National Institute on Drug Abuse

RESEARCH

MONOGRAPH SERIES

Anabolic Steroid

Abuse

1 

U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health

0 2
Anabolic Steroid Abuse

Editors:

Geraline C. Lin, Ph.D.

Division of Preclinical Research

National Institute on Drug Abuse

Lynda Erinoff, Ph.D.

Division of Preclinical Research

National Institute on Drug Abuse

Research Monograph 102

1990

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National institute on Drug Abuse

5600 Fishers Lane

Rockville, MD 20857

For sale by the Superintendent of Documents, U.S. Government Printing Office

Washington, D.C. 20402

Anabolic Steroid Abuse
ACKNOWLEDGMENT

This monograph is based on the papers and discussion from a technical

review on “Anabolic Steroid Abuse” held on March 6 and 7, 1989, in

Rockville, MD. The review meeting was sponsored by the Office of

Science and the Division of Preclinical Research, National Institute on

Drug Abuse.

COPYRIGHT STATUS

The National Institute on Drug Abuse has obtained permission from the

copyright holders to reproduce certain previously published material as noted

in the text. Further reproduction of this copyrighted material is permitted

only as part of a reprinting of the entire publication or chapter. For any

other use, the copyright holder’s permission is required, All other material

in this volume except quoted passages from copyrighted sources is in the

public domain and may be used or reproduced without permission from the

Institute or the authors. Citation of the source is appreciated.

Opinions expressed in this volume are those of the authors and do not

necessarily reflect the opinions or official policy of the National Institute on

Drug Abuse or any other part of the U.S. Department of Health and Human

Services.

The U.S. Government does not endorse or favor any specific commercial

product or company. Trade, proprietary, or company names appearing in

this publication are used only because they are considered essential in the

context of the studies reported herein.

DHHS publication number (ADM)90-1720

Printed 1990

NIDA Research Monographs are indexed in the Index Medicus. They are

selectively included in the coverage of American Statistics Index,

Biosciences Information Service, Chemical Abstracts, Current Contents,

Psychological Abstracts, and Psychopharmacology Abstracts.

iv
Contents

Page

Preface vii

Geraline C. Lin and Lynda Erinoff

Abuse Liability of Anabolic Steroids and Their Possible

Role in the Abuse of Alcohol, Morphine, and Other

Substances 1

Theodore J. Cicero and Lynn H. O’Connor

History of Anabolic-Androgenic Steroids 29

Charles D. Kochakian

Anabolic-Androgenic Steroids 60

John A. Lombardo

Anabolic Steroids: An Ethnographic Approach 74

Paul J. Goldstein

Incidence of the Nonmedical Use of Anabolic-Androgenic

Steroids 97

Charles E. Yesalis, William A. Anderson,

William E. Buckley, and James E. Wright

Androgens: Endocrine Physiology and Pharmacology 113

Stephen J. Winters

v
The Androgen-Induced Phenotype

C. Wayne Bardin, James F. Catterall, and

Olli A. Jänne

Reappraisal of the Health Risks Associated With the

Use of High Doses of Oral and Injectable

Androgenic Steroids

Karl E. Friedl

Page

131

142

Androgen Interaction Through Multiple Steroid Receptors 178

Olli A. Jänne

Anabolic-Androgenic Steroids Profoundly Affect Growth

at Puberty in Boys 187

Alan D. Rogol, Paul M. Martha, Jr., and

Robert M. Blizzard

Indications of Psychological Dependence Among

Anabolic-Androgenic Steroid Abusers 196

C.E. Yesalis, J.R. Vicary, W.E. Buckley,

A.L. Streit, D.L. Katz, and J.E. Wright

Anabolic-Androgenic Steroid-Induced Mental

Status Changes 215

David L. Katz and Harrison G. Pope, Jr.

Anabolic Steroids and Behavior: A Preclinical

Research Prospectus 224

Bruce B. Svare

List of NIDA Research Monographs 242

vi
Preface

The incidence and prevalence of anabolic steroid abuse, especially by adolescents, carries with it significant social as well as health-risk concerns.

There are a number of questions regarding this misuse that need to be

addressed. Do results from well-controlled studies support the efficacy of

anabolic steroids in increasing muscle mass and augmenting performance?

What information is available on the health consequences of misuse of anabolic steroids at suprapharmacological doses over extended periods of time?

Do steroids have the potential for development of tolerance and dependence,

and do they meet the criteria for abuse potential as defined in strict pharmacological terms? Are adolescents at particular risk? These are among the

questions that prompted the National Institute on Drug Abuse to undertake

this review on anabolic steroid abuse in an effort to understand the extent

and scope of the problem and to identify research priorities in this area.

The contents of this monograph encompass a wide range of topics beginning with the important question of whether anabolic steroids possess abuse

potential and whether they play a role in the abuse of other substances.

There follows an historical overview of the discovery and development of

anabolic steroids, a critical evaluation of the performance-enhancing effects

of anabolic steroids, and an ethnographic study of anabolic steroid abuse in

New York City. Next is a summary of the epidemiological evidence on the

incidence and prevalence of steroid use. To better understand the health

consequences of abuse, the normal endocrine physiology and pharmacology,

as well as molecular and receptor mechanisms underlying the actions of

anabolic steroids, are presented, followed by an appraisal of the health risks

associated with abuse. Since adolescents are of special concern, a detailed

account of the endocrinological effects of anabolic steroids in this special

population is included. Finally, this review is completed with a discussion

of the behavioral aspects of anabolic steroid use including indications of

psychological dependence and evidence for steroid-induced mental status

changes and aggressive behavior.

This monograph represents a “state-of-the-art” information resource concerning anabolic steroid abuse and suggests future directions for research. It is

vii
hoped that this monograph will serve to stimulate further research in this

area. The monograph should be valuable to members of the scientific community who are involved in drug abuse research; to those interested in the

field of anabolic steroids, including professionals in sports medicine, endocrinology, psychiatry, and education; and to government agencies with regulatory responsibility, drug enforcement responsibility, or both.

The editors would like to express their thanks to the authors of the chapters

in this monograph and to all the participants in the technical review on

which this monograph is based. We would especially like to thank

Dr. Marvin Snyder, Director, Division of Preclinical Research, for his role

in initiating and supporting this effort.

Geraline C. Lin, Ph.D.

Lynda Erinoff, Ph.D.

Division of Preclinical Research

National Institute on Drug Abuse

viii
Abuse Liability of Anabolic Steroids

and Their Possible Role in the

Abuse of Alcohol, Morphine, and

Other Substances1

Theodore J. Cicero and Lynn H. O’Connor

INTRODUCTION

The purpose of this chapter is to discuss the possible abuse potential of

anabolic steroids in man and animals. A second major goal is to provide

an overview of the relevant literature concerning the possible involvement

of steroids in the acute and chronic actions of more commonly abused

drugs, such as opiates and alcohol.

At the outset, several considerations should be borne in mind. First, there

seems to be little doubt that steroids are misused and that such use has

significant adverse effects, particularly when steroids are used by prepubertal

and pubertal adolescents, who are unusually susceptible to the disruptive

effects of steroids (Haupt and Rovere 1984; Lombardo, this volume; Taylor

1987; Wilson 1988). However, the issue of whether these compounds have

abuse liability in the classical, pharmacological sense of that term remains a

matter of debate and will be the primary focus of this chapter.

Second, there is a paucity of data relevant to the abuse potential of anabolic

steroids in humans, and even less information is at hand utilizing animal

models. Moreover, the absence of well-controlled, double-blind studies utilizing placebo controls severely limits the conclusions that can be drawn.

Specifically, as will be elaborated below, it is virtually impossible to distinguish between “expectancy” effects of steroid use and the immediate reinforcing properties of the drugs from the studies currently available.

Finally, steroid abusers rarely if ever abuse only a single steroid. Rather,

taking a number of steroids, other illicit and prescription drugs, and

hormones (growth hormone), a practice often referred to as “stacking,”

1
appears to be the normal pattern of use (Taylor 1987; Wilson 1988). Compounding this problem, the patterns of steroid use by regular users, including doses and frequency of administration, are highly variable, which makes

well-controlled studies in an experimental situation difficult at best and, perhaps, of somewhat limited value vis-à-vis an examination of “normal” steroid misuse in humans, Moreover, since these compounds are generally

obtained illicitly on the black market, their purity is frequently suspect,

which makes self-reported estimates of the doses and types of compounds

administered of questionable validity. For these reasons, it has proven to be

extremely difficult to assess the dependence liability of a given steroid in

polydrug-abusing individuals with highly irregular patterns of selfadministration.

This chapter is divided into several sections: first, an overview of the

actions of steroids in the brain; second, a discussion of the widely accepted

pharmacological criteria necessary to establish the abuse liability of drugs;

third, a critical evaluation of the extent to which steroids meet these criteria

in humans and animals; and, finally, the potential role of steroids in the

abuse liability of other substances. Discussion is confined to the abuse

liability of gonadal steroids, since there is little indication that users of

steroids self-administer other steroids, such as those secreted by the adrenal

gland.

STEROID ACTIONS ON THE BRAIN

Clearly, steroids affect numerous target organs, including the secondary sex

organs, muscles, liver, and brain, through specific steroid receptors. In this

chapter the effects of steroids on only the brain will be considered, as the

primary focus is to examine the motivating factors that lend to the selfadministration of steroids and, hence, their abuse liability. Since drugseeking behavior is undoubtedly mediated by the brain, as has been

unequivocally demonstrated with all other psychoactive compounds with significant abuse potential, a detailed discussion of the effects of steroids in

nonneuronal tissues is not pertinent to the current discussion. In the course

of the discussion of the abuse liability of steroids, however, we will briefly

address the issue of the mechanisms by which steroids may enhance muscular development and athletic performance, both of which appear to represent

the driving force behind the self-administration of steroids in humans.

Organizational vs. Activational Effects of Steroids

Just as certain muscles are acutely sensitive to the effects of steroid hormones, during certain stages of development the growth and differentiation

of the brain is also responsive to steroid hormones. These irreversible

actions of steroid hormones on the development of the structure and function of the brain, which occur either prenatally or very early in postnatal

life (before neural systems are fully developed), are generally referred to as

2
“organizational” effects of steroid hormones. The word “activational” is

reserved for those effects of steroids that occur during adulthood and

involve short-term, reversible activation of previously established neural

pathways. The activational effects of hormones are dependent upon the

nature of the particular organizational effects of steroids that occurred earlier

in life.

The utility of the terms “organizational” and “activational” has been supported by a wealth of experimental data, and these terms are now used

more generally to describe not only hormone effects on behavior, as they

were initially used (Phoenix et al. 1959; Young et al. 1964), but also a

variety of hormonally mediated structural and functional dimorphisms of the

nervous system. Recently, a number of significant exceptions to the criteria

distinguishing organizational from activational effects have been described

(Arnold and Breedlove 1985). Of particular interest is the finding that

steroid hormones can cause long-lasting and sometimes permanent changes

in brain morphology and behavior even when administered to adult animals.

For example, in adult animals, androgen influences the size of the somas

and nuclei of androgen-sensitive motor neurons of the spinal nucleus of the

bulbocavemosus in rats (Breedlove and Arnold 1981). Androgen influences

the volume of cell nuclei in the preoptic hypothalamic area of adult mongolian gerbils (Commins and Yahr 1984a; Commins and Yahr 1984b). In

adult female canaries and zebra finches, androgen influences the size of two

nuclei involved in song production (Gurney and Konishi 1980; Gurney

1981; Gurney 1982; Nottebohm 1980). In the arcuate nucleus, estrogen or

testosterone increases neuronal membrane exo-endocytotic pits (GarciaSegura et al. 1987). Also, estrogen injection or testosterone deficiency

promotes the formation of whorl bodies in the arcuate that are suggestive of

neuronal damage (Price et al. 1976; Brawer et al. 1980; Garcia-Segura et al.

1986). Estrogen influences synaptic morphology in the midbrain central

gray (Chung et al. 1988), and progesterone changes neuronal ultrastructure

in the ventromedial hypothalamic nucleus (Meisel and Pfaff 1988). In adult

rats, androgen influences regeneration of the hypoglossal nerve (Yu and

Srinivasan 1981), and estrogen promotes lesion-induced sprouting in the

arcuate nucleus (Matsumoto and Arai 1979; Matsumoto and Arai 1981) and

hippocampus (Scheff et al. 1988). Estrogen also causes changes in the

tuberoinfundibular dopamine neurons that persist for 22 months after

hormone exposure (Steger et al. 1989).

In addition to changes in brain morphology, brief periods of exposure to

steroid hormones in adulthood can cause long-lasting changes in behavioral

responsiveness. For example, in female rodents, short periods of hormonal

exposure can have long-lasting effects that facilitate behavioral responsiveness to a subsequent hormone injection (Collins et al. 1938; Whalen and

Nakayama 1965; Beach and Orndoff 1974; Gerall and Dunlap 1973; Parsons

et al. 1979). Similarly, in castrated rats and doves, restoration of sexual

behavior by hormone administration becomes increasingly more difficult as

3
the time since castration increases, unless small maintenance doses of hormones are given (Davidson 1972; Damassa and Davidson 1973; Hutchinson

1978). These studies suggest that sensitivity to a steroid is partly regulated

by the steroid itself and that, typically, prior exposure to estrogen or androgen increases sensitivity to that steroid. In contrast, prior exposure to other

compounds with abuse potential, as well as most psychoactive drugs, generally produces a period of tolerance.

Mechanisms of Steroid Action

A primary mechanism of steroid hormone action in the brain is through

interaction of hormone-specific receptor complexes with acceptor sites on

DNA. Through this interaction, steroids influence the synthesis of specific

messages and the production of proteins by cells. Actions of steroids that

involve changes in protein synthesis are slow changes requiring hours or

even days to produce observable physiological effects. For example, after

estradiol injection, a minimum of 11 to 18 hours is required for estradiol to

prime the nervous system for display of rodent sexual behavior (Eaton et al.

1975; Feder et al. 1977; Walker and Feder 1977), and optimal displays of

behavior do not occur until 36 to 40 hours after estradiol exposure.

Steroids also have direct actions on cell membranes mediated either by specific receptors for steroids on cell membranes (Ramirez and Dluzen 1987;

Robel et al. 1987; Simmonds et al. 1984; Towle and Sze 1983) or by interactions with neurotransmitter receptors (LaBella et al. 1978; Su et al. 1988).

Membrane effects of steroids appear to be rapid and of relatively short

duration.

Clearly, the existence of two separate and distinct mechanisms of steroid

action in the nervous system, one extremely rapid and the other quite slow,

needs to be taken into account when interpreting experiments designed to

elucidate the abuse potential of steroids.

CRITERIA TO ASSESS WHETHER A SUBSTANCE HAS ABUSE

POTENTIAL

It is widely accepted (Brady 1988; Brady and Lucas 1984) that, before any

substance can be classified as having abuse liability, the following criteria

must be met.

Self-Administration

The drug must be self-administered for its immediate reinforcing properties,

e.g., euphoria, feeling of well-being. Furthermore, it must be shown that

the drug is self-administered for sustained periods of time and that it is voluntarily ingested in preference to alternative substances. Operant conditioning paradigms have proved to be an extremely valuable tool in meeting this

4
criterion in humans and animals. An illustrative example of a standard

technique used in animals to assess whether a drug is self-administered and,

hence, has reinforcing properties is provided below.

Subjects are fitted with appropriate catheters or are otherwise permitted

access to the drug, e.g., delivery of aqueous drug solutions for oral consumption, and are then required to perform some task or goal-oriented

behavior to obtain the drug. For example, a common procedure used with

many substances of abuse is to insert an intravenous catheter through which

specified doses of drugs can be administered. The subject is required to

depress one of several levers that will deliver the active compound, placebo,

or, in many instances, other alternatives as well. If the drug has immediate

reinforcing properties, the active lever will be uniformly selected after a

training or acquisition period; various techniques can be employed to assess

the strength of the drug as a reinforcer (fixed- or variable-ratio schedules).

Using these methods, the experimenter can easily manipulate all experimental variables, determine the amount of “work” the subject will perform to

obtain the drug, and, most important, objectively determine the relative

reinforcing properties of the drug when compared to other more commonly

abused drugs, which are often used as standards.

Obviously, the example given is based on an animal preparation, but wellestablished paradigms have been developed in recent years that have permitted the same rigorous experimental analysis of drug-seeking behavior in

humans (Fischman and Mello 1989). The most important point to be

gleaned from this discussion is that it must be shown, under standardized,

well-controlled conditions, that any drug is self-administered for its reinforcing properties and that such behavior is robust and strongly motivated.

Drug Discrimination

The abused substance must be easily identified when the user is provided

the opportunity to discriminate his drug of choice from a variety of alternatives, including, most significantly, a placebo. Numerous procedures have

been developed to permit an assessment of drug-discrimination behavior.

Perhaps the most common technique is to first establish a strong pattern of

self-administration and then abruptly change the drug-appropriate operant

response by, for example, substituting the delivery of the active compound

with placebo or another compound devoid of activity, in which case selfadministration should cease. Alternatively, the operant conditioning paradigms used during the training and acquisition of self-administration behavior can be changed such that the subject will now have to modify its

behavior to seek out the active compound under a new set of experimental

conditions. Either of these techniques has been highly successful in assessing the discriminative properties of a variety of psychoactive substances.

5
Tolerance

Tolerance typically develops to all abused drugs such that more drug is

required to produce the desired pharmacological effect. The mechanisms

involved in tolerance may, in some cases, be an enhanced metabolism of

the drug or, most often, a diminished response of the central nervous

system (CNS) to the effects of the drug by as yet unknown mechanisms.

Tolerance must be clearly shown to occur by demonstrating that more drug

is required to produce a specific effect. Tolerance is often inferred in selfselection paradigms by noting increased patterns of drug administration with

time, but it can be assessed more directly by administering the drug at

various doses in tolerant and naive animals and measuring its subsequent

behavioral or physiological effects. Generally, a parallel shift in the do&-

response curve to the right, indicating that more drug is required in tolerant

animals to produce the same effect as in drug-naive animals, is considered

as a prerequisite to definitively establish whether long-term drug use has in

fact produced tolerance.

Physical Dependence

A withdrawal syndrome should rapidly ensue upon abrupt withdrawal of the

drug, which, in most cases, serves as a strong stimulus to continue to selfadminister the drug. Typically, physical dependence or the withdrawal syndrome is characterized by signs and symptoms opposite to those produced

acutely by the drug. This criterion is satisfied relatively easily, as, in most

cases, the withdrawal syndrome is striking and uniquely characteristic for

each drug.

DO ANABOLIC STEROIDS SATISFY THE CRITERIA FOR ABUSE

POTENTIAL?

