Structural Features Of Androgenic/Anabolic Steroids

  1. Structural Features Of Androgenic/Anabolic Steroids

    Structural Features Of Androgenic/Anabolic Steroids
    Written by Sanjac

    In this article, we will explore the differences between the different steroids by looking at their structures and learning how the shapes of the molecules influence their activities. As always, the author does not condone the use of steroids by persons not under the care and guidance of a qualified physician.

    The Basics: In order to have a good understanding of the structures we are going to examine, we'll start with the basics. Organic molecules (steroids) are made up primarily of carbon, hydrogen, and oxygen bound together in varying amounts and differing configurations. Nitrogen is found in Stanozolol, and Fluorine is found in Fluoxymesterone (Halo).

    Hydrogen can bind to only one other atom with a single bond. Carbon can have 4 bonds, either binding to 4 other atoms (as in CH4), or by forming multiple bonds to one of the atoms (as in CH2 =CH2 , which has a double bond between the carbon atoms). In the examples just given, the atoms are written out explicitly using the letters C and H for Carbon and Hydrogen. However, to simplify the picture for complex structures like steroids, the Hydrogen atoms are usually omitted, and the Carbon atoms are represented as the point where two (or more) lines intersect. For example, Benzene (C6 H6 ) is shown by both structures below, but the one on the right is a shorthand way to draw the structure. We will use shorthand to simplify the pictures in the rest of this article.

    All of the steroids of interest commonly have a 4-ring structure called Cyclopentaperhydrophenanthrene (easy for you to say!), and for identification purposes, the carbon atoms are numbered in a specific way to include the 17 carbon atoms in the base structure:

    The rings are given letter designations, and the A and D ring are the sites of most chemical changes in steroids. Two CH3 ("methyl") groups are often present in the basic structure, and they are numbered 18 and 19 in the picture above. The positions of most interest to us are 4, 17, and 19. For a good description of the rules of drawing and numbering steroids, go here. Let's take a look at an anabolic/androgenic steroid, testosterone, and examine the structure in a little detail.

    Testosterone, the "mother of all steroids" has one of the simpler appearing structures when viewed in shorthand:

    You can easily see the 4-ring structure along with the two-methyl groups, and testosterone has a double bond between carbons 4 and 5. Testosterone also has two oxygen atoms in its structure, one is double-bonded to carbon 3, and the other is a "hydroxyl" (OH) group at carbon 17. Sounds pretty simple, doesn't it? Well, we've left out a very important point about the structures so far. We have been representing the molecules as if they were all "flat", drawing them in the two dimensions of the page. In reality, the structures have 3-dimensional features that are very important to their chemical activities. The picture below is the same testosterone molecule, viewed in 3-D perspective, and some of the hydrogens have been left in the picture to give a more accurate representation. The bold lines indicate that the group on the wide end of each line is above the molecule, and the dashed lines indicate groups that are below.

    Things can get pretty complex in three dimensions, and what look like minor changes to a molecule in two dimensions can actually cause a big difference in the 3D structure.

    Testosterone and DHT
    Everybody knows by now that Testosterone can be converted to Dihydrotestosterone (DHT) by the enzyme 5-alpha reductase (5-AR). What actually happens here? The double bond in testosterone gets reduced (removed), and two hydrogen atoms are added, one at carbon 4 and one at carbon 5. The "alpha" in 5-AR means that the hydrogen that is added at carbon 5 is added alpha to the ring, and that means that it ends up under or behind the ring, when viewed in 3D. The opposite configuration (above the ring) is called "beta". In most anabolic steroids, the methyl groups C18 and C19, as well as the hydroxyl group at C17, are beta to the ring (they are above the plane of the ring structure).

    The left-hand side of the testosterone molecule is somewhat flat because of the double bond. When that double bond is removed, the structure gets more complex (less flat), and that contributes to the difference between the Androgen-Receptor binding abilities of the two steroids. Why doesn't 5-alpha reductase destroy the double bonds on other molecules? Because the enzyme molecule has a particular shape, and only those molecules that have the right shape to fit into the active region of the enzyme can be acted upon by the enzyme ("key-in-lock analogy"). So, for example, 5-androdiol will not be reduced by 5-alpha reductase, because the double bond is in a different position and the molecule does not have the right shape for this enzyme:

    Nandrolone, (Deca) will be reduced by 5-alpha reductase, and the resulting steroid (Dihydronandrolone) is thought to cause less hair loss and be less harsh on the prostate than either DHT or Nandrolone. That is why it is not advisable to use a 5-alpha reductase inhibitor (finasteride, Proscar) with Deca, since you will be preventing the formation of a milder steroid in the scalp and prostate. It is apparent that the shape of the molecule at the A ring is a strong determinant of the strength of receptor binding in tissues such as scalp and prostate.

    There is another type of reaction that occurs at the A ring in several steroids, and this reaction is called aromatization. This reaction is mediated by the enzyme aromatase, and it converts many androgens into estrogens. Specifically, it can convert testosterone (and some others) into estradiol, a strong estrogen.

    In the reaction above, three things have occurred. First, the methyl group, C19, has been removed. Second, two additional double bonds have been added in the A ring. Finally, the double-bonded oxygen has been reduced to a hydroxyl group. The result is that the A ring has been aromatized (the 3 double bonds have a lot of synergy and the ring is impervious to further reactions), and it has become flat. The estradiol picture below has been rotated to show this:

    The flatness of the A ring (on the left), along with its aromaticity (electron density), causes the estradiol molecule to have very different binding characteristics relative to the androgens. Getting back to the aromatase reaction itself, there are several items of importance. First, the C19 methyl is necessary for aromatase to function, since the reaction starts with several oxidation steps at this carbon. When it is finally removed, the electronic configuration is appropriate for the formation of a double bond within the ring, followed by hydrogenation of the oxygen, and migration of its double bond into the A ring. If the original steroid is lacking a C19 carbon (as in nandrolone), aromatase cannot do its job. Therefore, nandrolone does not aromatize like testosterone, and Deca causes less estrogenic side effects than testosterone. However, nandrolone does have some progestogenic properties all by itself, so it is not completely without possible "estrogen-like" side effects.

