You don’t always get what you want, even if you get what you need

One of the newer supplements on the market are the aromatase inhibitors. They purport to increase free testosterone levels by inhibiting the enzyme that is responsible for converting androstenedione to estrone as well as converting testosterone to estradiol. By preventing the breakdown of testosterone precursors and the breakdown of testosterone itself, the concentration of testosterone should theoretically increase.

Sounds great, doesn’t it?

If any of you have read the advertising, Gaspari Nutrition’s Novedex touts the Baylor University study in its ad literature. This paper was published in 2007.

Willoughby DS, Wilborn, C et al. Eight weeks of aromatase inhibition using the nutritional supplement Novedex XT: Effects in young, eugonadal men. International Journal of Sport Nutrition and Exercise Metabolism, 17: 92-108, 2007.

Introduction:

Lots of guys are interested in getting more muscular. Some of them turn to anabolic steroids. Others have tried testosterone precursors like androstenedione, but both of these substances are technically banned or outright illegal in many countries. However, if you can block, or partially block the action of the enzyme that converts androstenedione to estrone, and testosterone to estradiol (a task accomplished by the same enzyme), you should be able to increase free testosterone and therefore achieve an anabolic effect (e.g. increase lean mass, decrease fat mass) because estradiol is the main hormone that feeds back to your brain to tell it to produce less stimulating hormone to your testes (which is where testosterone ultimately comes from). This enzyme is in the class of aromatases. And thus, the ingredient in Novadex that was tested in this study is in the class of aromatase inhibitors.

[Edit: I forgot to mention that this study was funded by Gaspari Nutrition, and appropriately disclaimed in the paper.]

Methods:

The authors chose to study eugonadal men in this study. Eugonadal means that they were producing normal amounts of testosterone. Guys who had used any nutritional supplements in the 2 months prior to the study were excluded from participation (this included creatine). All of the subjects had at least 3 years of resistance training experience. So, we’re looking at non-beginner lifters who didn’t use creatine or androstenedione or steroids for 2 months before the study.

[I think it’s easy for novice readers to dismiss this study on the basis of these inclusion criteria, but I wouldn’t share that opinion. This study does use the right kind of guy: beginner lifters probably shouldn’t be using aromatase inhibitors right off the bad. Most non-beginners are probably using creatine, but as a researcher, you want to give your new “drug” as good of succeeding as much as possible. Having guys on creatine or other supplements means that you have to account for gains by creatine or other substances and therefore whatever gains you see, might not be attributable to Novedex. I suppose there’s an outside chance that there’s a synergistic effect, but I’m always leery of claims of synergy of two substances that, on their own, don’t do much, but together somehow magically make huge differences (not that I’m saying creatine does nothing, because the evidence for creatine is quite good)]

Measurements were taken at 0, 4, 8 and 11 weeks. The researchers measured percent body fat, fat mass, fat-free mass, total body water as well as total and free testosterone, testosterone precursors and metabolites. Blood tests for safety were also performed, but I’m not going to focus much on those.

The subjects were simply told to continue their workout and diet schedules. Logs of physical activity and diet were kept during selected intervals of the experiment.

Subjects were split into two groups, matched by age and body mass, then assigned to get either Novedex or a placebo.

[The reporting gets a bit sketchy here, since it’s not clear how they decided who would get which pill.]

The Novedex group took 4 Novedex capsules at bedtime. The placebo group took 4 placebo capsultes (maltodextrin) at bedtime. After 8 weeks of taking either pill every night, the subjects didn’t take either of the pills for 3 weeks. Subjects were not told which group they were in, and apparently, neither were the researchers.

[Again, the reporting gets sketchy because although the paper says, “double blind”, we’re not sure who they’re referring to as the second blind. We’re also not told that steps were taken to make sure people didn’t somehow figure out their group assignment).]

Statistics:

The researchers used 2×4 ANOVAs with repeated measures for every variable. This included their safety variables–about 45-50 of them ranging from complete blood count to triglycerides and urine ketones.

[That’s a lot of variables to test!]

They then did separate 1-way ANOVAs to test for differences between groups and between each of the time intervals.

[This is redundant and unnecessary, and actually increases your chance of finding a significant p-value when a true difference does not exist in the “real world”.]

The researchers estimated their required sample size on an unknown variable, presumably free testosterone, and figured they needed 8 subjects per group to detect a difference between the two groups of between 0.8 and 1.25.

[I have no idea if this was calculated on possible vales of free testosterone or not, or what the units of 0.8 or 1.25 are, or if this was a ratio difference or what. It also seems highly unlikely that you would need the same number of people to detect a difference of 0.8 as you would need to detect a difference of 1.25, but maybe you only needed 4 or 6 people to detect the larger difference? Their sample size estimation method wasn’t referenced.]

