Androgen Receptor Sensitivity: All Men Are Not Created Equal
In the real world, or at least as real as it gets in the gym, bodybuilders and lifters have long been aware that some people explode on fairly moderate anabolic steroid dosages, while others struggle to justify the risks for the returns they receive. Some of the variation is obviously due to work ethic, equipment, lifestyle, etc. However, one underlying factor determines maximal athletic performance, as well as the degree of benefit and exposure to risks associated with anabolic-androgenic steroids (AAS) use— genetics.
Charles Darwin is credited with recognizing that individuals within a species do not all thrive equally; some struggle and die, while others prosper and propagate by mating with selective members of the opposite gender. The crux of his theories is commonly referred to as ‘survival of the fittest’ or natural selection. Sadly, Darwin’s theories dominated the interest of biologists for decades, overshadowing the contributions of Gregor Mendel— whose experiments with peas led to the understanding of genes and genetic transfer. This was in 1865, nearly 100 years before Watson and Crick were credited with discovering DNA.
Genes are inherited from one’s biological parents, and contain the code for assembling the individual. Most genes are identical among people, even among primates in general (chimps, apes, etc). However, there are obviously clusters of people who have certain physical traits (the expression of these genes), and individuals who have nearly unique conditions. Most mutations (genetic changes) do not benefit humans— after all, we are the result of centuries or eons of natural selection. Those that remain in the gene pool are changes that alter traits by a matter of degrees: eye color, straight hair versus curly, enyzme activity, hormone action, etc.
The actions of testosterone are dependent upon the individual’s ability to produce the hormone, maintain a relatively steady concentration over time, tissue-specific recognition and stimulation, G-protein coupling, co-activator and co-suppressor activity, response elements within the chromosomes, transcriptional and translational events, and so on. The advances in science over the last few decades, particularly at the genetic and molecular level, have expanded the knowledge base to such breadth and depth that it is nearly impossible to be expert in all matters relating to androgen actions in humans.
Most experts in biosciences are forced to narrow their focus if they wish to advance understanding or be responsible for innovation or discovery. The days of the generalist have faded since the Renaissance, when a man could be a physician, mathematician, astronomer, physicist and barber— as long as he was cool with the church and had a steady supply of leeches.
The burden to modern-day researchers is picking through the vast and growing databases, selecting out the studies and reviews that expose a previously-unknown concept, explain the practical use of what is known, or connect-the-dots in understanding the relationship between seemingly unrelated findings or ideas.
There is a genetic trait that directly affects one component of the androgen response (such as building muscle). This trait affects the sensitivity of the androgen receptor, a vital piece in the anabolic pathway. The androgen receptor has a few regions in its molecular form where changes in the amino acid sequence (all proteins are chains of amino acids; the shape and function of the protein is determined by the sequence) can affect the sensitivity of the receptor for attaching to testosterone or other androgens, attaching to the chromosomes (DNA)— or relaying the receptor-stimulated gene messages to the rest of the cell (an event called ‘transcription’).
Androgen receptor sensitivity is actually pretty variable among men— some respond vigorously to testosterone, while others do not respond at all. There are a number of genetic males who develop as women, due to androgen receptor insensitivity. These women are unaware they are genetically male, unless a chromosome analysis is performed, usually as part of an infertility exam. This condition deserves a great deal of empathy, as these individuals are often married and seeking to begin a family when they discover they are 46XY— genetically male.
Transcription and Manly Men
The trait of interest in this article affects the transcription, or message-relaying effect of the androgen receptor. The androgen receptor binds testosterone normally, and travels to the cell nucleus (where the DNA is compartmentalized), but is unable to turn on and off the appropriate cell functions to the same degree as men who are more androgenized.
This trait, called the 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 protein chain; CAG is the sequence of cytosine-adenine-guanine, which codes for the amino acid glutamine.
Ironically, the androgen receptor gene is located on the X chromosome, which necessarily comes from the mother (assuming you are a male). Called the ‘sex chromosomes,’ females have 2 X (or XX), while men have an X and a Y (XY). One might think men who carry an extra X chromosome (XXY), a syndrome called Klinefelter’s, might be at an advantage— but in reality, these men have low serum (blood) testosterone concentration, small testicles, suffer from infertility, and are prone to gynecomastia.
The CAG would not appear to have a function, coding for a redundant stretch of glutamine inserted in a receptor that is otherwise identical to the androgen receptor of all normal men. However, as has been readily demonstrated, the longer the glutamine chain, the less efficient the androgen receptor is at turning on or off the genes that create the healthy male physiology.
Let’s compare it to an everyday example. A happily-married couple generally communicate well. Sitting side by side on the couch, the wife can tell the husband, “Trash needs to go out for tomorrow’s pickup.” If the television is on, her comment is still heard, just not as clearly. If she starts talking just as the late Billy Mays starts hawking an ‘as seen on TV’ product at the top of his lungs, his shouting makes it harder for the husband to hear. Making matters worse, the husband has moved into another room, knowing that “America’s Got Talent” is coming on next; likely, he barely hears her. Suppose the couple had argued about the wife’s addiction to all things David Hasselhoff and he is in the garage listening to Kid Rock songs in his project car 1970 Pontiac GTO that is sitting on blocks. There is no way he is hearing about the garbage, and it likely won’t go out.