The question of whether anabolic steroids satisfy the criteria for abuse

liability has not been unequivocally answered in large measure because of

the factors outlined in the introduction, particularly the absence of wellcontrolled, double-blind studies utilizing placebo controls. Some investigators have concluded that double-blind studies cannot be carried out to assess

the efficacy of steroids, since those assigned to the treatment group uniformly break the code because of some discriminative “beneficial” effects of

the steroids (mood enhancement, relief of fatigue) or possibly their unwanted and adverse side effects (Crist et al. 1983; Freed et al. 1975; Taylor

1987; Wilson 1988). This issue will be discussed in detail, but there

appears to be significant controversy regarding the discriminative properties

of steroids and whether in fact subjects can truly discriminate between

placebo and steroid administration. Even if one assumes that steroids can

be easily discriminated by users, these discriminative properties should be

exploited to examine whether the criteria described above can be met. Specifically, if these drugs can readily be identified by chronic users, then it

6
should be possible to examine whether they are self-administered in a freechoice situation, whether they can be discriminated from placebo or other

steroids, and, finally, whether tolerance and physical dependence actually

develop. Unfortunately, we are unaware of any properly designed studies

that have attempted to take advantage of the presumed discriminative properties of the steroids, which, it is claimed, render double-blind studies

impossible to carry out, to assess the abuse liability of these compounds.

There are, however, numerous other problems with many of the studies

reported to date, even in those that can be considered well designed and

double-blind. For example, subject selection criteria have been particularly

troublesome in terms of providing definitive conclusions. In all studies,

only those persons already using steroids can be employed as research subjects for obvious ethical reasons. Because of this necessary consideration,

the investigator has, at the outset, self-selected subjects who are highly

motivated to enhance their performance and, significantly, fully anticipate, in

most instances, that steroids will facilitate their exercise program. This

variable poses sufficient problems by itself, but, in some studies, (Johnson

and O’Shea 1969) subjects were assigned to treatment groups (active compound or placebo) on the basis of their willingness to take steroids. Those

who believed that the steroid was too dangerous to take or feared its side

effects based upon past history were assigned to the placebo group, whereas

those expressing no concerns were assigned to the steroid group. Since

both groups were athletes in training, it was assumed that motivational

factors were therefore controlled. This appears to be a specious argument,

since the regular users of steroids obviously expected that they would

benefit from their use, whereas those who rejected the use of steroids knew

that they were assigned to a placebo group and, hence, would be denied the

real or perceived beneficial effects of the steroids. Under these conditions,

it is perhaps not surprising that differences were shown between those

assigned to steroid administration vs. placebo administration.

Finally, most investigators have focused exclusively on the issue of whether

steroids enhance athletic performance or muscular development and, in some

cases, have even made an attempt to discriminate between expectancy

effects and the physiological actions of the steroid. However, the design of

these studies does not lend itself to addressing the essential criteria necessary to establish abuse liability, since the studies were chronic in nature and

did not use voluntary self-administration paradigms, which would be necessary to establish abuse liability as defined by the four criteria previously

outlined.

Reported Effects of Steroids

Before assessing the extent to which the use of steroids satisfies the criteria

for abuse liability, it is necessary to consider the pharmacological and

physiological effects of steroids, the motivating factors responsible for the

7
use and misuse of these compounds by regular users, and the numerous

problems that have been encountered in examining these issues under wellcontrolled experimental conditions.

Steroids are reported by regular users to produce euphoria, a sense of wellbeing, increased libido, aggression, improved self-image, and, most commonly, an enhancement of athletic performance and muscular development

(Haupt and Rovere 1984; Lombardo, this volume; Taylor 1987; Wilson

1988; Wilson and Griffin 1980). It is difficult to assess whether these selfreports represent immediate, discernible effects of the steroids or the expectation that the use of the steroid over time will produce these effects,

because of the inherent limitations in the design of most studies carried out

to date.

Despite the absence of a substantial data base regarding the real or perceived effects of steroids, there can be little question that the general public

and, particularly, many young athletes are convinced that steroids enhance

physique and athletic performance. Nonetheless, the results of the relatively

few available double-blind studies using placebo controls indicate that there

may be little scientific basis for this staunchly held belief. Although several

studies have shown, under appropriately designed conditions, that steroids

enhance athletic performance and that subjects can distinguish steroids from

a placebo over an extended time period, an equal or perhaps greater number

of studies have failed to demonstrate such effects (Haupt and Rovere 1984;

Lamb 1984; Wilson 1988; Wilson and Griffin 1980). The literature supporting each position is illustrated in table 1. While not exhaustive, this

listing of positive and negative studies represents those experiments in

which reasonable designs were employed with appropriate numbers of subjects. The studies represented by an asterisk in this table represent wellcontrolled, double-blind studies. As can be seen from this extensive review

of the literature, there are at least the same number, if not more, of negative studies as there are positive ones. Morecover, in many studies, the

actual improvement in performance was so negligible that the efficacy of

the steroids can be legitimately questioned, and it remains to be determined

whether larger numbers of subjects would have produced statistically and

biologically significant differences between groups. Nevertheless, on the

basis of this review, it would seem reasonable to conclude that there is little

compelling scientific evidence to support the concept that steroids enhance

athletic performance.

The latter conclusion is heavily underscored by the results of a particularly

important, well-controlled study by Ariel and Saville carried out in 1972,

the results of which have not been challenged in the intervening 18 years.

It was shown that subjects who were informed that they would receive daily

injections of an anabolic steroid but instead received placebo could not

recognize the difference and, notably, showed enhanced performance equivalent to that observed in those receiving the active compound. These

8
TABLE 1. A Summary of studies that have reported that steroid use

improved athletic performance or, conversely, had no

effect

Positive Studies Negative Studies

O’Shea 1971*

Johnson et al. 1972*

Freed et al. 1975

Ward 1973*

Ariel 1973*

Ariel 1974*

Win-May and Mya-Tu 1975*

Hervey et al. 1981*

Johnson and O’Shea 1969

O’Shea 1974

O’Shea and Winkler 1970

Crist et al. 1983*

Fowler et al. 1965*

Hervey et al. 1976*

Holma 1977

Ariel and Saville 1972

Loughton and Ruhling 1977*

Fahey and Brown 1973*

Stomme et al. 1974*

Johnson et al. 1975*

Golding et al. 1974*

Samuels et al. 1942*

*Well-controlled, double-blind studies.

striking results not only indicate the need for rigorously controlled doubleblind studies, but also point out the difficulty in documenting the primarily

anecdotal reports that steroids enhance muscular development or athletic performance. If steroids do indeed enhance performance, a commonly held

belief that is supported by intuitive and anecdotal evidence (Lombardo, this

volume), then it should be possible to design appropriate studies to distinguish between expectancy effects and the demonstrable physiological effects

of the steroids on athletic performance. Thus far, such studies are generally

lacking.

Finally, it should be noted that the mechanism by which steroids enhance

muscular development or athletic performance is not clear, if indeed steroids

have such effects at all (Wilson 1988). The results of many studies examining this issue have been inconclusive, but it has been suggested that the

effects of steroids in relieving fatigue may be more important in a vigorous

training program than any known physiological effects of the steroids, e.g.,

direct effects on muscle mass. Moreover, it should be noted that, at the

doses commonly employed by steroid misusers, all androgen receptors in

brain and other androgen-sensitive organs are completely saturated (Wilson

1988), indicating that the full spectrum of their androgenic and anabolic

effects should be expressed. Thus, the supraphysiological and suprapharmacological doses commonly used by steroid misusers may indicate either that

the drugs are ingested for actions other than their normal physiological

9
effects or that the subjects assume, perhaps incorrectly, that excessive doses

of steroids will produce greater effects. There are insufficient data on hand

to discriminate between these possibilities.

As a result of the factors discussed above, there is good reason to question

whether the most frequently stated reasons for steroid use in chronic steroid

misusers, i.e., enhancement of physique and athletic performance, is supported by any compelling scientific evidence concerning their efficacy in this

regard. Most important, however, these experiments stress the need for

reliance on well-controlled studies rather than anecdotal self-reports in

assessing the efficacy of steroid use and in distinguishing between expectancy effects and the actual pharmacological or physiological actions of

steroids.

Aside from the desired effect, a number of undesirable side effects follow

ingestion of suprapharmacological doses of steroids (Haupt and Rovere

1984; Pope and Katz 1988; Taylor 1987; Wilson 1988). These include,

most prominently, endocrine disturbances, particularly in adolescents; cardiac

and liver problems; stunted growth; testicular atrophy; psychiatric disturbances; and violent expressions of hostility, frequently termed “roid rage”

by chronic misusers. Despite the alarming incidence of these side effects,

chronic users are still apparently willing to risk them to obtain what they

believe will be a long-term desirable effect. Conversely, many users take

steps to avoid the side effects of the steroids by ingesting other substances

to counteract some of these adverse reactions, such as growth hormone and

various prescription drugs, legally or illicitly obtained. Regrettably, however, the results of several recent surveys of a large number of steroid

abusers indicated that, although many were aware of the side effects of

steroid misuse, substantial numbers had little appreciation for the possible

adverse consequences of chronic misuse (Fuller and LaFountain 1987;

Johnson et al. 1989; Wilson 1988).

Additionally, because steroids are taken at doses that can only be described

as suprapharmacological, well above the dose range necessary to produce

therapeutic or “beneficial” physiological effects, the side effects are so

readily discernible that, as discussed, double-blind studies may be very difficult to carry out. It is extremely important to note that the difficulty in

carrying out double-blind studies may be owing to the users’ ability to distinguish between the effects of the steroid and placebo based upon the side

effects of chronic misuse rather than any perceived beneficial effects. This

problem can easily be avoided if studies are carried out using dose ranges

below those that produce a constellation of undesirable side effects but that

would still be well within the range known to produce significant physiological effects, therapeutic effects, or both. These studies would be particularly important in terms of assessing whether steroid users ingest these compounds for their physiological effects or for some other reasons that have

yet to be defined.

10
One final factor, which must be considered in evaluating the effects of steroids and determining their abuse liability, is the reasons most often given

by individuals taking them on a regular basis. Several recent studies have

examined this issue (Fuller and LaFountain 1987; Johnson et al. 1989;

Taylor 1987; Wilson 1988). Not surprisingly, most users reported that, with

a regular program of exercise and proper diet, steroids improved their

physique and athletic performance and, thereby, their self-image, despite the

fact that their efficacy in this regard is not altogether clear. Interestingly,

some steroid misusers stated that even though they were not sure that the

steroid had any direct athletic-enhancing performance effects, they used

them because others against whom they were competing were suspected of

using them, and, hence, they could not risk the possibility of losing the

competitive edge. In addition, a relatively large number of adolescents

reported that peer pressure was a significant factor in their decision to use

steroids, and some reported that other presumed actions of the steroids, e.g.,

enhanced sexual performance, were strong motivating factors. These data

clearly point out the need for educational efforts, as regular users are apparently not well versed on the full spectrum of the actions of steroids, including their efficacy in producing a desired effect, and, most important, the

side effects associated with such misuse. Indeed, in all surveys examining

the factors responsible for the use of steroids, the individuals uniformly

reported that virtually all of their information concerning the efficacious

effects of steroids and their side effects came from friends, magazines,

information provided by “experts” at gyms, and, unfortunately, their

coaches, in many instances.

It is apparent that most studies have focused on the long-term use of steroids by athletes. We are unaware of a single study in which the shortterm, rewarding effects of steroids have been examined. The absence of

these data make it virtually impossible to distinguish expectancy effects of

the steroids from the immediate reinforcing properties of the drugs. Consequently, conclusions concerning their abuse liability, as defined pharmacologically by the four abuse-potential criteria discussed previously, are difficult at the present time.

Pharmacological Criteria for Assessing Abuse Potential

In discussing the available evidence regarding the extent to which steroids

satisfy the pharmacological criteria for abuse liability there are very few

studies that have directly examined this issue; much of the evidence represents self-reports, case histories, and anecdotal reports rather than systematic, well-controlled studies.

Self-Administration. Without question, human males self-administer steroids. Whether the drugs are self-administered for their immediate effects or

the expectation of long-term gain is, as mentioned above, unresolved. As

techniques are readily available to examine whether steroids have reinforcing

11
properties, as discussed in the section on criteria to assess whether a substance has abuse potential and elsewhere (Brady 1988; Brady and Lucas

1984; Fischman and Mello 1989), it is difficult to understand the complete

lack of attention to this critical issue. This paucity of data suggests either

that negative results have been obtained or, most likely, that the issue has

not been examined because investigators have correctly or incorrectly assumed that steroids are misused only for their long-term effects. Even if

one assumes that steroids have only long-term effects, it would be extremely important to determine whether they have sufficient discriminative properties to permit an evaluation of self-administration behavior. Clearly, however, these studies should be carried out under well-controlled conditions

consisting of at least the following: first, the use of doses within the physiological or therapeutic range rather than the suprapharmacological doses frequently taken by chronic users, which provide easily recognized side effects;

and, second, permitting the subjects to voluntarily select their drug of choice

from a variety of alternatives. These studies would be particularly important in determining whether steroids are self-administered for their direct

immediate physiological or pharmacological effects or for some other

reason.

As a particularly useful adjunct to human studies, the development of animal models would satisfactorily answer this question, since animals selfadminister drugs solely for their immediate rewarding effects rather than for

some long-term benefit. Unfortunately, no studies have shown that animals

will self-administer steroids, and, in fact, there are reports (Louis Harris,

personal communication) that rats could not be induced to self-administer

steroids under a variety of conditions known to be optimal for other abused

substances. However, unlike other abused substances, the most prevalent

mechanism of steroid action is a genomic one that occurs at an extended

time after steroid injection (see discussion of steroid actions on the brain).

If the rewarding effects of steroids are mediated by genomic actions of steroids in brain, they might not occur until hours or days after the injection.

This protracted period between injection and rewarding effects would render

self-administration paradigms in humans and, particularly, animals useless.

If, on the other hand, the rewarding effects of steroids were mediated by

interactions with neurotransmitter receptors, then perhaps these effects could

be discriminable. Nevertheless, it should be stressed that relatively little

attention has been paid to the development of appropriate animal models,

which would be extremely valuable in assessing the abuse potential of anabolic steroids, as they have been in the case of most commonly abused substances (Brady 1988; Brady and Lucas 1984).

Drug Discrimination. There have been no studies demonstrating that those

persons abusing steroids can discriminate between their steroid of choice vs.

other steroids or drugs or, for that matter, a placebo when given acutely.

There are, however, conflicting reports regarding the issue of whether steroid abusers can detect differences between steroids and placebo in terms of

1 2
the long-term physical or athletic performance-enhancing properties of these

compounds. Some studies have shown that differences can be discerned

(Crist et al. 1983; Freed et al. 1975) but only after extended periods, while

other reports suggest that subjects cannot discriminate steroids from other

compounds or even placebo (e.g., Ariel and Saville 1972). Moreover, in

most studies, only placebo has been used as an alternative. To appropriately address whether steroids have discriminative properties, it would be necessary to offer structurally related steroids, with different pharmacological or

physiological properties, as possible alternative choices. Of perhaps greater

concern, there are no drug-discrimination studies available in which the subjects were actually allowed to voluntarily choose between their steroid of

choice, placebo, or other compounds. Rather, all studies have simply involved randomly assigning subjects into drug or placebo groups and then

determining at long-term intervals (weeks or months) whether they could

appropriately identify the treatment group to which they were assigned.

Aside from the fact that such studies have produced equivocal results, as

discussed earlier, they do not appropriately address the issue of the discriminative properties of the drugs, as the studies have involved passive, nonvolitional administration, and the issue of what is being discriminated, e.g., side

effects or therapeutic effects, has not been addressed. Appropriately designed self-selection paradigms seem to be the only way in which the discriminative properties of the steroids can be assessed. As for the criterion

of self-administration of steroids, should the discriminative effects of steroids involve slow, genomic mechanisms of steroid action, the difficulties

involved in appropriately designing self-selection paradigms might be

insurmountable.

We are unaware of any studies demonstrating that animals can discriminate

steroids from other drugs, which is not surprising, since there is no evidence that they are self-administered.

Tolerance. It has been reported that the use of steroids increases in frequency and amount in chronic users (Taylor 1987). While this has been

interpreted as evidence of tolerance, there is no pharmacological evidence

suggesting that tolerance actually develops, i.e., that more of the steroid is

required to produce a specified pharmacological effect. Rather, the literature seems to be more consistent with the view that steroid abusers increase

their usage under the assumption that more steroid use will have long-term

advantages. As discussed previously, estrogen or androgen administration to

animals is associated with enhanced behavioral sensitivity, not tolerance. If

the misuse of steroids involves classical steroid hormone-receptor mechanisms, it is unlikely that tolerance would be demonstrable.

Physical Dependence. There is anecdotal evidence that the abrupt cessation of chronic steroid abuse leads to what has been termed a withdrawal

syndrome (Taylor 1987). In general, the reported signs and symptoms

(depression, decreased sexual desire, fatigue) seem to be the opposite of

13
those observed during steroid administration, a finding that apparently

satisfies the requirements for this criterion. However, it must be stressed

that in all cases the subjects either abruptly withdrew themselves from

steroids or their supply was suddenly terminated; hence, it is difficult to

determine what role expectancy may play in these self-reports. Once again,

double-blind studies would be required to address the important issue of the

dependence liability of anabolic steroids.

Summary

From the brief review provided above, it seems clear that the use of steroids is a goal-oriented behavior, which some claim provides evidence that

they are drugs of abuse (Taylor 1987). It remains to be determined

whether steroid self-administration is based on their intrinsic pharmacological or reinforcing properties, or rather for some anticipated effect, real or

perceived. As a result, it is unclear whether chronic users simply misuse

these compounds or whether steroids have significant abuse liability as

appropriately defined in a strict pharmacological sense.

In the preceding discussion, great pains have been taken to distinguish

between abuse liability and the misuse of drugs. Alhough to many observers this distinction may be a matter of semantics. there is an important distinction. Many compounds or drugs are misused for a variety of reasons,

such as the belief they may have some beneficial effect, but there is no

clear indication that they have immediate pharmacological or therapeutic

effects that would lead to their increased self-administration. By definition,

the misuse of a drug should be restricted to describe a pattern of use that

may or may not appear to be compulsive, for which there is no demonstrable therapeutic or otherwise beneficial effect. Since chronic users

clearly do not use the suprapharmacological doses of steroids for their

limited therapeutic value, and it is questionable whether the compounds

have any substantive beneficial effects, it seems clear that they are misused

substances like so many other drugs. On the other hand, abuse liability

must be rigorously defined by the four abuse-potential criteria previously

outlined. On the basis of the foregoing review of the litemture, it is

apparent that there is insufficient information to determine whether steroids

possess intrinsic abuse liability. It is hoped that this chapter will stimulate

the necessary research in humans to unequivocally answer this question, but,

at this time, it is extremely important that the casual use of the term “drug

abuse” to refer to the misuse of steroids is not only pharmacologically

inappropriate, but may lead to further confusion in an area of research

already clouded by inconclusive experiments and excessive reliance on selfreports and anecdotal accounts.

Whether or not one chooses to conclude that the current literature supports

the concept that steroids have abuse liability, this interpretation should not

minimize the fact that the misuse of steroids is becoming an increasing

14
social problem and that such use carries with it significant biomedical complications. Recent reviews (Fuller and LaFountaine 1987; Johnson et al.

1989) suggest an ever-growing use of anabolic steroids, particularly in adolescents, and little knowledge concerning the efficacious effects of the compounds, if any, or the potentially harmful side effects of long-term misuse.