Results:

The guys:

On average, the subjects were aged 26.1 (SD 4.4), were around 182 cm tall (71 inches, or 5’11″ish, weighed about 91kg (SD 14), or about 200 lbs, had a fat free mass of 75 kg (SD 9.5) 165 lbs, and had a body fat percentage of about 17 (SD 5.9)

Diet and Physical Activity:

The two groups did not really differ in any meaningful way from one another in terms of macronutrient ratios or total calories consumed. “Subjective” analysis of workout logs showed that none of the subjects changed up their workout routines.

Hormones:

Total testosterone and free testosterone were observed to increase at the 4 and 8 week points for the Novedex group. On average, total serum testosterone was noted to rise about 4 times (from about 5pg/ml to about 25pg/ml, with a very wide variance for total), and from less than 25ng/ml to just under 150ng/ml with a very large variance for free testosterone. However, even with this huge variance in effect between subjects in the Novedex group, there is no question it was larger than the non-existent change in testosterone of the placebo group. By the 11 week mark, both groups had returned to the week 0 level of total and free testosterone.

Body composition:

The authors reported that there were no statistically significant changes in body comp measurements except the the Novedex group loss more fat mass than the placebo group (about 3.5% on average). But looking at the graph and the data, I’d be hard pressed to make the same conclusion and I would attribute the two statistically significant p-values to be accidental due to the massive number of significance tests that were performed. Even if it really is “statistically significant”, I would say that the observed difference isn’t actually remarkable. At all.

In fact, if you look at the reported numbers, the placebo group started at an average body-fat percentage of 18.4 (SD 6.3) and at week 8 with a body-fat percentage of 18.7 (SD 6.5) for an average change of +0.3%, while the Novedex group started at an average body-fat percentage of 16.1 (SD 5.6) and at week 8, had an average body-fat percentage of 15.3 (SD 5.3), for an average change of -0.8%. That makes an average difference between the two groups of a mind-numbing 1.1% over 8 weeks.

Safety markers:

There were no marked differences in general blood work noticed.

Discussion:

We know that testosterone in _supraphysiological_ doses increases muscle mass and strength. However, even with a 4-fold increase of total testosterone and a 5-6-fold increase of free testosterone, 8 weeks of Novedex doesn’t seem to put a dent in body composition. Apart from the moderately poor reporting of this randomized controlled trial, it’s not bad. And the weaknesses in the study aren’t really fatal flaws because all the biases in this study either affect generalizability (as opposed to validity) or are all in the same direction as the findings. For instance, the fact that no beginner lifters were included in the study doesn’t affect the validity of the trial, only the generalizability (i.e. we can’t use this study as justification for beginner lifters to use Novedex, but there’s nothing glaringly wrong with the study itself). The fact that we don’t know who was blinded or whether some of the subjects figured out their “pill assignment” doesn’t really affect the validity of the study because if control group subjects found out they were on the placebo pill, they would have been biased to show that it did nothing (which it did anyways).

The only real weakness in this study of consequence is the coincidental finding of a “significant” reduction in fat mass (as determined by a significant p-value). But with so many tests of significance, we would expect there to be a very high chance (i.e. greater than 50%) that at least one of their tests would be significant by chance alone. And when you look at the actual numbers, you see that it probably is a coincidence that the p-value is less than 0.05, as opposed to being something meaningful, since none of the body comp numbers really changes at all.

One additional problem that you might (correctly) pick out is that this study involved only 16 guys. But again, this goes to narrowing the field of people this study applies to, not the overall validity of the study. If you don’t fit into a demographic profile that is similar to these guys, it’s really hard to use this study as justification to use Novedex.

One thing that I found very interesting is the range of values that subjects had in response to Novedex. The range of total testosterone and free testosterone in response to Novedex was pretty huge, which leads me to believe that there are probably guys who respond more than others on aromatase inhibitors. If there was a way to predict who was a responder, or if a larger study had been done so that a sub-analysis of high-responders vs. low-responders could be performed, I think we would have had a winner of a study on our hands. Maybe we would have seen substantial changes in body comp that would justify the use of Novedex. However, the average change in fat-free muscle mass and fat mass wasn’t very large and unfortunately, neither were the variances, which means that in spite of very impressive increases in testosterone levels, these increases don’t seem to translate to a noticeable benefit. You can get what you want (more testosterone), but still not get what you need (more muscle, less fat), even if you’re a theoretical high-responder.

The bottom line: Unfortunately, this study leaves us with more questions than answers. If the fact that this study is cited in the ads for Novedex is why you’re thinking of, or have decided to use Novedex, you might want to reconsider your decision. Of course, anyone can try just about anything based on hype or anecdotal personal testimonials, but that’s not why you’re reading this, is it?