Methylated Compounds and Oral Dosing
Chemists realized that by replacing the hydrogen atom at the steroid's 17th alpha position with a carbon atom (a process referred to as alkylation), its structure would be notably resistant to breakdown by the liver. The carbon atom is typically added in the form of a methyl group (CH3), although we see oral steroids with an added ethyl
(C2H5) grouping as well. A steroid with this alteration is commonly descirbed as a C-17 alpha alkylated oral, although the terms of methylated or ethylated oral steroid are also used. The alkyl group cannot be removed metabolically, and therefore inhibits reduction of the steroid to its inactive 17-ketosteroid form by occupying one of the necessary carbon bonds. Before long, pharmaceutical companies had utilized this advance (and others) to manufacture an array of effective oral steroids including methyltestosterone, as the added alkylation changes the activity of this steroid considerably. One major change we see is an increased tendency for the steroid to produce estrogenic side effects, despite the fact that it actually lowers the ability of the hormone to interact with aromatase. Apparently with 17-alkylation present on a steroid, aromatization (when possible) produces a more active form of estrogen (typically 17alpha-methyl or 17alpha-ethyl estradiol). These estrogens are more biologically active than estradiol due to their longer half-life and weaker tendency to bind with serum proteins. In some instances, 17alpha-alkylation will also enhance the ability of the initial steroid compound to bind with and activate the estrogen or progesterone receptor. An enhancement of estrogenic properties is also obvious when we look at methandrostenolone, which is an alkylated form of boldenone (Equipoise®), and Nilevar and nandrolone, which often need to reach doses of 300-400 mg weekly for a similar level of effect.
In an attempt to solve the mentioned problems with liver toxicity we see with c17-alpha alkylated compounds, a number of other orals with different chemical alterations (such as Primobolan®, Proviron®, AndriolË, and Anabolicum Vister) were created. Primobolan® and Proviron® are alkylated at the one position (methyl), a trait which also slows ketosteroid reduction. Andriol® uses a 17beta carboxylic acid ester (used with injectable compounds, discussed below), however, here the oil-dissolved steroid is sealed in a capsule and is intended for oral administration. This is supposed to promote steroid absorption through intestinal lymphatic ducts, bypassing the first pass through the liver. In addition to 1 methylation, Primobolan® also utilizes a 17 beta ester (acetate) to further protect against reduction to inactive form (here there is no lymphatic system absorption). Anabolicum Vister uses 17beta enol ether linkage to protect the steroid, which is very similar to esterification as the ether breaks off to release a steroid base (boldenone in this case). While all of these types of compounds do not place the same stress on the liver, they are also much less resistant to breakdown than 17 alkylated orals, and are ultimately less active milligram for milligram.
Esters and Injectable Compounds
You may notice that many injectable steroids will list long chemical names like testosterone cypionate and testosterone enanthate. In these cases, the cypionate and enanthate are esters (carboxylic acids) that have been attached to the 17-beta hydroxyl group of the testosterone, therefore, contains much less base hormone than 100 mg of a straight testosterone suspension). In some instances, an ester may account for roughly 40% or more of the total steroid weight, but the typical measure is somewhere around 15% to 35%. Below are the free base equivalents for several popular steroid compounds.
It is also important to stress the fact that esters do not alter the activity of the parent steroid in any way. They work only to slow its release. It is quite common to hear people speak about the properties of different esters, almost as if they can magically alter a steroid's effectiveness. This is really nonsense. Enanthate is not more powerful than cypionate (perhaps a few extra milligrams of testosterone. Personally, I have always considered Sustanon a very poor buy in the face of cheaper 250 mg enanthate ampules. Your muscle cells see only testosterone; ultimately there is no difference. Reports of varying levels of muscle gain, androgenic side effects, water retention, etc. are only issues of timing. Faster releasing testosterone esters will produce estrogen buildup faster simply because there is more testosterone free in the blood from the start of the cycle. The same is true when we state that Durabolin® is a milder nandrolone for women compared to Deca. It is simply easier to control the blood level with a faster acting drug. Were virilization symptoms to become apparent, hormone levels will drop much faster once we stop administration. This should not be confused with the notion that the nandrolone in Durabolin® acts differently in the body than that released from a shot of Deca-®.
