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In part 1 of this article we discussed the mistake of thinking about androgen receptors (testosterone receptors) in the same way we think of other receptors such as beta-receptors. Beta-receptors down regulate in response to beta-adrenergic stimulation whereas there is good evidence that androgen receptors increase in numbers in response to androgens. We also discussed the various affects of testosterone on muscle growth. Testosterone does far more than simply increase the rate of protein synthesis!

Now in part 2 we will finish our discussion of androgen receptor regulation as it pertains to the way muscle cells grow. The very mechanism of real muscle growth opens the door for increased androgen receptor number in response to testosterone treatment.

Don’t forget Satellite cells!

Satellite cells are myogenic stem cells, or pre-muscle cells, that serve to assist regeneration of adult skeletal muscle. Following proliferation (reproduction) and subsequent differentiation (to become a specific type of cell), satellite cells will fuse with one another or with the adjacent damaged muscle fiber, thereby increasing the number of myonuclei for fiber growth and repair. Proliferation of satellite cells is necessary in order to meet the needs of thousands of muscle cells all potentially requiring additional nuclei. Differentiation is necessary in order for the new nucleus to behave as a nucleus of muscle origin. The number of myonuclei directly determines the capacity of a muscle cell to manufacture proteins, including androgen receptors.

In order to better understand what is physically happening between satellite cells and muscle cells, try to picture 2 oil droplets floating on water. The two droplets represent a muscle cell and a satellite cell. Because the lipid bilayer of cells are hydrophobic just like common oil droplets, when brought into proximity to one another in an aqueous environment, they will come into contact for a moment and then fuse together to form one larger oil droplet. Now whatever was dissolved within one droplet (i.e. nuclei) will then mix with the contents of the other droplet. This is a simplified model of how satellite cells donate nuclei, and thus protein-synthesizing capacity, to existing muscle cells.

Enhanced activation of satellite cells by testosterone requires IGF-1. Those androgens that aromatize are effective at not only increasing IGF-1 levels but also the sensitivity of satellite cells to growth factors.3 This action has no direct effect on protein synthesis, but it does lead to a greater capacity for protein synthesis by increasing fusion of satellite cells to existing fibers. This increases the number of myonuclei and therefore the capacity of the cell to produce proteins. That is why large bodybuilders will benefit significantly more from high levels of androgens compared to a relatively new user.

Testosterone would be much less effective if it were not able to increase myonucleation. There is finite limit placed on the cytoplasmic/nuclear ratio, or the size of a muscle cell in relation to the number of nuclei it contains.4 Whenever a muscle grows in response to training there is a coordinated increase in the number of myonuclei and the increase in fiber cross sectional area (CSA). When satellite cells are prohibited from donating viable nuclei, overloaded muscle will not grow.5,6 Clearly, satellite cell activity is a required step, or prerequisite, in compensatory muscle hypertrophy, for without it, a muscle simply cannot significantly increase total protein content or CSA.

Mr. Haycock,

I consider myself well versed on steroids and how they work, but one thing that continually has me puzzled is this; if there is only one androgen receptor that all steroids bind to in order to induce growth, how come there are so many diverse effects of different synthetic steroids. Some make you bloat, others don’t. Some give you insomnia, other don’t. Some give you hiccups and make you snore, while yet again, others don’t. No one has been able to offer me an explanation for this. Any insight you might shed on this would be really appreciated.

Thanks in advance.

Answer:Much of the confusion about the wide range of side effects of steroids comes from their various non-genomic actions. As the term “non-genomic” doesn’t seem to come up very often in locker room steroid conversations let me explain.

Most people know that there is only one typical, or sometimes called “classical”, androgen receptor (AR). The AR is an intracellular receptor, meaning that it resides within cells (as apposed to the membrane surface) and once bound to an androgen, travels to the nucleus of the cell and binds to the DNA where it initiates the expression of various proteins.

The AR exerts a wide range of effects even though there is only one typical AR. Testosterone (Test) is able to exert different effects in different tissues by virtue of it acting “as is” in some tissues, and acting as its 5-alpha reduced counterpart dihydrotestosterone (DHT) in the same and/or other tissues.

DHT has different binding properties than Test. DHT binds stronger, and stays bound longer than Test. This subtle difference in the strength and duration of binding is able to produce a tremendous range of different actions in the body from the time you’re a fetus to a full grown adult.

Some synthetic steroids are more like Test, and others are more like DHT. But this still doesn’t explain all the differences seen among synthetic androgens. The differences beyond binding properties can then be explained by these “non-genomic” properties mentioned earlier.