Consequently, this apparent epidemic of steroid use is a serious problem of

drug misuse, which should be examined. It is not entirely clear how this

problem should be tackled. Certainly, educational efforts must be made, but

rigorous scientific inquiries should be undertaken to examine, under wellcontrolled, double-blind conditions, the prevalence of misuse, whether users

are truly dependent on the drugs or rather are motivated to use the drugs by

expectancy effects or other factors, and, ultimately, whether there is evidence of true abuse liability as defined pharmacologically. With this information in hand, both users of steroids and those who legally or illicitly

prescribe them may be able to make better informed decisions.

Finally, it seems clear that animal models of steroid use and abuse must be

developed, since they will ultimately provide valuable insights into the

mechanisms involved in the abuse liability of steroids. Animal models have

proven to be extremely useful tools in studies of the abuse potential of

other drugs and their development in this area would be extremely valuable.

ROLE OF STEROIDS IN THE ABUSE OF OTHER SUBSTANCES

Steroid Modulation of the Acute Pharmacological Effects of Substances

of Abuse

There is increasing evidence that steroids may participate in the acute and

chronic effects of many abused substances.

It has been postulated that drug-induced alterations in the levels of testosterone may contribute to the mood changes associated with the acute effects of

drugs, particularly alcohol (Mendelson and Mello 1974; Mendelson and

Mello 1976; Mendelson and Mello 1979). These conclusions have not

gained widespread acceptance for several reasons. For example, alcohol

intoxication in some individuals produces aggression or hostility, whereas in

others it generates passivity. In both groups of individuals, alcohol reduces

serum testosterone levels; hence, there appears to be essentially no correlation between the mood-altering effects of alcohol and serum testosterone

levels. In addition, it has been difficult to establish correlations between

testosterone levels and mood shifts or passive-aggressive behavior under

normal, drug-free conditions in humans or animals (Bancroft 1978; Doering

et al. 1974; Mayer-Bahlburg et al. 1974; Persky et al. 1971; Sturup 1968).

Despite these reservations and somewhat contradictory evidence against a

relationship between alcohol-induced changes in serum testosterone levels

and the behavioral effects of the drug, it would be unwise to dismiss the

possibility of a link between steroids and alcohol’s mood-altering properties.

15
Specifically, because of the slow onset and genomic effects of the steroids,

poor correlations between the acute behavioral effects of alcohol and druginduced modifications in steroid levels might be expected. Rather, it might

be more profitable to focus on long-term correlations between serum testosterone levels and behavioral disturbances induced by chronic alcohol abuse.

However, it should be noted that recent studies (Winslow and Miczek 1988;

Winslow et al. 1988) have shown that there is, in fact, a strong positive

correlation between acute changes in serum testosterone levels and mood

shifts (passive-aggressive behavior) in nonhuman primates, but that these

effects were dependent upon several factors, such as social context and

endocrine status at the time of alcohol administration. These latter observations are particularly important, since they demonstrate not only that

steroids may mediate at least some of alcohol’s effect on behavior but that

they may also help to explain the somewhat controversial nature of this

relationship in humans reported in earlier studies.

In the female, attempts have been made to ask a somewhat different question: Do the marked alterations in sex steroids throughout the menstrual

(human) or estrous (animal) cycle modify the acute response to abused

drugs? The literature is now replete with evidence that the effects of opiate

agonists and antagonists on reproductive hormones are markedly influenced

by the stage of the estrous cycle in which they are administered (Cicero

1980a; Cicero 1980c; Cicero 1984; Cicero 1987). Similarly, the effects of

alcohol on reproductive hormones are also affected by the stage of the

estrous or menstrual cycle (Dees et al. 1985; Dees and Kozlowski 1984;

Mello 1988; Mello et al. 1985; Mello et al. 1986a; Mello et al. 1986b;

Mendelson et al. 1989). However, there is virtually nothing known about

whether other pharmacological or physiological actions of alcohol or opiates

are affected or whether the effects of other commonly abused drugs (marijuana, cocaine) are modulated by intrinsic fluctuations in female sex

hormones.

As to whether there are alterations in drug-seeking behavior as a function of

the menstrual or estrous cycle, there is little information at hand. While not

conclusive, a limited number of studies suggest that the use of marijuana

(Mello and Mendelson 1985) and alcohol (Belfer and Shader 1976, Belfer

et al. 1971; Podolsky 1963) may increase during various phases of the menstrual cycle that appear to correlate with changes in mood swings. Clearly,

these findings should be extended to determine whether a causal relationship

exists between the self-administration of marijuana, alcohol, or both, and

normal fluctuations in ovarian and pituitary hormones during the menstrual

cycle in humans. At present, the data suggest a correlation, but causeeffect relationships are unclear, since an enhanced self-administration of a

psychoactive compound at various points in the menstrual cycle could

simply be related to alterations in mood, independent of steroid fluctuations

per se. Nevertheless, these are exciting findings, and it would be of

1 6
substantial interest to determine whether the self-administration of other

drugs is similarly affected during the menstrual cycle.

We are aware of no systematic reports in the literature that would suggest

that the self-administration of drugs of abuse is influenced by the menstrual

cycle in nonhuman primates or the estrous cycle in animals. This paucity

of data is difficult to understand, since such studies are clearly feasible and

would provide valuable insights into the role of steroids in the abuse liability of commonly used drugs. Animal models would permit a degree of control of experimental variables that is clearly not feasible in humans and

would, in the long run, provide much more definitive data.

In the male, the role of steroids in mediating the effects of substances of

abuse has also been examined. There is now considerable evidence that

steroids modulate the endocrine responses to opiates and to alcohol (Cicero

1980c, Cicero 1982a; Cicero 1982c; Cicero 1984; Cicero 1987). For example, recent studies in this laboratory have shown that in the testosteronedepleted, castrated male rat, the effects of morphine and alcohol on serum

luteinizing hormone (LH) levels are diminished such that the normally suppressive effect of the drugs on serum LH levels was virtually abolished in

long-term castrated male rats (Cicero et al. 1982b; Cicero et al. 1990). Interestingly, in these studies, we found that the castration-induced insensitivity to morphine and alcohol appeared to be selective to LH secretion because long- and short-term castrated and sham-operated rats were equally or

more sensitive to other CNS effects of the two drugs. However, it should

be noted that we have not assessed the full pharmacological profiles of

morphine or alcohol in the castrated animal. It would be of substantial

interest to determine whether other acute effects of these two drugs are affected in animals in which steroid concentrations are systematically altered.

Given the discrete localization of steroids in the CNS, it should be possible

to design studies to examine the effects of alcohol and morphine in castrated animals in which specified steroid levels are maintained and to examine

how specific behavioral or physiological measures thought to be mediated

by brain areas richly innervated by steroid-containing neuronal systems are

affected.

The results discussed above clearly indicate that, in male animals, steroids

may mediate at least some of the acute effects of alcohol and opiates. This

area of research is in very early stages of development, but it promises to

be. rewarding in terms of defining the possible role of steroids in mediating

the actions, and consequently the use, of psychoactive compounds.

We are unaware of any studies in human males in which the possible role

of steroids in mediating the effects of psychoactive compounds have been

investigated. This is undoubtedly due to the absence in the human male of

the very large and prominent rhythms in serum steroid levels that are

observed in females. In addition, there are relatively few physiological

17
conditions in which persistent increases or decreases in serum testosterone

levels are observed, a fact that imposes restrictions on the types of experiments that can be. carried out. Nevertheless, there are circadian rhythms in

testosterone release in the male, and, consequently, it should be possible to

determine whether these fluctuations in any way modify the acute effects of

a variety of commonly abused substances. At the present time, however,

the castrated male rodent seems to provide an extremely valuable model to

examine the role of testosterone in mediating the acute and chronic effects

of abused substance-s, as the investigator has complete control of circulating

serum testosterone levels throughout the course of the experiments.

Although the foregoing results suggest that steroids may play an important

role in the acute effects of alcohol and opiates on reproductive function in

the male rat, several extremely interesting questions remain to be examined:

Do steroids participate in the nonendocrine effects of alcohol and morphine?

Are the effects of other abused substances similarly affected by manipulations in the steroid milieu? Is the development of tolerance and physical

dependence to morphine and alcohol altered by steroids? Are the reinforcing

properties of these drugs affected by steroids? We are unaware of any systematic studies addressing these important issues. This is clearly an important area of research that deserves much greater attention.

One extremely interesting question, not discussed above, should be singled

out for immediate, intensive study in view of the currently available evidence regarding an interaction between steroids and the effects of abused

substances. Specifically, does the misuse of steroids by young athletes for

prolonged periods of time result in any modifications in the effects of alcohol or other commonly abused drugs and, of perhaps greater interest, does

the use of steroids lead to an enhanced self-administration of other abused

substances? The literature reviewed in this section suggests that this possibility should be explored, but at the present time we are unaware of any literature relevant to this extremely important question. Clearly, this should

be investigated and such studies can be easily carried out, initially by appropriately designed epidemiological studies.

Role of Steroids in the Development of Tolerance to Alcohol and

Morphine

As discussed above, there is very limited information concerning the issue

of whether steroids participate in the development of tolerance to and physical dependence on substances of abuse. However, there have been several

recent attempts to examine whether drug-induced depressions in serum testosterone levels might be involved in the development of tolerance to these

drugs (Cicero 1980a; Cicero 1980b; Cicero 1982a; Cicero 1982b; Cicero

1982c; Cicero 1984; Cicero 1985; Cicero 1987).

18
One particularly promising line of investigation has been an examination of

the possibility that testosterone mediates the development of metabolic tolerance to alcohol, which is in part reflected by increases in the alcohol

dehydrogenase (ADH)-dependent metabolism of alcohol. This system was

initially selected for study, because it has been shown that testosterone modulates liver ADH activity. For example, castration leads to immediate increases in the ADH-dependent metabolism of ethanol in the male rat, and

this effect is completely reversed by testosterone (Cicero et al. 1980; Cicero

et al. 1982a; Israel et al. 1977; Israel et al. 1979; Mezey and Potter 1985;

Rachamin et al. 1980). Because narcotics and alcohol share the ability

to substantially depress serum testosterone levels (Cicero 1980a; Cicero

1980b; Cicero 1982a; Cicero 1982b; Cicero 1982c; Cicero 1983; Cicero

1984; Cicero 1985; Cicero 1987), a number of investigators have examined

whether the chronic administration of alcohol or morphine led to testosterone-reversible increases in the metabolism of ethanol (Cicero et al. 1982a;

Israel et al. 1977; Israel et al. 1979; Mezey and Potter 1985; Rachamin

et al. 1980; Rachamin et al. 1984).

The results of these studies demonstrated that chronic morphine or alcohol

administration, at doses sufficient to markedly depress serum testosterone

levels (greater than 85 percent), produced large increases in liver ADH

activity and the in vivo clearance of ethanol, which were equivalent to those

observed in the castrated male rat. However, it has been shown (Cicero

et al. 1982a; Israel et al. 1979; Rachamin et al. 1984) that, in contrast to

the castrated male rat, testosterone replacement only partially reduced the

effects of long-term ethanol or opiate administration on the induction of

ADH and the in vivo metabolism of alcohol. Thus, it appears that druginduced changes in serum testosterone levels can only partially account for

the development of metabolic tolerance to alcohol. However, further studies

of this issue seem to be warranted, as the hormonal changes associated with

castration and ethanol or morphine administration are not simply confined to

changes in testosterone; many other direct and indirect effects on other hormones occur as a result of treatment with these two drugs and castration.

Consequently, systematic studies should be carried out to determine whether

any of these well-documented changes in hormonal status contribute to the

effects of the chronic intake of alcohol or morphine on the development of

metabolic tolerance to alcohol.

As should be obvious from the foregoing studies, there is very little information available about the role of steroids in mediating the chronic effects

of commonly abused substances, particularly in the development of tolerance

and physical dependence. However, there are some suggestive data available and, given the fact that steroids exert powerful effects on the organization and function of the CNS, drug-induced changes in steroid levels may

very well participate in the long-term effects of substances of abuse on the

brain. In this connection, it has been observed by many investigators that

all commonly abused depressant drugs such as alcohol, barbiturates, and

19
morphine have profound effects on the reproductive endocrine axis resulting

in persisting reductions in serum testosterone levels (Cicero 1980a; Cicero

1980b; Cicero 1982a; Cicero 1982b; Cicero 1982c; Cicero 1983; Cicero

1984; Cicero 1985; Cicero 1987). This shared property of these substances

has led many investigators to suggest that long-term reductions in serum

testosterone levels would lead to changes in testosterone-dependent organs

including the brain, which may be similar to the well-documented changes

associated with castration. Whether these changes simply represent a mechanism mediating some of the adverse consequences of long-term drug abuse

or are involved in the processes associated with tolerance and physical dependence remains to be determined. With the availability of an appropriate

animal model to examine these issues, progress in evaluating this issue

should be readily attainable.

CONCLUSION

Review of the literature suggests that the abuse liability of anabolic steroids

has been studied in very little detail. It must be concluded at this time that

the use of steroids by humans does not meet the criteria necessary to establish that steroids have significant abuse liability as defined in pharmacological terms. It should be noted, however, that very few investigators have

carried out studies designed to directly answer this question. Consequently,

it would be unwise to definitively conclude that steroids lack abuse liability.

Rather, the only appropriate interpretation of the status of research in this

area is that there is insufficient information at hand to draw any meaningful

conclusions. Obviously, given the now widespread use and misuse of steroids, much more detailed studies are required to determine whether they

have significant abuse liability analogous to that observed with more commonly abused substances such as opiates, stimulants, depressants, and

alcohol.

Whether or not it can be concluded at this time that steroids have significant abuse liability, there seems to be little question that steroids are misused by an increasing number of individuals for a variety of anticipated

effects, including most prominently an enhancement of physique and athletic

performance. Aside from the fact that the evidence concerning the efficacy

of steroids in this regard is not compelling, it must be recognized that users

believe that these compounds produce such effects, and the misuse of steroids is, consequently, becoming an important problem in society that cannot

be ignored. It is hoped that this chapter has not only placed into context

the distinction between the abuse liability and misuse of steroids but will

also serve as a stimulus to investigators to carry out more extensive studies

to examine more fully the incidence and motivating factors responsible for

the use of steroids, their efficacy in producing the anticipated effects, the

distinction between expectancy and the immediate reinforcing properties of

steroids, and, finally, whether these compounds have abuse liability in the

true sense of this term. The latter would be particularly important to

20
having these compounds scheduled under the Controlled Substances Act by

the Drug Enforcement Agency, as has been suggested (Taylor 1987).

Aside from the important problems related to the misuse or abuse liability

of steroids, there is now a growing body of data that suggests that steroids

may be involved in mediating the acute effects of substances of abuse on at

least certain parameters and could be involved in those processes associated

with tolerance and physical dependence. Although this is a very new area

of research, it is a very promising approach that is worthy of much further

investigation. Three particularly fruitful areas of research are: (1) whether

intrinsic changes in sex steroids modulate the acute or chronic effects of

abused substances; (2) whether drug-induced alterations in the steroid milieu

in humans and animals are involved in mediating the acute and, particularly,

chronic effects of substances of abuse; and (3) whether the acute effects of

commonly abused drugs or their self-administration are modified by longterm steroid misuse in chronic users.

FOOTNOTES

1. This chapter was not presented at the National Institute on Drug Abuse

Technical Review Meeting on anabolic steroid abuse held on March 6-7,

1989.

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ACKNOWLEDGMENTS

The authors’ research described in this chapter was supported in part by

U.S. Public Health Service grants DA 03833, AA 07144, and AA 03935.

Theodore J. Cicero is a recipient of Research Scientist Award DA 00095.

AUTHORS

Theodore J. Cicero, Ph.D.

Professor of Neuropharmacology in Psychiatry

Lynn H. O’Connor, Ph.D.

Research Assistant Professor of Neuroendocrinology

Department of Psychiatry

Washington University School of Medicine

4940 Audubon Avenue

St. Louis, MO 63110

28
History of Anabolic-Androgenic

Steroids1

Charles D. Kochakian

INTRODUCTION

It has been known for centuries that castration of the male results in the

loss of not only fertility but also the secondary male sex characteristics.

Castration was practiced by farmers to domesticate animals for work or to

improve meat production, by churches to preserve the trained soprano voices

of choir boys, by the Ottoman Empire and China to produce eunuchs as

guards of harems and as servants, and by religious cults as late as the early

20th century, e.g., Skoptzs of Russia (Hoskins 1941).

MALE HORMONE

Transplantation of Testis in Capons: Blood-Borne Factor

The general consensus was that changes after castration were mediated

through the nervous system. The first inkling as to the real regulation of

these changes was provided by Berthold (1849), professor of medicine at

Gottingen. In a simple and excellently designed experiment with only six

roosters, he demonstrated that the well-known regression of the comb, wattles, and behavior that occurred after castration (figure 1) was prevented by

the return of a testis to the abdominal cavity.2 The transplant developed a

new blood supply and maintained the castrated roosters in the normal manner. Berthold correctly deduced that since the transplanted testis no longer

had its nerve connections, it produced something that was secreted into the

blood and was transported to the target tissues to regulate their growth and

maintenance. The importance of this study was not the successful transplantation of the testis but the interpretation of the results.3

 Hunter had

earlier (Forbes 1947) successfully transplanted testis and other tissues incidental to his studies on teeth. He seemed to be interested in compatibility

of tissues.

29
A. Normal brown leghorn cock. B. Brown leghorn capon. (After Domm

FIGURE 1. Effect of castration on the comb and wattles of the brown

leghorn rooster

SOURCE: Moore 1939, copyright 1939, Williams and Wilkins Publishing Co.

In the subsequent 60 years, Berthold’s results were questioned. Attempts by

others to repeat the transplantation experiments were unsuccessful, except

for Lode, who in 1891 did confirm Berthold’s experiment; however, his

results were ignored. After another 20 years, Pezard (1911) successfully

repeated the effects of castration in roosters and, in 1912, fragmented the

removed testes and deposited the fragments in the abdominal cavity of the

castrated rooster (capon) (Pezard 1912). The combs and wattles of the

capons were maintained. Shortly thereafter, an increasing interest in the

development of the male reproductive tract resulted in many studies in laboratory rodents with attempts to produce extracts of the testis that would

reverse the effects of castration (Moore 1939).

Testis Extract

Pezard (1911) also reported that an aqueous extract of pig testes maintained

the comb and wattles of the capon.4

F.C. Koch, professor of biochemistry

at the University of Chicago, stimulated by the studies in the biology department by Lilly on the freemartin (Moore 1939) and by C.R. Moore on

the development of the reproductive tract in male laboratory rodents, assigned McGee, for his doctoral dissertation, the extraction of bull testes. In

1927, McGee reported that an alcohol extract of bull testes stimulated the

growth of the capon comb. Gallagher and Koch extended this seminal observation (Gallagher and Koch 1930; Gallagher and Koch 1934a). They

improved the extraction procedure to produce a highly purified and active

30
preparation and developed the response of the capon comb into a quantitative assay method, which, with minor modifications, was adopted by most

laboratories as the standard assay for “male hormone” activity (Gallagher

and Koch 1930; Gallagher and Koch 1934a). At about the same time, regeneration of the accessory sex organs of the castrated rat (Moore and

Gallagher 1930; Moore 1939) and the seminal vesicles of the castrated

mouse (Voss 1930) were also suggested as methods of assay.

