Cortisol – catabolic or anabolic?
By Sławomir Ambroziak
Keywords: cortisol, testosterone, catabolism, anabolism, receptors, transcription factors, coregulators, coactivators, corepressors, selective steroid receptor modulators, SERMs, SARMs, SVDRM, SGRM.
If testosterone is probably the most popular hormone amongst athletes, then cortisol – the most hated.
We all know that testosterone is an anabolic hormone that is one that stimulates muscle protein accumulation processes and thus contributes to muscle strength development and weight gain. On the contrary, cortisol is called a catabolic hormone that acts contrary to testosterone, interfering any positive effect of the latter on our muscles.
In this situation, it would seem that the lower levels of cortisol the faster development of our muscles. For this reason, many athletes aim to dramatically reduce its production, reaching for various pharmacological methods. However, scientific studies and clinical observations clearly show that too low levels of cortisol can be as fatal to the muscles as its excess. For example, the most common symptoms of Addison’s disease (adrenal insufficiency and deficiency of cortisol) are: increasing fatigue and muscle weakness, decrease in muscle mass and muscle aches. However, in Cushing’s disease, in permanent stress and during anti-inflammatory steroid therapy (in other words in situations associated with a significant excess of cortisol or its derivatives) we can observe extreme muscle weakness, a dramatic decrease in muscle mass and a clear, unfavourable change of muscles and fat ratio. What is more, not only do high doses of cortisol inhibit protein production, but also promote fat storage.
All these facts seem to agree with what is emphasized in literature – that cortisol has catabolic or anti-anabolic properties only if in excess, whereas if it’s within the low range of physiological values – it acts as an anabolic.
This fact has been known for many decades, however for a long time we could not explain it satisfactorily. In my book – „Legal Anabolics” – I explained it using slightly earlier views, which in light of recent research were not completely accurate. In the last chapter of my book I promised that if there were any new facts about anabolism and anabolic steroids, I would definitely post them on my website in order to complete the book. And today we know much more about the dual activity of cortisol (i.e. anabolic-catabolic), which is why I will try to explain below the reasons of this phenomenon.
Once upon a time it was believed that…
Anabolic activity of testosterone consists in the hormone binding to the androgen receptor (AR) in muscle cells, leading to the formation of a so-called transcription factor. Now, the transcription factor affects the relevant genes, stimulating them to produce a variety of muscle proteins (each gene contains in itself a 'recipe’ for a certain protein).
In addition to testosterone, androgen receptors also bind other male sex hormones (androgens) or their synthetic analogues – the so-called anabolic-androgenic steroids. This explains why three hormones: androstenedione, dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT), as well as numerous drugs such as Dianabol or Stanazol, have anabolic properties that are similar to testosterone. For some people this effect may be stronger, for others – weaker. If a chemical compound acts similarly, but weaker than the actual hormone, it is called a partial agonist. If it is capable of producing a maximal response greater than the endogenous agonist for a target receptor, it’s called superagonist. In this case androstenedione and dehydroepiandrosterone are the partial agonists, and dihydrotestosterone and anabolic-androgenic steroids – most commonly – superagonists.
However, since all steroid receptors are very similar, androgen receptors also bind female sex hormones, i.e. estradiol and progesterone. If a compound binds to a hormone receptor, but its activity is very low or none, then it is called an antagonist (opponent). In other words, the antagonist takes place on a receptor and blocks agonist-mediated response; at the same time it doesn’t provoke a biological response itself upon binding to a receptor, thus counteracts the effects of agonists and their receptors interaction. Progesterone is an androgen receptor antagonist (and thus testosterone). However, estradiol issue is a bit more complex, therefore, I will explain it in another article on this page „Estrogens – androgens.”
It is worth mentioning it in this article because for many years the mechanisms mentioned above have been used to explaine the phenomenon of different activity of high and low cortisol levels.
It was assumed that cortisol may be a partial and extremely weak agonist of androgen receptors. If its level in our body is really low, then it binds only to free androgen receptors found in muscles, yet unoccupied by testosterone (in most tissues there is an excess of receptors over the number of molecules of their respective hormones). Now, its partial agonist properties cause anabolism to speed up slightly. But when cortisol level raises – due to stress, over-training or pharmacological treatment – the hormone begins to bind to a much greater number of androgen receptors, blocking testosterone access to them. Due to the fact that cortisol acts immeasurably weaker than testosterone, it eventually inhibits anabolic processes that take place in muscle cells.
