Why you’ll never be an Olympic champion – a ballad of androgen receptor sensitivity.

Nature is not fair…
In the real world, and especially in the gym world, bodybuilders and weightlifters have long been aware that some people explode after quite moderate doses of anabolic steroids, while others become paranoid about the actual content of the drug in the flasks they buy. Some of these differences are due to work ethic, training conditions, lifestyle, etc. However, there is one underlying cause that determines an athlete’s maximum capabilities and the degree of benefits and risks associated with the use of anabolic-androgenic steroids – genetics.

Charles Darwin was the first to observe that individuals of a species are not equally adapted to life – some struggle and die, while others thrive and pair up with selected members of the opposite sex to spread their genes. The crux of this theory is contained in the slogans ‘survival of the fittest’ or ‘natural selection’. Unfortunately, Darwin’s theory dominated scientific circles for centuries, overshadowing the findings of G. Mendel, whose discovery experiments allowed us to understand gene coding and gene transfer.

We are not equal
In all humans, the number and type of genes are identical, and it could be said that this is the rule for all primates (chimpanzees, gorillas, etc.). However, it is clear that some of us show some different physical characteristics (expression of specific genes) and in some cases certain traits are virtually unique. Most of the mutations (genetic changes) that occur are associated with a variety of diseases – we are, after all, the carefully worked-out result of the action of natural selection over 3 000 00 years. In the genetic pool of a population, therefore, there is no room for the ‘occurrence’ of a mutation; and when one does occur, the individual carrying it is, unfortunately, simply ‘eliminated’ from the pool. Genes that change only particular traits remain in the genetic pool: eye colour, hair shape, enzyme activity, hormone action, etc.

The action of testosterone depends on the individual production of this hormone, the maintenance of a relatively constant concentration of it in the blood, its recognition by individual tissues, the coupling of G-proteins, gene transcription and translation, etc…. The development of science over the past few decades, particularly in the field of genetics and at the molecular level, has broadened the horizons of our knowledge to such an extent that it is now no longer possible to be an expert in the entire field of knowledge related to the effects of androgens on the human body.

Most experts in the field of biological sciences are forced to narrow their field, as this is the only thing that will enable them to deepen their understanding of a particular issue or to become the author of an innovation or discovery.In academia today, we have practically given up the possibility of being a doctor, mathematician, astronomer, physicist and hairdresser at the same time. To achieve something in this field, you simply have to have a specialisation.

Modern science is about wading through vast and ever-growing databases, selecting studies and results that reveal previously unknown issues, finding practical applications for what we already know, and “connecting the dots” between seemingly unrelated discoveries or ideas.

Why you’re not an Olympic champion

There is a genetic trait that directly affects one component of the body’s androgenic response (including building muscle mass). This trait affects the sensitivity of androgen receptors – a key component of the anabolic pathway. The androgen receptor has several regions in its molecular structure, where changes in the order of arrangement of amino acids (all proteins consist of chains of amino acids, and the shape and function of the protein is determined precisely by their arrangement) can affect its sensitivity and ability to combine with testosterone or other androgens, attach to chromosomes (DNA) or transfer receptor-stimulated information from genes to other parts of the cell (so-called transcription).
The sensitivity of androgen receptors varies widely among men – some respond very strongly to testosterone, others virtually not at all. There are men who, because of androgen receptor insensitivity, have developed as women. These women are not even aware that they are genetically male unless a chromosome analysis is carried out on them, usually during tests to diagnose the causes of infertility. This type of condition requires a great deal of empathy from us, because such women are often married and would like to have a child and suddenly find out that – from a genetic point of view – they are 46XY, i.e. male.

The secret to success

The trait discussed in this article affects the transcription or transmission of information by androgen receptors. These receptors bind testosterone and travel to the nucleus of the cell (where the DNA becomes compartmentalised), but are no longer able to turn on and off relevant cell functions to the same extent as in men who are more androgenic.
This feature, called CAG repeat polymorphism, relates to the glutamine molecule attached to the androgen receptor. The CAG is part of the DNA sequence, the gene that produces androgen receptors. It takes three nucleotides (basic DNA bricks) to encode the information of one amino acid in a protein. CAG is a cytosine-adenine-guanine sequence, encoding the amino acid glutamine.