In the meantime, Pezard and Caridroit (1926) transplanted two fragments of

the comb of a normal rooster to its back through an incision in its skin and

found that they were maintained. One week after another rooster was castrated, two fragments of the comb were transplanted to its back. Both the

comb in situ and the transplanted fragments exhibited the usual postcastration regression. He deduced, as had Berthold, that the active principal was

in the blood and that it acted directly on the comb. On the basis of this

observation, Funk and Harrow, in 1929, assumed that the active substance

should be cleared by the kidney and appear in the urine. A crude cocentrate of alcohol-treated male urine stimulated the growth of the capon comb

(Funk and Harrow 1929). Acidification of the urine, suggested by earlier

studies on extraction of estrogens from female urine, followed by chloroform extraction, provided an oily active concentrate (Funk et al. 1930).

Further purification and an increase in yield was effected by stronger acidification prior to chloroform extraction, followed by hydrolysis of the extract

with sodium hydroxide solution, which removed many impurities and also

estrogens (Funk et al. 1930). Other investigators (Freud et al. 1930; Loewe

and Voss 1930) almost simultaneously developed similar extraction procedures. Thus, relatively simple methods for the production of highly active

concentrates of what was designated “the male hormone” became available.

ANDROGENS

Isolation and Characterization of Androsterone

Butenandt in Windaus’ laboratory at Gcttingen succeeded in isolating 15 mg

of a pure substance from an extract of 25,000 L of male (policemen’s)

urine prepared by the Schering Corporation of Berlin by a modification

of the Funk and Harrow procedure (Butenandt 1931; Butenandt and

Tscherning 1934a). Butenandt had unsuccessfully attempted to isolate the

active substance in bull testes before exploring the urine extract. Analysis

of the urinary product indicated a hydroxyl and a ketone attached to a polycyclic nucleus like that of cholesterol; the compound was named androsterone (andro=male, ster=sterol, one=ketone) (Butenandt and Tscherning

1934a).

The structure of cholesterol had been and was being intensively studied in

the laboratories of Windaus. The final elucidation of the ring structure of

this compound was in the process of being accomplished (Fieser and Fieser

31
1959). Ruzicka, in the meantime, had become intrigued by the possible

polycyclic structure of the compound and a possible relationship to the terpenes, which he had been successfully studying for the perfume industry.

He reasoned that chromic acid oxidation of cholesterol should yield the

polycyclic nucleus with a keto group at the site of the removed side chain.

Therefore, he diverted the efforts of his young collaborators to this task

(Ruzicka 1973; Ruzicka et al. 1934). Apparently Windaus had not considered that the polycyclic ring structure of cholesterol could survive the oxidative procedure and did not attempt to isolate the potential keto product.

This is surprising, since he did isolate the intact side chain as the expected

ketone. Ruzicka saturated the double bond of cholesterol prior to oxidation

and treated the neutral fraction of the oxidized mixture for semicarbazone

formation. He obtained the anticipated insoluble ketone derivative, albeit in

small yield. The free compound possessed the comb-growth-producing

property, but only at about one-seventh that of androsterone. It was

assumed to be a stereoisomer of androsterone. Ruzicka’s group then immediately proceeded, by known selective reductive and oxidative methods, to

convert cholesterol to androsterone and its three possible isomers (figure 2)

(Ruzicka et al. 1934). Thus, the chemical structure of androsterone and its

relationship to the sterols was established.

Synthesis, Isolation, and Characterization of Testosterone

Studies on bull testes and on male urine were being conducted in parallel in

a number of laboratories (Freud et al. 1930; Tausk 1984). Therefore, when

androsterone was synthesized, its biological and chemical properties were

compared with those of the testis extract. Two major differences became

evident. The testis extract was more active in the stimulation of growth of

the seminal vesicles and prostate of the castrated rat and mouse (Freud

et al. 1930) and was labile to hot alkali (Gallagher and Koch 1934b). The

alkaline lability, based on the recent studies with progesterone, suggested

the presence of an unsaturated ketone in the testis product (Fieser and

Fieser 1959; Tausk 1984). Both Ruzicka and Wettstein (1935a) and

Butenandt and Kudszus (1935) recognized this possibility and immediately

reported the synthesis of androstenedione from cholesterol. The compound

possessed the chemical lability of the testis extract and showed a substantial

increase in biological activity, but it was not as biologically active as the

testis extract. Both investigators quickly converted the ketone at position 17

to a hydroxyl (Butenandt and Hanisch 1935; Ruzicka and Wettstein 1935b)

(figure 3). This compound proved to have both the chemical and biological

properties of the partially purified bull testis extract? In May 1935, David

of Laqueur’s group (David 1935) in Amsterdam reported the isolation of a

crystalline compound from bull testes (10 mg from 100 kg), which had the

chemical and biological properties of the newly synthesized compound, and

named it testosterone (testo=testis, ster=sterol, one=ketone). Shortly thereafter, the Amsterdam group reported that the chemical structure of their

compound was identical with that of the recently synthesized compound

32
FIGURE 2. Androsterone and homers

SOURCE: Fieser and Fieser 1959, copyright 1959, Reinhold Publishing Co.

(David et al. 1935). The slight delay in the report of the chemical structure

was due to difficulty in the identification of the unsaturated keto character of the compound (Tausk 1984).

Family of Related C19 Steroids

It was becoming apparent that the body produced more than one compound

with male hormonelike activity. Butenandt and Dannenbaum (1934) had

already isolated a second compound from the male urine extract, an artifact

(chlordehydroandrosterone) of dehydroandrosterone formed during the hydrochloric acid hydrolysis of the urine. Furthermore, they indicated that there

probably were several more related compounds present in the urine, a conjecture which was amply confirmed over the subsequent years (Dorfman and

33
FIGURE 3. Synthesis of androstenedione and testosterone from cholesterol

via dehydrepiandrosterone

SOURCE: Fieser and Fieser 1959, copyright 1959, Reinhold Publishing Co.

Ungar 1965). Thus, there was a family of compounds, and they were soon

given the generic name of androgens (andro=male, gen=to produce).

Testosterone has the potential to be converted by tissue enzymes to 27 compounds (Kochakian 1959), three sets of nine steroids each: (1)

androstenes, (2) 5 androstanes, and (3) 5 androstanes with a difference

of only 2 H+ between adjacent compounds (figure 4). The polycyclic

nucleus of each compound had nine potential sites for -hydroxylation and also potential hydroxylation of the two angular methyls at C18 and

C19. Thus the tissues have the possibility of producing at least another 540

compounds. Moreover, the unsaturated steroids may be converted to estrogens. In addition, a keto group may be formed at each of the nine positions on the ring nucleus, e.g., adrenosterone, and unsaturation may be

introduced in the 3 and 16 positions by dehydration. Desaturation, however,

at the 4 or 5 positions of the androstanes apparently does not occur. The

metabolizing enzymes and the potential steroids, therefore, form a symphony

that is kept in balance by delicate and skillful directorship to maintain a

harmonious condition in the body. Many of these compounds are already

recognized (Kochakian 1959; Kochakian and Arimasa 1976); others may be

expected to become evident as the study of the metabolism of these steroids

is extended to normal and abnormal conditions in both vertebrate and invertebrate animals and in humans.

The demonstration that testosterone could be prepared from cholesterol permitted organic chemists to synthesize all of the possible oxidized and

reduced modifications (figure 4) and other modifications in search of a

34
FIGURE 4. The chemical interrelationship of metabolites of testosterone

NOTE: The steric positions of the 17-hydroxyls are opposite to the accepted positions. This diagram

was prepared in 1944 before the exact steric positions of the 17-hydroxyls had been established. Also, it is now apparent that the reverse reaction of and steroids to the or

steroids does not occur.

SOURCE: Kochakian 1959, copyright 1959, Williams and Wilkins Publishing Co.

more biologically active compound for oral as well as parenteral administration. These two objectives were quickly achieved. The substitution of a

methyl for the hydrogen yielded a highly effective oral compound,

methyltestosterone, which was immediately accepted for clinical use. The

later substitution of an ethyl instead of the methyl provided an even more

effective steroid. Testosterone in the early studies appeared to be completely ineffective by oral administration. Later studies in mice (Kochakian

1952) and in man (Johnsen et al. 1974) demonstrated that testosterone was

active by mouth if administered in sufficient quantity. An inefficient

process.

35
It was observed early (Kochakian 1938) that the addition of fatty acids or

impurities from extracts enhanced the biological activity of a parenterally

administered oil solution of testosterone. These studies suggested that esters

of testosterone would prove efficacious. The acetates of testosterone and

related compounds already were available; they had been prepared to establish the presence of hydroxyl in the molecule. On bioassay, the acetate of

testosterone proved to be more efficacious and also to provide a more prolonged activity. The propionate was even more effective (Kochakian 1938)

and became the standard compound for parenteral administration. The further prolongation of activity with the propionate prompted the synthesis of

several other esters with even greater extension of activity, which correlated

with the length of the carboxylic acid of the ester. The prolongation has

been extended as long as 4 months after the single injection of testosteronetrans-4n-butylcyclohexyl-carboxylate (Weinbauer et al. 1986). The introduction and recognition of dihydrotestosterone, 19-nortestosterone, and

19-nortestosterone as effective agents was followed by the preparation of

esters of the steroids. The rate of availability (absorption) of the esters to

the tissues is an important factor in their effectiveness. Unfortunately, this

property of these compounds has not been studied.

One of the esters (testosterone undecanoate) also proved to be orally more

effective than free testosterone. It was absorbed through the lymphatic

system and avoided rapid metabolism to less active forms by the enzymes

of the liver. The minimum effective quantity still was much greater than

that of a parenterally administered ester, e.g., 4x40 mg per day by mouth

was less effective than 50 mg per week of testosterone isobutyrate by

injection to transsexual women (Heresova et al. 1986).

ANABOLIC ACTIVITY AND NITROGEN BALANCE IN DOG

AND MAN

The demonstration of male hormonelike activity in male urine provided not

only a ready source of this substance for the isolation of androsterone but

also stimulated many biological studies. Murlin, the discoverer of glucagon,

was prompted to investigate whether this material also was responsible for

the difference in basal metabolic rate (BMR) between males and females.

He assigned two medical students in 1931 to conduct a pilot study as their

class project. They found that a Funk and Harrow-type extract of medical

student urine increased the BMR of a castrated dog. In the fall of 1933, I

was appointed as a graduate assistant to confirm and extend this exciting

observation (Kochakian 1984). In spite of repeated experiments at several

dose levels, I was unable to confirm the increase in BMR. Thereupon,

Murlin suggested the investigation of protein metabolism. This suggestion

probably was prompted by his earlier studies on nitrogen balance during

pregnancy in dogs (Murlin 1911). The urine extract produced an immediate

and strongly positive nitrogen balance in two castrated dogs (figure 5). The

results were reported in 1935 (Kochakian 1935; Kochakian and Murlin

36
FIGURE 5. Effect of “male hormone” urine extract on nitrogen

metabolism and body weight of the castrated dog

SOURCE: Kochakian and Murlin 1935, copyright 1935, American Institute of Nutrition.

1935) at the same time that androsterone, then androstenedione, and testosterone were being characterized and synthesized. The experiments were

immediately repeated with androstenedione (Kochakian and Murlin 1936),

which I synthesized, and testosterone and testosterone acetate (Kochakian

1937), which had become commercially available, to give results identical

with those of the urinary extract. Shortly thereafter, Kenyon et al. (1938)

reported identical results in eunuchoid men with the commercially available

testosterone propionate. Kenyon, of the University of Chicago, was an unusual clinician with a keen interest in basic research. He not only became

37
very interested in the research activity in the biology and biochemistry

departments, but also recognized the potential application to clinical

deficiencies. He developed a close friendship with Moore, Koch, and

Gallagher, which produced many fruitful discussions. I was fortunate to

make his acquaintance through our membership and participation in the

Josiah Macy, Jr. Foundation Conferences on Bone and Wound Healing

(later designated as the Metabolic Aspects of Convalescence).

PARTIAL DISSOCIATION OF ANABOLIC FROM ANDROGENIC

ACTIVITY

Renotrophic Activity of Androgens in Mice and Rats

The potential therapeutic value of the anabolic activity of testosterone and

its commercial availability stimulated many investigations in diverse anabolic-deficient conditions (Reifenstein 1942; Landau 1976), including intensive

studies in women with breast cancer. A strong impetus was given to these

investigations by the Josiah Macy, Jr. Foundation Conferences under the

organization of Frank Fremont-Smith and the leadership of Fuller Albright.

Clinical use of testosterone, however, always presented the objectionable

accompanying vitilization, especially in women and children. A possible

answer to this problem appeared imminent. As one aspect of my program

to elucidate the nature and mechanism of the anabolic action, I decided to

compare the effect of a number of steroids on their relative ability to stimulate growth in the sensitive mouse kidney (anabolic) (figure 6) (Selye 1939;

Pfeiffer et al. 1940) with that in the seminal vesicles and prostate (androgenic). The synthesis of the many modifications of testosterone provided a

ready source of steroids for my proposed study. These steroids were made

available through the generous cooperation and support of Ernst Oppenheimer, director of research at CIBA Pharmaceutical Products, Summit, NJ.

In 1942 I reported (table 1) (Kochakian 1942) that androstanediol (figure 7) possessed the same renotrophic (anabolic) as, but lesser

androgenic activity than, testosterone at physiological doses (figure 8). The

dichotomy disappeared with excessive doses, which produced comparable

maximum responses in both organs (Kochakian 1946; Kochakian 1977). A

similar relationship was noted in the rat (table 2) (Kochakian 1977).

The partial separation of the two biological activities by reduction in the Aring of testosterone suggested the testing of steroids with an oxygen substituent in only the 3- or 17-position. These compounds proved to be too insoluble to be absorbed in sufficient quantity by parenteral administration

(implanted pellets) to provide a growth response in either of the organs. I

decided, then, to test them by oral administration. Not all of the monooxygenated steroids could be assayed, because of their limited quantities.

The available steroids, however, produced an exciting result. The lack of

an oxygen substituent at the 3-position gave a compound, methyl

androstan which possessed a similar renotrophic but a much lesser

38
FIGURE 6. The effect of castration and testosterone propionate on the

weight of several organs of the mouse

NOTE: The body weight and the seminal vesicles, prostate, kidney, salivary glands, lachrymal glands,

and the bulbocavernosus and “levator ani” muscles exhibit a log-dose response to active steroids. Thus, the castrated mouse is a potential model for multiple assay.

SOURCE: Kochakian 1975, copyright 1975, Pergamon Press.

(one-third) androgenic effect than methyltestosterone (Kochakian 1953)

providing further confirmation of importance of the nature of the A-ring for

androgenic activity.

Myotrophic Activity of Androgens in Guinea Pigs

Papanicolaou and Falk (1938) had reported that the temporal and the masseter muscles of the guinea pig were much larger in the male than in the

female and that castration of the male resulted in female-size muscles.

Administration of testosterone propionate restored the weight of the muscles

in the castrated male and increased those of the female to those of the

male. They assumed this to be a general effect on skeletal muscles. These

observations were made incidental to their studies on the reproductive cycle

of the female guinea pig, which led to the now well-known “Pap smear”

for vaginal cancer. I reported a confirmation of these results with the

39
TABLE 1. Comparison of effect of chemical structure on the renotrophicandrogenic activities of various steroids in the castrated

mouse

Steroid

Steroid

Absorbed

mg/30 days

Increase

Sem. Ves.

Kidney and Pros. K/Sv. Pr.

mg mg mg/mg

Androsterone

Methyl androstane-

-diol

Androstane diol

Hydroxy-17-methyl

androstan-3-one

Testosterone

Normal mice

-Androstane-3,17-dione

Androst-4-ene-3.17-dione

13.0 65 20 3.3

2.6 261 157 1.7

1.7 202

0.2 193

0.14 125 144 0.9

— 162 216 0.7

32.3 60 95 0.6

10.6 84 173 0.5

137

148

1.5

1.3

SOURCE: Kochakian 1944, copyright 1944, American Physiological Society.

FIGURE 7. A comparison of the renotrophic and androgenic activities in

castrated mice at different doses of androstane diol

NOTE: The 17 hydroxyl was later proven to be in and not the position.

SOURCE: Kochakian 1946, copyright 1946, American Physiological Society

40
FIGURE 8. A comparison of the renotrophic and androgenic activities in

castrated mice at different doses of testosterone

SOURCE: Kochakian 1946, coyright 1946, American Physiological Society.

TABLE 2. Comparison of the renotrophic and androgenic action of

various androgens at 1 mg/day for 21 days in the rat

Treatment

Castrated

Normal

Androstane- diol

Hydroxy androstan3-one

Testosterone propionate

Androst-4-ene-3,17-dione

Increase

Body Sem. ves.

Rats Weight Kidney and pros. K/Sv. Pr.

(No.) g g g g/g

12 2 (2.00)

6 0 —

(0.21)

2 25 0.94 3.30 0.29

2 14 0.50 2.83 0.18

8 21 0.22 4.27 0.05

2 10 0.15 1.70 0.09

NOTE: Rats on constant food intake for nitrogen balance studies; body weights approximately 300 g.

The figures in parentheses are the absolute values.

SOURCE: Based on data in Kochakian 1977: Kochakian 1964.

temporal muscle (figure 9) (Kochakian et al. 1948). The increase in weight

was due to hypertrophy (figure 10). A comparison of the effectiveness of

several steroids revealed that andrastane diol produced a dichotomy between the growth of the muscle and the accessory sex organs similar

41
FIGURE 9. Comparison of the size of the temporal muscle of the male

and female guinea pig and the effect of castration and

testosterone propionate

SOURCE: Kochakian 1975, copyright 1975, Pergamon Press.

FIGURE 10. A comparison of the diameter of the fibers in the temporal

muscle of the normal and castrated guinea pig

42
to that observed in a comparison of renotrophic and androgenic activity in

the mouse and rat. The study was then extended to include 47 other

muscles to determine the general nature of the response (Kochakian and

Tillotson 1957; Kochakian 1975). The increase in size of the different

muscles differed not only for the several steroids but also for the individual

muscles (tables 3 and 4). The sensitivity of the muscles to the steroids was

greatest in the head and neck region and gradually diminished from head to

hindquarters (figure 11). The more responsive muscles exhibited a more

favorable myotrophic than androgenic activity with -androstane

diol and the other androstanediols. Of further interest was the effect of

dihydrotestosterone DHT). It was more active than testosterone in

its androgenic effect and even more active in the myotrophic effect (tables

3 and 4). Furthermore, although testosterone and dihydrotestosterone

produced no significant difference in the increase in weight of the uterus of

the ovariectomized rat, they differ in their actions at the cellular level. Testosterone markedly increased the height of the luminal epithelium and stimulated glandular secretion, but dihydrotestosterone was ineffective in

these actions. On the other hand, dihydrotestosterone stimulated a greater growth of the myometrium (Gonzalez-Diddi 1972).

FIGURE 11. Response of the individual muscles of the castrated guinea

pig to testosterone stimulation

SOURCE: Kochakian and Tillotson 1957, copyright 1957, The Endocrine Society.

