will renew those receptors. This is why why there is a synergy between androgen and training in bodybuilders while steroids only work to a limited extent in untrained persons.
MESO-Rx: So why has there been no reaction to this in the U.S.?
Dharkam: I do not know but they sure made it in my country. If you look at a steroid user, it is so obvious. If only the body part that he trains grows, it is simply that he renews or re-opens the androgen receptors of this specific muscle by training.
MESO-Rx: Does this re-opening only take place in steroid users or does training also increase the number of androgen receptors in natural bodybuilders? And saying “re-opening” do you mean that more receptors are being made, or the life of steroid receptor is extended? Or both?
Dharkam: This is a good question. When I say “re-open” this is not strictly correct. A bodybuilder who has never taken steroids does not suffer much androgen receptor downregulation. Training will simply increase the number of ready-to-work androgen receptors. He will have far more receptors than the average untrained Joe. This is why the first cycle of anabolics is very often the best. Plenty of receptors. As the cycle continues, the number of androgen receptors will go down. But with proper training targeted at re-opening the androgen receptors, we can prevent the stagnation we see in numerous western bodybuilders after several drug cycles. Where do the receptors come from? I assume their expression is increased. I do not know if their half life is extended.
MESO-Rx: How should we train to re-open those receptors? Does this strategy work the same in natural bodybuilders and steroid users? I seem to recall that the study on upregulating steroid receptors was done on endurance athletes, who are notorious for having low testosterone.
Dharkam: Natural bodybuilders will not react the same way as steroid users. Remember, natural bodybuilders want more androgen to get the most of their endogenous testosterone, but their training capacity is limited as they do not want to overtrain which reduces androgen production. On the other hand, steroid users have enough androgen hormones, what they need is more receptors. So goals and limitations are radically different. Their training strategies should reflect those different goals. Too much training in natural bodybuilders will reduce their testosterone level to almost zero. With zero testosterone, you can have all the receptors you want you will not grow, period. On the other hand, steroid users need to avoid undertraining. They do not really care what happens to their androgen level, it is artificially high. But they want enough training and the right kind to increase their androgen receptor level, which is reduced by high exogenous androgens.
MESO-Rx: Let’s see if I understand you: Natural bodybuilders want to use training to both increase their testosterone level and up-regulate androgen receptors. But the only goal of steroid users is to increase androgen receptor levels no matter what the cost, because they can artificially control their androgen level. How would you explain Dorian Yates? He does very little training, but he has grown quite large. Are you saying that if he increased his training load, he’d get bigger?
Dharkam: Correct — different goals, different training strategies. As far as Yates is concerned, if you look at his video, you will realize that he does far more sets that what most magazines claim. Since muscle contraction is one of the main up-regulators of androgen receptors, the harder your muscle contracts, the more androgen receptors you’ll get. A Yates training season is likely to induce more intense contractions than most bodybuilders will ever experience.
Another common question for Yates or any other bodybuilder is, wouldn’t they be bigger faster by training another way. It takes 5 to 10 years to make a good pro. That’s far too long. It should not take more than 6 to 12 months. It only shows us we are doing things the wrong way.
To make things more complicated, intense muscle contractions are not the only up-regulators of androgen receptors. Training volume is another important aspect. Many people will not grow by following Yates’ training style. They need frequent, moderate intensity training. Many Blacks in Europe only respond to this kind of stimulation. By the way one can only respond to this kind of training with steroids. They lose mass when they train less often with more weight. It means there are different ways to up-regulate androgen receptors. You just have to figure out which one is the most efficient for you.
MESO-Rx: So far, so good. Can you tell us how training can induce an androgen receptor up-regulation?
Dharkam: Androgen receptors are not the only receptors affected by weight training. Levels of muscle GH-receptors, IGF-receptors, cortisol-receptors,… are all altered by exercise. As far as the mechanism of actions are concerned, it is still too early to tell. We know that the degree of tension applied on a muscle, the training frequencies, … are important factors. Also, positive reps do not produce the same kind of effects than eccentric reps on androgen receptor level. Furthermore, not all the different muscle groups respond with the same up regulation of androgen receptors. This is why some muscles respond better to training than others.