It is also worth noting that while the ester is typically hydrolyzed in general circulation, some will be hydrolyzed at the injection site where the steroid depot first contacts blood. This will cause a slightly higher concentration of both free steroid and ester in the muscle where the drug had been administered. On the plus side, this may equate to slightly better growth in this muscle, as more hormone is made available to nearby cells. Many bodybuilders have come to swear by the use of injection sites such as the deltoids, biceps, and triceps, truly believing better growth can be achieved if the steroid is injected directly into these muscles. The negative to this is that the ester itself may be irritating to the tissues at the site of injection once it is broken free. In some instances it can be so caustic that the muscle itself will become swollen and sore due to the presence of the ester, and the user may even suffer a lowgrade fever as the body fights off the irritant (the onset of such symptoms typically occurs 24-72 hours after injection). This effect is more common with small chain esters such as propionate and acetate, and can actually make a popular steroid such as Sustanon (which contains testosterone propionate) off-limits for some users who experience too much discomfort to justify using the drug. Longer chain esters such as decanoate and cypionate are typically much less irritating at the site of injection, and therefore are preferred by sensitive individuals.
Although never complete, scientists had some success in their quest to separate the androgenic and anabolic properties of testosterone. A number of synthetic anabolic steroids had been developed as a result, with many being notably weaker and stronger than our base androgen. In order to first assess the anabolic and androgenic potential of each newly developed steroid, scientists had generally used rats as a model. To judge androgenic potency the typical procedure involved the post-administration measure (% growth) of the seminal vesicles and ventral prostate. These two tissues will often respond unequally to a given steroid, however, so an average of the two figures is used. Anabolic activity was most commonly determined by measuring the growth of the levator ani, a sex organ (not skeletal) muscle. This tissue may not be the most ideal one to use though, as it contains more androgen receptor than most skeletal muscles (the AR is still less abundant here than in target tissues such as the ventral prostate). In integrating both measures, the anabolic index is used, which relates the ratio of anabolic to androgenic response for a given steroid. An anabolic index greater than one indicates a higher tendency for anabolic effect, and therefore classifies the drug as an anabolic steroid. A measure lower than one in turn assesses the steroid as androgenic. There is some variance between experimental results and the actual real world experiences with humans, but (with a few exceptions) designations based on the anabolic index are generally accepted. Below are discussed a few factors that greatly affect anabolic/androgenic dissociation.
Nandrolone and 19-norandrogens
The section of this book dealing with DHT conversion is important, because it helps us understand the anabolic steroid nandrolone and many of its derivatives. Nandrolone is identical to testosterone except it lacks a carbon atom in the 19th position, hence its other given name 19-nortestosterone. Nandrolone is very interesting because it offers the greatest ratio of anabolic to androgenic effect of the three natural steroids (see Synthetic AAS Chemistry).This is because it is metabolized into a less potent structure (dihydronandrolone) in androgen target tissues with high concentrations of the 5-alpha reductase enzyme, which is the exact opposite of what happens with testosterone. Apparently the removal of the c4-5 double bond, which normally increases the androgen receptor binding capability of testosterone, causes an unusual lowering of this ability with nandrolone.Instead of becoming three to four times more potent, it becomes several times weaker. This is a very desirable trait if you want to target anabolic effects over androgenic. This characteristic also carries over to most synthetic steroids derived from nandrolone, making this an attractive base steroid to use in the synthesis of new, primarily anabolic, steroids.
