Banning Prohormones: The Threat and the Legal Issues

Estimated reading time: 19 minutes

Introduction

In December, 1996, Patrick Arnold announced the public availability of androstenedione, a natural precursor to testosterone which could be legally sold for oral consumption as a dietary supplement. Since then, various prohormones have been produced and marketed for the purpose of enhancing testosterone and nortestosterone (nandrolone) levels, including androstenediol, norandrostenedione, and norandrostenediol.

Prohormones remained largely unknown to the general public until August, 1998, when home-run slugger Mark McGuire publicly revealed that he used androstenedione as an athletic performance enhancer. Suddenly, young athletes everywhere were clamoring for this new wonder supplement, and the news media, always ready to ply the public with myths of “roid rage,” began to create a frenzy over this “potentially dangerous” steroid.

In June, 1999, the Journal of the American Medical Association (JAMA) released an article based on a study of the use of oral androstenedione for testosterone enhancement and adaptation to resistance training. The study, commissioned by EAS and performed by Douglas S. King, Ph.D., of Iowa State University in Ames, concluded that “Androstenedione supplementation does not increase serum testosterone concentrations or enhance skeletal muscle adaptations to resistance training in normotestosterogenic young men and may result in adverse health consequences.”1

In the same issue of JAMA, Charles E. Yesalis III, M.P.H., Sc.D., of Pennsylvania State University in University Park, wrote:

“However, if a supplement is in fact what most medical professionals consider to be a potentially harmful drug, action is needed to protect the public. In the case of androstenedione, the study by King et al contributes to the evidence suggesting that the government should carefully consider intervening and remove androstenedione and its derivatives from the market.”2

So begins the threat of government regulation.

Prohormones 101

For those still unfamiliar with prohormones and the terms commonly used to describe them, let’s begin with a brief, general, and fairly simplistic overview. (For a more in-depth examination, please refer to the excellent writings of Bill Roberts elsewhere in the MESO-Rx archives: Prohormones of Anabolic-Androgenic Steroids).

Androstenedione is a molecule very similar to testosterone, the principal male sex hormone. Its sole difference is that where testosterone has a hydroxyl group in a certain position, androstenedione has a keto group. Most simply, you can think of it as “one step away” from testosterone — its “precursor.” The body can convert androstenedione to testosterone (and vice versa) by use of a specific enzyme that is present in the body in fairly large amounts. Oral androstenedione supplementation very briefly increases blood levels of testosterone. It is this ability to act as a direct hormonal precursor (a “prohormone”) of testosterone that makes it attractive to those seeking a sports aid. But while androstenedione is a precursor of testosterone, it is also, unfortunately, a precursor of estrone, an estrogenic hormone. As such, it can have adverse estrogenic effects similar to those of illegal anabolic steroids, such as gynecomastia (feminized swelling of the nipples). Also, testosterone itself converts (“reduces”) not only to estrone, but to a potent androgenic compound known as dihydrotestosterone (DHT). Increased blood testosterone levels will increase the reduction to DHT, sometimes leading to hair and skin problems.

Slight variations of androstenedione are commercially available. These include 4-androstendiol (4-AD) and 5-androstenediol (5-AD), which differ chemically by the position of the chemical double bond in the steroid molecule (hence the “4” and “5” designations). Like androstenedione, they also have both androgenic and estrogenic activity (but in the case of 4-androstendiol, the estrogenic conversion is only indirect).

Other prohormones available for purchase are the so-called “norandro” products. Instead of being precursors of testosterone, these are precursors of a compound called nortestosterone, also called nandrolone. Nandrolone is a sex hormone found in certain animals including horses. It exhibits a higher “anabolic” (tissue-building, i.e., muscle-building) activity in humans in relation to its androgenic activity than does testosterone. Since nandrolone metabolizes to a weaker compound (dihydronandrolone) than testosterone does, precursors of nandrolone are much less likely than testosterone to cause hair and skin problems. Available variations are 19-nor-4-androstenedione (19-nordione), 19-nor-4-androstenediol and 19-nor-5-androstenediol (19-nordiols).

Can Prohormones Currently be Considered Anabolic Steroids?

