Thread: for VETERANS
03-15-2002, 04:24 PM #1
An Insider look to androgen receptors
You all know by now that the reason we are men is due too the action of androgens. Almost every male characteristic is effected, to some extent by their levels. A liking for Monday night football, aggression, hairiness, baldness, reading girlie magazines in the toilet, and greater muscularity than our female counterparts are all signs of androgens' actions.
In order for a hormone such as testosterone (the major natural androgen produced by the testicles) to have a biological effect, it must have access to functional receptors. You have all heard the "key in the lock" analogy to decribe hormone-receptor binding. The hormone binds to the receptor by having a complimentary shape, similar to the way a key fits into its lock. If the hormone is an agonist, when it joins with the receptor, it causes the receptor to be activated and signal the interior of the cell. If the hormone is an antagonist, it fits into the receptor, but does not activate it....in other word the key fits the lock, but will not turn. Therefore no signal is sent, and while that receptor is occupied with the antagonist, it can't be occupied and activated by an agonist.
It has been shown that testosterone's acts as an agonist on the one defined androgen receptor (AR) type to provide both the anabolic and androgenic actions; and it has also been shown that androgens act on the glucucorticoid receptor (GCR) as an antagonist, thereby blocking the catabolic effects of cortisol (the major GC) on muscle. More on that later.
Okay, that's most of the jargon out of the way, but it will come in handy shortly. Back to testosterone....we all know the more you put in, the greater the effect. But what is not so well known, is that the biological response to a certain dose is determined just as much by the level of androgen receptors as by what the dose of androgen is. Now conventional wisdom (if that is not a contradiction in terms) has it that all or nearly all of the androgen receptors are occupied at physiological levels of testosterone (70mg/wk). If that was the case, we would not see so much empirical evidence backed up by the occassional scientific study of the classic dose response curve...the more androgens you take, the higher your lean body mass.
In fact if you don't take several times the physiological level, you won't even notice a response. Most of the early studies on anabolic steroids used doses of, for example, 10mg dianabol per day which is the recommended dose for androgen replacement in hypogonadal males. In normal males however, you only see results at around 30 - 40 mg dianobol per day. Now if all the androgen receptors were occupied at 10mg per day, the response to 40mg per day would not be any greater than the response to 10mg per day.
The point is, that the receptor levels do decrease as the dose increases, but to what extent, is unknown. I scanned the scientific litereature on androgen receptor downregulation, and the only study of any relevance showed that endurance trained rats had higher AR levels than sedentary controls (previously shown to occur with any type of exercise in, and that androgen administration lowered receptor levels in both groups. It has been suggested that the great response almost everyone experiences on their first course may be due to fact that the receptors have not yet been downregulated by previous cycles. I don't know how true that is but most of the empirical data suggest there may be something in it.
I think the best way to determine if receptor downregulation is occuring, is to keep track of the changes produced by the same dose on consecutive cycles. If your response is significantly diminished, then your receptors are obviously downregulated. One other easily tested parameter is to have your Sex Hormone Binding Globulin (SHBG) levels determined by blood test. It is a parameter that should be measured regularly with other health related measures (look out for a future article on using blood test info....what to test for and what it means). I do not have any evidence to support the association between increases in SHBG and downregulation of receptors, but it is known that SHBG increase with high androgen levels. I believe that it is a good indicator of the way your system is responding to a certain dose.
If any of you have heard of the mythical receptor mapping that is spoken about from time to time, consider this. If you want to donate a slice of muscle, I can tell you what your receptor levels are like. That's easy, but you can't do squat with a blood test. Also the receptor levels will vary between different muscles. So don't believe everything you hear that "sounds" scientific.
To summarise the whole course of events, when androgens are injected, they bind to carrier proteins in the blood. Namely albumin and SHBG, and different angrogens will have varying affinity levels for the carrier proteins dependant on their molecular make-up. Ideally, we would want an androgen with low binding affinity for the carrier proteins so that more of it will circulate as free or unbound form (which is the active fraction able to bind to receptors). The free androgen then binds to androgen receptors also with different affinities dependant on their molecular configuration. Here we want high binding affinity.
The number of functional receptors is equally important as the dose in determining the biological response. Androgens can act as either agonists on AR, or as antagonists on GCR. Interestingly it appears that the molecular changes required to make an AAS orally active also increases the binding and subsequent antagonism of the GCR (the C-17 alkylated steroids such as stanozolol , oxymethylone, methandrostenelone). It is not however good to totally inhibit the GCR, because when this was done with the abortion pill, RU486 (both a progesterone and GC antagonist) the anobolic effects of AAS were no longer seen in rats. Knowing the many necessary functions of GC's, I think they are not a very safe thing to mess with. Ask Andreas Munzer.
I hope this article will encourage you to appreciate the complexities of the issue...and we did not even get into what happens after the AR is bound and activated, the so-called post-receptor mechanisms.
The most important thing to remember is, if you give a man a fish, you feed him for a day. If you teach him to fish, you feed him for life. So, educate yourselves by reading as much quality information as possible (such as this publication) and use it to refine your training/supplement programs. Happy fishing.
An Insider look to androgen receptors
03-15-2002, 04:34 PM #2
So how do we control downregulation to make every cycle as good as the first is the answer that we must be in search of.
Nice post, lots of facts.
That was great info, Dr. Evil takes it a bit further in his post. This is a must read as a supplement to this post.
Last edited by Methuselah; 03-15-2002 at 04:48 PM.
03-15-2002, 05:01 PM #3
Last edited by timvds; 03-15-2002 at 05:05 PM.
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