Prohormones, Dosage and Mental Masturbation

This month, I’ll review a couple of very interesting prohormone studies. They deal with the first-generation prohormones, androstenedione and 19-norandrostenedione. Of course, these two prohormones are illegal in the United States, but these studies are interesting because they help answer a lot of questions about these products that we asked ourselves for years. So even though all this is probably little more than a session of mental masturbation, here is this month’s column.

19-norandrostenedione Is Ineffective Orally In Rats

An article came out recently that examined the anabolic/androgenic activity of the prohormone 19-norandrostenedione (nordione). This was a popular prohormone back in the late ‘90s, and it was introduced to the marketplace shortly after the original prohormone androstenedione (andro) was first sold. Nordione was touted as a less androgenic alternative to andro, and was fairly popular for a while.

This recent study, entitled “Anabolic and androgenic activity of 19-norandrostenedione after oral and subcutaneous administration—Analysis of side effects and metabolism,” appeared in the journal Toxicology Letters. Researchers utilized the classical Hershberger assay, which takes castrated rats and examines the effect of steroids on their tissues. Androgenic effects and anabolic effects are measured by the change in weight (versus control) of the levator ani muscle.

Researchers first administered nordione to castrated rats by subcutaneous injection. They used 1.0 mg/kilogram bodyweight per day, which is around 60 milligrams per day for a 100-kilogram man (after compensating for body surface area). They also had a control group (placebo injection) and a reference group that was administered an equivalent amount of testosterone propionate. The experiment lasted 12 days, after which the rats were sacrificed (a nice way of saying ‘killed’).

Scientists found that the weight of the seminal vesicles and prostate gland remained pretty much unchanged compared to the control group, while the weight of the levator ani muscle increased substantially— although somewhat less than it did in the testosterone propionate group. This is consistent with the known ‘low androgenic/high anabolic’ effect of 19-nortestosterone derivatives.

The second phase of the experiment used the same protocol, and looked at the effect of oral supplementation of nordione. Researchers used oral doses of 0.1, 1.0, and 10 mg/kg bodyweight (roughly equivalent to 6, 60, and 600 milligrams per day for a 100-kilogram man). After 12 days, the animals were sacrificed and the organs examined.

Surprisingly, in contrast to the subcutaneously-injected rats, the ‘oral’ rats did not show any significant increase in weight of any of the organs, indicating that no anabolic or androgenic activity was occurring. This comes as somewhat of a surprise, as traditional theory assumes that oral administration of prohormones results in substantial conversion to active compounds in the liver— which go on to exert their pharmacological effect on the body. As a matter of fact, the levels of the target hormone (19-nortestosterone) in the highest dosed ‘oral’ group exceeded that of the subcutaneous injection group (two to three times higher). Yet the oral group did not show anabolic effects, while the subcutaneously injected group did. In fact, the high-dose oral group actually lost weight.

How can we explain these results? The authors propose a couple of explanations. The first one considers that liver metabolism of androgens is different for oral supplementation versus injection. Orally-administered androgens undergo ‘first-pass’ liver metabolism, which causes formation of metabolites in different proportions than what are seen with injectables. Some of these metabolites may possess androgen antagonist activity, which would counteract the effect of the nortestosterone formed.

Another explanation involves the differences in pharmacokinetics between the two routes of administration. Oral dosing results in significant but brief peaks in blood hormone levels, while injections provide more even and sustained levels. In this study, the hormone was administered orally in one daily dose, and so perhaps this dosing did not result in long enough exposure of the body’s tissue to 19-nortestosterone.

What is the lesson here? That’s hard to say, as this was just one study. But it does reinforce what I already know— that prohormones administered orally are not as effective as those administered transdermally. Although transdermal administration does not result in the same bioavailability as subcutaneously-injected hormones, it does provide favorable pharmacokinetics due to its prolonged time-release actions.

I have a couple of questions. First, I wonder what the results would have been if the daily oral dosage was split up (i.e., administered three times a day instead of once), which is generally the way people consume oral prohormones. Additionally, I am curious as to whether these results are specific for nordione, or if they are common with other ‘diones’ and perhaps ‘diols’ as well.

