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Bodybuilding Pharmacology
Pro-hormone Surprise

When another pro-hormone supplement was analyzed, it was found to contain the anabolic steroid drug methandienone, formerly sold as Dianabol and under various other trade names.

Pro-hormones are substances that can be converted into active hormones by specific enzymes in the body. Pro-hormone supplements are currently sold over the counter courtesy of the 1994 Dietary Supplement Act, which permits the sale of any naturally occurring substance that is considered safe until proven otherwise.

Although they were introduced just a few years ago, pro-hormone supplements have evolved considerably. The first one available was DHEA, a natural adrenal steroid. While DHEA offers several health benefits, particularly for those over 40 whose DHEA production is naturally declining, it proved problematic for younger men and women. In younger men oral DHEA supplements most often metabolize to androstenedione, another adrenal steroid and a direct precursor of testosterone synthesis. Unfortunately, androstenedione can take another pathway'into estrogen conversion'and that happened to a lot of young men who took DHEA. Ironically, androstenedione usually converts into testosterone in young and older women. On the other hand, it's the major androgen produced in women's bodies and the natural source for their testosterone synthesis.

When it became apparent that DHEA wasn't the best pro-hormone for bodybuilding purposes'at least in men'androstenedione itself came on the market. That led to estrogen-based problems, including gynecomastia, or excess male breast tissue; water retention and increased subcutaneous fat deposits, meaning the fat that's just under the skin.

The first truly successful pro-hormone in terms of testosterone conversion was called 4-androstenediol, or 4-AD. Some studies showed that it was at least three times more effective than androstenedione at converting into testosterone, and it appeared to produce fewer estrogen-related side effects. The major problem with 4-AD was that when people took it orally, about 85 percent of the dose was deactivated in the liver in a process called first-pass metabolism. That mandated an improved delivery system.

Patrick Arnold, the leading authority on pro-hormone metabolism and development, came up with the idea of using a cyclodextrin delivery system for pro-hormones. Coating the pro-hormone matrix with carbohydrate allowed it to be absorbed through the oral mucosa in a sort of Trojan-horse effect, bypassing first-pass liver metabolism. The technology had previously proven effective for actual testosterone-based drugs. The advantage of cyclodextrin pro-hormones was that you could not only absorb more of the supplement but also use lower doses, lessening the chance of side effects.

Since then other types of delivery systems have been introduced, such as transdermal (through the skin) delivery. More recently, Pat Arnold brought out 1-AD, which appeared to be the first truly effective pro-hormone supplement. Also called 1-testosterone, its advantages include no conversion into estrogen or problems with conversion into dihydrotestosterone (DHT), a testosterone metabolite that's linked to such side effects as acne, male-pattern baldness and prostatic enlargement.

While 1-AD may justifiably be called the pick of the litter of currently available pro-hormone supplements, some problems are emerging. They aren't directly related to 1-AD's metabolic activity but rather issues such as quality control and proof of efficacy. No published study in any reputable medical journal has yet examined 1-AD's anabolic efficacy. That doesn't mean it doesn't work as advertised, only that there's no proof involving healthy human athletes. When such experiments were done on androstenedione, it turned out that andro was an effective pro-hormone'for converting into estrogen, not testosterone, in men.

A forthcoming study analyzed several popular supplements that are marketed to bodybuilders and other athletes.1 Among the supplements studied were a commercial version of 1-AD and an unidentified supplement that, judging by its contents, appears to be a thermogenic, or fat-burning, product. The fat burner turned out to be contaminated with various pro-hormones, including 19-nor, 4-AD and DHEA'and testosterone itself. The popular 1-AD product tested contained boldenone, a veterinary anabolic steroid commonly sold under the trade name Equipoise. According to the authors, one capsule of the pro-hormone supplement could cause a positive drug test for boldenone two to six hours after you took it. The 1-AD supplement also contained DHEA, 19-nor and 5-AD, all pro-hormones, and the level of 19-nor was great enough to lead to a positive test for nandrolone for two to 24 hours.

How could boldenone be present in an over-the-counter supplement? It turns out that 1-AD is the 5-alpha reduced version of boldenone. The enzyme 5-alpha reductase converts testosterone into dihydrotestosterone, a more androgenic form of the hormone, but with less anabolic activity. Since 1-AD looks like boldenone, it exhibits similar properties, such as being far less androgenic than DHT but much more anabolic. Interestingly, if you manipulate the structure of 1-AD by attaching a 1-methyl group, you get a popular oral anabolic steroid called Primobolan. The addition of the methyl group, however, changes the metabolic properties, making it more bioavailable than 1-AD. That's one reason why Primobolan is a prescription drug and 1-AD isn't.

So it appears that boldenone exists naturally in 1-AD but still shows up on drug tests. The other pro-hormones in the analyzed sample are more difficult to pin down and could be due to a problem with quality control or manufacturing procedures. That, of course, is giving the chemists the benefit of the doubt: that the substances weren't purposely added.

Another study found a far more serious problem with certain 1-AD supplements.2 The researchers purchased a commercial product that was manufactured by an American company and sold in Great Britain and over the Internet as '1-T Matrix.' When analyzed with sophisticated procedures, it was found to contain the anabolic steroid drug metandienone, formerly sold as Dianabol and under various other trade names. The amounts of the active drug in the products varied among the three bottles tested, but all contained significant levels of it, enough to lead to a positive drug test for metandienone.

