by Josh Hodnik
Bodybuilders have long known that some people grow easily on a moderate dose of anabolic steroids, while others must use much higher amounts only to experience slight changes. Some of the variance may be due to diet, training, aqnd lifestyle. However, there is one mitigating factor that determines a person’s size and strength, as well as how they respond to anabolic-androgenic steroids, and that is genetics.
There is a particular genetic trait that affects one component of the androgen response. The trait affects the sensitivity of the androgen receptor, a vital piece in the anabolic pathway. Androgen hormones, such as testosterone and DHT, work by stimulating molecules in muscle cells, which activate specific genes to produce proteins. They also affect the activation rate of enzyme systems involved in protein metabolism, thus enhancing protein synthesis and inhibiting protein degradation.
The effectiveness of anabolic steroids is dependent upon the sensitivity of the androgen receptor sites in muscle and other tissues. Androgen receptor sensitivity is actually variable among men. Some respond easily to testosterone, while others do not respond at all. The genetic trait, called CAG repeat polymorphism (CAG), refers to a glutamine-tag attached to the androgen receptor. CAG refers to the DNA sequence of the gene that produces the androgen receptor. It takes three nucleotides (the building block units of DNA) to code for one amino acid in a protein chain; CAG is the sequence of cytosine-adenine-guanine, which codes for the amino acid glutamine. It has been demonstrated that the length of this glutamine chain can determine how efficient the androgen receptor is at turning on or off the genes that create healthy male characteristics.
When testosterone, or any other steroid for that matter, enters a cell, it binds with an androgen receptor. There are different co-factors in the cells that either enhance or impair the ability of the receptor to connect with and stimulate the cell to respond. These co-factors attach to the testosterone-androgen receptor complex and travel to the nucleus, and bind to the chromosomes at specific androgen response elements. This complex then pairs up with another complex to turn on the testosterone sensitive genes.
Genes are information; they do not function as anything other than data storage. In order for the information they contain to become new cell structures or change function, the information has to re-enter the cell in a form that the machinery of the cell can understand. This is known as transcription. Transcription creates a chemical memo of sorts, or instructions from the head office. It was briefly mentioned that the length of the CAG repeat can affect androgen receptor efficiency. The longer the CAG repeat, the higher degree of separation, and the less likely the proper information is passed along. Because of this, longer CAG repeats decrease the response of the body to the hormone testosterone.
Men with extremely long CAG repeats experience symptoms similar to those shown by men with testosterone deficiency, such as reduced fertility, gynocomastia, lowered bone density, insulin resistance, elevated cholesterol, decreased muscle, depression, as well as neurological problems. On the other hand, men with short CAG repeats develop prostate cancer earlier, have a higher risk of male pattern balding, and lower HDL (good cholesterol).
Genetics are sometimes discussed, but usually in a broad sense, when talking about a person’s ability or inability to grow. Sometimes this discussion involves the genetic trait linked with a particular body part or the dominance of one type of muscle fiber, but genetics involving the androgen receptor isn’t something that’s really thought about. The CAG repeat could in fact have more influence on athletic ability and gaining muscle mass and strength than any other genetic trait.
Men with short GAC repeats respond to naturally produced testosterone much better than men with longer GAC repeats, leading to more muscle mass and strength. For example, two men could both have a normal total testosterone number of 600. One of the men has an extremely short repeat, while the other has extremely long GAC repeat. The man with the short GAC repeat has the probability of having more than average muscle mass and less than average body fat, and depending on diet, lifestyle, and training; he could in fact make the same type of gains that other may make when taking anabolic steroids. The short GAC repeats lead to the androgen receptors being highly sensitive, which leads to them responding to the testosterone more efficiently than normal. On the flip side, the man with the extremely long GAC repeat is almost completely resistant to the testosterone. He will experience higher body fat, lower muscle mass, and other symptoms associated with testosterone deficiency, even though testosterone concentrations are in a normal range. In this case, the androgen receptors do not respond as they should, making circulating testosterone almost worthless. This is the same scenario when anabolic-androgenic steroids are used. Just like testosterone, their effectiveness is dependent, first and foremost, on the sensitivity of the androgen receptor, which is determined by CAG length. Its rare, but CAG length could be long enough to make even high doses of steroids completely ineffective. Most people are unaware that some people are non-responders to steroids due to CAG repeats length. They just assume that when someone doesn’t grow from a steroid cycle, the steroids were either fake, or the person didn’t exert any effort into training and diet.
Of course, there are those that are fortunate enough to explode from taking the lowest dose of anything anabolic. These are the super-responders, or the ones with extremely short CAG repeats.
The CAG repeat length is not something that is routinely tested for. Very few labs measure this, and as of today, its not part of a routine physical or evaluation for low testosterone. If there is a history of marginal response to anabolic steroids, it very well could be due to long CAG repeats and low androgen sensitivity. Unfortunately, there is no way to alter or treat this trait, but this could all change in the near future.