Anabolic steroids are designated as Schedule III controlled substances by federal regulation; that same regulation gives the following broad description:

“The term anabolic steroid means any drug or hormonal substance, chemically and pharmacologically related to testosterone (other than estrogens, progestins, and corticosteroids) that promotes muscle growth[.]”3

The regulation then lists twenty-seven specific compounds that are included in the definition.4 It also includes what is intended to be a “catch-all” provision”:

“Any salt, ester, or isomer of a drug substance described or listed in this paragraph, if that salt, ester, or isomer promotes muscle growth.”

Identical wording has been drafted in federal statute.5 Furthermore, many states also have statutory controlled substances schedules with similar or identical definitions of anabolic steroids.6 Like the federal statutory and regulatory provisions, these state laws designate numerous anabolic steroids by name and include both the broad descriptions and the “catch-all” provisions referred to above.

Could prohormones fall under the broad definitions and “catch-all” provisions of the presently existing laws?

It is unquestionable that androstenedione and other prohormones can be chemically classified as steroids. Simply put, steroids belong to a class of hormones synthesized from cholesterol. All steroids share the same basic four-ring carbon structure, but differ in the number of carbon atoms attached to the number 17 carbon atom in the structure, and in the manner in which hydrogen (H), oxygen (O), and the hydroxyl (OH) groups are attached to the carbon atoms. However, in order to be classified as “anabolic steroids” under the broad legal definition, they must conform to the required criteria. Prohormones already meet most of the criteria for that legal classification in that:

• they have a molecular structure related to testosterone;
• they have a pharmacology related to testosterone; and
• they are not an estrogen, progestin or corticosteroid.

However, prohormones must also meet the fourth and final criterion: they must promote muscle growth. This criterion is also an element of the “catch-all” provision. It is this criterion that remains in question.

Researchers specifically found that androstenedione did not “enhance skeletal muscle adaptations to resistance training[.]”7 Although the JAMA editorial speculated that this might be possible if higher dosages were used, or if the substance was injected,8 no studies have confirmed those speculations and the editorial conceded that, based on the published study, “androstenedione does not meet the fourth criterion.”9

The supplement industry may be its own worse enemy in terms of supplying the basis for immediate prosecution of prohormones as anabolic steroids. For example, rumors have circulated amongst the strength training community that someone may attempt to market prohormones in a nasal spray. Although intranasal administration of prohormones would almost certainly lead to greater absorption, and thus to greater bioavailability, it would be directly contrary to the legal limitations on the methods for consuming dietary supplements.10 In terms of immediate prosecution, it might also be the “straw that broke the camel’s back.”

The claims made by supplement sellers in marketing prohormones may also be their undoing. It is natural for them to promote their products in the most glowing terms possible, yet it is fairly clear that the only criterion lacking in the classification of prohormones as anabolic steroids is a finding that they promote muscle growth. Although most sellers refrain from making that statement in verbatim terms, they frequently refer to these substances as “anabolic.” Not only does that term reflect the actual adjective used in the legal classification, it also has a medical definition that closely resembles the missing criterion: “building up of the body substance.”11 An informal perusal of prohormone advertisements in bodybuilding magazines reveals numerous references to the term “anabolic,” as well as claims such as the following: “If you can’t grow on [the product] – you can’t grow on anything – PERIOD”; “especially effective for strength and size gains …showing the advantages of anabolic steroids without the side effects”; “…we performed studies involving [bodybuilders who] experienced dramatic muscle gains of up to 22 pounds in just 60 days”; “[the product] is like stacking a moderate amount of testosterone with a moderate amount of nandrolone decanoate.”12 When coupled with the fact that androstenedione and other prohormones are sold almost exclusively for use in bodybuilding and resistance training, it is not a great stretch of logic to presume that the continued popularity of these substances is based on successful promoting of muscle growth.13 It is somewhat doubtful that the manner in which these substances are advertised and sold would be sufficient to classify them as anabolic steroids without supporting scientific studies, but one thing is certain: those seeking to criminalize these substances will not fail to highlight the claims and informal “studies” offered by the manufacturers and marketers of these products.