MESO-Rx: What you are saying is that you can modulate the level of muscle androgen receptors by using different training strategies.
Dharkam: Yes, this is why it is so important for bodybuilders (natural or not) to understand how the way they train will affect androgen receptor level. For example, if some techniques up-regulate androgen receptor level, others will down-regulate it. It is not necessarily bad as long as you are aware of which strategy is doing what. You just take more days off when your muscles are “poorer” in androgen receptors. On the other hand, it is a waste not to train more frequently when the androgen level and the receptor level are both high.
MESO-Rx: But more precisely by what mechanism does muscle tension influence muscle androgen level? And is this validated by research, or it’s your speculation?
Dharkam: Let me first state again that training affects androgen receptors of the trained muscle ONLY. The most likely mechanism of actions is that training induces the local release of different growth factors. For example, Platelet Derived Growth Factor (PDGF) could be at least partially responsible for the up-regulation. Of course we all try to find substances that can duplicate this upregulating effect.
MESO-Rx: You mean like Prostaglandin F2?
Dharkam: Ah, the cat’s out of the bag.
MESO-Rx: Do anabolic steroids block cortisol receptors? Or do they reduce the number of cortisol receptors? Do they do anything on cortisol receptors? They must be doing something, because too many weightlifters complain about joint pains after cycle.
Dharkam: First, let’s review the theories of anabolic steroid effects on cortisol receptors. The first theory claims androgens bind cortisol receptors without activating those receptors. In short, anabolics would block cortisol receptors. Our researchers were unable to see such a thing in test tube. I know some old studies showed it. Most including very recent ones are unable to reproduce those results. Of course, that is in test tube It could be different in real life. But if androgen did block cortisol receptors in bodybuilders, we would see a sudden increase in cortisol level. According to all the blood tests I have see this is not the case. Within a few days, the body would produce more cortisol receptors. I think it is not a secret for anyone to say that the studies of Rosen and Mayer (the first scientists to have shown a possible cross reaction between androgen and cortisol receptors) were flawed.
MESO-Rx: Can you expand on that point.
Dharkam: Oh yes. Simply said they postulated that there were no androgen receptors on muscles. That was in the 70’s. We now know this is not true. The receptors they thought to be cortisol receptors could have been in fact androgen receptors. But to be fair, there are several Russian studies showing a possible cross reaction. I just do not buy it.
MESO-Rx: So you’re saying that this theory is unlikely to happen in real life?
Dharkam: If it did the body would compensate in doing two things: in a matter of a few hours cortisol level would skyrocket. In a few days the body would create new cortisol receptors on the muscles. Even if the theory was correct, it would not explain the muscle gains seen with anabolics as the body would overcome any blocking effect at the cortisol receptors.
MESO-Rx: What about the second theory?
Dharkam: It claims that steroids will reduce the number of cortisol receptors on the muscles. It seems to be able to do that without touching the cortisol receptors according to some studies but not all. Again it might be possible, but I do not think it happens in real life. Whenever the brain would detect this reduction in receptor level, it would increase the cortisol release. The blood concentration of cortisol would increase in parallel with the down regulation. So, no anabolic effect would be seen as the decrease in cortisol receptors would be canceled out by more cortisol.
MESO-Rx: But this has been shown to take place in animal muscles with trenbolone!
Dharkam: This is true and not only with trenbolone but also with other androgens such as testosterone, nandrolone,… But let’s talk about the most documented anabolic: trenbolone. From the animal studies where cortisol receptor downregulation was seen, we learn that trenbolone is not truly anabolic. In fact, trenbolone reduces protein synthesis rate: it is a mild androgen blocker. Let me state that again, in animals, trenbolone is an androgen receptor blocker. On the other hand trenbolone reduces muscle catabolism even more. That is how it produces its muscle building effects.
