Injectable anabolic steroids are usually available as esters of the parent drugs. Often, a drug in its original form may lack certain properties that are desired: for example, good solubility in oil or fat. There may be a part of the molecule to which one may add an additional chemical group to give the new molecule desired properties, but in such a way that over time in the body, the modification will be removed, restoring the parent drug. If the modified molecule is itself not active, needing to be converted back to the parent drug, then this is aprodrug. Anabolic steroids such as testosterone cypionate and nandrolone decanoate are prodrugs. Since esters of anabolic steroids are so often used in bodybuilding, in this article we will examine them closely.
At a particular position (#17) all anabolic steroids have a hydroxy group, consisting of an oxygen and hydrogen, represented by OH. This can be replaced by an ester group: for example, propionate (OOCCH2CH3). This results in improvement in solubility in oil and reduction of water solubility, both of which are useful for reasons later to be discussed.
How do esters differ in structure?
While quite an array of names exist and make the issue seem complicated, the main difference between different esters is simply the number of carbon atoms in the ester. Propionate, as shown above, has three carbons, whereas acetate has two, isobutyrate has four, enanthate has seven, cypionate has eight, and decanoate has ten. On occasion there are more unusual esters, such as cyclohexylmethylcarbonate (used in Parabolan) which has eight carbons and one more oxygen than the above esters do.
How do esters change the physical properties of steroids?
Testosterone, nandrolone, and other anabolic steroids have poor solubility in either water or oil. Esterifying them improves oil solubility. This enables useful dosages of perhaps 100 mg or more per cc. But the more carbons the ester has, the lower the water solubility becomes, and the higher the partition coefficient (ratio between lipid and water solubilities) becomes. If the partition coefficient is high, then at any moment a high proportion of the prodrug is dissolved in oil or body fat, and only a small proportion is dissolved in water.
This is important. If testosterone itself is given in oil solution, it transfers too easily from oil to the water in the blood. The result is that an oil injection of testosterone gives a sudden spike in testosterone levels, which rapidly drops. Injections would be required at least twice per day, and perhaps even more often. Improving the oil solubility and decreasing the water solubility slows this transfer, and extends the half-life of the drug to several days or more.
The number of carbons also has a small effect in that it reduces the parent drug’s proportion of the total weight. E.g., it would take 344 mg of testosterone propionate, or 401 mg of testosterone enanthate to give the same amount of testosterone as in 288 mg of testosterone suspension.
How are esters converted back to the parent drug?
The ester bond is fairly easily broken under the right conditions. If the molecule is dissolved in water, this can occur by a simple chemical reaction, yielding the parent drug and a carboxylic acid.For example, if the steroid used is testosterone propionate, testosterone and propionic acid are released. Carboxylic acids are safe and natural in the body in reasonable amounts. It should not be thought that these are strong acids because they are not: they are acids in the same sense that, e.g., Vitamin C or lactic acid are acids. Furthermore, the amount of carboxylic acid present at any time is extremely low.
The carboxylic acids do not have any activities of interest. Once the ester group is removed, it has done its job, and the parent drug acts in its normal manner.
Besides the simple chemical hydrolysis described above, the esters can be removed by enzymes in the blood calledesterases,though water still is required for the reaction. The great majority of hydrolysis occurs with the help of these enzymes or by non-specific reactions with proteins. These reaction cannot take place while the esterified steroid is dissolved in fat. Thus, while the esterified steroids are dissolved in fat, they are protected from hydrolyis, and thus serve as a depot for the drug, giving extended duration of action.
What is the significance of the partition coefficient?
Differences in partition coefficient seem to account almost fully for the differences between various esters of anabolic steroids, as shown by Chaudry and James.1,2To understand their work, though, it is necessary first to consider the methods they used to obtain their data on the anabolic and androgenic effects of the drugs tested.
These scientists are not using those terms in the manner which many bodybuilding authors do. The anabolic effect is measured by increase in weight of the levator ani muscle in the rat, and the androgenic effect is measured by increase in weight of the seminal vesicles and prostate. These measurements are neither perfectly indicative of muscle-building value to bodybuilders nor to any particular undesired side effect except perhaps prostate enlargement. Despite the limitations of the method, this was the assay method available.
A number of esters of nandrolone were studied, using various single doses, but only the results from a single dose of 1 mg are given here. The results are as follows:
|Parent Drug||Ester||# of Carbons||Anabolic Effect||Anabolic / Androgenic Ratio||PRC** (P) x10-3|
*extrapolated from P of the butyrate ester
** partition ratio coefficient
The anabolic effect was found to be predictable according to the equation:
log (anabolic effect) = 7.33 log P – 0.636 log P2–17.8
The accuracy of predictions was quite high (r = 0.970) and the F value, indicating the statistical significance of the equation, was very high at 61. Thus, the observed anabolic effect of these ester prodrugs of nandrolone was found to be highly correlated with partition coefficient.