It is the opinion of these writers, however, that in the absence of formal scientific support for the proposition that prohormones promote muscle growth, an attempt to prosecute users or sellers of prohormones under the “catch-all” definition of anabolic steroids would almost certainly meet with failure. But, that doesn’t mean that someone won’t try, particularly in cases where a prosecutor might be hungry for publicity or politically motivated by other governmental forces. Those in the government determined to remove prohormones from the market will examine all angles by which to do so immediately. Failing to find a suitable basis under existing law, they will turn toward amending the laws to specifically ban these substances.

Can the Laws be Amended to Classify Prohormones as Anabolic Steroids?

Federal law specifically defines the characteristics of a “dietary supplement”; androstenedione and other prohormones currently fall under that definition.14 Anabolic steroids are considered drugs and are classified as Schedule III controlled substances.15 In order to abolish the status of prohormones as dietary supplements and classify them as controlled substances, the government would follow certain general regulatory procedures:

1. A petition would be submitted to the Administrator of the Drug Enforcement Administration (DEA) to make a new rule regarding the status of prohormones.
2. The Administrator must then gather “necessary data” and present it to the Secretary of Health and Human Affairs (Secretary) with a request for scientific and medical evaluation, as well as a request for the Secretary’s recommendation as to whether prohormones should be controlled substances.
3. If the Secretary recommends that prohormones not be controlled substances, that recommendation is binding on the DEA; but if the Secretary does recommend a controlled substance classification, the Administrator must start proceedings for that classification.
4. The Administrator must then schedule a time and place for hearings to be held on the proposal and must give at least 30 days advance notice of the hearings in the Federal Register; the Administrator may also publish notice of the time during which interested parties may file written comments or objections.
5. Persons interested in the subject may request a hearing, and they must file notice of their intent to participate in that hearing within 30 days after the publication. If they wish to file written comments or objections, they must waive their participation in the hearing, and within the designated time, file a written statement of their positions, including all relevant matters of fact and law.
6. Once hearings have been held, the Administrator must publish a final order in the Federal Register, which cannot take effect until at least 30 days after the publication of the final order.16

As a result of the study published in JAMA, and the editorial opinion that followed, attempts at government regulation are clearly a source of imminent concern. Barry McCaffrey, President Clinton’s anti-drug chief, announced in July 1999 that he was trying to finance a study that could lead to the specific regulation of androstenedione as a controlled substance. “I’d like to expedite the examination of androstenedione and determine whether it can be classified an anabolic steroid under the Anabolic Steroids Control Act.”17 To prove that androstenedione promotes muscle growth, McCaffrey suggested a study on animals, lasting a few months and costing approximately $25,000.18 McCaffrey’s comments suggest that some governmental officials already recognize that there is insufficient evidence upon which to classify prohormones as anabolic steroids.

But not all governmental officials and anti-prohormone crusaders may agree. Even before such studies are completed, the findings and speculations from the published study and editorial may be used to support regulation of prohormones, including the following:

[a] Administration of 100 mg of androstenedione substantially increased free testosterone levels (despite the fact that the authors failed to make that finding).19 This increase, coupled with a greater yield from higher dosages, might result in levels of free testosterone which would be high enough to effect a substantial increase in muscle mass and thus allow androstenedione and other prohormones to be classified as controlled substances under the broad definition of anabolic steroids previously discussed.

The authors claimed that “[i]ngestion of 100 mg of androstenedione did not affect the serum concentrations of either free or total testosterone.”20 They simply chose not to acknowledge that free testosterone levels, after an interesting dip at 30 minutes, showed a mean increase over baseline of about 12% and a maximum increase over baseline of about 22% at ninety minutes after ingestion.21 Total serum testosterone also showed a general pattern of increase over placebo. Although individuals in the placebo group happened to start with about 10% lower mean total serum testosterone levels than those in the androstenedione group, after a dip at 30 minutes the androstendione group showed higher mean total testosterone levels than the placebo group throughout the balance of the testing period (at certain points as much as about 20% higher).22 It can be reasonably speculated that higher dosages might be even more effective toward increasing free and total testosterone levels. However, it must be remembered that the critical issue is not whether androstenedione briefly increases testosterone levels, but whether it promotes muscle growth. Whether such very brief increases in free or total testosterone levels are sufficient to have any effect on muscle growth is completely unknown.23 It would be difficult for proponents of regulation to argue this point in the absence of any supporting evidence.