MESO-Rx: If I understand you, trenbolone reduces both muscle synthesis and degradation rates at the same time. But it reduces degradation rate far more than synthesis. So, the balance of the two is positive and muscle mass can be increased.
Dharkam: Right. Now, let’s apply that to humans. If true we would have a mild anti-androgen effect with a strong anti-catabolic effect. Think about it, this drug would be perfect for women. No androgenic effect, just bigger muscles.
MESO-Rx: Ok, I see your point. It does not take a genius to see this is not the case in humans. Trenbolone being a strong androgenic steroid so it rules out any possibility of being an androgen receptor blocker.
Dharkam: True. Trenbolone would not cause any acne in that case. In fact if we apply the animal results to humans, trenbolone could cure acne. Isn’t that funny? And if we cannot apply this effect of trenbolone, who would extrapolate its effect on cortisol receptors to humans? We have to get use to the idea that sometimes animal findings just do not apply to humans.
MESO-Rx: What is the third theory?
Dharkam: The last theory states that androgens can alter cortisol effects by acting at the post receptor level on something called HRE: hormone response element.
MESO-Rx: Let’s stop right here, this looks complicated. Cortisol binds its receptor normally. It sends a message. Then what?
Dharkam: Then the androgen prevents the message from arriving properly. This is like a letter you try to send. The first cortisol theory states that you cannot put it in the mail box as the opening is blocked. The second theory states that you cannot post your letter as you cannot find a mail box. But the last theory states that you can find a mail box, and you can put your letter into it. But the letter is stolen along the way before it reaches its destination. This would mean a post (after) mail box defect. In scientific terms, we call it a post receptor defect. Let’s not go any further. This is the most documented theory. But again the body would compensate with more cortisol and more receptors.
MESO-Rx: Didn’t you tell me that a recent study performed on HIV+ humans does not seem to support those theories?
Dharkam: They were unable to see any cross reaction between androgen and cortisol receptors even at the HRE level. Of course, it is hard to extrapolate from that study as it was not performed in healthy trained people. But this still provides some indications anyway.
MESO-Rx: OK. But what if we combine all the theories into one. It would mean a cortisol receptor blockage (theory one) plus a reduction in cortisol receptor level (second theory) plus the post receptor defect (third theory)?
Dharkam: This is possible but again there would be a huge boost in cortisol secretion. This is not what I have seen in steroid user blood tests. Here is a last detail to convince you. Cortisol receptors are found all over the different muscles. If anabolics acted to reduce cortisol catabolic effect, it would do it all over the body. This is not what I have seen in my athletes. Someone who never trains calves does not get bigger calves with steroids. A muscle grows only if specifically stimulated.
MESO-Rx: I see where you are going. Every single muscle would grow, not just the trained muscles.
Dharkam: Exactly. A bodybuilder who only works his arms would see his legs and calves grow too. The cortisol muscle wasting effect takes place 24 hour a day, 365 day a year. It takes place in all the muscles. A reduced cortisol wasting effect will make every muscle grow.
MESO-Rx: You are ruling out any effect of anabolics on cortisol?
Dharkam: I did not say that. Androgens do influence cortisol but not at the receptor level. Some anabolics tend to increase cortisol level. Most attenuate training-induced rises in cortisol level.
MESO-Rx: Which anabolics control the cortisol increases that result from training?
Dharkam: I cannot tell you that. Not that it is a well kept secret but it depends on the users. The same anabolic will increase cortisol in some while it will keep it at a moderate level in others. This is why we rely on blood tests so much. In fact, this is one parameter we use to determine which steroid or which combination of steroids suit the user best.
MESO-Rx: So I guess I will not ask you about dosages or stacking?
Dharkam: They must be tailored to meet the specific user needs.
MESO-Rx: If some steroids reduce cortisol level we should expect growth all over, not just the trained body parts.