Today we know more…
Although it may seem unaccountable, today we know that cortisol doesn’t bind to androgen receptors. So far the ability of such bonds has not been demonstrated in any study. And it seems to be peculiar because – as mentioned above – all steroid receptors are very similar and most of the steroid hormone binds to most of them, although with a very different end result. Nevertheless, it turns out that cortisol can block testosterone.
The principle mechanism of cortisol action in our body is evidently the same as testosterone and all other steroid hormones. Cortisol binds to glucocorticoid receptors – GR – what turns them into transcription factors that affect genes. It stimulates genes to protein synthesis what makes it act just like any anabolic steroid – for example testosterone. There is a hitch though: what proteins are formed in muscle cells by dint of cortisol activity? It is well-known that due to testosterone activity genes stimulate among others muscle cells synthesis and contractile protein fibres formation, thus increasing size and strength of our muscles. However, we lack clarity as to what proteins are synthesised in the muscles influenced by cortisol. It appears that apart from protein useful for strength and muscle mass development (such as contractile protein fibres, enzymes catalysing energy processes and anabolic hormone receptors), there are other types of protein formed that inhibit the processes mentioned above (such as catabolic enzymes or infamous myostatin, which prevents muscles growth). It is also known that in the presence of cortisol our liver produces plasma albumin, which plays an important role in supplying amino acids into our muscles.
We can now assume that at low concentrations of cortisol there is an increase in the production of proteins promoting muscle mass development, whereas at high cortisol level – in the production of proteins that interfere with muscle growth. The difference lies, however, in a slightly different place. We needed this elucidation to explain the previously mentioned mechanism of blocking testosterone with cortisol.
I do believe you remember that once it had been thought that cortisol blocked androgen receptors, then later it was proved that it didn’t bind to them. You should also remember the hormone binds to its receptor (GR) and transforms it into a transcription factor that acts on genes. It turns out that this transcription factor not only binds to the relevant genes, but also to genes relevant to other hormones and their receptors. The only difference is that it does not stimulate protein production like when activating “its own” genes, but just the opposite – it inhibits protein synthesis. This is most likely the way in which cortisol blocks testosterone – not at the level of receptors, but at the genomic level.
At low concentrations of the hormone, cortisol bound to its receptor activates predominantly the appropriate genes and stimulates anabolism. However, at high concentrations it blocks testosterone activity what interferes with anabolic processes. It is worth noticing that a similar inhibition may also occur with other transcription factors activated by other hormones.
Transcription factors, which are formed as a result of a hormone binding to its receptor, trigger anabolic processes by binding to the relevant gene fragment called hormone response element (HRE). In the case of cortisol, however, it has been demonstrated that its genes have both positive or negative HRE. When cortisol transcription factor is bound to a positive HRE (called GRE), the first phase of protein anabolism begins (transcription). But when it’s bound to a negative HRE, it inhibits this process. It has been observed that it happens when the negative cortisol HRE (called nGRE) reaches a gene binding site of another transcription factor, strongly stimulating anabolism AP-1. Cortisol complex binds to nGRE and blocks it, thus prevents AP-1 from developing its anabolic activity.
Again, we presume that low cortisol levels only affect positive HRE, and high ones – the negative.
The crux of the problem
Now we come to the most important, science-based differences between the activity of high and low levels of cortisol. I’ve simplified a bit some issues above. I’ve mentioned that a steroid hormone binds to its receptor and transforms it into a transcription factor. In reality, two receptors bind two molecules of a hormone and then they join together to form a double molecule – dimer. Therefore, a transcription factor is actually a double molecule.
Various researches have revealed a very interesting property of cortisol. It occurs that a low level of cortisol in the body elicits a formation of dimers mainly. However, if a cortisol level is high, one cortisol molecule binds to one receptor and acts as a single bio-molecule i.e. monomer.