[b] Dosages substantially higher than the 300 mg per day used in the long-term part of the study, and taken for a longer period of time and/or by injection, might produce observable muscle growth.24

While the JAMA editor concurs with the study authors that the eight week administration of androstenedione did not increase testosterone levels, he hypothesizes that heavier administration might promote muscle growth and justify classification of the substance as an anabolic steroid. Actually, again contrary to the authors’ claim, the study did indeed show a mean increase in free testosterone levels in the androstenedione group of about 12% over baseline by the eighth week; the placebo group showed no change at all.25 Proponents of regulation could point to this increase and further speculate that combining a high-protein diet with higher dose androstenedione administration might promote muscle mass.26 However, the authors’ conclusions that androstenedione neither increased testosterone levels nor enhanced muscle size and strength at 300 mg daily casts the arguments of proponents of classification into the realm of unsupported speculation. Further, regarding the JAMA editor’s reference to injecting androstenedione, it should be noted that administration by injection automatically removes the substance from the definition of “dietary supplement.”27 Therefore, any manufacturer who marketed injectible androstenedione would not be protected by the Dietary Supplement Health and Education Act of 1994.

[c] A significant decrease in “good” HDL cholesterol was noted (about 14%), along with an increased concentration of serum estrogen levels.28 These changes may predispose the user to additional health risks.

To date, no death or serious illness or injury has been reported as a result of ingesting androstenedione or any other prohormone. However, proponents of regulation may likely attempt to argue the safety factor as a basis. One argument would be that the possibility of an unfavorable decrease in HDL cholesterol could be an indicator of a risk for heart disease. This, too, is a rather weak argument because the decrease in HDL cholesterol observed in the original study was considered by the researchers to be “clinically relevant,” but insufficient to be “typically considered to constitute a risk factor for cardiovascular disease.”29 Further, there was an observed reduction in serum triglycerides which is considered a favorable change for cardiac risk and may very well offset any decrease in HDL levels.30 The increased estrogen levels, noted by the study authors to be associated with gynecomastia, cardiovascular risks, and certain cancers,31 could be argued – especially when combined with lowered HDL levels — to present health risks requiring immediate restriction of availability. Of course, these health risks are irrelevant to classification as an anabolic steroid. If regulation proponents raised this issue as their primary (if not only) basis for immediate action, they would need to rely upon a different procedural mechanism than classification as an anabolic steroid.

Can Prohormones be Classified as Drugs?

Federal law defines the meaning of “drug” by referring to several categories; the category into which prohormones would most likely fit is “articles (other than food) intended to affect the structure or any function of the body of man or other animals[.]”32 By definition, prohormones are “dietary supplements,” not “food,” so they could qualify as “drugs” under that definition, but they are exempted from classification as drugs because they meet the specific criteria for classification as dietary supplements.33 However, the claims currently being made about prohormones may have a substantial effect on whether they lose their classification as dietary supplements and are eventually classified as drugs.

A dietary supplement does not automatically become a drug simply because a claim is made regarding a relationship between the supplement and certain diseases or health-related conditions, but there are limitations on that exemption.34 The Secretary of Health and Human Services has the power to establish regulations for testing the validity of such claims if such regulations would:

• enable consumers to develop and maintain healthy dietary practices;
• enable consumers to be informed promptly and effectively of important new knowledge regarding nutritional and health benefits of food; or
• ensure that scientifically sound nutritional and health information is provided to consumers as soon as possible.35

If the claims made about prohormones failed to meet the requirements of such a regulation, they could be deemed “misbranded foods.”36 Once that occurred, prohormones could be deprived of their status as dietary supplements and would then be open to classification as drugs.

