You’ve probably heard of SERMS (Selective Estrogen Receptor Modulators) and SARMS (Selective Androgen Receptor Modulators). These are synthetic hormones that mimic some of the actions of the relevant endogenous hormones (estradiol, testosterone), while displaying little or none of certain other associated biological actions. For instance, with SERMs, the compound may display the bone anabolic activity of estradiol, while possessing minimal stimulation of estrogen-dependent sexual tissues such as breast or uterus. Additionally, with SARMs, the compound might have potent anabolic effects upon muscle tissue, while showing no stimulation toward growth of the prostate gland.
Glucocorticoids are another class of natural steroid hormones that perform profound and vital functions in the body. Unlike androgens and estrogens however, glucocorticoids are not sex hormones and they are manufactured in the adrenal glands rather than the gonads. Glucocorticoids are also different from androgens and estrogens in that their roles in the body are essential to life, and not just to reproduction and maturation.
Natural endogenous glucocorticoids include the primary hormone cortisol, as well as its precursors/metabolites cortisone and corticosterone. These work by binding to the glucocorticoid receptor and forming an activated complex, which then turns on or off specific genes in the cell nucleus that govern the various physiological actions associated with glucocorticoids. These physiological actions include changes in the function of the immune system, as well as changes in metabolic function.
The immunosuppressant actions of glucocorticoids are often exploited for the treatment of diseases in which an overactive immune system is a culprit— such as leukemia, rheumatoid arthritis, and lupus. One consequence of this immunosuppressant activity is a potent anti-inflammatory effect and this also is a very pharmacologically valuable effect of glucocorticoids. This anti-inflammatory action is taken advantage of in the treatment of many injuries or conditions in which inflammation is dangerous and/or debilitating— such as acute spinal cord injury, asthma, and sports-related chronic connective tissue dysfunctions.
The metabolic effects of glucocorticoids, on the other hand, are generally considered as negatives. In regard to carbohydrate metabolism, glucocorticoids increase the production of glucose in the liver— a process known as gluconeogenesis. In addition to this, they also impair the utilization of glucose in peripheral tissues such as muscle, by creating a condition of insulin resistance. This ramped-up glucose production, coupled with impaired glucose disposal, results in hyperglycemia and potentially type 2 diabetes.
As far as the metabolic effects on fat are concerned, that is a pretty nasty situation as well. Excessive glucocorticoids cause a gross redistribution of body fat away from the periphery (arms, legs) and toward the trunk, the face, and the upper back.
Additionally, triglycerides can be greatly elevated in the blood. The protein metabolic actions are particularly scary to the bodybuilder, as glucocorticoids reduce protein synthesis and increase protein degradation in the muscle. Muscle (and skin) protein is broken down to amino acids, which are then used to feed the ramped-up gluconeogenesis in the liver. Mineral metabolism is also affected, with calcium being lost from bone, which can lead to osteoporosis and increased risk of fracture.
Keeping all these facts in mind, you can see that there is a need for a selective glucocorticoid that has pharmaceutically desirable immunosuppressive/anti-inflammatory actions, while possessing minimal adverse metabolic side effects. For years it was thought this was not possible, since none of the synthetic glucocorticoids that researchers synthesized ever really showed any differentiation between these two actions. Plus, there was no known biological mechanism that could be targeted to custom tailor a molecule that had such selectivity.
With androgens, there is the 5alpha-reductase enzyme, which is highly concentrated in skin and prostate, but not in muscle. This enzyme amplifies the activity of circulating testosterone, by converting it to the stronger DHT, so molecules were developed (i.e., nandrolone, methenolone) that resisted the amplification effects of 5alpha-reductase. With estrogens, scientists took advantage of the fact that there were two estrogen receptor subtypes which were selectively expressed more or less in certain tissues, so molecules were developed that had greater affinity for one over the other. Unfortunately though, no receptor subtypes for glucocorticoids were known, nor were any relevant steroid metabolizing enzymes that could be exploited.
The search for selective glucocorticoid receptor modulators (SGRM) recently gained new life. It was discovered that the immunological and anti-inflammatory actions of glucocorticoids are regulated by a mechanism called transrepression, while the metabolic actions are regulated by a mechanism called transactivation.
This is how it works. When a glucocorticoid binds to the glucocorticoid receptor, it translocates to the nucleus. There it does two things. First and foremost, it directly activates certain genes, which then go on to direct the manufacture of proteins that regulate many of the biological actions of glucocorticoids. This is called transactivation and in the case of glucocorticoids, the functions affected by the transactivation route are the undesirable metabolic functions.
On the other hand, the desirable immunosuppressive/anti-inflammatory actions are carried out via the act of transrepression. In transrepression, the glucocorticoid receptor complex acts to suppress certain proteins called transcription factors. Transcription factors are proteins that bind to DNA and regulate the transfer of genetic information from DNA to messenger RNA. Nuclear Factor Kappa Beta is one important transcription factor involved in the regulation of genes related to immune system function, and the glucocorticoid receptor complex prevents it from interacting with these genes.
Several SGRM candidates have been developed, with most of them being non-steroidal in chemical structure. One in particular has been designated ZK 216348. This compound has been found to show substantial dissociation between transactivation and transrepression activities in-vitro. Its performance was promising, when tested in-vivo. The compound exhibited similar anti-inflammatory activity in a skin model, compared to prednisolone (a common prescripton glucocorticoid), while demonstrating a much weaker effect on elevation of blood glucose levels and atrophy of skin.
While none of these SGRMs have reached the clinical stage of development, the progress thus far is promising. What does this mean to athletes? Well, if a compound similar to ZK 216348 reaches the marketplace, it means that doctors may be able to exploit its powerful anti-inflammatory potential in sports injuries, while reducing the worries of tissue degeneration often seen with excessive cortisone administration.
The concern of adverse effects on performance due to diminished muscular glycogen levels may also be lessened for those who rely on glucocorticoid medicines to treat certain chronic conditions (asthma, psoriasis). I will keep an eye on the development of this technology and give you updates, should there be any significant breakthroughs.
source:musculardevelopment.com