Higher partition coefficients were also strongly correlated with higher anabolic/androgenic ratio.
It was also found that the times of first and second peaks of drug level after injection were predictable from P with good accuracy and high significance.
How can the greatly higher anabolic effects of the long chain esters be explained?
While the authors do not make note of it in either article cited, there is a simple explanation for the observed result. Long chain esters of anabolic steroids are not many more times potent than short chain, if indeed they are any more potent at all. Yet in the above study, the undecanoate ester was found to give 3.5 times the effect of the propionate ester. Why?
There is a difference in pharmacokinetics (the time course of the drug in the body). Although the same 1 mg dose is being given in each case, it is either present in the serum of the animal at a relatively high concentration for a relatively short time for the shorter chain esters, or at lower concentration for a longer time for the longer chain esters. This difference can be quite large: the undecanoate ester can be predicted to have a half-life 36 times longer than that of the propionate ester.3
With most drugs, response is not proportional to the dose, but to the log of the dose. Assuming that the dose is well into the effective range, taking ¼ the dose does not result in only ¼ the result, but in ½ the result.
Viewed in this light, if the nandrolone propionate had been given in 36 divided doses over the same length of time that nandrolone undecanoate was in the system, in a manner to match its pharmacokinetics, one would expect 1/6 the result from each individual dose before accounting for molecular weight differences. The cumulative response would be 36 times 1/6, or six times the observed result from the single large dose. If we then correct for the lower molecular weight of the propionate ester, which delivers more nandrolone per mg. than does the undecanoate ester, we would predict 3.3 times more response than from the single large dose. In fact the observed response of the undecanoate ester was 3.5 times that of the propionate ester. This difference is within experimental error.
This calculation I have performed is also supported by experimental evidence performed by van der Vies4. His research showed that when the dose of nandrolone was divided into frequent small injections in such a pattern as to mimic the pharmacokinetics of esters, the anabolic effect became identical to that of the esters.
Thus, pharmacokinetics, the log dose/response curve, and differences in molecular weight are sufficient to account for observed differences in anabolic effect between different esters of an anabolic steroid, or between an ester and the parent drug.
This correlates with my observation that anabolic effect of testosterone esters is equal, so long as each is administered reasonably frequently: at least once per half-life, and preferably twice. E.g., if testosterone propionate yielding some given amount of testosterone per week is administered daily, or at least every other day, it will give results comparable to testosterone cypionate administered at least once every week, and preferably twice per week, that yields the same amount of testosterone per week.
How can the differences in anabolic/androgenic ratio be accounted for, and how significant are they?
Partition coefficient is key information for determining how a drug will be distributed in the body. The ratio of solubility between oil and water gives good relative predictions of the ratios of solubility between blood and target organs. Different target organs, for example the levator ani muscle vs. the prostate, may have different solubility properties. A more lipophilic drug (one with a high partition coefficient) would distribute much moreso into a more lipophilic target organ than into a less lipophilic one. It may then be the case that the longer chain esters partition more preferentially into muscle and less preferentially into the skin and prostate, but this is not demonstrated.
For this to be the case, it would be necessary for the esterified steroids to be distributed throughout the body after slow release from the oil depot injection site, rather than to have only free parent drug released from the injection site. This is an agreement with the findings of Jameset al.3which demonstrate that the esters do indeed become distributed throughout the body after injection.
I don’t, however, expect that differences in distribution are the primary reason for observed differences in anabolic/androgenic ratio between different steroid esters. There is another possible explanation for differences in this ratio. In the same work referenced above concerning anabolic effect as a function of pharmacokinetics, van der Vies showed that if nandrolone is administrated with frequent dosage patterns designed to give the same trend of serum levels as seen with either phenylpropionate or decanoate, nandrolone itself gave the same anabolic/androgenic ratios as each of these esters of nandrolone.
What application does this information on anabolic/androgenic ratio have to female bodybuilding?
Since keeping androgen levels constant and moderate gives a higher anabolic/androgenic ratio than using the same total amount of drug per week but allowing levels to spike and then subside, female bodybuilders are better advised to use either long acting esters, or if short acting esters are used, to inject small doses frequently (twice per half-life). And for the same reason, a given amount of oral steroids per day is better taken in divided doses than in a single larger dose.
This is probably because tissues with sex-specific traits exhibit thresholds to effect of androgens. Below the threshold, nothing happens, but above it, cellular differentiation occurs. Thus, while female levels of androgens are about 10% that of a male’s, 10 years of female levels of androgen will not grow as much beard or change the voice as much as one month of male levels. The threshold simply is not crossed at the lower levels, but is crossed at the higher levels.
Female bodybuilders will do better to avoid spikes in androgen level that cross this threshold. Therefore, consistent low doses are better than spiking with intermittent high doses, and advice to use 100 mg/week of testosterone propionate to avoid virilization simply makes no sense (and in practice, often fails.)
It should still be noted that some women will suffer virilization with almost any dose of anabolic steroid, regardless of dosing pattern.