Another possible avenue for classification of prohormones as drugs, and perhaps a more inviting one, would be to have them declared an “adulterated food.” A dietary supplement may be deemed an adulterated food if it:

• presents a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use; or
• is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury.37

The findings of the study and editorial published in the JAMA would seem to invite such an attack on the status of prohormones as dietary supplements by the Food and Drug Administration (FDA), particularly in light of the comments that altered cholesterol levels could increase the risk of heart disease.38 However, depriving prohormones of their status as dietary supplements to classify them as drugs would require regulatory hearings before the Secretary of Health and Administrative Affairs. The weakest part of this approach is that the FDA bears the burden of establishing these risks. Even if the government established these risks before the Secretary, the matter could be brought before a federal court, which would decide the issue without regard to what the government had already established in administrative hearings.39 Under those circumstances, an attack on the status of prohormones could be very costly for the government.

Conclusion

Comments from members of the scientific community and governmental agencies suggest serious interest in banning prohormones. In Senate committee hearings on October 20, 1999, Dr. Gary Wadler, Associate Professor of Clinical Medicine at New York University School of Medicine, stated:

“When a celebrated athlete like Mark McGwire admits using androstenedione – and make no mistake, androstenedione is a steroid – and million of kids witness the presumed power of these drugs – we are clearly on a slippery slope to disaster. * * * Substances like androstenedione were never contemplated by this legislation, and if it requires the reclassification of steroid supplements as prescriptive drugs, then let the process begin.”40

In those same hearings, drug czar Barry McCaffrey stated:

“Andro, currently classed as a food supplement, is believed by many to improve performance. The DEA is engaged in a scientific process to determine if Andro actually produces muscle growth – and, in turn, whether it should be classed as a steroid.”41

Since a significant question remains as to whether the current data suggests that prohormones meet all of the essential criteria that legally define anabolic steroids, it is unlikely that any enforcement measures will be undertaken without a recommendation from the Secretary of Health and Human Affairs and a final order after formal regulatory hearings. At such hearings, certain findings and speculations from the published study and editorial could be argued to support classification of prohormones as anabolic steroids. However, in the absence of scientific studies establishing that prohormones promote muscle growth (contrary to the findings published in JAMA), the case for classification as anabolic steroids would be weak. An alternative approach to regulation would involve attacking the status of prohormones as dietary supplements and classifying them as drugs. While avenues exist to support this approach, the necessary procedures could be quite costly for the government. For the immediate future, it appears that the government’s interest in restricting the sale of prohormones will be unsatisfied.

Footnotes

1 King DS, Sharp RL, Vukovich MD. Effect of oral androstenedione on serum testosterone and adaptation to resistance training in young men: a randomized controlled trial. JAMA. 1999;281:2020.

2 Yesalis CE. Medical, legal and societal implications of androstenedione use. JAMA. 1999;281:2044.

3 21 C.F.R. 1300.01.

4 21 C.F.R. 1300.01(b)(4) lists the following specific androgens: (i) Boldenone; (ii) Chlorotestosterone (4-chlortestosterone); (iii) Clostebol; (iv) Dehydrochlormethyltestosterone; (v) Dihydrotestosterone (4-dihydrotestosterone); (vi) Drostanolone; (vii) Ethylestrenol; (viii) Fluoxymesterone; (ix) Formebulone (formebolone); (x) Mesterolone; (xi) Methandienone; (xii) Methandranone; (xiii) Methandriol; (xiv) Methandrostenolone; (xv) Methenolone; (xvi) Methyltestosterone; (xvii) Mibolerone; (xviii) Nandrolone; (xix) Norethandrolone; (xx) Oxandrolone; (xxi) Oxymesterone; (xxii) Oxymetholone; (xxiii) Stanolone; (xxiv) Stanozolol; (xxv) Testolactone; (xxvi) Testosterone; and (xxvii) Trenbolone.

5 21 U.S.C. 802(41)(A).

6 e.g., Ohio Revised Code §3919.41; Florida Statutes §893.03; Texas Health & Safety Code §481.104; and New York State Consolidated Laws: Public Health §3306. [It is interesting to note that in New York, anabolic steroids are scheduled under a higher class (Class II) of controlled substances.]