43
TABLE 3. Relative myotrophic and androgenic potencies of several C19 steroids

Steroid

Sem. Ves. Clavo- Stemo- Retractor

and Pros. Digastric Masseter trapezius Temporal mastoid Penis

Androstan ol,3-one 150 380 320

Testosterone 100 100 100

Methylandrostan ol,3-one 100 140 120

Androstane diol 50 60 70

Methyltestosterone 50 60 50

Methylandrostane diol 16 30 20

Androstene-3,17-dione 17 10 10

Androstane-3,17-dione 16 20 10

Dehydroepiandrosterone 15 10 4

Epiandrosterone 5 10 6

280

100

80

280

40

9

—

20

20

—

230

100

90

70

30

20

10

10

10

4

190

100

100

90

20

—

3

8

3

—

150

100

80

30

100

4

20

8

4

30

NOTE: The respective values are compared to those of testosterone set at 100.

SOURCE: Kochakian and Tillotson 1957, copyright 1957, The Endocrine Society.
TABLE 4. Ratio of myotrophic to androgenic (seminal vesicles and prostates) activity of several C19 steroids

Steroid Digastric Masseter

Clavotrapezius Temporal

Stemo- Retractor

mastoid Penis

Androstan ol,3-one 2.5 2.1

Androstane dial 1.2 1.4

Methylandrostane ol,3-one 1.4 1.2

Methylandrostane -diol 1.8 1.2

Testosterone 1.0 1.0

Methyltestosterone 1.2 1.0

Androstane-3,17-dione 1.3 0.8

Epiandrosterone 2.6 1.2

Androstene3,17-dione 0.8 0.8

Dehydroepiandrosterone 0.7 0.3

1.9

5.7

0.8

0.6

1.0

0.7

1.4

—

—

1.5

1.5

1.4

0.9

1.3

1.0

0.5

1.3

0.8

3.6

0.7

1.3

1.8

1.0

—

1.0

0.4

0.5

—

0.2

0.2

1.0

0.6

0.8

0.3

1.0

1.9

0.5

5.8

1.3

0.3

NOTE: The respective values are compared to those of testosterone set at 1.0.

SOURCE: Kochakian and Tillotson 1957, copyright 1957, The Endocrine Society.
Nitrogen Balance in Rats

Although both the mouse kidney and several muscles of the guinea pig

exhibited typical log-dose responses, they were not simple enough to be

attractive as routine assay procedures. Nitrogen balance studies in the dog

were too expensive and time consuming. The extension of the nitrogen

balance studies to castrated rats as another phase in the delineation of the

nature and mechanism of the anabolic action of steroids, showed a logdose-response effect, but again the procedure was not sufficiently simple to

provide a routine assay method (figure 12) (Kochakian 1950). However,

FIGURE 12. The effect of testosterone propionate on the body weight and

nitrogen balance of the adult castrated rat

SOURCE: Kochakian 1950, copyright 1950, American Physiological Society.

46
the comparison of a number of natural steroids indicated testosterone propionate to be the most active steroid; androsterone showed only a trace of

activity. Therefore, the anabolic activity in the urine extract could not have

been due to the presence of androsterone. Furthermore, the urine extract

was much more potent than androsterone in the stimulation of regeneration

of the accessory sex organs of the castrated rat (Kochakian 1938).

Levator Ani Assay

The suggestion by Eisenberg and Gordan in 1950 that the observations of

Wainman and Shipounoff (1941) on the dependency of the “levator ani”

muscle of the rat to testosterone be used as representative of the anabolic

action of androgens gained attention. Hershberger et al. (1953) reported a

quantitative assay procedure in the castrated rat and found that 19-nortestosterone stimulated a greater response in this muscle than in the accessory sex

organs. The “levator ani” muscle later proved to be the sex-linked dorsal

bulbocavernosus muscle, but the assay, because of its inexpensiveness, simplicity, and use of the common laboratory animal, received wide use as a

screening procedure. Overbeek et al. (1961) and Overbeek (1966) have

made a careful study of the assay procedure and stipulate conditions to provide results that will permit a valid comparison of the biological activity of

the steroids.

The synthesis of modifications of the natural compounds rapidly followed,

approximately 2,000, to provide an interesting comparison of chemical structure with biological activity (Overbeek 1966; Vida 1969; Camerino and

Sziacky 1975; Potts et al. 1976; Hilger and Hummel 1964). Many of the

more active compounds (tables 5 and 6) have been further studied and confirmed by nitrogen balance experiments in castrated rats (table 6) by minor

modifications of Kochakian’s procedure (1984) and in monkeys and humans

(tables 7 and 8) (Kochakian 1975; Potts et al. 1976).

The partial separation of the effect of the modified steroids on the “levator

ani” muscle from that on the seminal vesicles or prostate of the castrated

rat was achieved by modifications in the A-ring of both the orally and

parenterally active steroids (tables 5 to 8). The efficacy of the parenterally

active steroids was further enhanced by the esterification of the

hydroxyl to provide an extended activity.

In several instances, the modification of the steroid not only effected a

greater growth of the “levator ani” muscle than of the seminal vesicles or

prostate, but also produced, in the weight of both of the organs, a greater

increase than that produced by the unmodified steroid. In general, as in the

case of the mouse and guinea pig experiments, the partial separation of the

anabolic from the androgenic activity was due partly to a lesser stimulation

of the growth of the accessory sex organs with a greater stimulation of the

growth of the “levator ani” muscle. Esterification of the steroids further

47
TABLE 5. Comparison of levator ani and ventral prostate potencies of

various steroids

Steroid

Relative Potency Ratio

Levator Ventral L.A./

Ani Prostate Prostate

Testosterone Propionate

Testosterone

Methyl testosterone

Testosterone

Methyltestosterone

Dihydrotestosterone

2-Hydroxymethylene methyl-4,

Dihydrotestosterone

Stanazol

1-Methyl dihydrotestaterone Acetate

1-Methyl dihydrotestasterone Enanthate

19-Nortestosterone

Ethyl-19-nortestosterone

19-Nortestosterone Phenylpropionate

Wy3475

100 100 1

14 194 0.07

159 168 0.9

5 9 0.6

9 9 1.0

74 50 1.5

7 5 1.4

13 3 4.3

118 2 7 4.4

59 8 7.4

6 1 4 1.5

80 12 7

220 14 16

340 17 20

SOURCE: Edgren 1963, copyright 1963, Rhodes International Publishing Co.

enhanced the dissociation (table 5). Toth and Zaker (1982) postulated that

reduction decreased the binding affinity of the reduced steroid to the

androgen receptor in the accessory sex organs.

The failure of the “levator ani” assay to reveal a steroid with an increased

effect on the skeletal muscle and minimal or no effect on the accessory sex

organs of the rat could indicate that the selection of this muscle as representative of the anabolic action of testosterone was a poor choice (Kochakian 1975). The translation to clinical usage of the apparent favorable differential action has been a disappointment. Dianabol hydroxy

methylandrost-1,4-diene-3-one), however, appeared to be a promising prospect. At very low doses, it initiated protein anabolism without any apparent

sexual effects (Liddle and Burke 1960; Kochakian 1975).

Early doubt was cast on the selection of the “levator ani” muscle (Nimni

and Geiger 1957) and was supported by the revelation that the muscle in

reality was the sex-linked dorsal bulbocavernosus muscle (Hayes 1968).

Furthermore, its response to castration and testosterone administration is like

that of the accessory sex organs rather than like the skeletal muscles of the

rat (Kochakian 1975) or those of the guinea pig (Kochakian and Tillotson

48
TABLE 6. Summary of nitrogen-retaining, myotrophic, and androgenic

activities of several orally active steroids relative to

methyltestosterone

Steroid

Anabolic Activity Activity Ratio

Nitrogen Levator Androgenic Nitrogen Levator

Retention Ani Activity Retention Ani

Methyltestosterone 1.0 1.0 1.0 1.0 1.0

Methandrostenolone 1.2 0.35 3.4

10 — —

2.1 0.6 3.5

2.3 — —

0.9 0.45 2.0

Oxymetholone 1.75 0.2 8.75

3 — —

1.5 0.3 5.0

Norethandrolone 3.9 0.19 20

2

2 (0-19) — (10.5)

5.6 — —

0.7 0.2 3.5

1.0 0.34 3.1

Methylandrostano- 9.7 0.24 4.0

lisoxazole 2 0.24 8.3

Stanozolol 10.0 0.33 3.0

2 0.33 6

3.2 0.3 10.6

SOURCE: Arnold et al. 1963, copyright 1963, The Endocrine Society.

1951). A more representative tissue, such as a true skeletal muscle, possibly would reveal a steroid that would have a sufficient differential from its

androgenic effect to make it a useful agent for the stimulation of anabolic

activity with a minimal androgenic effect. Although testosterone and many

of its natural metabolites have been assayed for the separation of their

effect on 47 different muscles from their effect on the accessory sex organs

of the guinea pig (Kochakian and Tillotson 1957), none of the large number

of the synthetically modified steroids has been submitted to a similar

examination.

At present the dissociation of anabolic from androgenic activity seems to be

an impossible dream; nevertheless, encouragement may be derived from the

fact that several natural and synthetic steroids already have been recognized

to have a differential between androgenic and several of the other biological

properties of testosterone sufficient to permit beneficial clinical applications

(Kochakian, in press). Furthermore, the separation of the anti-inflammatory

49
TABLE 7. Comparison of steroid protein activity index (SPAI)* of some

newer oral steroids in convalescent adults

Steroid

Number Dosage

of Assays mg/day

Average

SPAI

Testosterone Propionate

19-Nortestosterone

Norethandrolone

Oxandrolone

4-Hydroxy methyltestosterone

Methandrostenolone

Stanozolol

Hydroxy methylandrost-4-ene-

(3.20)-pyrazol

Norbolethone

12 10-25 +6

14 25-75 +9

1 0 30-60 +8

27 10-20 +20

14 15-45 +11

1 6 5-30 +16

1 0 6-12 +29

9 15-25 +30

6 7.5-10 +34

*SPAI=steroid protein anabolic index, the formula of which is:

NBSP=nitrogen balance in steroid period; NISP=nitrogen intake in steroid period; NBCP=nitrogen

balance in control period; NBIP=nitrogen intake in control period.

SOURCE: Albanese 1965, copyright 1965, Fort Orange Press.

TABLE 8. Comparison of the nitrogen-retaining activity of orally

administered steroids in man

Relative Activity

Methyltestosterone 1

Ethyl-19-nortestosterone 2

Fluoro-llP-hydroxy methyltestosterone 3

2-Hydroxy-methylene-4,5-dihydro Methyltestosterone 3

Oxandrolone 6

Methyltestosterone 10

SOURCE: Liddle and Burke 1960, copyright 1960, Helvetica Medica Acta.

activity from the water balance property of cortisone has been effected by

the alteration of the chemical structure to prednisone and particularly to

dexamethasone.

50
Therapeutic and Other Applications

Many of the modified steroids are more active than testosterone (tables 5 to

8). The more active compounds have been used therapeutically in a variety

of conditions (Camerino and Sziacky 1975; Kopera 1976; Kopera 1985) in

man, in animal husbandry (meat production), in sports (Ryan 1976; Wright

1980; Haupt and Rovere 1984; Wilson 1988) and in horse and dog racing,

with controversial results.

ANABOLIC-ANDROGENIC STEROIDS

These steroids became known as “anabolic steroids,” but none of them

exhibited a complete separation of anabolic from androgenic activity. They

are now being more correctly recognized as “anabolic-androgenic steroids”

(Kochakian 1976).

Although the new designation is more descriptive of the two better known

effects of these compounds, it is not all-inclusive. Testosterone, directly or

indirectly through its metabolites, influences the development and function

of practically every organ in the body (Kochakian 1975). The tissues influenced by testosterone can be classified into at least four categories:

Complete Influence. The accessory sex organs and the bulbocavemosus

muscles are decreased after castration to vestigial organs by the loss of

cells and atrophy of the residual cells and are increased by testosterone

administration to at least double their size in castrated and normal

animals.

Supplementary Influence. The kidney, liver, heart, skeletal muscles,

bone, bone marrow, salivary and orbital glands, urinary bladder, skin,

sebaceous glands, and body hair are partially regressed after castration

without an apparent loss in the number of cells and are restored to normal or greater size by testosterone administration.

Reverse Influence. Castration results in an increase in the size of the

thymus, spleen, adrenals, and lymph glands. Testosterone administration

decreases the thymus to a vestigial organ but only partially decreases

the size of the adrenals, spleen, and lymph glands. Testosterone also

causes a loss of scalp hair (male baldness).

Structural and Functional Changes in Specific Cells. The dendritic

length and size of motoneurons in the lumbar region of the male rat are

reduced by castration and restored by testosterone administration (Kurz

et al. 1986; Breedlove 1984; Breedlove 1985). These units are involved

in the mediation of the effect of steroids on the bulbocavernosus

muscles (“levator ani muscle”). The ability of specific cells in the brain

51
to accumulate and metabolize testosterone is less in the castrated male

and the female rat and is enhanced by testosterone administration.

These changes and the resulting metabolites of testosterone are correlated

with behavior (Balthazart and Schumacher 1985). LH and FSH secretion

by the anterior pituitary is enhanced after castration and decreased by testosterone administration. The degrees of responses of the tissues in category

(1) are characteristic and the same for all species, but those in the other

categories vary greatly among the different animal species and, in some

instances, even among strains of the same species (Kochakian 1975). Furthermore, parallel changes are not produced in these tissues by the many

anabolic-androgenic steroids. Some of the less studied, responsive tissues,

e.g., epethelial cells of the gastrointestinal tract, have not been included in

the classification.

What was conceived originally to be a male sex hormone has proven to be

also a general supplementary metabolic agent. Perhaps Parkes (1966) was

more prophetic than he realized when he reacted to the name for the crystalline substance isolated from bulls’ testes as the “dreadful name,

testosterone.”

FOOTNOTES

Most of the material in this chapter was taken with permission from a

lecture presented at a seminar of the Reynolds Historical Society of the

University of Alabama at Birmingham on November 6, 1986 and published in Ala J Med Sci 25:96-102, 1988. The lecture was recorded on

videotape and is available from the Reynolds Historical Library. The

lecture was also presented at the “Panel on Steroid Abuse,” sponsored

by the National Institute on Drug Abuse on March 6, 1989, and is

published in an abbreviated version in Trends Biochem Sci 11:399-400,

1966.

The effectiveness of the transplant attached to the intestine suggests that,

in contrast to the rat, the secreted hormones of the rooster testis as it

passes through the liver is not converted to less active or inactive

metabolites. A pellet of testosterone propionate implanted in the spleen

of castrated rats does not stimulate the regeneration of the accessory sex

organs (Biskind and Mark 1939). In a comparable study with ovariectomized rats, estrogen stimulated estrus, but progesterone implanted in the

mesentery of rabbits did not produce the typical endometrial changes in

the uterus (Kochakian et al. 1944).

Berthold’s experiments and interpretation of the results clearly anticipated the fundamentals of endocrinology, which were enunciated 56

years later by Starling (1905), who named the blood-borne factors “hormones” (excite or arouse).

52
In 1889, considerable excitement and stimulation were generated by the

claims of Brown-Sequard (1889), a respected French scientist, that crude

extracts of testis reversed the effects of old age not only in experimental

animals but also in man, including himself. The claims, on the basis of

our present knowledge, seem untenable. Yet it is remarkable that the

dramatic effects on energy and other physical functions occurred presumably by suggestion. These reports stimulated many other similar

studies with not only crude extracts but also transplants, with equally

spectacular reports (Hoskins 1941; Moore 1939).

The enormous royalties from the patented synthetic procedures permitted

Ruzicka (1973) to pursue his hobby of collecting 17th-century Dutch

and Flemish masters, which he gave to the Zurich Museum of Paintings.

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58
AUTHOR

Charles D. Kochakian, Ph.D.

Professor Emeritus (Experimental Endocrinology)

and former Director

Laboratory of Experimental Endocrinology

Medical Center

University of Alabama at Birmingham

Correspondence to:

3617 Oakdale Road

Birmingham, AL 35223

59
Anabolic-Androgenic Steroids

John A. Lombardo

INTRODUCTION

The use of anabolic-androgenic steroids (AS) by athletes to enhance their

athletic performance has been reported since the 1950s (Wright 1978). Androgen use has spread to different groups of athletes, who use these drugs

for various reasons. The common thread among all these groups, however,

is the goal of enhancing muscular capacities and athletic performance and

being successful (winning). Androgen use by weightlifters in order to enhance strength and thereby perform better in an event in which there is a

direct correlation between strength and success is well known (Starr 1981).

Bodybuilders, who are judged on muscle size, shape, definition, and symmetry, also see a direct correlation between the use of androgens and success

in their activity. The throwers in track and field (hammer, shotput, discus,

and javelin) are another group in which the use of androgens is frequently

reported (Ljungqvist 1975; Todd 1987). Strength is a key factor in the

ability to project a hammer, shot, discus, or javelin further than the competition. In collision sports such as football, in which the lean body mass and

strength as well as the ability to efficiently repair “collision damage” are

significant factors in the ability to succeed, players would benefit from the

use of androgens in order to maximize their gains in these areas. This is

especially true at Division I college and professional levels. At these

levels, there is the greatest fame and financial reward; there are also more

competitors for fewer positions.

In addition to these groups in which the use of androgens has been suspected and fairly well documented, other groups use androgens to allow frequent high-intensity work (Buckley et al. 1988; Anderson and McKeag

1985). Through these increases in the amount and intensity of training,

performance is enhanced. These include the sprinters, middle- and longdistance runners in track, and swimmers who do not wish to gain lean body

mass and in whom strength is not as great a factor. However, these athletes can be more successful if they can sustain training at a higher intensity level, over a longer period of time, or both.

60
Physical appearance has attained an important place in the present-day

society. Self-esteem may be directly related to the size, shape, and attractiveness of one’s body. To overcome genetic limitations or to speed the

process of “bulking up,” many individuals who are not involved in competitive athletics have become users of androgens. These “look-gooders” do

not have a single competitive event or finite athletic career as their goal,

but aim to overcome physical, psychological, emotional, and social limitations-especially low self-esteem. These are long-term problems being controlled or treated by physical conditioning with chemical enhancement; this

method does not solve these problems, but compounds them.

The benefits that are desired by individuals who use androgens therefore

include (1) alteration of body composition (increased lean mass and reduced

fat); (2) increase in strength; (3) increase in endurance; (4) hastened recovery from exercise (ability to perform more frequent or higher intensity

workouts); and (5) enhancement of athletic performance.

The question that needs to be answered is “Do androgens give the benefits

desired by these individuals who take them?” There are two sources of

information on this question. One is the scientific literature, both animal

and human studies; the other is anecdotal evidence given by the athletes and

users. It is important that scientists base their knowledge on accurate data.

Scientifically, the literature is extremely confusing and contradictory.