Within the last 5 years or so, more attention has been drawn to the non-genomic effects of steroids and trying to understand them. They are called “non-genomic” because they don’t directly involve the steroid bound to the AR acting directly on the cells DNA.

It is now understood that steroids can act on the cell membrane to bring about various second messenger effects. These second messenger pathways involve kinase pathways driven by classical receptors (MAPk, ERK, MEK, etc), as well as cyclic AMP, lipase and other kinase pathways (PI3K, PKA, PKC, etc), including ion fluxes (Ca), which are driven by atypical receptors. All in all, steroids affect cells through several different pathways and at least one atypical steroid receptor, none of which involve what most people consider the true “intracellular” mechanism of steroid action.

Most all of these non-genomic affects of steroids are acute, or immediate. Meaning, they occur within seconds or minutes of the steroid interacting with the cell. This helps to explain why so many different organs have androgen receptors or are sensitive to androgen levels. For example, in tissues taken from rats, (in order of sensitivity):

Anabolicum Vister (quinbolone) is a prodrug of boldenone. It is the exact same molecule but with a cyclopentenyl ether modification at the 17beta hydroxy position. Unlike the ester modifications at the 17 position commonly used for injectable anabolic steroids, this modification provides enhanced oral bioavailability.

As with esterified compounds, the Anabolicum Vister molecule is not active in its modified form, and becomes effective only when the cyclopentenyl ether group is metabolically removed, yielding boldenone. At this point, properties are the same as boldenone delivered via de-esterification of injected boldenone undecylenate or other boldenone ester. The duration of action of this oral form is almost undoubtedly much shorter, however.

Quinbolone is not very potent (effective per milligram) compared to injected boldenone undecylenate (Equipoise) or any injected anabolic steroids, or to most oral anabolic steroids. I know of no athletes who use this product.

Quinbolone is the chemical name of active ingredient in Anabolicum Vister. Anabolicum Vister was a registered trademark of Parke Davis (Italy) in the United States and/or other countries prior to cancellation.

There is as much misinformation about steroids as there is good information had among bodybuilding enthusiasts. Go to any gym and you will hear some kid spouting off to his buddies about how steroids do this, or how they do that, or whatever. This soon starts somewhat of a pissing contest (excuse the expression) as to who knows more about steroids. It’s the same kind of titillating and infectious banter that adolescent boys get into about girls and sex. With steroid banter you hear all the popular terms like Deca, Test, GH, gyno, zits, raisins, “h-u-u-u-ge”, roid, freak, monster, roid-rage, “I knew this guy once”, etc., etc.. If by some rare chance they are smart and have been reading this or some other high quality bodybuilding site on the net, they may actually get a few details right. More often than not they know just enough to be dangerous. Fortunately steroids haven’t proven to be all that dangerous. Not only that, but most of these guys who are infatuated with steroids won’t ever use or even see them except in magazines.

This kind of ego driven gym talk doesn’t really bother me until they begin giving advice to other clueless people who actually have access to them. Spewing out steroid lingo gives other less experienced kids the impression that these kids actually know what they are talking about. That’s how all of the psuedo-science folklore about steroids perpetuates. This is also why most people who actually use steroids know little about them. This last fact should bother anyone who cares about bodybuilding and/or bodybuilders.

I started out with this article planning on giving some textbook style explanation as to why using steroids doesn’t down regulate androgen receptors (AR). Then after considering some of my critics views that I tend to write articles that hardly anyone can read, I decided to write an easy to read, yet informative explanation about what androgens actually do and how this precludes androgen receptor down regulation. I still have a few references but not so many that it looks like a review paper.

Androgen receptors down-regulate….Don’t they?

One misunderstood principle of steroid physiology is the concept of androgen receptors (AR), sometimes called “steroid receptors”, and the effects of steroid use on their regulation. It is commonly believed that taking androgens for extended periods of time will lead to what is called AR “down regulation”. The premise for this argument is; when using steroids during an extended cycle, you eventually stop growing even though the dose has not decreased. This belief has persisted despite the fact that there is no scientific evidence to date that shows that increased levels of androgens down regulates the androgen receptor in muscle tissue.