7 King, et al, supra. JAMA. 1999;281:2020.

8 Yesalis, supra. JAMA. 1999;281:2044.

9 Id.

10 21 U.S.C. 321 (ff)(2)(A); 21 U.S.C. 350(c)(1)(B).

11 Taber’s Cyclopedic Medical Dictionary.

12 Flex, Vol. 17, #8, October 1999; and MuscleMag, #209, November 1999.

13 On the other hand, raw glandular extracts and amino acid tablets were successfully marketed and sold to athletes for years as promoters of muscle growth before their ineffectiveness was commonly recognized.

14 21 U.S.C. 321 (ff).

15 21 U.S.C. 802(41)(A); 21 U.S.C. 812, Schedule III(e). See also 21 C.F.R. 1300.01(b)(4); 21 C.F.R. 1308.13(f).

16 21 C.F.R. 1308.41-1308.45.

17 Pennington, Bill. “From the Highest Level, a Call for Action” [http://search.nytimes.com/library/sports/baseball/071199bbo-drug-policy.html] New York Times on the Web. July 11, 1999.

18 While the study reported in JAMA was funded by a supplement company, private funding for further studies to determine if androstenedione promotes muscle growth will be hard to find. This is because, whatever the result, the supplement company loses. If the study concludes that androstenedione doesn’t work, sales will drop. If the study concludes that it does work, proponents of regulation will seek to ban it as an anabolic steroid, taking it off the market.

19 King, et al, supra. JAMA. 1999;281:2022 (Fig.2).

20 Id. at 2023.

21 Id. at 2022 (Fig.2).

22 Id.

23 It must be noted that the conclusion of the researchers in this study was that androstenedione did not promote any increased muscle size or stength. Critics of this study can easily cite various methodological flaws — such as the small study size or the lack of adequate dietary protein — as reasons for the final data. Further, it should not escape notice that for many years, medical researchers conducted studies which concluded that anabolic steroids do not promote increased muscle size or strength. For an interesting examination of how study results were engineered to show that steroids do not work through the use of intentionally flawed designs, see, Taylor, W.N., Anabolic Steroids and the Athlete (Jefferson, NC; McFarland & Co., 1982). Even as late as 1984, in the highly publicized anti-steroid book Death in the Locker Room: Steroids & Sports (South Bend, IN; Icarus Press, 1984), then-medical-student Bob Goldman seriously presented his theory about how steroids work in a subchapter devoted to the “placebo effect.”

24 Yesalis, supra. JAMA. 1999;281:2044.

25 King, et al, supra. JAMA. 1999;281:2024 (Fig.4).

26 The study participants adhered to a diet of only 85-98 grams of protein daily, which is recognized to be inadequate for individuals undergoing resistance training. Inadequate protein intake may have been the common limiting factor in gains for both the androstenedione and placebo groups. Id. at 2022.

27 21 U.S.C. 321 (ff)(2)(A); 21 U.S.C. 350(c)(1)(B).

28 King, et al, supra. JAMA. 1999;281:2025 (Table 1), 2027.

29 Id. at 2027.

30 King, et al, supra. JAMA. 1999;281:2025 (Table 1).

31 Id. at 2027.

32 21 U.S.C. 321(g)(1).

33 21 U.S.C. 321 (ff).

34 21 U.S.C. 321(g)(1); 21 U.S.C. 343(r)(1)(B).

35 21 U.S.C. 343(r)(5)(D); 21 U.S.C. 343(r)(7)(A).

36 21 U.S.C. 343.

37 21 U.S.C. 342(f)(1).

38 King, et al, supra. JAMA. 1999;281:2025 (Table 1), 2027; Yesalis, supra. JAMA. 1999;281:2044.

39 21 U.S.C. 342(f)(1).

40 Wadler, Gary. “Hearing on The Use of Performance Enhancing Drugs in Olympic Competition Before the Full Committee on Commerce, Science, and Transportation, United States Senate” [http://www.senate.gov/~commerce/hearings/1020wad.pdf] October 20, 1999.

41 McCaffrey, Barry R. “Before the Senate Committee on Commerce, Science, and Transportation” [http://www.senate.gov/~commerce/hearings/1020mcc.pdf] October 20, 1999.