ANIMAL STUDIES

The animal studies on the effects of androgens on weight and athletic performance are fairly consistent. Studies using male rats and monkeys have

consistently shown no increase in body weight or improvement in performance (Young et al. 1977; Hickson et al. 1976; Richardson 1977). However, the activities generally studied were swimming and running on a

treadmill. These do not compare favorably with progressive resistance

training. Also, there is the difficulty of simulating the psychological drive

of competition in the animal.

Interestingly, however, when castrated males (Kochakian and Endahl 1959;

Heitzman 1976) and females (Exner et al. 1973; Heitzman 1976; Nesheim

1976; Hervey and Hutchinson 1973) are studied, significant increases in

nitrogen retention and lean body mass in these animals have been found

consistently.

HUMAN STUDIES

The literature on the effects of androgens on lean body mass, strength, and

aerobic capacity in humans presents a great deal of contradiction and

confusion.

61
A number of studies have shown an increase in aerobic capacity as measured by VO2 max (the maximum oxygen uptake as measured by a maximum exercise test) with the use of androgens (Albrecht and Albright 1969;

Johnson and O’Shea 1969; Keul et al. 1976). However, there are also a

number of studies using VO2 max as a criteria that have shown that there

is no change in endurance with the use of androgens (Fahey and Brown

1973; Hervey et al. 1976; Johnson et al. 1972; Johnson et al. 1975). The

theory being proposed when these studies were begun was that androgens

would stimulate the bone marrow and therefore increase the oxygen-carrying

capacity of the blood by increasing the red cell mass.

Two questions arise when looking at increases in endurance and androgens:

1. Is the VO2 max that was used in these studies an accurate indicator of

success in endurance events?

2. Is it sensitive enough to record changes that would be significant in the

results of an endurance event?

The answers to these questions are unknown.

A number of training studies have shown no significant increase in lean

body mass with the use of androgens (Crist et al. 1983; Fahey and Brown

1973; Fowler et al. 1965; Golding et al. 1974; Stromme et al. 1974),

although other studies have shown significant increases with the use of

androgens (Hervey et al. 1976; Hervey et al. 1981; Stamford and Moffatt

1974; Ward 1973; Johnson et al. 1972; O’Shea 1971; Loughton and Ruhling

1977) (table 1).

Some more contradictory findings are discovered when the literature on the

effects of androgen on strength training are reviewed. Some studies show a

significant increase in strength with androgen use (Ward 1973; Stamford

and Moffatt 1974; Hervey et al. 1981; O’Shea 1971), while others show

there are no significant differences between control and androgen groups

(Golding et al. 1974; Stromme et al. 1974; Hervey et al. 1976; Fahey and

Brown 1973; Crist et al. 1983; Loughton and Ruhling 1977; Fowler et al.

1965) (table 1).

Hervey’s two studies show a classic comparison. Hervey and colleagues

(1976) found significant increases in fat-free mass but no significant increases in strength in a double-blind crossover study using physical education

majors. However, Hervey and associates (1981) found significant increases

in not only fat-free mass but also in strength when the study group was

experienced weight trainers. Findings such as these lead the investigators to

ask why there are so many differences in the studies reporting the ergogenic

effects of androgens. Some of the reasons for these differences include the

following.

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TABLE 1. Training and performance studies using AS

KEY: Mod.=moderate; Frequency=frequency of workouts (days); Met.=methandrosteneolone; Nand.=Nandrolone; Exp.=experienced weight

trainer, Inexp.=inexperienced weight trainer; LBM=lean body mass; SF=skin folds; Ant.=anthropometric; UW=underwater weighing;

BWT=body weight.
1.

2.

3.

4.

5.

The weighr training experience of the subjects. Many of the studies

utilize inexperienced weight trainers who will make significant early

gains when beginning a strength training program. These large gains in

strength will not be significantly increased by the androgens in this

early part of the program. Experienced weight trainers, on the other

hand, have plateaued, and their gains in strength are smaller with continuation of their regular training. In these individuals, drug-assisted

gains that might be small in comparison to the larger gains by the

novice lifter will be significant compared to the smaller gains that could

be attained in a 6-week training study (Wright 1978; Yesalis et al.

1989).

The intensity of training. Many studies utilize low-intensity, short duration, and low-frequency workouts, which are not comparable in terms of

physiologic and biochemical effects to the high-intensity, long duration,

and high-frequency workouts performed by many athletes who use

androgens. These are not fair comparisons when assessing the efficacy

of androgens on high-intensity weight training programs (Wright 1978;

Yesalis et al. 1989).

Dietary controls. Many of the studies did not control dietary intake.

There was no mention of the amount of calories or the percentage of

carbohydrates, protein, and fat in the diet of the subjects. These factors

are extremely important when one is looking at a study measuring lean

body mass and strength as indicators of efficacy (Wright 1978; Yesalis

et al. 1989).

Dosage of the drug. The athletes are using dosages 10 to 20 times

therapeutic levels. No studies have approached these doses. Ethically,

these studies could not be done, since the long-term effects of these

doses are not known. The question of benefits of the high-dose and

multiple drug regimens commonly used by the athletes remains unanswered (Wright 1978; Yesalis et al. 1989).

Specificity of testing. Some of the studies used isometric or isokinetic

testing with isotonic training. The sensitivity and specificity of these

measurements have been questioned (Wright 1978; Yesalis et al. 1989).

Table 2 has a review of these factors and others that affect the results of

studies (Yesalis et al. 1989).

WOMEN AND CHILDREN

There have been no studies performed on two groups of individuals in

which the use of androgens has reportedly increased. These are young

males and women. Studies in these two groups pose an ethical problem.

However, in view of the animal studies on castrated males (Kochakian

64
TABLE 2. Reasons for lack of consensus on AS effects on health and

performance variables in human subjects

Subjects

Diet

Training Programs

Testing Programs

Drugs

Study

Drugs Mechanisms

Action

Dosages

Length of Study

Placebo Effect

Data Interpretation

Legal and Ethical

Issues

The number of subjects, their experience in weight

training, and their physical condition at the start of

the study varied.

Most not controlled or recorded.

Volumes and intensities varied.

Strength often not measured in the training mode.

Body compositions often assessed from skinfold estimales. Health effects often mismeasured (not organ

specific) or not measured.

Variable, and few have reported on athletes selfadministering multiple drugs.

Some crossover, some single blind, some double

blind, some not blind, some no controls.

Unknown and varying degrees of anabolic, anticatabolic, and motivational effects depending upon the

circumstances.

Variable, only two studies administered dosages

approximating those currently used by competing

athletes.

Variable and generally short; very few have reported

on prolonged training and AS self-administration.

Well documented for most drugs; yet most data suggest that athletes can readily detect AS administration

making it virtually impossible to conduct blind

studies.

Variable, dependent upon the background and experience (scientific, clinical, athletic, administrative), general perspective, and goals of interpreters.

Preclude design and execution of well-controlled

studies using doses and patterns of administration of

drugs with unknown long-term effects in healthy

volunteers in a manner comparable to those of many

current AS users.

SOURCE: Yesalis et al., in press.

65
and Endahl 1959; Heitzman 1976) and females (Exner et al. 1973;

Heitzman 1976; Nesheim 1976; Hervey and Hutchinson 1973) and the

effects of andmgens, a positive ergogenic effect can be expected.

SUMMATION

After a critical review of the literature and in view of the overwhelmingly

consistent anecdotal evidence, I wholeheartedly agree with the statement of

the American College of Sports Medicine Position Stand (1984) on the Use

of Anabolic-Androgenic Steroids in Sports when it states that:

Anabolic/androgenic steroids, in the presence of an adequate diet,

can contribute to increases in body weight often in the lean mass

compartment . . . The gains in muscular strength achieved through

high intensity exercise and proper diet can be increased by the use

of anabolic/androgenic steroids in some individuals.

It is extremely difficult to make any statement about endurance other than

stating that, using VO2 max as an indicator of endurance, there is not significant evidence to show that anabolic-androgenic steroids improve

endurance.

MECHANISM OF ACTION

A number of mechanisms have been proposed for the actions of androgens

on muscular strength and lean body mass. These include (1) increase in

protein synthesis; (2) inhibition of the catabolic effect of glucocorticoids;

(3) effects on central nervous system and neuromuscular junction; and

(4) placebo effect.

Rogozkin (1976; Rogozkin 1979) has shown that exercise increases the rate

of transcription as measured by increased RNA polymerase activity. He has

also shown that androgens further increase the rate of transcription over that

found with exercise alone.

The interaction between the catabolic glucocorticoids and the anabolic

androgens is not completely understood. However, there are some connections that are known. Goldberg (1969) has shown that glucocorticoids are

catabolic, causing protein degradation and muscle atrophy. Konagaya and

associates (1986) have shown that glucocorticoid blockade decreases muscle

atrophy. Doerr and Pirke (1976) have shown that cortisol causes a decrease

in the nocturnal rise in testosterone. Snochowski and coworkers (1981)

have shown that there are separate receptors for androgens and glucocorticoids, but they did not find competitive binding for these receptors. Mayer

and Rosen (1975) have shown that testosterone can displace dexamethasone

from glucocorticoid receptors. Many studies have shown that physical and

psychological stress can decrease testosterone and increase cortisol levels.

66
This has been shown by Aakvag and colleagues (1978) in Army recruits

undergoing severe physical and psychological stress. Wheeler and associates (1984), Guglielmini and coworkers (1984), Villaneuva and colleagues

(1986), Urhausen and Kindermann (1987), and Mather and associates (1986)

have shown that in strenuous exercise for more than 3 hours, there is an

increase in cortisol and a decrease in testosterone, while with exercise for

less than 3 hours, there is an increase in testosterone. This is all with

submaximal work. No work has been done in the area of chronic exercise

of 2 to 3 hours on successive days, although this is the training regimen of

many athletes at this time. Based on this evidence, one can speculate that

one of the actions of the androgens is inhibition of the catabolic effect of

glucocorticoids in athletes undergoing strenuous physical training. This

inhibition may occur by maintaining a steady-state level of androgen by

exogenous supplementation. More research is needed in this area.

There are known to be androgen receptors in both the brain and alphamotor neurons, the size and number of which can be influenced by the use

of androgens (Sar and Stumpf 1977; Stumpf and Sar 1976). There has

been an implication that androgens can facilitate the release of acetylcholine

at the neuromuscular junction and elevate monoamine levels in the central

nervous system (Vyskocil and Gutmann 1977). Electroencephalographic

recordings have shown changes in individuals given anabolic steroids (Itil

et al. 1974; Itil 1976). Aggression has been associated with increases in

testosterone in both animals (Simon et al. 1985) and humans (Persky et al.

1971; Kreuz and Rose 1972; Ehrenkranz et al. 1974; Scaramella and Brown

1978). Brooks (1980) has suggested that this increase in aggressive behavior is a mechanism for the action of androgens. Perhaps the increases in

aggression and energy that the athlete feels may be a result of the neurologic changes previously discussed.

The placebo effect has been suggested as the mechanism of action of androgens by Ryan (1981). This has been shown to be effective in one study

(Ariel and Saville 1972).

The mechanism of action of androgens is most likely not any one of these

but a combination of them.

ATHLETIC PERFORMANCE

Do androgens enhance athletic performance? To answer this important

question, it is necessary to understand the multifactorial nature of athletic

performance. Rarely, if ever, is there a solitary factor that contributes to

success; success is a result of optimal development of many factors

(Lombardo 1987) (table 3). The following is a list of the factors contributing to athletic performance.

67
1. Level of conditioning. Conditioning includes not only strength but also

flexibility and endurance (both cardiovascular and muscle endurance).

The importance of these various aspects of conditioning differs among

sports.

2. Skill. Development of skill is a learned behavior based on genetic predisposition and repetition (practice). Some sports successes may require

not only development of gross motor skills but also fine and complex

motor skill development. This is an extremely important factor in success in most sports.

3. Diet. One of the most neglected areas, until recently, is nutrition. An

athlete’s diet provides the fuel that the athlete needs to perform. A

high-performance athlete, like a high-performance car, needs premium

fuel. The fund of knowledge in this area is rapidly expanding and the

role of diet is increasing as the field of nutrition develops.

4. Psyche. Many phrases, such as “getting up for a game,” “raising the

intensity level,” and “concentrating,” have long been a part of sports.

As the field of psychology applies its knowledge and energy to the

world of sports, new phrases such as “focus,” “visualization,” and

“relaxation” have been added to sports jargon. This is another rapidly

developing area that is a major factor in athletic performance.

5. Opponent. Often the individual or team against whom one is competing

makes a difference. Due to style of play or strengths and weaknesses

of an opponent (commonly referred to as “matchups”), performance and

success is affected.

6. Arena. The home field advantage is a real phenomenon that occurs in

the world of sports. It may be the influence of the spectators, the

familiarity with environment, maintenance of daily routine, or a combination of these and others, which gives the home team an edge.

7. Sleep. Proper rest is important in the performance of any task, especially when complex motor skills are involved. Because of pre-event

anxiety, a new environment, or the circuslike atmosphere surrounding

certain events, athletes may have difficulty sleeping.

8. Drugs. Drugs can have two effects. If the athlete is abusing illicit

drugs, such as cocaine or marijuana, or legal drugs, such as alcohol, his

or her athletic performance can be adversely affected. The ergogenic

drugs are used to enhance performance. Some of these drugs and procedures will positively affect the performance of the athlete and potentially make a difference in the outcome of an event.

68
9. Genes. The most important factor and one over which the athlete has

absolutely no control is genetic makeup. Many of the characteristics

that are key to success in sports are a result of these genetic expressions. These have been referred to as “natural ability,” “raw talent,” or

“God-given ability.”

In events in which centimeters or milliseconds are the difference between

success and failure, how much does manipulation of one factor contribute?

When 20 to 30 pounds of lean mass can make the difference between a

professional contract worth over $100,000 a year and the adulation and

fame of such a career and the $40,000 to $50,000 a year and routine of

many jobs, how many athletes will use androgens to reach their goal?

CONCLUSION

The individual who takes androgens desires an increase in strength, lean

body mass, or decreases in recovery time between workouts to enhance

athletic performance or to “look good.” The scientific studies that have

been reported in this area are fraught with problems. However, it can be

concluded that androgens are associated with increases in strength and lean

body mass, especially in experienced weight trainers, when performing highintensity work in the presence of an adequate diet. This can be concluded

through the available scientific evidence and the overwhelmingly consistent

anecdotal reports of the athletes. Recovery time is based solely on anecdotal evidence, since it has not yet been studied.

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AUTHOR

John A. Lombardo, M.D.

Professor and Chairman

Department of Family Medicine

The Ohio State University

1114 University Hospitals Clinic

456 West 10th Avenue

Columbus, OH 43210

73
Anabolic Steroids: An

Ethnographic Approach

Paul J. Goldstein

INTRODUCTION

The intent of this chapter is to make two sorts of contributions. The first

is conceptual—to provide a sociological framework and a substance abuse

perspective from which the emergent social problem of anabolic steroid misuse may be viewed. The second contribution is to present some preliminary

empirical findings from participant observation research that was done in

health clubs and gyms in the New York City area. As part of this effort,

interviews were conducted with bodybuilders, personal trainers (PTs), and

gym staff.

The poor quality of available data on the use and effects of anabolic steroids and their frequent contradictory nature is consistently bemoaned. There

is clearly a need to advance beyond anecdotes, rumors, and locker room

gossip. Yet, it is important to realize that reports of such “gossip” provide

an insight into the manner in which users perceive anabolic steroids, their

motivations for use, and both their functional and dysfunctional experiences

with these substances.

The approach employed herein is part of a methodological tradition common

to the study of drug abuse. It focuses on understanding users’ interpretations of the etiology and meaning of drug abuse within their own sociocultural environment. This tradition, with its roots in phenomenology, is

usually called qualitative methodology, or ethnography. Its primary focus is

on users’ perceptions of meaning and the contexts of initiation and sustaining of drug-abusing behavior (McBride and Clayton 1985).

Data about the nature and scope of anabolic steroid use are difficult to

collect, and becoming more so, owing to recent upgrading of penalties for

both steroid possession and sale. The Anti-Drug Abuse Act of 1988 upgraded Federal penalties in this area. Some States had preceded the Federal

Government in this regard, e.g., California; others have followed suit since

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the Federal legislation; others are considering doing so. For example,

Georgia has recently upgraded penalties for steroid trafficking to a thirddegree felony status. This has reportedly made steroid users and traffickers

in that State more reluctant to talk to researchers. According to one social

scientist, who had been interviewing high school and college steroid users,

mainly football players, many participants in competitive athletics will no

longer discuss their steroid experiences with outsiders because they are

afraid of being turned in (John R. Fuller, personal communication, January

1989).

The key informants, or “guides,” who have been introducing me into various health clubs and gyms in New York City and Long Island all cautioned

me against publicly declaring any special interest in steroids. I was told

that everybody would just “clam up” if they learned that was my primary

interest. I have been presenting myself simply as a sociologist interested in

the workout and fitness world.

There are three principal areas in which information about steroid use

and distribution must be generated: epidemiology, distribution, and

consequences.

EPIDEMIOLOGY

Some sources provide a rough indication of the extent of steroid use. The

Mayo Clinic estimated more than 1 million regular steroid users in America

(Couzens 1988). It has been suggested that as many as 96 percent of professional football players may have taken steroids (Jacobson 1988; Schuckit

1988). It has also been suggested that between 80 and 99 percent of male

bodybuilders have taken steroids (Schuckit 1988, Hecht 1984; Lee 1985).

There has been talk of increasing steroid use among female bodybuilders, as

the trend in that sport has moved away from the goal of obtaining a

“dancer’s physique” towards increasing muscularity (Lee 1985).

Buckley and colleagues (1988) found that 6.6 percent of a national sample

of 12th-grade males reported using or having used anabolic steroids. Other

scattered high school level epidemiological information includes an unscientific survey by Miami’s South Plantation High School student newspaper in

1986. It sampled 200 of the school’s 2,000 pupils. Sixty-five percent

knew someone who was taking steroids (Miami Herald 1988). This sort of

statistic is important because other research in the substance abuse field has

shown that having drug-using peers is one of the best predictors of drug

use. Eleven percent of high school football players in Arkansas were

reported to be using anabolic steroids (Herrmann 1988). Thirty-eight percent of high school football players surveyed in Portland, OR, knew where

to get steroids (Charlier 1988).

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Many individuals who are informed about the high school scene stress the

importance of the steroid issue. Fred Rozelle, Executive Secretary of the

Florida High School Activities Association, stated that “We face a lot of

problems, but we feel that the number one concern is steroids” (Phillips and

Lohrer 1989, p. 4D). Don Leggett, a Food and Drug Administration (FDA)

official, said, “Bulging muscles are in. Guys want to look good at the

beach. High school kids think steroids may enhance their ability to get an

athletic scholarship, play professional sports, or win the girl of their heart.

Steroid use in this country has spread down to general people” (Penn 1988,

p. A1). A Philadelphia physical therapist, who works with athletes, stated,

“People think the cocaine issue is big. It’s not as big as anabolic steroids.

Among kids, it’s epidemic” (Charlier 1988, p. A20).

Within the context of epidemiology, substance abuse researchers have

tended to emphasize the concepts of a drug-using “career” or a “natural

history” of drug use. Such careers, or natural histories, may be conceptualized as having three steps:

1. Initial stage of exploration.

2. Continuing stage, in which use is regular, and the identity of the user is

established.