Every degree of separation reduces the strength of the message, “Take out the garbage,” and represents a greater risk of a negative consequence— garbage piling up in the house another week, in this example. Each CAG repeat is like a degree of separation between the husband and wife. When testosterone enters a cell (for the biology geeks, this is restricted to the genomic effects of testosterone), it binds with an androgen receptor. There are different co-factors in the various cell types (skeletal muscle, fat, liver, etc.) that either enhance or impair the ability of the receptor to connect with and stimulate the cell to respond. These co-factors attach onto the testosterone-androgen receptor complex and travel as a unit to the nucleus, and bind to the chromosomes (DNA) at specific androgen response elements— think of it as assigned parking spaces. The complex then dimerizes (pairs up with another complex) to actually 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 occurs through transcription. Transcription creates a ‘chemical memo,’ or instructions from the head office. The longer the CAG repeat, the higher the degree of separation, and the less likely the message is to be affected.
A great deal of research has been performed on CAG repeats and testosterone action. One clear expert in this area is Dr. Michael Zitzmann of the Institute of Reproductive Medicine at the University of Munster, Germany.
Again, the length of CAG repeats has been shown to decrease the response of the body, or tissue and cell cultures in the lab, to the hormone testosterone. Dr. Zitzmann has published a number of studies and reviews, showing that men with short CAG repeats demonstrate a more ‘androgenic’ profile, whereas those who have longer CAG repeats are less robust.
Men with extremely long CAG repeats exhibit signs and symptoms similar to those shown by men with testosterone deficiency, including insulin resistance/type 2 diabetes, gynecomastia, reduced fertility, ‘soft’ bones, higher body fat, increased cardiovascular risk, elevated LDL (bad) cholesterol, as well as neurological and psychological problems. Conversely, men with short CAG repeats develop prostate cancer earlier, have a higher risk of male pattern balding, lower HDL (good) cholesterol, and are more prone to aggressive behavior.
One might think that a simple solution to these CAG repeat-associated problems might be increasing testosterone (e.g., testosterone injections). In fact, this does not appear to be the perfect solution, as men with longer CAG repeats are more prone to certain negative side effects, protected from others, and do not receive the same degree of certain benefits. Nonetheless, so long as adverse events are closely monitored (changes in PSA, cholesterol, hematocrit, mood, etc.), men with long CAG repeats can benefit over their baseline when treated with testosterone.
CAG Length and Bodybuilding: Does Size Matter?
Of course, the interest of bodybuilders and athletes is any effect of CAG repeats on physical performance or body composition. Men with longer CAG repeats suffer from all sorts of performance handicaps compared to their short-CAG cohorts. Lengthening of CAG repeats may contribute toward decreased muscle mass, increased body fat, weaker bones, decreased aggressiveness, increased depression, reduced insulin sensitivity, and harm cardiovascular health through elevations in heart rate and blood pressure.
Some interesting observations were noted. There is a racial trend in CAG repeat length; with men of African descent having fewer CAG repeats, followed by Caucasians, then East Asians.16 Former sports analyst and bookie ‘Jimmy the Greek’ Snyder was strongly criticized and fired from CBS for making a comment that American blacks were more physically gifted— in his opinion, as a result of being selectively bred for stronger slave stock during the colonial and pre-Civil War period of U.S. history. Snyder’s comment was certainly insensitive and likely indicative of the attitude and beliefs formed as a result of his upbringing and culture. However, this measure of CAG repeat length does show that there are some racial traits that may imbue physical advantage to certain groups. As social barriers and geographical obstacles are being overcome, this molecular discretion will likely fade over generations.
It is important to be aware that any performance-related genetic trait only represents potential, and must be developed through individual effort before its advantages or disadvantages may be realized.
The question for the young, healthy man may be, “How do I know what my CAG repeat length is, and what can be done about it?” Very few labs measure this, and no clinician performs this test as part of a routine physical or even during an evaluation for hypogonadism (low testosterone). For the bodybuilder, athlete, or recreational AAS user, there is little value to knowing personal CAG length at this time.
Even if one were to learn of a long CAG repeat polymorphism, there is no treatment. However, for those who do not seem to respond to AAS use, at comparable dosages and training to his peers, this may be an early sign of a long CAG repeat polymorphism. There is value to being aware of this, as this trait may lead to early signs of hypogonadism, or other metabolic conditions, even in the presence of ‘normal’ serum (blood) testosterone concentrations. Those who respond very vigorously to AAS may wish to acknowledge the increased risk seen in men with shorter CAG repeats, and more closely monitor cholesterol changes, PSA, mood, and hair loss.16
Even anti-aging practitioners would be hesitant to treat a man with normal testosterone concentrations— but a history of marginal AAS response, early onset of signs and symptoms of hypogonadism, and a normal testosterone concentration should suggest that a CAG repeat length determination be performed. Men with extremely long CAG repeats may benefit clinically from improved quality of life and protection from hypogonadal-related condition, with testosterone replacement treatment maintaining circulating testosterone in the upper region of the normal range.
People are not stamped out of some cosmic dough with a cookie-cutter. We all differ slightly from each other, and the differences can often go undetected unless a person places himself in extreme conditions or becomes ill. Certainly, training and pursuing muscular development is a rare state in this fine country suffering from obesity, addiction, and sloth. Those who use AAS may discover that they are predisposed to easily gaining size and strength, or face genetic hurdles that make progress more difficult and limited. While those who find they are resistant to AAS-induced benefits face disappointment early in life, it may provide a clue that might aid in getting proper health treatment as they age.
by Dan Gwartney, MD