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Bodybuilding Pharmacology: Pro Test

Nandrolone is the generic name for a group of anabolic steroids, the most familiar of which include injectables such as Deca-Durabolin and Durabolin.

During the recent Olympic Games in Sydney, Australia, much of the attention that should have been reserved for the international athletic competition was diverted to the question of which athlete would show up positive in the next drug test. Even when superlative American track star Marion Jones was doing her best to capture five gold medals on the field, her husband, shot-putter C.J. Hunter, who wasn’t competing, was getting even more attention than she was, as it was disclosed that he had failed four consecutive drug tests. Still more controversial was the drug he tested positive for: nandrolone.

Nandrolone is the generic name for a group of anabolic steroids, the most familiar of which include injectables such as Deca-Durabolin and Durabolin. Hunter claimed that he never took anabolic steroids of any type, and he suggested that his positive test for nandrolone may have resulted from his use of ‘contaminated’ iron pills. Unless Hunter suffered from anemia or had experienced some kind of occult-related blood loss, he shouldn’t have been taking an iron supplement’but that’s another story.

Many other athletes have tested positive for nandrolone during the past three years. That’s curious because of all the anabolic steroids available, nandrolone is probably the worst choice for athletes who have to take a drug test. With present drug-testing procedures, nandrolone metabolites are detectable for 18 months or more. That means that you could get busted for nandrolone even if you haven’t used it for a year and a half. Most athletes are aware of that, and they avoid using nandrolone. So how does that jibe with the recent upsurge in nandrolone-positive drug tests? A few newly published studies may provide the answer. For example, in one study, when three normal men, who were not using any type of anabolic steroid or drug, ate 310 grams of pork, they excreted nandrolone by-products in their urine in levels that would have resulted in a positive drug test for nandrolone.1

A more likely explanation is what C.J. Hunter alluded to: contamination of supplements sold over the counter. A new study shows that the problem may lie with some popular pro-hormone supplements,2 specifically androstenedione, which is used to increase testosterone levels. The subjects were 41 healthy men, ages 20 to 44, who were randomly assigned to one of several groups: One group took 100 milligrams of andro a day for seven days, another took 300 milligrams a day for seven days, and a control group took no andro. For comparison purposes four more subjects took 10 micrograms of 19-norandrostenedione.

While 19-nor pro-hormones will definitely lead to increased urinary excretion of metabolites that are similar to those produced by nandrolone steroids(though in far lower concentration), andro isn’t supposed to do that. Yet all the subjects taking andro in any dose had nandrolone metabolites in their urine. Those taking the 100-milligram dose had slightly more than the minimum level for a positive drug test. Those getting 300 milligrams of andro a day had a nandrolone-metabolite level that was about 4 1/2 times higher than the minimum for a positive test. The results showed that 20 out of the 24 men taking andro supplements would have tested positive for nandrolone.

Another problem that became evident in this study involves the purity of commercial pro-hormone supplements. Of the nine brands used, one contained no steroids at all; that means it had no andro or even any 19-nor pro-hormones, although the label said it contained 50 milligrams of andro. Brands that were supposed to have 100 milligrams of andro actually varied in content from 35 to 103 milligrams. One brand even contained 10 milligrams of testosterone! In fact, six of nine brands of andro used in the study were mislabeled in terms of the product’s andro content. As for why andro supplements would contain nandrolone metabolites, the authors can only speculate. They point out that aromatizable steroids’steroids that can be aromatized, or converted into estrogen’can lead to a pathway that produces nandrolone metabolites. Andro is subject to such conversions. Other studies show that some men apparently produce nandrolone metabolites in their bodies; however, none of the research so far has shown levels high enough to yield a positive drug test.

The most probable scenario goes back to C.J. Hunter’s excuse: The andro was contaminated during processing. That could have involved poor quality control, such as mixing the andro material in the same equipment that was used for 19-nor supplements and so allowing enough of the 19-nor to leach into the andro supplement to cause positive drug tests. Admittedly, that’s sheer speculation, but it doesn’t change the fact that many andro supplements are indeed contaminated with nandrolone metabolites, and some athletes who thought they were using just andro probably got busted for nandrolone because of it.

If some other recently reported events turn out to be true, pro-hormones aren’t the only over-the-counter supplements that may be tainted with nandrolone metabolites. German javelin thrower Carolin Suboll, 19, who was the runner-up at the European Junior Track and Field Championships, recently tested positive for nandrolone after using a creatine product. She wasn’t suspended from competition, however, because analysis of the supplement in question found it contained a high enough concentration of nandrolone metabolites to cause a positive test.

If the story’s true’I have no definite confirmation’it’s certainly ironic, since German-made creatine has a reputation for being among the purest, least adulterated creatine in the world. That’s assuming, of course, that the supplement she used was of German origin.