3. Cessation from use (usually preceded by growing ambivalence towards

regular use and unsuccessful attempts at detachment).

Exploration Stage

Steroid use may be viewed as a search for a competitive edge in athletics.

Many athletes have a win-at-any-cost mentality. Of course, this mentality is

common to areas other than athletics. The rhetoric in these other areas is

remarkably similar to the steroid rhetoric. For example, I recently received

a brochure for a February 1989 conference on “Achieving Excellence.” The

conference included seminars in financial planning, organization, innovation,

and leadership skills. One of the presenters was Nancy K. Austin, author

of the 1985 publication A Passion for Excellence: The Leadership Difference. The brochure announced her presentation as follows:

Nancy K. Austin highlights how “winners”—even those in

mundane, decaying, battered or regulated environments—

create and sustain their competitive edge. They don’t just

do a percent or two better than the rest, they do hundreds of

percentage points better . . . This presentation will highlight

those who have achieved extraordinary results under fire and

how they succeeded while others faded away.

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I suspect that if a pill or an injectable were available that was touted to

guarantee such a competitive edge in business, or in grant writing, it would

be used eagerly. Steroids function in this fashion with regard to athletics

and body development. Of course, what happens is similar to the arms

race. Those with early access to an innovation do have an edge. Soon,

however, the ‘have nots’ catch up. In the case of steroids, the word now is

that everybody is doing it and competitive steroid users no longer have an

edge; they must use just to stay even with their rivals.

There can be no question that there has been an escalation of muscularity in

those areas in which muscularity is important. Professional athletes are

bigger and stronger now than they ever were. The old cinema muscle men,

like Victor Mature, look fairly puny compared to modem titans like Arnold

Schwarzenegger. Charles Atlas, in his famous advertisements of three

decades ago, looks like a pretty ordinary guy today. Competitive bodybuilders claim that persons who won major titles 10, or even 5 years ago,

would have little chance against today’s competitors. One bodybuilder

claimed that today “the only way you can make even the beginnings of an

amateur is by taking steroids.”

The use of performance enhancers in athletic competitions are neither new

nor limited to steroids. Participants in 6-day bicycle races in 1879 were

alleged to have prepared as follows: the French used a mixture made from

a caffeine base; the Belgians ate sugar cubes dipped in ether; others drank

alcohol cordials; and sprinters used nitroglycerine (STASH 1978). In 1886,

a British cyclist died from using a drug containing ephedrine, a stimulant

alleged to mask fatigue and remove physiological restraints intended to prevent overexertion (STASH 1978). In remarks to the January 1984 meeting

of the FDA Endocrinologic and Metabolic Drugs Advisory Committee,

Thomas Murray of the Hastings Center noted that performance enhancers

were popular at the turn of the century. Vin Muriani, a widely used mixture of coca leaf extract and wine, was advertised as the wine for athletes.

It was reportedly used by French cyclists and by a champion lacrosse team

in Peru (Hecht 1984).

A variety of other substances or techniques are employed by athletes who

try to give themselves an edge on the competition. These include special

dietary regimens, vitamins, bicarbonate loading (for short events), caffeine

loading (for long events), and such psychological techniques as hypnosis.

Some gyms sell a wide variety of products to their clientele. A blender

will mix up an Aminofuel or Carbofuel drink for $2. For an extra $1 a

banana will be added. Fruit punchlike concoctions that are billed as being

rich in amino acids are sold for $2. In speaking with gym regulars, it

becomes clear that some persons lack the sophistication to discriminate

between such products and steroids.

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For young high school athletes, getting big and strong enough to compete

on the collegiate level may be vital for their future. Don Reynolds, chairman of the drug abuse committee of Florida High School Activities Association, stated, “I think there is a lot more steroid use than we think there is.

High schools is where it’s at. That’s where the competition for college

scholarships begins” (Phillips and Lohrer 1989, p. 4D). Parents may contribute to this pressure to obtain athletic scholarships.

Steroid use should also be viewed in the context of the search for substances that increase feelings and appearances of strength. Steroid research

has been likened to the search for a “superman formula” (Schuckit 1988).

Stories of great strength have intrigued our imaginations for centuries. We

have television series like “The Bionic Man”; comic book superheroes like

Superman and the Hulk; biblical supermen like Samson; legendary strongmen like Hercules; that staple of carnivals, the sideshow strong man; professional wrestlers; a long list of male movie stars, such as Victor Mature,

Steve Reeves, and Arnold Schwarzenegger, whose muscular bodies were

their main attraction for the ticket-buying public. Weight-lifting competitions are popular Olympic events. Bodybuilding contests attract large audiences and are frequently shown on cable television. Children watching

Saturday morning cartoon shows aspire to the impossible-to-achieve muscularity of superheroes such as He-Man. Popeye’s spinach eating produces

the great strength that allows him to vanquish his comical opponents.

Clearly, there is something about muscular development and great strength

that taps into something very basic to the male mentality. Sexual attractiveness is part of this. Young boys want to impress the girls with their

muscles. One young man that I spoke to in a gym remarked that it is

tough for high school kids when a muscular guy takes their girl away.

Some boys feel that they cannot compete with a guy who has a great body.

It is a real incentive for them to try to develop their own bodies as fast as

possible. Steroids present the promise that such aspirations can be achieved

through chemistry.

In health clubs and gyms, I have observed the frustration felt by those who

are working out intensely, yet who are not achieving substantial results.

This frustration is intense for persons who are working out next to someone

who is enjoying good results, i.e., getting bigger and stronger much more

rapidly than they are. Such frustrated persons become targets of pushers

who offer a short cut to physical development. Pushers may compliment

persons on their successful workout regimen but stress that, if the person

continues to work out at such a pace, it may take 5 or 6 more years of

struggle and pain before the person will look that certain way. Of course,

there is a way to get there a lot sooner. That way is, of course, the use of

anabolic steroids.

78
Successful bodybuilders, especially competitors, are usually approached in a

different fashion. Pushers of steroids may begin their sales pitch to successful bodybuilders by saying such things as the following:

1. “You’re looking good, but you look unfinished. You need something in

order to get that finished look.”

2. “You look good enough to enter a competition. But you don’t look

good enough to win. You’ll need something else for that.”

However, a former steroid user and PT who has worked with adolescents

cautions against attributing most steroid use to competitive bodybuilders or

other athletes.

Forget that! I think the majority of people who use steroids

don’t have any idea of going into a contest. Let’s not go in

a direction that these steroids arc being used by bodybuilders

who aspire to be Mr. Universe. That’s baloney. Steroids

are being used mostly by men and women and young kids

just for their ego.

. . . I see the kids using it today. It just blows my mind.

They are using at a young age for one reason only, for their

egos. Whcthcr to get dates, whether to be part of a gang

. . . The peer pressure is enormous for strength. If you’re

not a rock singer, you damn well better be a muscle man.

. . . once bodybuilding hits you, it doesn’t matter. Once the

idea of strength and size, and feeling good about yourself

and being admired and looked at hits you, you could be

from anywhcrc.

Users also describe a euphoric state produced by steroids. One user said,

“The anabolics make you feel good mentally. They are a high.”

Continuing Stage

For whatever reasons people begin steroid use, it appears that the addictive

nature of the substance. the habituating effect of the workout routine itself,

and the feelings of muscularity and strength that arise create a syndrome of

continued and habitual use.

Addiction is a difficult concept to operationalize. Previous research with

heroin users indicated that individuals who are typically classified as heroin

addicts, in fact, have patterns of use that contain many peaks and valleys,

and days of nonuse arc frequently intermixed with days of use (Johnson

et al. 1985). In other words, operational definitions of addiction, especially

79
those employing a medical model, may be of limited value in predicting

actual behavior of substance users in their environments over time.

The classic behavioral definition of addiction was that advanced by Alfred

Lindesmith (1947). Essentially, he argued that persons might begin using a

drug for a variety of reasons, usually involving positive feelings produced

by the drug. Individuals might continue to use the drug for this reason.

However, real addiction sets in when the individual experiences negative

feelings, such as pain or dysphoria in the absence of the drug, attributes

these negative sensations to the lack of the drug, and begins to administer

the drug to ward off the negative sensations rather than attempting to

achieve a positive feeling.

A variety of knowledgeable sources, including Robert Voy, have argued that

an addiction syndrome exists with regard to anabolic steroids (Jacobson

1988; Schuckit 1988). Craig Whitehead, who directed the drug rehabilitation unit of the Haight-Ashbury Clinic, stated, “The dependence many

people develop on steroids is classic” (Cowart 1987a, p. 427).

The addiction syndrome that has been described to me by habitual steroid

users harmonizes well with Lindesmith’s definition. Users claim that steroids function to anesthetize the body. Steroids enable the user to work out

intensely without feeling pain. However, when the user stops taking steroids, muscles and joints (especially) become very sore. Old injuries or

strains that were not even noticed before begin to be very painful. The

ex-user cannot work out anywhere near the level that he or she did while

taking steroids. It is just too painful now. Indeed, common everyday

physical tasks may become difficult and painful. Psychological feelings of

depression set in. If the user returns to steroids, the pain disappears. The

depression disappears. One’s body feels good again. One can return to

one’s workout regimen.

A PT whom I interviewed described some manifestations of this addictive

state of mind.

I hear it all the time. I heard it just yesterday . . . three

guys . . . I asked them how they’re doing. They said,

“Well, good. I just got back from skiing. I can’t wait to

get back on the stuff.” That’s all you hear. And another

guy, “How you been?” “Good, doing all right, you know,

maintaining, but in 2 weeks I got all my stuff together now,

I’m going back on the stuff.” These arc not competitive

bodybuilders. These are just gym guys who are printers and

going to school.

A steroid user described to me the manner in which steroids affect the

psychology of users and function to perpetuate use.

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If you never use [steroids], you use your natural inclination

to drive forward. Whatever may have been your driving

force, whether it was to show your father that you can succeed in life, or whether it was being insecure and needing to

have assurance from the world that you can be somebody

. . . If you have that burning up so hard in you, then you

can make it with that. But once you get on the steroids,

you’ll lose that ability to call upon self. It then controls

you, and you actually lose the ability to ever do that again.

There’s a part of you that goes and never comes back . . .

If you do it for one little 12-week cycle, and you can

manage to get off it, and you say, “this was not for me,”

God bless you. But if you’re stuck on that stuff for a year,

you’re hooked for life. You’re no longer a virgin . . .

you’re finished. You forget a lot of the innocence that you

had. Or a lot of the natural drive that is in there. ‘Cause

this stuff gives you a new level of aggression and power

that you can’t achieve on your own by thinking it out on

your own anymore. You just can’t. You try! Like you’re

lifting a dumbbell, and you give up. “I ain’t going to do it.

I’m leaving.” But you go to the gym when you’re on that

stuff, and everything is going good, and your levels are real

built up high . . . You take that weight, 40 pounds heavier,

and you do it. Screaming! Crazy joy! Ecstasy! It is like

having an orgasm. It’s better. You don’t have any idea

what it’s like . . . It’s total orgasm. Oneness. It is like a

one cell creature reproducing itself. It’s just incredible . . .

The fire. the escalation of joy and excitement, the conquering of it. And it’s nowhere near as exciting when you’re

off the stuff as when you’re on it. You just feel so good

that you just want to buy 20 bottles more. That’s the way

it is. It’s crazy.

Some users say that feelings of power become so associated with steroid

use that persons begin to use steroids for social situations in which they

feel insecure. For example, adolescents may take steroids before going to a

party because they feel nervous, and the steroids give them a sense of being

able to handle the situation. In this case, the drugs address basic feelings

of inadequacy. One user stated, “You get to believe in the drugs so much,

that if you need a crutch, you will take a few extra pills.”

Several factors appear inextricably linked in a steroid addiction syndrome.

For example, steroid users find it almost impossible to analytically separate

the drug from the workout itself. They say that one would just not exist

without the other. Without the drug, there would be no workout. Without

the workout, there would be no need for the drug. It should be noted that

persons who do not use steroids, yet who are also committed to working

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out, frequently talk about the addictive nature of a workout regimen. But

serious steroid use and habitual working out seem to dissolve into a unitary

lifestyle. One user vividly described this reality.

You get into the vicious cycle of doing more and more and

more and doing new sophisticated stuff . . . Then once

you’re on the stuff, you feel differently. See you’re on it

and all of a sudden you’re making the gains . . . And

you’re strong. And you have no pains like you had before.

You’re very euphoric. You kind of feel indestructible. And

nothing matters. They can steal your car. You know, so

what? If you caught the guy, you would kill him. But if

you didn’t, all right, the car’s gone. As long as the gym is

open . . . Don’t steal your food. Don’t steal your steroids.

But you can take my car, my wife, take anything you want.

That’s really how you become. And you don’t know it.

You’re in this fog.

The gym culture itself tends to perpetuate steroid use. The gym culture is

very competitive. Bodybuilders are always comparing themselves to other

gym regulars or to the proverbial “new guy” as to who is biggest and

strongest. Persons who are getting bigger and stronger may feel puny and

weak, because a gym buddy is progressing faster than they-lifting more

weight or adding more lean muscle. Girls hanging around the gym gravitate towards the biggest, strongest guys. Friends exert pressure to get back

on “the stuff.” The grapevine is filled with gossip about who is selling

what. Special “deals” may be offered. The peer pressure to continue

steroid use is strong.

Cessation From Use

Steroid users that I have talked with tend to cease their use for one of two

reasons. Most younger persons seem to “mature out” when they reach an

age at which career, marriage, and all the trappings of conventional lifestyles become more highly valued than a macho image of great strength and

size. Older, long-term steroid users tend to quit only when their health is

seriously threatened. A long-term steroid user, who had been a highly successful competitive bodybuilder, claimed to have almost died from liver

problems about 3 years ago.

After I got sick, I had to come off it, or I never would have

come off it. I would never have come off of steroids if I

didn’t get sick. Never! I’d still be using it today and trying to compete at 40. But I was forced. I almost died. So

you choose between that and living. You find out living is

not so bad.

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DISTRIBUTION

Until recently, black market sale of steroids was estimated at more than

$100 million per year (Couzens 1988; Penn 1988; Kahler 1989). However,

this estimate was recently upgraded to between $300 and $400 million per

year by Leslie Southwick, Deputy Assistant Attorney General (1990).

It has been estimated that more than half the steroids smuggled into the

United States are counterfeit, frequently bearing the names of reputable

manufacturers. Most supplies are alleged to come from Mexico (Penn

1988; Kahler 1989). These counterfeits are often produced in crude, unsanitary laboratories and are of dubious purity. Counterfeit steroids are also

being manufactured in this country, in makeshift laboratories that are springing up around the United States. My own sources in gyms in the New

York City area have suggested that as much as 80 percent of the steroids

that they encounter are counterfeit.

One clandestine laboratory, Fountain Valley Research Laboratories, Inc.,

located 35 miles south of Los Angeles was shut down recently. It produced what were labeled as East German steroids. The labels read:

Eigentum Der DDR-Versenden Gesetzlich Verboten—“Property of GDR,

export prohibited.” The steroids fetched $180 per bottle. “East German

steroids are rated the best,” said a California lawman. “Their athletes have

the reputation of being better, bigger, and stronger” (Penn 1988, p. A20).

The Department of Justice has recently expressed an interest in the use and

trafficking of steroids. Assistant Attorney General John Bolton stated the

following.

Not only are we concerned with the risks associated with the

unprescribed use of legitimate steroids (by adolescents), risks

such as upsetting the hormonal balance and stunting growth,

but of equal or greater concern is the unauthorized use of

illegitimate steroids which have no FDA approval and are

made under less than sanitary conditions. We think it’s a

very dangerous problem . . . You will see a lot more prosecutions. Prosecution of steroid cases is a priority for the

civil division. (Kahler 1989, p. 29)

Justice officials have reportedly obtained Federal convictions or guilty pleas

against 60 steroid traffickers in the 2 1/2 years preceding October 1988.

About 120 more persons face charges (Penn 1988). In December 1988,

former British Olympic medalist David Jenkins was sentenced to 7 years in

prison followed by 5 years probation and was fined $75,000 for his role in

arranging for a Tijuana plant, Laboratorios Milano de Mexico, to produce

anabolic steroids and smuggle them across the border for distribution in the

United States (Kahler 1989).

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There are indications that traditional drug traffickers are involved in steroid

distribution. There are also indications that they are conducting their business in the traditional ways of drug traffickers The following account

appeared in the Wall Street Journal.

According to criminal charges filed in San Diego last year,

when a man in Phoenix reneged on a steroid deal, his

supplier sent an emissary named Leonard T. Swirda.

Mr. Swirda took along an accomplice carrying a 12 inch

club, a double edged knife and leather gloves weighted with

metal, says the indictment, which accuses Mr. Swirda of

beating and cutting the dealer. In a separate action,

Mr. Swirda last May was indicted for cocaine trafficking in

Spokane, Washington. (Penn 1988, p. A1, A20)

The underground world of steroid use and trafficking is prone to the same

sorts of hustles and scams that we are more used to hearing about with

regard to street drugs, such as cocaine or heroin. One common hustle concerns the difference in price between generic and name brand steroids.

Brand names, of course, fetch a higher price. Inexperienced users are frequently sold generic steroids, but are charged brand name prices.

A former steroid user, speaking of the great prevalence of bogus steroids,

recalled a product called Bolasterone.

Bolasterone. It swept the country. They made millions.

Millions, these California guys. All it was, was vegetable

oil, a little bit of testosterone, and liquid aspirin. And they

called it Bolasterone. And they hyped it up so much. It

was selling for $250 to $275 a bottle. You would do anything to get this stuff. [They said] “Mr. Olympia used it!

Secretly.” I tell you, Madison Avenue could not have come

up with a better campaign to sell this stuff . . . If you had a

bottle of it, I me-an you could sell it for anything . . . [It

was hyped] through the grapevine. Underground. The network is incredible. From gym to gym to gym . . . They’ll

say, “Did you see M.? He put on 15 pounds in a week.”

“What the hell is he using?” “Don’t say anything. He’s

using Bolasterone!” “Wow. What the hell is it? Can you

get it?” “Yeah, I can.”

It is difficult to estimate actual costs to users because of a wide variability

in patterns of use. Serious long-term uses may spend as much as $200 to

$400 per week on steroids and the accompanying pharmacopoeia. Since

such users may go on cycles of steroid use lasting 12 to 14 weeks, each

cycle can cost in the thousands of dollars. Users are generally afraid of

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being caught short in the middle of a cycle, and like to have all the drugs

that they will be using in hand before they start their cycle.

Cycles generally begin with a few pills of this kind, a few pills of that kind

during the first week; gradually the number and strength of pills is increased; then injectibles are introduced into the cycle. As the weeks go by,

the number of pills and shots increase until a plateau is reached; for example, about the ninth week of a 14-week cycle. Then users come back

down the same way they went up.

Younger, or less experienced or committed users, will use considerably less.

Some persons may be long-term users, but take only one injection per

week. Adolescents may go on shorter cycles, perhaps only 6 weeks. Some

adolescents will only use when they have the money to do so. These

youngsters may take a very few pills or shots on an irregular basis.

