Monday, August 22, 2011

Beyond Vida's Book, Part 1/2: Androgen, Progesterone, Estrogen & Corticosteroid Receptor Activities of ALLmost All Anabolic Steroids - WADA Prohibited Compounds.

Image 1: Data on the interaction of androgens
with the progesterone receptor is scarce,
this study has it!
This is only blogpost #499, yet at the same time, its a premiere! It's the first time that I am aware of that something you read at the SuppVersity has been covered by the "competition" before. Kudos to my dutch friends from ergogenics.org, who dug up a 2008 paper by Corine J. Houtman et al. (Houtman. 2008) with extensive CALUX(R) bioassay data on the androgen, progesterone, estrogen and corticosteroid receptor response to allmost all popular steroids - it would probable be the "A", as in 4-androstenediol (the "good old 4-AD"), to "Z", if there actually was a common androgen with a "z" as its first character.
Note! Due to the fact that the sheer amount of data from this study exceeds the time I can spend on analyzing and compiling it for you, today, this is going to be a two part series, with the second part on what the authors describe as "potential" AAS (among these are such illustrious names as 7a-methyl-19-nor-T aka Trestolone or MENT) will follow tomorrow. And don't get mad at me for that, at least it does have the advantage that you can comment / pose questions today and have them answered in detail, by tomorrow ;-)
The original intention of the study obviously was to demonstrate that by the means of the mammalian androgen receptor responsive reporter gene assay (AR CALUX® bioassay), the anti-doping agency would be able to identify hitherto unknown "designer steroids", which would not show up in the usual tests, where the chemical structure of the substance you are looking for must be known beforehand. The CALUX bioassay, on the other hand, directly measures the transcriptional activity of a specific steroid receptor when it is exposed to a given substance and is thus a very reliable measure of the biological effect a certain anabolic will have on the cellular level.
Figure 1: Enzymes, their cellular location,
substrates and products in human
steroidogenesis
; DHEA is the first
compound in the left androgen column
(figure by Slashme and Mikael Häggström)
While it is of course grandiose to be able to measure receptor activity directly, a non-negligible weakness of these bioassays is that they do not provide any insight into the effects of downstream-metabolits of the tested androgen. Let's take dehydroepiteandrosterone (DHEA) as an example. It is well known that after several enzymatic reactions DHEA can eventually be converted to estrogen (cf. figure 1), if however you measure the transcriptional activity of DHEA at the estrogen receptor it turns out to be 0.0813% of 17β-Estradiol (E2). This example clearly shows that, at least in the case of aromatizeable steroids such as DHEA, CALUX provides only part of the overall picture. Keep that in mind, when you are trying to interpret the data!
Other than "Vida" in his famous rat studies, these assays obviously do not provide any information about the "anabolic" value of the respective compounds. Oxandrolone, for example, is known as a highly anabolic steroid, which has about 6x the anabolic activity of testosterone. Nevertheless, its activity at the androgen receptor is only 1% of that of dihydro-testosterone (DHT) and thus no more than 1/20 of the androgen receptor activity of testosterone (cf. figure 2). Accordingly, the following data will not really tell you how much muscle an athlete will be able to accrue whilst taking a certain steroid, but rather which androgen, progesterone, and estrogen related side-effects he or she may experience in the course of that cycle.

Figure 2: Relative potency at the
androgen (reference: DHT) and
progesterone (reference: ORG2085)
receptor of androgens that are
officially prohibited by WADA
(based on Houtman. 2008)
If you have a look at the androgens from the WADA's list of prohibited compounds in figure 2, you will notice that compared to the synthetic progestin 16a-ethyl-21-hydroxy-19nor-4-pregnene-3,20-dione (ORG2085) only a handful of compounds exhibits a significant transcriptional activity at the progesterone receptor:
  • 17a-ethyl-19-nor-T (norethandrolone) - 24%
  • norbolethone - 21%
  • tetrahydrogestrinone (THG) - 7%
  • gestrinone - 5%
  • 17b-trenbolone - 3%
If the occurrence of trenbolone as the last item on the list of androgens with a high activity at the level of the progesterone receptor puzzled you, you obviously have not heard of the dreaded "progestin-gyno" this powerful steroid is supposed to induce!? While 3% of the activity of a synthetic progestin does not sound much, trenbolone is a 6423x more potent activator of the progesterone receptor than testosterone and it is still 525x more active than nandrolone aka "deca", another of the commonly used mass and strength agents the use of which is rumored to have induced gynecomastia in a non-negligible number of drug using athletes.

Only 4-chloro-19-nor-T, 19-norclostebol (4%), 19-nor-androstenediol and methyl-androstenediol (0.1%) exhibit transcriptional activity >0.1% of that elicited by estradiol at the estrogen alpha and beta receptors and none of the tested androgens from the WADA list has an activity >0.002% (this is fluoxymesterone) of that of dexamethasone at the corticosteroid receptor. In order not to overcomplicate things, I have decided to exclude this additional data from figure 2.
This is only part 1! Don't forget to check back tomorrow for more information on metabolites and isomers, such as 4AD & Co., other exogenous androgens that are not yet on the WADA anti-doping list, such as 7a-methyl-19-nor-T (Trestolone,  MENT) and other steroids!