Ironically, the androgen receptor gene is located on the X chromosome, which comes from the mother and is called the ‘sex chromosome’ Women have a pair of these chromosomes (XX) and men have one X and one Y (XY). You might think that men with an extra X chromosome (XXY), suffering from Klinefelter syndrome, might have some genetic advantage – but in reality they have low blood testosterone levels, small testes, are infertile and easily develop gynaecomastia.

It may seem that CAG has no function, coding for superfluous glutamine on a receptor that is otherwise no different from the androgen receptors of healthy men. However, it has been shown that the longer the glutamine chain, the less the androgen receptor is able to control the switching on and off of the genes responsible for the formation of a healthy male individual.

The devil is in the detail

Genes are information, they have no function other than storing data. In order for the information they contain to become a new cell or to affect a change in some function, it must re-enter the cell in a form that the mechanism of that cell can understand. This happens through transcription creating a ‘chemical note’, an instruction from HQ. The longer the CAG repeat, the higher the degree of separation and the less likely the message is to reach the addressee).

Men with extremely long CAG repeats exhibit signs and symptoms similar to those of men with testosterone deficiency, including insulin resistance, type II diabetes, gynaecomastia, reduced fertility, ‘soft’ bones, increased body fatness, increased risk of cardiovascular disease, higher LDL (bad cholesterol) levels, and neurological and psychological problems. Conversely, men with short CAG repeats develop prostate cancer more quickly, have a higher risk of localised alopecia, lower HDL (good cholesterol) levels and more frequent aggressive behaviour.

One might think that a simple solution to the problems caused by CAG repeats would be to increase testosterone levels (e.g. with injections of the hormone). In reality, this is not an ideal solution, as many men with long CAG repeats are more susceptible to some side effects and resistant to others and do not get the same benefits as healthy men. Nevertheless, as long as side effects remain under close observation (changes in PSA, cholesterol, haematocrit, mood, etc.), men with longer CAG repetitions can enjoy the benefits of testosterone administration.

Of course, bodybuilders and other athletes focus attention on whether CAG repetitions have an impact on performance or body composition. From an athletic performance perspective, men with longer CAG repetitions are at a much greater disadvantage than their counterparts with shorter repetitions. Increased CAG repetitions can contribute to decreased muscle mass, increased body fatness, weaker bones, lowered aggressiveness threshold, depressive states and decreased insulin sensitivity. It can also negatively impact cardiovascular health by increasing heart rate and blood pressure.

“Racist” controversy

The researchers made some interesting observations. The length of CAG repeats is influenced by ethnicity: men of African descent have fewer of them, followed by members of the Caucasian race and then Asians. Former sports analyst and bookmaker, Jimmy “The Greek” Snyder, faced a wave of criticism and was fired from CBS for spreading the idea that black Americans are more athletically gifted – according to him, this is the result of selective slave breeding during colonial times and before the Civil War. Snyder’s comment was, of course, tactless and the result of beliefs instilled in him when he was young. However, measurements of the length of CAG repeats indicate that there are indeed some race-dependent characteristics that may give certain groups an advantage. As social and geographical barriers disappear, the difference at the molecular level also disappears – within a few generations it may disappear altogether.

It is important for us to be aware that any genetic trait associated with sport only represents an individual’s potential and must be developed through personal effort. Only then do individual genetic traits come into play.

The question that a young, healthy man might ask himself should be: “How do I know the length of CAG repeats and how do I use this knowledge?”. Very few laboratories take these measurements and in no clinic are they part of routine testing, even for the diagnosis of hypogonadism (low testosterone). For bodybuilders and other athletes using SAA, knowing the length of CAG repetitions in one’s own body is currently of little value.

Even if one had such knowledge, there are no treatments that can change this length. However, people who do not respond well enough to SAAs despite adequate doses and training may take this as a sign of a polymorphism of long CAG repeats. Awareness of this is of value, as this trait can lead to early signs of hypothyroidism or metabolic disease, even when serum testosterone levels are normal. Individuals who respond very well to SAA may become interested in the increased risk noted in men with short CAG repeats and pay closer attention to their cholesterol levels, PSA, mood changes and hair loss….