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The following is by: Karlis Ullis, MD, and Joshua Shackman, Ph.D.


In December, 2000, the American Medical Association passed resolution urging Congress to draft legislation banning all testosterone precursors from over the counter sale, including androstenedione - the supplement made famous by baseball player Mark McGwire. The justification was that testosterone precursors are dangerous since "the consumption of which may result in …potential harm to the health and well being of the athlete and patient" (1). This article will explore the validity of this claim by reviewing the existing data on testosterone precursors and safety, and also by examining the theoretical risks of androgen precursors. Only studies on administration of testosterone precursors to male adults will be looked at, as testosterone precursors are generally marketed to men and thus most of the research uses male test subjects as well. It will be strongly demonstrated that the dangers of testosterone precursors are greatly exaggerated, and that these supplements in fact have a fairly solid safety record.


Background

Commonly available testosterone precursors include 4-androstenediol (called 4AD and sold under the brand name Androdiol®), androstenedione (adione) and dehydroepiandrosterone (DHEA). All three of these precursors have been sold for many years on an over the counter basis, and have been marketed as performance enhancing and testosterone boosting supplements. Adione and 4AD are direct precursors to testosterone that require only one enzymatic reaction to convert to testosterone. DHEA on the other hand is a precursor to adione, and thus is an indirect precursor to testosterone.


Oral and sublingual administration of 4AD has been established in several studies to be effective at raising testosterone levels in humans (Brown et al, 2002, Ziegenfuss, et al, 1998). Adione has also been demonstrated to be effective at boosting testosterone levels, although not to the same extent as 4AD (Ziegenfuss, et al, 1998). DHEA has also been shown to be mildly effective at elevating testosterone levels through its conversion to adione.


Safety of 4AD

While there have been no studies of daily use of 4AD taken by itself, two studies have been conducted on supplements that contain 4AD as the main active ingredient in an overall mixture of ingredients. The first of these studies (Ziegenfuss and Kerrigan, 1999), gave 14 young men daily doses for four weeks of either a mixture of 375 milligrams of 4AD with 75 milligrams of other androgen precursors, or a placebo. Potential toxic effects of the 4AD-based mixture were measured through blood tests for levels of liver and kidney enzymes, as well as blood lipids. At the end of the study, there was no measured toxicity in any of the subjects taking the 4AD product. In fact, a positive effect from the 4AD mixture was measured, as those taking this product had an average increase in HDL-C levels. This is considered a positive benefit, as higher HDL cholesterol levels are associated with a reduced risk of heart disease.


It should also be pointed out that no reduction in luteinizing hormone (LH) was observed in the 4AD group. LH is the main hormone that signals the testicles to produce testosterone. One concern raised about testosterone precursors is that they may lead to testicular shrinkage and disruption of natural testosterone production in the body. The fact that no drop in LH was observed in this study can be seen as a clear indication that the risk of testicular shrinkage is low with the use of 4-AD.


The second study on a 4AD-based product gave subjects either a mixture including 300 milligrams per day of 4AD and four different herbal extracts, or a placebo (Brown, et al, 2001). While liver and kidney enzymes were not measured, other results of this study were supportive of the safety of 4AD. No changes in prostate specific antigen were observed in this study, suggesting a lack of increased risk of prostate cancer from this product. Also, total testosterone levels did not change after four weeks of supplementation, which like the Ziegenfuss study also suggests that testosterone production in the testes is not harmed by 4AD supplementation. The only significant contradiction between the Ziegenfuss study and the Brown study is that in the latter study a small decrease in HDL-C levels was observed in the 4AD-mixture group.


It should be noted that critics of 4AD often refer to a particular study that shows a decrease in HDL cholesterol levels from "androstenediol" supplementation (Broeder, et al, 2000). However, this study actually looks at 5-androstenediol (5AD), a very weak testosterone precursor with completely different properties as 4AD (it actually possesses dual androgenic and estrogenic properties). This confusion has lead to some to unfair conclusions about the safety of 4AD.