A study called ‘The Andro Project’ examined the physiological and hormonal effects of using an oral supplement of either 200 milligrams of androstenedione (andro) or androstenediol (4-AD) in 50 men, ages 35 to 65.3 The men were randomly assigned to an andro group, a 4-AD group or a placebo group. They also engaged in a high-intensity weight-training program throughout the study. None of the subjects used any type of androgenic drugs, and they all began with normal testosterone levels.

During the 12-week study all the men using pro-hormone supplements showed a significant increase in aromatization. The andro group also showed a 16 percent increase in total testosterone levels after one month; however, they dropped back to baseline by the end of the study. The authors indicated that the drop in testosterone at the end was caused by the increased aromatization coupled with a drop in the body’s endogenous testosterone production.

They base that presumption on a drop in luteinizing hormone (LH) that averaged 18 to 33 percent. LH is a pituitary hormone that controls testosterone synthesis in the Leydig cells of the testes. An increase in estrogen levels relays a feedback message to the hypothalamus in the brain to stop releasing gonadotropin-releasing hormone (GRH), which prevents the pituitary release of LH.

Neither pro-hormone supplement increased any training adaptations beyond what the placebo group achieved in terms of enhanced body composition, such as fat loss, or increased strength. Both pro-hormones did, however, lower protective high-density-lipoprotein (HDL) cholesterol sufficiently to pose a 6.5 percent increase in cardiovascular risk. In contrast, the placebo group showed a 5.1 percent rise in HDL levels during the study, pointing to the beneficial effect of weight training in preventing cardiovascular disease. Based on those results, the authors concluded that ‘testosterone precursors do not enhance adaptations to resistance training when consumed in dosages recommended by manufacturers.’

One problem with the study is that the subjects, as with those in previous studies, had higher levels of bodyfat. That’s significant because higher bodyfat levels lead to an increase in the aromatization of testosterone into estrogen. Bodyfat is a rich source of aromatase, the enzyme that catalyzes the aromatization process.

Another problem is the form of supplement used in the experiment. Oral pro-hormones must make a first pass through the liver, which degrades a large amount of the supplement. The liver also contains a system that directly converts testosterone into estrogen; however, the fact that total testosterone levels did rise during the first month of the study shows that some pro-hormone survived the first-pass liver metabolism.

According to pro-hormone guru Patrick Arnold, who played an integral role in the development of many of today’s pro-hormone supplements, the researchers in this study weren’t sure which type of pro-hormone they used. For example, one of the researchers that Arnold communicated with wasn’t certain which isomer of androstenediol they’d used. That’s significant because the 4 and 5 isomers of androstenediol follow different pathways. In addition, while DHEA levels rose in the subjects using androstenediol, Arnold points out that the 4-AD form cannot be converted into DHEA, while the less effective 5-AD acts as a direct precursor for DHEA synthesis in the body. All studies have shown that 4-AD is vastly superior to 5-AD in terms of conversion into testosterone and that 5-AD is also more readily converted into estrogen’which may explain the high estrogen conversion rates seen in the study.

Arnold also says that the older oral versions of any type of pro-hormone simply aren’t the most efficient. Because of the way they’re metabolized, he notes, the oral forms have a greater chance of increasing estrogen while depressing protective HDL.

‘I say this for two reasons,’ says Arnold. ‘First, I have seen the blood tests for sublingual and transdermal [pro-hormones] and have seen this firsthand. Also, the aromatase enzyme and lipoprotein synthesis occur in large part in the liver, and considering the extensive exposure to the liver that occurs with oral first-pass metabolism, it makes sense that effects involving those systems are accentuated.

‘I would bet that you could take testosterone itself, administer it orally and see augmented aromatization and adverse lipoprotein effects [lowered HDL, increased LDL] compared to nonoral administration. I’d like to see an independent research group examine the effect of mode of administration so that we can establish the real picture.’

Arnold’s views make sense. I’d also like to see a similar study done with some of the newer delivery systems for pro-hormones, such as the cyclodiol sublingual types. They feature far less pro-hormone because they’re far more efficiently absorbed. They avoid the big barrier of first-pass liver metabolism. I suspect that they wouldn’t lead to a comparable increase in estrogen, as occured in this study, nor would they result in the potentially adverse cardiovascular changes that took place. Subjects for such studies should have no more than 15 percent bodyfat levels to avoid the confounding effects of increased aromatization. Until such a study is published, it would be premature to label pro-hormone supplements as useless.