Dharkam: Well, I did not exactly use the word reduce. Training tends to increase the cortisol level. The more one trains the higher the cortisol level should be. This is not always true as we can find exceptions but it is generally true in most people. Taking the right steroids will blunt or prevent this effect of training. Steroids do not reduce the cortisol level, they reduce stress-induced rise in cortisol. This is different. It is more correct to say that it keeps the cortisol effect neutral when compared to the average natural bodybuilders. Again, natural bodybuilders should keep that in mind whenever they look at a pro bodybuilder’s training routine.
MESO-Rx: I see. Certain steroids — which may be different from person to person — allow users to avoid the major obstacles caused by too much cortisol.
Dharkam: It avoids cortisol negative effects before they can take place so there is no need to fix it.
MESO-Rx: But as cortisol causes wasting, anabolics are anti-catabolic not catabolic?
Dharkam: Again there are several kinds of catabolism. It seems that anabolics reenforce the “positive catabolism” while reducing the “negative catabolism.” So it is not correct to say it is an anti-catabolic drug. Also the cortisol wasting effects are due in large part to its anti-anabolic effects (it reduces the anabolic drive). Restoring this anabolic drive has to do with anabolic rather than anti-catabolic properties of androgen.
MESO-Rx: If the proper steroids prevent cortisol rises and if they do not act at the receptor level, how do you explain the pain killing effect experienced during a cycle?
Dharkam: During is the right word. Once steroids are stopped, the effect is gone. If this effect was mediated at the cortisol receptor level, this would not take place at the end of a cycle. Remember we said steroids moderated cortisol level. Once the cycle is stopped, the cortisol level will start to rise as the preventive effects of anabolics slowly disappear. Sometime there is an overshoot in cortisol production.
MESO-Rx: What you mean is if anything, cortisol level is higher at the end of the cycle than during…
Dharkam: So if the pain killing effect of anabolics was due to androgen acting on cortisol receptors, the pain would not come back at the end of a cycle.
MESO-Rx: I see. But how do you explain the anti-inflammatory effect produced by anabolics?
Dharkam: I did not use the term anti-inflammatory. I use the term pain killer. Can you give me the name of a natural pain killer?
Dharkam: Very good. Opioids are pain killers. Their effect is mimicked by drugs such as morphine.
MESO-Rx: Do you mean that steroids act on opioid receptors just like morphine?
Dharkam: Not exactly like morphine but this is basically what I have suggested. Do you know how morphine influences cortisol level?
MESO-Rx: It tends to keep cortisol secretion low especially in case of stress.
Dharkam: Exactly. I will not go much further into this theory. But by acting on some opioid receptors, anabolics effect both cortisol concentration and pain.
MESO-Rx: Morphine also reduces testosterone secretion. Wouldn’t androgens down-regulate their own secretion?
Dharkam: Correct again. This is one of the numerous negative feedbacks of androgens on their own secretion.
MESO-Rx: Is this the only way that anabolics reduce pain sensation?
Dharkam: No, there is research showing that anabolics act on the nervous system where they reduce the perception of pain. So we are far away from cortisol. And you can understand why the pain comes back upon steroid withdrawal.
Here are some take-home points:
- Proper weight training increases androgen receptor level on the trained muscles.
- This explains the synergy seen between anabolics and training in bodybuilders.
- Natural bodybuilders and drug users should be aware of the different effects of the different training techniques and frequencies on androgen receptor level.
- The primary goal of a natural bodybuilder is to increase testosterone level with intense, short training sessions. Upregulating androgen receptor level will potentiate testosterone anabolic effects.
- The primary goal of a steroid user is to re-open androgen receptors at any cost!
Overall, natural bodybuilders should not train like drug users. And the training of drug users should be radically different from that of natural bodybuilders. In other words, drug free athletes need to avoid training advice from champions and listen to natural bodybuilders even though they are not as big as professional bodybuilders.
- Stein TP. 1999 Jan. Am J Physiol. 276:E155-62.
- Fagan JM, Goldberg AL. 1986 Apr. Proc Natl Acad Sci U S A. 83(8):2771-5.