The argument for AR down-regulation sounds pretty straightforward on the surface. After all, we know that receptor down-regulation happens with other messenger-mediated systems in the body such as adrenergic receptors. It has been shown that when taking a beta agonist such as Clenbuterol, the number of beta-receptors on target cells begins to decrease. (This is due to a decrease in the half-life of receptor proteins without a decrease in the rate that the cell is making new receptors.) This leads to a decrease in the potency of a given dose. Subsequently, with fewer receptors you get a smaller, or diminished, physiological response. This is a natural way for your body to maintain equilibrium in the face of an unusually high level of beta-agonism.

In reality this example using Clenbuterol is not an appropriate one. Androgen receptors and adrenergic receptors are quite different. Nevertheless, this is the argument for androgen receptor down-regulation and the reasoning behind it. The differences in the regulation of ARs and adrenergic receptors in part show the error in the view that AR down-regulate when you take steroids. Where adrenergic receptor half-life is decreased in most target cells with increased catecholamines, AR receptors half-live’s are actually increased in many tissues in the presence of androgens.1

Prostaglandins are part of a class of substances called eicosanoids. Eicosanoids are a group of substances derived from fatty acids and include prostaglandins, thromboxanes, and leukotrienes, all of which are formed from precursor fatty acids by the incorporation of oxygen atoms into the fatty acid chains. This reaction is called oxygenation and is carried out by cyclo-oxygenase enzymes. Prostaglandins and their metabolites have been found in virtually every tissue in the body.

The discovery of prostaglandins and determination of their structure began in 1930, when Raphael Kurzrok and Charles Lieb, both new York gynecologists, observed that human seminal fluid stimulates contraction of isolated uterine muscle. A few years later in Sweden, Ulf von Euler confirmed this report and noted that human seminal fluid also produces contraction in intestinal smooth muscle and lowers blood pressure when injected into the blood stream. It was Von Euler who came up with the name prostaglandin for this mysterious substance. The name prostaglandin seemed appropriate because he thought it originated in the prostate gland. Today, we know that prostaglandin production is not limited to the prostate, in fact, there is virtually no soft tissue in the body that doesn’t produce them. The name, however, has stuck with us through the years. If Von Euler had known his name for prostaglandins would still be with us into the next millennia, I’m sure he would have chosen to name them “Von Eulers” or “UVEs” instead of prostaglandins. By 1960, several specific prostaglandins had been isolated in pure crystalline form and their structures determined. Because our concern with prostaglandins involves primarily PGF2a, and perhaps PGE2, we will not go into detail about the myriad of other prostaglandins. Just know that prostaglandins are abbreviated “PG”. The additional letter and numerical script indicate the type and series. The various types differ in the functional group present in the five-membered ring.

While scientists were studying the structure of these new compounds, other research was being done to determine their role in human physiology and their potential as drugs. Initially these compounds were extremely expensive to synthesize and/or isolate in sufficient quantities for research. In 1969, the price of prostaglandins dropped dramatically with the discovery that the gorgonian sea whip, or sea fan, is a rich source of prostaglandin-like materials. Now however, there is no need to rely on natural sources because chemists have developed highly effective laboratory methods for the synthesis of almost any prostaglandin or prostaglandin analog.

Endogenous production from Arachidonic Acid

Prostaglandins (PGs) are not stored in the tissues of your body. PGs are produced in response to some physiological trigger. The starting material for PG synthesis are unsaturated fatty acids that have 20 carbon structures. The fatty acid that is used to make PGF2a is arachidonic acid.

Functions of prostaglandins in the body

Prostaglandins are classified as autocrine (effecting the same cell that produced it), as well as paracrine (effecting adjacent cells), regulators. They do not really fit into the category of hormones, nor are they neurotransmitters, instead they are simply considered as a corollary of the endocrine system.

The following are some of the regulatory functions of prostaglandins in various organs and systems of the body:

Inflammation & Pain – PGs promote many aspects of the inflammatory response. They are involved in the sensation of pain associated with inflammation and vasoconstriction and/or dilation, and the development of fever. PGs, when injected directly into the hypothalamus, induce fever. Anecdotally, the use of PGF2a also induces a rise in body temperature presumably by interacting with the hypothalamus as well.

Reproductive systems. PGs may play a role in ovulation and corpus luteum function in the ovaries and in contraction of the uterus. Excessive PG production may be involved in premature labor, endometriosis, dysmenorrhea (menstrual cramps), and other gynecological disorders. PGs are often given to induce labor.

Gastrointestinal tract – The stomach and intestine produce PGs. PGs are believed to inhibit gastric secretions and influence gastric motility as well as fluid absorption. Drugs such as aspirin that inhibit prostaglandin production can lead to overproduction of gastric secretion. This predisposes the person to gastric ulcers.