What are the half-lives of different esters?
Shorter chain esters have shorter half-lives, because of their lower partition coefficient. Testosterone cypionate has a half-life of 8 days5, the enanthate ester has a half-life of 4 days6, and nandrolone decanoate has a half-life of 8 days7. These figures are only approximate. The difference between these values for cypionate and enanthate probably includes difference attributable to different measuring techniques. The actual difference is probably not more than two days.
In the rat, where half-lives of anabolic steroid esters are similar to those in humans but somewhat shorter, the half-lives of the phenylpropionate, decanoate, and laurate esters are 1, 5, and 10 days respectively.3The same trend would be expected in man.
Half-life is linearly related to log partition coefficient, which is itself linearly related to the carbon chain length, the exception being if the ester is an unusual one such as phenylpropionate. This was shown by Jameset al.3for the formate through valerate esters of testosterone in the rat. The half-life of testosterone propionate was approximately 4 days, and each carbon added to or subtracted from that chain length changed half-life by about 1.5 days.
How are steroid esters made, and can esters be made of prohormones?
The most convenient method of synthesis of steroid esters is reaction of the steroid in a 2:1 mixture of pyridine and theanhydrideof the desired ester: for example, propionic anhydride would be used to make the propionate ester. A large excess (at least 10 times) of the anhydride compared to the steroid would be required. This would then be purified by diluting with at least 10 parts of water to each part of pyridine, adding 1 part ether, decanting the water after shaking, and then washing with 10 parts water repeatedly in a separatory funnel. This would be followed preferably by recrystallization or chromatography for purification.
Esters cannot be made of dione prohormones because they do not have an –OH group. Esters can be made of the diols, but purification by recrystallization probably is not possible because the product would be a mixture of 3aand 3besters, which could be expected to yield an oily mess, or perhaps an amorphous solid. Further difficulties would include the fact that for the diols, the starting material from at least some manufacturers is of considerably less than 100% purity. I personally would not even consider injecting the product of the above reaction without some further purification besides the water wash. An even more serious consideration is that by esterifying the prohormone, one is arguably manufacturing a controlled substance. To say the least, this is a real no-no with the Drug Enforcement Agency, even moreso than possession or importing, both of which are already quite serious crimes. Therefore I cannot recommend manufacturing esters of diol prohormones, but for the sake of completeness in an article on steroid esters, I thought I would mention how they can be made and what the difficulties are.
While there are a number of interesting oral steroids that, at first glance, would be appealing candidates for making esters, in fact there are very good reasons why no such products are available. Indeed, there are absolutely no 17-alkylated steroid esters on the market.
First, they would be difficult to synthesize. The 17-methyl group which works to block liver enzymes from reacting with the steroid molecule will also hinder the material one would use to make the ester from reacting with the steroid.
More seriously, there is the fact that a 17-methyl would also block enzymes in the body from hydrolyzing (removing) the ester, which would be necessary to yield the active steroid.
So I do not expect that you will ever see esters of Winstrol, Dianabol, or any 17-alkylated steroid on the market, and don’t recommend that anyone try making them. They would probably be inactive, or if they have any activity, it would be very low.
Summary, and Practical Implications
Shorter chain esters must be injected more frequently than longer chain esters if consistent blood levels are desired. Consistent blood levels probably lead to the greatest efficiency of use for the drug and the highest anabolic/androgenic ratio. The activity of long chain esters can be mimicked by frequent administration of short chain esters.
While it has been alleged popularly that some esters aromatize more than others, there is no support for this in the scientific literature, and the concept makes relatively little sense since the ester itself is very far removed from the site of reaction of aromatization. The claims in this area seem flawed: for example, in World Anabolic Review 1996, the text makes plain that the comparison being made is between a weekly dose of 350 mg of testosterone propionate vs. a weekly dose of over a gram of testosterone enanthate or other long chain esters. While it is surely true that, as they say, side effects of the latter will be more pronounced than those of the former, it is unreasonable to attribute this difference to the ester used.
All testosterone drugs aromatize, and if estrogenic effects are not desired, then anti-estrogenic agents should be used for any of the esters and in the same manner, regardless of the ester used.
While the theory of the effects of esterification of steroids is interesting and somewhat complicated, the practical implications are simple. Differences between parent drugs are far more important than differences between esters of the same drug. And if the ester is different, the key difference to the bodybuilder is in half-life of the drug. Longer half-lives add convenience, and shorter-half lives allow the drug to exit the body more quickly. Short half-life also can allow fairly rapid drug clearance to occur before drug testing. Testosterone propionate is therefore a drug of choice for the tested athlete. And if a brief alternating cycle plan is being used, a short half-life allows high dosing during the “on” weeks with rapid clearance to non-inhibiting levels during the off weeks. Besides these things, however, there are no significant differences between drugs resulting from use of different esters.
(A shorter version of this article previously appeared in Peak Training Journal. New information has been added for MESO-Rx.)