I should mention that no adverse effects were observed in the animals given nordione, which is not a surprise because natural prohormones are not associated with the same toxicities as synthetic steroids (i.e.,17alpha-alkylated compounds). Of course, researchers did not look at cosmetic side effects such as gynecomastia, and we do know that users of nordione were quite susceptible to gyno because of its high estrogen conversion and lack of conversion to naturally anti-estrogenic 5alpha-reduced metabolites.

All in all this was an interesting study, however far too late for practical application (at least in the U.S.)— since nordione and all the other natural prohormones were banned a few years back.

4-androstenedione Is Effective In Hypogonadal Men

4-androstenedione (‘andro’) was the original prohormone (unless you count DHEA). Introduced in 1996, it sold quite well for a while and reached its peak of popularity in 1998 when it was found in Mark McGwire’s locker. Soon afterward, newer and better prohormones such as 4-androstenediol took its place as the preferred supplements for testosterone elevation.

Andro had its problems. At the dosages that were typically used, a substantial elevation in serum estrogens was seen, as well as a weak or non-significant elevation in testosterone. The result of this imbalance made users susceptible to gynecomastia. Furthermore, it just did not seem to do much for people, at least when used at the recommended dosages. This lack of efficacy and increase in estrogens was confirmed by several studies done on young males given andro.

A study in 2005, however, examined andro again— but this time a different population of males was used and a higher dose was administered. The study, “4-Androstene-3,17-Dione Binds Androgen Receptor, Promotes Myogenesis in Vitro, and Increases Serum Testosterone Levels, Fat-Free Mass, and Muscle Strength in Hypogonadal Men,” was published in the Journal of Clinical Endocrinology and Metabolism.

Researchers studied the effects in andro in hypogonadal men. These are the same men who are prescribed testosterone replacement therapy, and they are usually defined as males who have serum testosterone less than 300 ng/dl and experience symptoms of low testosterone.

Before they looked at the in vivo effects of andro, researchers did a series of experiments designed to prove that andro has the ability to activate the androgen receptors and stimulate muscle growth, in vitro. Mind you, they were not looking at the effects of andro after converting to testosterone, but rather the effects of andro itself. The reason they examined this was probably political— so they could define andro as an ‘anabolic steroid’ once and for all, without the confounding issue of whether it was intrinsically active (note that this study was performed before the prohormone ban in 2005).

Researchers found that andro had the ability to bind and activate the androgen receptor, as well as increase the expression of key myogenic markers and stimulation of myotube formation. Of course the potency of straight andro was much, much less than that of testosterone or dihydrotestosterone— but the authors proved their theoretical point.

They chose nine men between the ages of 19 and 65 who had testosterone levels of less than 300 ng/dl. The men had to be relatively healthy otherwise, and men who participated in resistance exercise or moderate to heavy endurance exercise were excluded— as such activity would interfere with the measurement of pure hormonally-initiated anabolic effects. Dosing was set at 500 milligrams, three times a day (1,500 mg total andro per day), and they took the andro for 12 weeks.

After 12 weeks of of andro, levels of testosterone and free testosterone were elevated into the normal range (levels varied substantially between doses). Estrone and estradiol were also elevated, and SHBG was decreased quite substantially. Most importantly, fat-free mass increased by an average of 1.6 kilos in the subjects, and maximal muscle strength increased an average of 4.3 kilograms in the bench press and 18.8 kilograms in the leg press. These increases in strength and lean body mass are rather remarkable, as they are similar in magnitude to those observed in hypogonadal men given standard testosterone replacement therapy. Furthermore, other than a decrease in HDL cholesterol, no other indicators of toxicity were observed.

So what does this study tell us? That the theory of androstenedione behaving as an effective testosterone elevator does have merit. It just took the right dose and the right subjects (hypogonadal males) for its efficacy to be demonstrated. On the other hand, by demonstrating its efficacy, you also reveal andro as an effective anabolic agent, which lends credence to the argument that its classification as a controlled substance was justified.

It’s all interesting stuff— even if it’s all a moot point in today’s world.