That report is particularly disturbing, since there's no natural way that Dianabol could exist in an over-the-counter pro-hormone supplement. It's not, however, the first time a manufacturer has added active drugs to over-the-counter products. More than a decade ago an Arizona-based company added methyltestosterone to a supplement. The FDA caught it, and the company subsequently went out; its owners had prior convictions. An oft-quoted line from 'Forrest Gump' says that 'life is like a box of chocolates: You never know what you're going to get.' When applied to some pro-hormone supplements, those words have never been more true.

Steroids and Long-term Risks

A major question about anabolic steroids is how they will affect the future health of long-term users. As this column and other sources have chronicled, steroid use is linked to a bevy of side effects. For example, many oral anabolic steroids are linked to liver problems. Other steroids can cause distressing cosmetic effects, such as acne and male-pattern baldness. Easily the most serious possible consequences of steroid use are those that affect cardiovascular function. Nearly all oral steroids lower a protective cholesterol carrier in the blood called high-density lipoprotein (HDL) by stimulating processes in the liver that rapidly degrade it.

Critics of steroid use'and they are legion'cite the many possible side effects, implying that injudicious use of anabolic steroids will lead to a shorter life span. After all, how can drugs that have such apparent potent physical effects not cause long-term harm? Smoking and excess drinking have an adverse effect on longevity in most people, so why not steroids?

In a study of mice published six years ago, one group of rodents got a six-month steroid regimen that mimicked that of typical human athletes. The six-month steroid use in the mice equaled human use for 15 consecutive years. Thirty-five percent of the mice that got steroids were dead after a year and only 12 percent of the drug-free control group. That led the authors to suggest that long-term human use of steroids would likely lead to reductions in life span.

But there are always dangers when you try to apply animal-based findings to human physiology. In this case it turns out that mice are far more prone to kidney failure and diseases than humans. That's significant because most of the steroid-using mice died from kidney complications. So it could be that the steroids merely sped up the inevitable, which means that extrapolation to humans based on the results of this study would be dubious.

A new study examined a group of 32 male bodybuilders and powerlifters.3 Fifteen of the subjects had not used any steroids for 12 to 43 months, though they'd previously averaged 720 milligrams a week of various steroid drugs for 26 weeks over a period of nine years. Seventeen athletes were still using various anabolic-steroid drugs, averaging 1,030 milligrams weekly for 33 weeks, and had used them for the past eight years. Five of the past users and six current users also injected growth hormone, in doses ranging from two to 16 I.U. daily for at least one year. Nine past users and 15 current users took clenbuterol, with doses ranging from three to 20 times the therapeutic dose range. Men in both groups also used various anti-estrogen drugs.

An examination of the men revealed that nine former and 12 current drug users had previously suffered from gynecomastia. Of those, five and seven, respectively, had undergone plastic surgery to treat or remove the gyno. One past and five current users showed significant elevations in blood hemoglobin and white cell counts, as well as other blood cells. That's not surprising, since steroids promote the production of red blood cells by stimulating the synthesis of a specific kidney hormone. In fact, one popular oral steroid, oxymetholone, or Anadrol-50, was at one time a popular treatment for a certain type of anemia.

Another expected finding was that 15 of 17 current steroid users had low HDL levels, as did two former users. Current users had testosterone levels that averaged 290 percent above normal, but their estrogen levels were 400 percent above normal. That was no doubt the result of the conversion of testosterone-based drugs into estrogen by way of the aromatase enzyme found throughout the body. Current users also had 84 percent lower levels of sex-hormone-binding globulin (SHBG), a protein that binds with testosterone in the blood; 94 percent lower levels of luteinizing hormone (LH), a pituitary hormone that controls testosterone production in the body; and 91 percent decreased follicle-stimulating hormone (FSH), another pituitary hormone. The last-named effects are due to the fact that steroids suppress pituitary hormone output.

The current users showed maximum estrogen levels that were higher than the upper limit for women. Clearly, whatever they used to block estrogen failed miserably. Thirteen of the men had testosterone levels in the lower 20 percent range, while two others showed below-normal testosterone. Whether the low testosterone levels of the former users were just natural manifestations or the result of their long-term use was unclear from this study. Some of the former users did, however, show some slight liver enzyme abnormalities, the significance of which is also uncertain.

All other steroid-induced effects on blood chemistry, blood lipid levels and liver function had returned to normal a year after most of the ex-users stopped taking the drugs. Note, however, that most of the former steroid users did show low-normal and low testosterone levels. That could point to a continued depression of the body's natural testosterone synthesis that could be related to long-term steroid use. As noted above, steroids depress the body's natural steroid production through a feedback mechanism from the blood to the brain.

Based on this study, however, it appears that most steroid side effects return to normal after the user gets off the drugs. On the other hand, considering the former steroid users' varying testosterone levels, it's also apparent that steroids have effects on each individual that cannot be accurately predicted. So some users may fare worse than others upon discontinuing these drugs.

1 Delbeke, F.T., et al. (2003). Prohormones and sport. J Steroid Biochem Mole Biol. In press.
2 Geyer, H., et al. (2003). High doses of the anabolic steroid metandienone found in dietary supplements. Eur J Sports Science. 3(1).
3 Urhausen, A., et al. (2003). Reversibility of the effects on blood cells, lipids, liver function and hormones in former anabolic-androgenic steroid abusers. J Steroid Biochem Molecular Biol. In press.

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