    There are other ways to prevent aromatization by aromatase. One way, obviously, is to administer a drug which will inhibit the enzyme. Arimidex and Cytradren will accomplish this. Another way is to alter the A ring of the testosterone molecule so that it cannot aromatize. Oxymetholone (Anadrol) and oxandrolone (Anavar) are two effective steroids that use this principle.

    Oxandrolone cannot aromatize because the oxgen atom in the A ring cannot accept any more bonds (2 is the max for oxygen). Oxymetholone cannot readily aromatize because the carbon at the "2" position is incapable of forming a double bond within the A ring (there are some reaction pathways that are possible, but that is beyond the scope of this article). Then why does Anadrol cause estrogenic side effects? Well, the side of the molecule near the A ring is very flat (similar to estradiol), as shown below, so the "key" may fit the lock (there is also some tautomeric activity here, which is kinda like the aromaticity which exists in estrogens). It has also been speculated that the side effects are caused by progesterone-like properties of Anadrol.

    On the topic of progesterone, this molecule looks very much like testosterone, except for a change at C17. An acetyl group replaces testosterone's Hydroxyl group at C17. This changes not only the shape, but also the polarity (direction of magnetic charge) of the molecule. These changes make progesterone very different from testosterone with respect to receptor-binding, and testosterone does not bind to the progesterone receptor, and vice versa.

    Dianabol vs. Equipoise
    Many claim that Equipoise (boldenone) does not aromatize or give estrogenic side effects, but that dianabol does. This is interesting, because the two molecules are strikingly similar. In fact, at the A ring (where aromatization takes place), they are identical. The only differences are at the D ring. The "R" in the Boldenone molecule is shorthand for a carbon chain (in this case, undecylenate).

    Why, then, does Dbol give side effects that Equipoise does not? First, the 17-alpha methyl group affects the way the liver functions, and certain growth factors may be released. Second, the Dbol may actually develop higher concentrations in the blood (spikes right after the pills are taken), and give a higher rate of aromatization than Boldenone. The Boldenone will not give a spike in concentration, since the liver very effectively deactivates it in one pass, and it is released slowly from the ester "depot". The spikes of high concentration of Dbol can give a higher Estradiol concentration over time because the estrogens are not deactivated as quickly as the androgens are in the liver. In fact, the estrogen that will form from Dbol is the 17-alpha methylated estradiol, which is likely to stay in the system for a long time, because the liver will have a very hard time degrading it. So, the estrogen level can build up over time with the use of Dbol.

    17 alpha Alkylation
    Why does the addition of a methyl group make a molecule of steroid more difficult to degrade in the liver? In chemical terms it is called "stearic hindrance", which means, "getting in the way". The liver uses enzymes to add hydroxyl groups to steroids, primarily at the 11 and 16 carbon atoms (on the C and D rings). Let's look at a steroid molecule where the 11th and 16th carbons are represented with asterisks:

    The methyl group (CH3) under the ring on the right side of the molecule can prevent the steroid from fitting into the correct position of the enzymes that deactivate steroid molecules. Therefore, the 17 alpha alkylated steroids are much more difficult for the liver to process into waste products.

    Other Steroid Structures
    A number of chemical modifications have been made to the basic steroid structure in order to decrease side effects or increase anabolic effects. Stanozolol uses the idea of modifying the A ring to prevent aromatization (same concept as used with oxymetholone). Contrary to some beliefs, Stanozolol will not in any way aromatize. Also like oxymetholone, the left side of the molecule is very flat, and it may occupy estrogen receptors, although it may be an antagonist (by not activating the receptor).

    Trenbolone is purported to be the best AAS for mass gains and strength gains. The structure of trenbolone is unlike any of the other commonly available steroids. The molecule cannot undergo aromatization by aromatase, but the presence of four (conjugated) double bonds lends some planarity to the molecule, as well as electron delocalization. So it is very likely that trenbolone can have some estrogen-like properties. The 17-alpha alkylated version, known as methyl trienolone, is reported to be very active in extremely small doses (mcg?). This indicates that trenbolone itself is readily metabolized by the liver, and it may not have the toxicity that some attribute to it.

    Masteron and mesterolone are derivatives of DHT, with an alpha-methyl group on the A ring at either C1 (mesterolone) or C2 (masteron, drostanolone). While these steroids cannot aromatize, and cause very little side effects, the presence of the alpha-methy group on the A ring reduces the effectiveness of the steroid.

    Fluoxymesterone (Halotestin) contains a Fluorine atom alpha to (below) the structure at C9, and a hydroxyl group at C11. This steroid may be reduced by 5-alpha reductase, but it is questionable whether it will aromatize to a significant degree, because of the electronegativity of the Fluorine. Other than that, the C11 hydroxyl group may cause this steroid to be less potent than it would be without it (remember that hydroxylation at C11 and C16 are intermediate steps in the deactivation of steroids in the liver).

  2. Well...

    That was quite a read... I like it

    I already gave you enough karma, so...NO KARMA FOR YOU!!!


    Read This Book!!: Anabolic Steroids and the Athlete by William N. Taylor M.D.

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