On the other hand, when I asked the lead author of the new study, Craig E. Broeder, Ph.D., director of the Human Performance Lab at East Tennessee State University, about some of the questions it raised, he noted, ‘It’s possible that using different delivery systems for pro-hormones other than oral versions may improve the situation, but I don’t believe it would. To date, little, if any, controlled data exists on the delivery-system issues. I had the opportunity to review one article last year for a well-respected sports-nutrition journal. The delivery system used in that study was sublingual. They didn’t see the same negative changes, but they only got minimum positive effects. The study had a tremendous number of data-collection flaws, however, which the researchers didn’t control for a variety of issues. Based on the three reviewers’ concerns about the quality and methodological flaws of the study, it was not accepted for publication.

‘If we look at things such as intramuscular testosterone injections, we see that aromatization and HDL decreases still occur. Even with the testosterone-patch delivery system, which is often used when people still have the ability to synthesize their own testosterone and are only boosting current low-normal levels, we still see similar negative effects if the dose is too high and the drug is used without cycling on and off.

‘Regarding any confounding effects of body composition, none were observed in this study. Bodyfat ranged from averages of 14.5 percent in the normal group to 24.2 percent in the above-normal group. With the placebo stage of the study, estradiol levels rose as follows: normal bodyfat group, 15.5 percent; above normal, 9.6 percent. When they were taking the -diol pro-hormone, estradiol increased 80.4 percent in the normal bodyfat group, 22.4 percent in the above-average group. With the -dione pro-hormone, estradiol increased 123.2 percent in the normal group and 91.6 percent in the above normal group.’

Broeder also noted that although it wasn’t reported in the study, the risks for prostate and pancreatic cancer rose with use of the pro-hormone supplements. The risk profiles increased ‘very dramatically,’ he said, and should be a focus of future research. A forthcoming article in the Journal of the American Medical Association will examine the cancer connection more closely.

Reports do suggest a connection between higher androstenedione and estrogen levels in men who have pancreatic cancer;4,5 however, the cases all occurred with low serum testosterone levels.6 Thus, while people who have pancreatic cancer show higher levels of androstenedione and estrogen, low testosterone is part of the picture as well. In a healthy person, theoretically, andro would have to permanently lower testosterone while increasing estrogen to duplicate the hormonal pattern of pancreatic cancer. I don’t think that’s occurred in any healthy people.

Long-term increased testosterone levels are a risk factor for prostate cancer. To link such cancers definitively to pro-hormone use would require case studies of people who acquired them that way. As far as I know, no such cases have been published. Indeed, various anabolic steroid drugs have been linked to cancer for years, yet the incidence of cancer in athletes who use even large amounts of steroids is relatively low in proportion to the total number of users. That doesn’t mean it isn’t possible, only that it’s not as frequent as is often suggested.

According to Broeder, however, epidemiological data links the onset of certain types of cancer, in this case, prostate and pancreatic cancer, to specific hormonal profiles. Men with prostate cancer show elevated androstenedione or estrogen levels, or both. The connection between cancer and androstenedione relates to the elevated estrogen produced by the aromatization of andro to estrogen. The body appears to be unable to shut down the elevated estrogen production, which promotes cancer. Broeder says that people who use oral andro supplements are mimicking the hormonal pattern associated with cancers of the prostate and pancreas.

This, by far, is the most serious side effect linked to pro-hormones, and we need further research to definitely prove the cause-and-effect relationships. Again, however, I doubt that any cases of cancer linked to pro-hormones have turned up. Until they do, it remains speculation. To play it safe, however, it’s probably prudent for anyone who has a family history of prostate or pancreatic cancer to avoid using androstenedione pro-hormone supplements.

1 Le Bizec, B., et al. (2000). Consequence of boar edible-tissue consumption on urinary profiles of nandrolone metabolites. Mass spectrometric detection and quantification of 19-norandrosterone and 19-noretiocholanolone in human urine. Rapid Commun Mass Spectrom. 14:1058-65.
2 Catlin, D.H., et al. (2000). Trace contamination of over-the-counter androstenedione and positive urine test results for a nandrolone metabolite. JAMA. 284:2618-2621.
3 Broeder, C.E., et al. (2000). The andro project: physiological and hormonal influences of androstenedione supplementation in men 35 to 65 years old participating in a high-intensity resistance-training program. Archives of Internal Medicine. 160:3093-3104.
4 Fernandez-del Castillo, C., et al. (1990). Pancreatic cancer and androgen metabolism: high androstenedione and low testosterone serum levels. Pancreas. 5:515-518.
5 Fyssas, I., et al. (1997). Sex hormone levels in the serum of patients with pancreatic adenocarcinoma. Horm Metabol Research. 29:115-118.
6 Sperti, C., et al. (1992). Androgen profile in patients with pancreatic carcinoma. Italian J Gastroenterol. 24:328-31. IM

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