Every cell in our body (including muscle cells) is equipped not only with transcription factors, which are hormone receptors (also known as nuclear receptors), but also with the so-called non-nuclear transcription factors. Their anabolic activity is not induced by a direct binding to a hormone, but is a result of hormone activity on a receptor localized in a cell membrane, initiating a cascade of signals transmitted by specialized transmitters. For strength and muscle mass development the most important non-nuclear transcription factors are: NF-kB, already mentioned AP-1 and STAT, which activate protein synthesis in response to signals from such potent anabolic hormones like insulin, somatotropin, IGF, MGF, IL-6 or IL-15.
This brings us to the heart of the issue. As it turns out, monomer complexes of cortisol and its receptors are able to bind and thus make those transcription factors inactive. This mechanism is known as biological crosstalk, where one or more components of a signal transduction pathway affect a different pathway.
GR monomers, which are formed when there’s an excess of cortisol, have at least three more properties – unfavourable for the development of strength and muscle mass.
I have described a transformation of a receptor into a transcription factor in a very simple words. In fact, not only does a receptor bind its hormone and then join a second hormone-receptor complex, but it sldo binds some additional enzymatic proteins called coregulators. Coregulators are divided into coactivators and corepressors. Without going into details, coactivators relax nuclear protein envelope (histones) and make transcription factors way to genes. Corepressors have an opposite effect; they bind histones together, thus inhibit gene expression. As you can see, they do their best to ensure that our muscles do not grow too fast.
As it turns out, monomers reduce the activity of coactivators, while making it easier for corepressors to join transcription factors. It is not difficult to guess that this has a pernicious effect on anabolic processes.
When a transcription factor starts copying genetic information (transcription – 'rewriting’), then our 'recipe for protein’ flows from DNA to RNA. RNA forms so-called pre-initiation complexes, necessary in the next stage of protein anabolism – translation. Translation is a process of decoding and producing in accordance with the instruction given specific amino acids chains that that will later fold into an active protein. RNA polymerase plays a very important role in the anabolic activity of RNA as it catalyses the transcription of DNA. And here again, our ubiquitous GR monomers have their time and inhibit the activity of RNA polymerase, thus reduce the rate of anabolic processes.
I have mentioned above about the transcription factors that are activated by hormones via special transmitters. It is worth noting that some specific enzymes called kinases are the most important transmitters here. Not only do kinases activate transcription factors and thus the first step of protein anabolism – transcription, but also they activate the pre-initiation complexes that have their part in the second stage of protein anabolism that is translation. As you can see, these enzymes activated by various anabolic hormones play an extremely important role in the process of protein synthesis as well as in strength and muscle mass development. mTOR kinase seems to be one of the most popular ones; it has been proved that the enzyme is activated by leucine, which is the primary mechanism of the anabolic activity of the popular dietary supplement. Unfortunately, our GR monomers inhibit the activity of this entire subset of kinases, which includes the well-known mTOR kinase.
Last but not least…
Cortisol acts through its steroid receptors as well as other cellular mechanisms, which may explain so different activity of high and low values of this hormone. From the perspective of muscle mass and strength development these mechanisms can in fact be divided into positive and negative ones. It is well-known that any benefits are associated with rather low concentrations of cortisol, while any detrimental effects – with very high.
GR receptors exist not only inside our cells, but are also located in cell membranes. Therefore, cortisol may send information via signalling pathways mentioned above, using special transmitters. Cortisol makes use of two such routes: the first one is associated with a transmitter called cAMP and protein kinase A (PKA), whereas the other one is relying on phosphatidylinositol as well as phosphatidylinositol 3-kinase (PI3k) and serine-threonine kinase (Akt).
These routes are of considerable importance for muscle development. Both in fact lead to the activation of relevant transcription factors in muscle cells and stimulate anabolism of key proteins including muscle contractile proteins. Both also elicit activity of a family of enzymes called nitric oxide synthases (NOS) that catalyse the production of nitric oxide (NO); this may explain the observed increase in NO levels in muscle tissue influenced by cortisol. However, this effect may require a much more complexed mechanism. I truly believe we all know that nitric oxide has a large part in shaping our muscles. This is why we use widely known NO-boosters, such as AAKG. Its effect on muscle development is quite complex and I discuss it extensively in my book – „Legal Anabolics”.