Safety of Adione

There have been several recent studies completed on adione supplementation, although only a few have looked at the safety of this supplement. One study (King, et al, 1999) looked at the effects of 300 milligrams per day of adione given to young men over a eight week period. While the main purpose of this study was to look at effects on body composition and exercise performance, several measures of safety were also looked at in this study. No changes in liver enzymes were observed in this study, suggesting no liver toxicity risks were associated with adione. LH levels were also unchanged, which like the studies on 4AD suggests a lack of a risk of testicular shrinkage or other disruptions to the endocrine system.


The only potentially harmful effect observed in this study is that test subjects taking adione showed a decrease in HDL cholesterol levels. While this suggests an increased risk of heart disease, this was balanced out by an observed decrease in triglyceride levels (a sign of decreased risk of heart disease). No overall increase in heart disease risk was measured in the subjects taking adione. Elevated estrogen levels were observed in this study, but the estrogen levels remained in the normal range. Estrogen can reduce the risk of heart disease, although it may also increase the risk of various cancers. Since estrogen levels remained in the normal range, and estrogen may have health benefits, this observed elevation cannot be considered a health risk.


Other studies have confirmed the results of the King study in terms of safety. A longer study on adione (Broeder, et al, 2000) showed similar results in terms of LH levels. While decreased HDL cholesterol levels were observed in the Broeder and King studies, another study (Wallace, et al, 1999) found no change in blood lipids from adione supplementation for 12 weeks. The Wallace study also found no liver toxicity or increased risk of prostate cancer from adione supplementation.


DHEA

DHEA has been shown to be very safe when administered to male adults, even at high doses. Three different studies have looked at the effects on male adults of a very large dose of 1,600 milligrams of DHEA administered daily for one month. One study found a significant drop in LDL cholesterol levels after one month, a strong sign of an actual reduction in heart disease risks (Nestler, et al, 1988). Two other studies found no effect on cholesterol levels from the same amount of DHEA administered over one month (Usiskin, et al, 1990, Welle, et al, 1990).


It should be noted that 1,600 milligrams is an amount far higher than recommended by any manufacturer of DHEA. Normally, DHEA is sold in pills or capsules with 5 to 50 milligrams of DHEA. These studies are strong evidence in support of the safety of DHEA. More recent studies have also confirmed the safety of DHEA in male adults, including a lack of liver toxicity (Brown et al, 1999, Wallace, et al, 1999).


While far from being conclusive, evidence of the relative safety of DHEA is also evidence in favor of the safety of adione. This is because DHEA is a direct precursor of adione, and large doses of DHEA are likely to lead to large increases in adione levels.


Conclusion

A lack of liver toxicity has clearly been demonstrated for adione, 4AD, and DHEA over a wide range of doses and durations. Effects on LH have been shown to be minimal or non-existent in the doses used in these studies, an indicator that there is not much risk of testicular shrinkage or damage to the hypothalamic pituitary testicular axis (HPTA) from these supplements.


Testosterone precursors may impact blood lipids in an adverse way, although evidence on this issue has been contradictory. Some of these studies have actually shown that testosterone precursors may decrease the risk of heart disease. In addition, no effect on prostate cancer risk as measured by PSA has been shown in any of these studies.


More research needs to be done on the effects of 4AD by itself, not just as part of a mixture of other supplements. Also, studies on the effects of androgen precursor supplements over periods of longer than 12 weeks have not yet been done. More research should also be done to assess safe dosing levels for women of these supplements. However, for the time being there does not appear to be a major health threat to male adults from using testosterone precursor supplements at doses and durations used in recent research studies.


About the Authors

Karlis Ullis, M.D., is a board-certified physician and an assistant clinical professor at the UCLA School of Medicine. He has worked with intercollegiate, professional, and Olympic athletes and served as team physician in five Olympic games. He practices in Santa Monica, California, and is the author of "Age Right" and Super "T" ( 1999, Simon & Schuster) His next book will be The Hormone Revolution Weight-Loss Plan (Avery Press), which will be released in January, 2003.


Joshua Shackman, Ph.D., is an assistant professor of Management and Health Sciences at Touro University International, and coauthor of The Hormone Revolution Weight Loss Plan. He lives in Los Angeles.

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