5-alpha Irreducible Steroids
When we look at the other mild anabolic steroids Primobolan®, Winstrol®, and Anavar, none of which are derived from nandrolone, we see another interesting commonality. These steroids are DHT derivatives that are unaffected by 5alpha-reductase, and therefore become neither weaker nor stronger in androgen responsive target tissues with high concentrations of this enzyme. In essence, they have a very balanced effect between muscle and androgen tissues, making them outwardly less androgenic than testosterone. This is why these steroids are technically classified as anabolics, and are undeniably less troublesome than many other steroids in terms of promoting androgenic side effects. However, if we wanted to look for the absolute least androgenic steroid, the title would still go to nandrolone (or perhaps one of its derivatives). Female bodybuilders should likewise take note that despite the recommendations of others, steroids like Anavar, Winstrol and Primo are not the least risky steroids to use. This is of great importance, as male sex hormones can produce many undesirable and permanent side effects when incorrectly taken by females (See: Side Effects, Virilization).
3-alpha Hydroxysteroid Dehydrogenase
The 3-alpha hydroxysteroid dehydrogenase enzyme is also important, because it can work to reduce the anabolic potency of certain steroids considerably. As follows, not all potent binders of the androgen receptor are, as a rule, great muscle-building drugs, and this enzyme is an important factor. dihydrotestosterone is a clear example. Just as the body converts testosterone to DHT as a way to potentiate its action in certain tissues (skin, scalp, prostate, etc.), it also has ways of countering the strong activity of DHT, in other tissues where it is unneeded. This is accomplished by the rapid reduction of DHT to its inactive active metabolites, namely androstanediol, before it reaches the androgen receptor. This activity occurs via interaction with the 3-alpha hydroxysteroid dehydrogenase enzyme. This enzyme is present in high concentrations in certain tissues, including skeletal muscle, and DHT is much more open to alteration by it than other steroids that possess a c4-5 double-bond (like testosterone). This causes dihydrotestosterone to be an extremely poor anabolic, despite the fact that it actually exhibits a much higher affinity for the cellular androgen receptor than most other steroids. Were it able to reach the cellular androgen receptor without first being metabolized by 3a-HSD, it certainly would be a formidable muscle-building steroid. Unfortunately this is not the case, explaining why injectable dihydrotestosterone preparations (no longer commercially produced) were never favorite drugs among athletes looking to build mass. This trait is also shared by the currently popular oral androgen Proviron®, which is, in essence, just an oral form of DHT (1-methyl dihydrotestosterone to be specific) and known to be an extremely poor tissue builder.
Anabolics and Potency
One must remember that being classified as an anabolic just means that the steroid is more inclined to produce muscle growth than androgenic side effects. Since both effects are mediated through the same receptor, and growth is not produced by androgen receptor activation in muscle tissue alone (other CNS tissues, for example, are integral to this process as well), we find that a reduction in the androgenic activity of a compound will often coincide with a similar lowering of its muscle-building effectiveness. If we are just looking at overall muscle growth, androgenic steroids (usually potent due to their displaying a high affinity to bind with the androgen receptor in all tissues) are typically much more productive muscle-builders than anabolics, which usually bind with lower affinity in many tissues. In fact, with all of the analogues produced throughout the years, the base androgen testosterone is still considered to be one of the most effective bulking agents. The user must simply endure more side effects when acquiring his or her new muscle with this type of drug. Individuals wishing to avoid the stronger steroids will, therefore, make a trade-off, accepting less overall muscle gain in order to run a more comfortable cycle.
Another way of evaluating the potential ratio of anabolic to androgenic activity is the practice of comparing the relative binding affinity (RBA) of various steroids for the androgen receptor in rat skeletal muscle versus prostate. When we look at the detailed study published in 1984, we see some recognizable (and expected) trends. Aside from dihydrotestosterone and Proviron® (mesterolone), which undergo rapid enzymatic reduction in muscle tissue to inactive metabolites, the remaining anabolic/androgenic steroids seem to bind with near equal affinity to receptors in both tissues. They seem to be relatively “balanced” in effect. This study also discusses the unique activity of testosterone and nandrolone compounds, which are good substrates for the 5a-reductase enzyme found in androgen target tissues (such as the prostate), and seem to provide the most notable variance between anabolic and androgenic effect in humans due to this local metabolism. When it comes to real-world use in humans, anabolic steroids do not always behave in 100% uniformity with their anabolic and androgenic profiles as determined by animal models, so all such figures need to be taken with a small grain of salt.
Wlliam Llewellyn (2011) - Anabolics