It is worth mentioning that a popular (and banned) stimulant Clenbuterol develops its anabolic effects via the signalling pathway related to PKA. Several potent anabolic hormones such as insulin and IGF act through a pathway associated with PI3K and Akt. The anabolic effects in a low cortisol environment occur due to a high sensitivity of GR receptors. High level of cortisol eliminates the occurrence of any anabolic effects because – as we remember – GR monomers inhibit the activity of other kinases, associated with PKA, PI3K and Akt signalling pathways, which are important to muscle protein anabolism at the level of translation. What is more, excess cortisol interferes with nitric oxide production because it lowers NOS level.
As a compound soluble in fat (lipophilic), cortisol is easily accumulated in biological membranes, made up predominantly of fat. For strength and muscle mass development the tendency of cortisol to accumulate in the membranes of lysosomes and mitochondria is a very important factor. Low cortisol levels stabilize these membranes what is very favourable for us. However, high cortisol levels favour the oxidation of these membranes and the loss of their stability. It is fatal to our muscles because these organelles store catabolic enzymes that destroy muscle proteins. So when the membrane loses its right tightness, enzymes leak into cells, digest protein and destroy our muscle mass.
In addition, as shown by research studies, mitochondria with excess cortisol accumulated in their membranes produce much less energy in the form of ATP. As you probably know, ATP is a source of energy that enables fibril contractions and muscle protein anabolism.
What the future may bring
Although today we know exactly what the differences between low and high concentrations of cortisol are, but it still begs the question: „What do we need this knowledge for after all?” I will say right away that it’s not just about 'art for art’s sake’. This knowledge will be useful for pharmacologists who are looking for new drugs…
Recent experiments with so-called selective steroid receptor modulators are a very popular direction of new drugs search. The oldest drugs in this group are Selective Estrogen Receptor Modulators (SERMs); a good example of a drug from this group is Tamoxifen, which is probably known to most of us. However, recently the first drug from a group of selective androgen receptor modulators (SARM) called Ostarine hit the market. There are also selective modulators of vitamin D receptor (SVDRM), which I’ve written about recently. Nevertheless, we are urgently looking for one more – SGRM – selective glucocorticoid receptor modulators.
A selective steroid receptor modulator acts as an agonist of a hormone in some tissues or metabolic processes, while in others – as an antagonist or a weak partial agonist. This is possible thanks to the coregulators mentioned above. You should know by now that they are divided into transcription corepressors and coactivators as well as that anabolic processes work on a similar basis as gas and brake pedals in a car. It occurs that each tissue has a specific set of cell coregulators. Binding an appropriate hormone or hormone agonist to its receptor results in binding a specific set of coregulators – with a predominance of co-activators – and activating transcription, whereas antagonist binding leads to binding mainly or solely corepressors and transcription inhibition. However, selective modulator binding increases the overall ability of a receptor to bind coregulators, and the rest (transcription activation or inhibition) depends on the fact whether the cells in a tissue are dominated by coactivators or corepressors.
But what would all this be for…? Well, you probably know that testosterone increases bone and muscle mass, but also – unfortunately – the size of our prostate, leading to hypertrophy and dysfunction of this gland. A model SARM would act as an androgen receptor agonist in our bones and muscles, while being an androgen receptor antagonist in our prostate. This would help in strengthening bones and developing muscles, while given our prostate protection.
And what hopes do pharmacologists put on finding SGRM? The researches in this field are taking their own, divergent course…
Firstly, scientists are trying to find such compounds that create only GR receptor monomers discussed above, usually arising under the influence of high doses of cortisol or its synthetic analogues. The point is that most or all of the anti-inflammatory properties of these compounds used as drugs result from GR monomers activity, while the adverse effects – from the dimers activity. This is not of much interest to us because – as we remember – it is mostly monomers that have a detrimental influence on our muscles.
Scientists also work on finding such molecules which – after binding to GR in the muscle cells – would form only dimers, while eliciting binding of the right coregulators group. This group would activate a transcription of these genes that store our 'protein recipe’ needed for strength and muscle mass development. On the other hand, it would inhibit the genes responsible for encoding any harmful proteins – for example myostatin. Such compounds could be combined with cortisol or classic steroid anti-inflammatory drugs what would prevent occurring any adverse effects of these drugs, mainly muscle weakness and damage called steroid myopathy.
It is not difficult to guess that these SGRM will arouse interest of many athletes!