As with most drug use, a primary way of supporting one’s own steroid use

is trafficking in the substance. Also, since many users do not use that

much, they are able to support their steroid use by working, getting money

from women, stealing from their parents, or engaging in petty theft. Competitive athletes may be supplied by coaches, promoters, or other interested

parties.

Steroid use may also be supported by male friends. Older or wealthier

homosexuals are frequently interested in the company of young, male bodybuilders. These homosexual liaisons may involve sexual activity or remain

at the friendship level. Older bodybuilders report that this phenomenon was

more common prior to the advent of AIDS than it is today.

Male bodybuilders may obtain employment for which their muscularity

especially qualifies them. Some examples of these sorts of jobs include

bouncers, male dancers in such clubs as Chippendales, and models.

PTs

One of the hallmarks of the sociological approach is a focus on social

structure and social roles. David Matza summarized the sociological

approach nicely in a discussion of delinquency.

The distinguishing feature of sociological theory, in contrast

to formulations stressing personality, lies in the prominence

of the social situation. Sociology brings to the foreground

the social circumstances that form the backdrop for personality theory. (Matza 1964, p. 17)

In doing ethnographic research in health clubs and gyms, I was struck by a

particular social role—the PT. PTs enjoy a high status in the “workout”

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world. They are the cognoscenti, the knowledgeable insiders, the gurus.

They instruct their clients in a wide variety of areas including workout

techniques, diet, nutritional supplements, and sometimes in the use of

steroids. PTs typically work with a heterogeneous clientele that may

include overweight housewives, professional football players, competitive

bodybuilders, adolescents who want to look better, and simple gym

habituees.

Most clients do not appear interested in ascertaining potential PTs’ educational or professional credentials; they are more concerned with how PTs

look. If a PT has a title, e.g., Mr. America, that seems to carry the most

weight with potential clients. The title is proof of the PT’s ability to condition a body; it is a real status thing to be able to say that Mr. America is

one’s PT. Additional status is held by PTs with ties to professional

athletics. It enhances clients’ status to be able to say that their PT trains

football players. It is also fun to feel like an insider, e.g., to get some

gossip about sports celebrities.

Individuals become PTs for a variety of reasons. The basic reason is, of

course, money. PTs tend to be young men and women beginning a career

in the fitness business, young athletically oriented persons who reject a 9-to5 office existence, or older athletes who are retired from competition and

who may have few marketable job skills. Health clubs pay very low

wages. At one health club that I visited, the fitness director, who had 3

years experience. a bachelor’s degree, and some credits towards a masters

degree, mode $19,000 per year. There is a need to supplement salary by

taking on private clients, who will pay about $25 per hour.

Bartering is not uncommon among PTs. For example, one young female

PT that I spoke with has a client who is a psychiatrist. They exchange

hours of physical training for hours of therapy.

PTs’ income may be erratic. Clients go in and out of phases of life dedicated to working out. Clients are usually fairly wealthy and may do lots of

traveling. They may go south during the winter, cutting substantially into a

PT’s income.

PTs may recruit and see clients at a number of different health clubs or

gyms. They may spend some mornings at this gym; some afternoons at

that gym; some evenings at yet another. They may also go to client’s

homes. Their network of contacts tends to be far reaching.

There appears to be a growing professionalization of the fitness field,

exemplified by the growth of degree programs in physical education, biomechanics, exercise physiology, and so on. New young holders of professional certifications are in conflict with older fitness and bodybuilding

trainers whose knowledge is experiential rather than learned from books.

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Older PTs used their own bodies as their laboratories, experimenting with

various workout routines, nutritional programs, and drugs, including steroids.

The success of particular regimens was subjectively determined and also

objectively determined in terms of looks, performance, and titles achieved.

I have observed conflict in health clubs between younger credentialed PTs

and older noncredentialed PTs. They argue over which pieces of equipment

to install and what sort of training regimens are appropriate to use. They

are in competition for clients, scarce jobs, and the acceptance of their point

of view as to how the subject matter in their field should be taught. The

situation may be viewed, from the standpoint of occupational sociology, as

a case of developing professionalism, which poses interesting sociology-ofknowledge issues, regarding experiential vs. academic knowledge.

The prevalence of PTs is difficult to estimate. Most trainers that I spoke

with were reluctant to make any quantitative estimates. The best “guesstimates” that I was able to obtain were that there are about 1,000 PTs in

New York’s Nassau County going to persons homes, and about 1,500

working in clubs. The American College of Sports Medicine certifies

trainers, but it appears that most trainers work without certification, and,

hence, it would be difficult to ascertain how many PTs there actually are.

For comparative purposes, there arc approximately 1,200 Aerobics & Fitness

Association of America (AFAA)-certified aerobics instructors teaching on

Long Island, which includes Nassau and Suffolk counties, according to Peg

Jordan, editor of American Fitness magazine. However, about 50 percent of

all Long Island instructors have had no professional training at all. That

percentage is better than the national average in which only an estimated

17,000 of 100,000 acrobic instructors are AFAA certified (Hancock 1989).

PTs play an interesting role with regard to steroid use and distribution.

Some may be users themselves. PTs may be motivated to use steroids

because they feel a need to look perfect. Their ability to secure and

maintain clients may depend on how good they look, how good their clients

perceive them as looking, and how they perceive themselves as looking.

More important, PTs, as bodybuilding gurus, have a strong influence on

their clients. This influence may be exerted to encourage or discourage

steroid use. Experienced PTs, because of their wide networks of contacts,

may be pressured by clients to supply them with steroids. PTs may be

financially motivated to supply steroids to clients that ask for them. In

addition to the profit to be made from selling steroids, PTs are primarily

concerned with maintaining clientele. If they do not supply steroids to a

client that requests them, the client may find another PT that will supply

steroids. The original PT then loses a client. One PT remarked that, for

this reason. he will not train bodybuilders anymore.

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It just got to be too nuts. What with you trying to please

everybody. Who wants this, who wants that, and you’re

watching everybody self-destruct. I couldn’t take it. When

you train bodybuilders, that one-to-one trainer will certainly

be looked upon as the guru of many things. And certainly

it affords the trainer an opportunity to make a lot of money.

But it isn’t the one-to-one trainer who is the source of distribution of the stuff. Really. It occurs, and it happens, but

he isn’t the main. He doesn’t get into it to do that.

Older PTs, especially those who are or have been steroid users themselves,

express horror at the naivete with which many young persons approach the

use of steroids. Many PTs feel a responsibility to coach the young person

in the proper use of these substances to minimize the potential health consequences. A 57-year-old man who claimed to have taken one shot of decadurabolin per week, “forever,” said that the kids today were worrying him.

[They are] . . . using so much stuff. I walk into the gym,

and they’re all 17 years old, and they all look like pus

heads . . . They are all puffed out with water. And they

have very little muscle. Because they are just throwing crap

into their bodies. They have no idea . . . And who knows

what they are doing to their insides . . . They’re stupid by

taking the steroids so wrong.

A PT remarked that everyone is different and that steroid users must be

medically monitored, both while on cycles and when between cycles.

Blood tests . . . white cell counts. We’re looking to see

liver, kidney problems. We are looking to set pancreatic

and pituitary problems. We want to see their testrosterone

levels, estrogen levels. nitrogen levels. We want to see their

blood-sugar level, thyroid, adrenal, and if they have normalized, they can go back on them. If it’s 4 weeks, they can

go back on them. If it is 4 months, they have to keep

taking the test until they’re normal. If not, no sense going

back on it again. The body won’t react. They just keep

getting worse. You do need a healthy body to keep this

stuff working to the maximum.

Additional factors mentioned as important were levels of minerals, such as

calcium and magnesium. Steroids are calcium depleting.

With regard to steroids currently being used, I am told that the trend today

is towards veterinary steroids. One user described this trend in the following way.

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Veterinary drugs are cheaper, they come in much larger

quantities and they’re much better . . . They’re more anabolic. The androgenic ones tend to build fat, hold water

. . . Race horses are the biggest users of anabolic steroids.

They cannot breed a horse that’s full of water and fat.

Every tiny micro-ounce must be muscle, or he’s not going to

win a race. He cannot carry any extra weight. So if you

have ever seen a race horse up close, it’s built like the

greatest bodybuilders of the world. They are tipped to the

bone. And they are very muscular and thick. So that has

certainly seeped its way down . . . in the last 20 years.

And a lot of the drugs they are using now are the veterinary

drugs. The Winstrol-V, [and others] . . . They come in

these huge 50-cc bottles.

I don’t think the veterinarians are selling them to bodybuilders. I think they’re a lot more sensible than that. But

it is filtering down through the veterinary market. I think

maybe the distributors or the salesmen have found the

market.

CONSEQUENCES

Some experienced steroid users place much of the responsibility for the

current problem on pharmaceutical companies, and suggest that the nature

and scope of health consequences are likely to increase in the future. A

long-term steroid user stated the following:

Athletes that used them in the late forties, they . . . used it

very sparingly, so anybody who developed a tumor here or

there, it had to be very scarce. Then the fifties came, and

some synthetics came in to being used. Then the sixties

came, and a little more research got involved in it. Around

the late sixties or early seventies, the drug companies

realized there was a hell of a market here for the stuff. So

they threw some dollars into research. Now the steroids are

so sophisticated and are getting even more sophisticated.

The old ones are not even available anymore. They got a

whole new line . . . The more powerful ones weren’t being

used, certainly not as often as today. Now, in the eighties,

and going into the nineties, they are using anabolics that . . .

work so fast, they are so powerful . . . I don’t think the

body has caught up with the dosage or the science of it all

. . . And not as many people were using it as they are

today, because the sport [bodybuilding] was not as popular

in the past as it is today . . . So 20 years from now, you’re

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going to see a whole bunch of people dying. But you are

going to have to wait 20 years.

There is a long list of health consequences that have been associated with

the use of anabolic steroids. Unfortunately, good clinical documentation

and elaboration, obtained through rigorously controlled experimental studies,

is lacking in most areas. However, the list of commonly discussed health

consequences of steroid use includes liver problems (tumors, peliosis hepatitis), kidney problems, hypertension, psychiatric problems (depression,

aggression), sexual problems in males (testicular atrophy, decreased sperm

production, gynecomastia), sexual problems in females (menstrual irregularities, shrinkage of breast tissue, hypertrophy of the clitoris, facial hair, deepened voice), acne, physical injuries, cholesterol difficulties, cardiovascular

problems, stunted growth in adolescents, male pattern baldness, fetal damage, gallstones, and so on. Since most of these topics are covered by other

chapters in this volume, I chose to focus my discussion of health consequences on only two areas that are of traditional interest to drug abuse

researchers: (1) interactions between steroids and other drugs, and

(2) needle sharing.

Steroids and Other Drugs

In the area of health consequences, the National Institute on Drug Abuse

(NIDA) should have a special interest in interaction effects between steroids

and other drugs of abuse. In this regard, experienced steroid-using bodybuilders hold a taken-for-granted prohibition against using cocaine while on

a steroid cycle. They claim that there is a great danger of heart attacks if

the two substances are mixed. One user stated that whenever he reads of a

young athlete dying suddenly of a heart attack, he immediately suspects an

interaction between steroids and cocaine.

Amphetamines may be used to help drive the workout regimen. Long-term

steroid users report that, as the years go by, steroids lose their ability to

provide the driving force for the workout routine. At this point, “speed”

may come to be used. Under the influence of speed, bodybuilders report

going “nuts,” working out until totally exhausted, and then “falling out.”

No one that I have spoken with reported any specific interactions between

alcohol and steroids. In fact, most of the bodybuilders who shared their

experiences with me were very moderate drinkers or abstainers. Interestingly, one person observed that, in his opinion, persons who have great tolerance to alcohol tend to have a great tolerance to steroids.

Those who get drunk on a beer really get a lot of side

effects real quick on steroids. Migraine headaches, bloody

noses, deep acne--tremendous scarring of the face. It is

funny . . .

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Experienced steroid users also report using a wide variety of other drugs

along with steroids. The primary purpose of these other drugs is to cope

with the side effects of the steroids. For example, in order to prevent or

retard the spread of acne, antibiotics are used. Nolvadex is medicine used

in the treatment of breast cancer. It is an antiestrogen. Bodybuilders may

use Nolvadex during steroid cycles to keep their estrogen levels down.

When coming off a steroid cycle, human chorionic gonadotropin (HCG) and

Clomid are used. HCG is a polypeptide hormone produced by the human

placenta. It is derived from the urine of pregnant women. The use of

exogenous hormones (steroids) tends to depress the body’s natural hormone

production. Heavy steroid users wish to return to normal levels of testosterone as quickly as possible when they come off a steroid cycle. They

claim the body is usually sluggish and just takes too long to return to normal hormonal activity. HCG is reportedly used to simulate an estrogen

buildup in the male, which “shocks” the system into a more rapid recovery.

Clomid, a female fertility drug, is alleged to perform the same trickery.

Teslac and Halotestin are also reported to accomplish this result.

Long-term steroid users claim that there is a right way to do steroids, which

involves full knowledge of pharmacological “chain reactions.” The above

discussion has just presented a few of the substances that are commonly

employed by anabolic steroid users who were interviewed in the New York

City area. Some of these users maintain amazing pharmacopeias.

There are two contrary health-consequence aspects of this multiple drug use.

The first relates to the utility and dangers of this wide range of drugs being

used by the most pharmacologically sophisticated steroid users. The other

health-consequence aspect refers to the fact that many users are not sophisticated; they are not aware of potentially damaging side effects or the

means for circumventing them. Many young men can barely afford the

steroids that they are using. They see the purchase of these other substances as a low-priority item in an already strained budget. A sophisticated PT stated the following.

These. kids, of course, don’t know anything about this . . . I

get the reaction from them like I have two heads. Some of

them don’t want to listen to it. They say, “I’m just taking

my ‘tes’ or my Dianabol ‘cause my friend is taking them.”

But anybody who is serious about going on them . . . and

who is really interested in his health and going on a couple

of cycles will have to absorb this.

Needle Sharing

Persons using injectable steroids are prone to all the health hazards common

to needle users of any substance. This includes diseases associated with

9 1
bacterial infections caused by injections with nonsterile equipment. This

practice may lead to localized infection problems, such as abscesses and

cellulitis, or systemic problems such as endocarditis, hepatitis, and AIDS.

A competitive bodybuilder reported that a number of his colleagues had

problems when they were first learning how to inject themselves.

A lot of people don’t know how to do it. They do it eventually because they feel they have to. Or they get a friend

who learned from a friend, who learned from a sister who is

a nurse. That’s generally how it works. And you learn

how to put it in a muscle. A lot of guys have come to me

that they hit a vein and they are black or blue . . . You hit

too much in the same site and you get tumors all the time.

A lot of bodybuilders had to get those cut out . . . Actually

you get huge fibroid lumps that develop from hitting the

same sites.

Harold Connelly, an Olympic gold medalist in the hammer throw, testified

to the following before a U.S. Senate Committee in 19’73.

It was not unusual in 1968 to see athletes with their own

medical kits, practically a doctor’s, in which they would

have syringes and all their various drugs . . . I know any

number of athletes on the ‘68 Olympic team who had so

much scar tissue and so many puncture holes on their backsides that it was difficult to find a fresh spot to give them a

new shot. (Hecht 1984, p. 14)

All competitive athletes that I have spoken with denied using dirty needles

or sharing needles. As one person stated, “The guy who’s selling you

the needles wants you to buy 100 needles. He don’t want to sell you two

needles.”

However, in some inner-city gyms, I did get reports that heterosexual

lovers, perhaps spouses, who are working out together, will sometimes share

needles. It’s part of the “we do everything else together so why not this”

feeling. A young woman told me that such couples decide which muscles

they will work on that day, inject into that muscle sharing the needle, and

then go and do their workout.

A 1984 letter to the editor of The New England Journal of Medicine from

six physicians at Nassau Hospital in New York described a case of AIDS in

a bodybuilder using anabolic steroids. This was a 37-year-old white male

who denied any history of homosexual activity. He did admit to injecting

cocaine intravenously on one occasion approximately 6 months prior to

hospital admission. During the 4 years before admission, the patient had

92
injected anabolic steroids intramuscularly on a weekly basis. The needles

were often shared with other bodybuilders at various gyms. The physicians

state that their experience with this patient indicates that intramuscular

injection of anabolic steroids through shared needles may serve as a mode

for dissemination of the AIDS virus. “Because this practice appears to be

common among many athletes . . . persons at risk must be warned”

(Sklarek et al. 1984, p. 1701).

A recent issue of Sports Illustrated featured a story on Benji Ramirez, a 17-

year-old boy from Ashtabula, OH, who was alleged to have died from

steroid-related heart problems. While there appears to be some question as

to both the cause of death in this case and the nature and extent of

Ramirez’s actual involvement with steroids, the story does contain the

following account.

Another of Ramirez’s classmates . . . says that on two occasions last summer he purchased steroids from Ramirez and

used them in his company. In both instances, Ramirez

injected the classmate in the buttock and then injected

himself (Telander and Noden 1989, p. 78).

It is not clear from this account whether the boys shared the needle. The

possibility seems to be present here and in other cases in which naive

youngsters with limited financial resources may be involved with injectable

steroids.

NEEDS FOR FURTHER RESEARCH

It is customary, and frequently gratuitous, to end a research paper with a

statement of the need for future research. However, in the area of anabolic

steroids, that need is clear and immediate. The following sorts of data are

needed.

1. Good epidemiological data are needed regarding incidence and prevalence of steroid use in different populations.

2. Data are needed on the frequency and volume of steroid use in different

populations, including data on concomitant use of other substances with

steroids.

3. Data are needed regarding the consequences of increasing criminal

penalties for use or possession of steroids.

4. Data are needed on the health consequences and other effects of longterm use of steroids.

93
5.

6.

7.

8.

9.

10.

11.

12.

Data are needed on the natural history of steroid use in different populations, including patterns of use and cessation associated with different

stages of life.

Given the general trend in society towards drug testing and the specific

trend towards steroid testing in both amateur and professional athletics,

data are needed on (a) what should be done when a steroid-problem

area, e.g., high school football, is identified, and (b) what should be

done when a specific steroid user is identified.

Data are needed on the patterns of steroid distribution, and how they

are similar to or different from distribution patterns associated with

other substances. Of special interest in this regard is the extent to

which systemic violence may be beginning to be associated with black

market steroid sales.

Data are needed on the cost of steroid use, and how users support their

consumption.

Data are needed on the extent to which counterfeit steroids have penetrated the market, and the specific sorts of problems associated with

these substances.

Data need to be generated on the extent of needle sharing among steroid users. Special attention should be paid to gay populations in this

regard.

Data are needed on the effect of steroid use among persons with existing mental disorders.

The role of steroid use in sports injuries needs to be further explored.

REFERENCES

Buckley, W.E.; Yesalis, C.E.; Friedl, K.E.; Anderson, W.A.; Streit, A.; and

Wright, J.E. Estimated prevalence of anabolic steroid use among male

high school seniors. JAMA 260(23):3441-3445, 1988.

Chapman, ES. Steroid edge: Real or illusion. Washington Post, October

18, 1988. p. 8.

Charlier, M. For teens, steroids may be bigger issue than cocaine use.

Wall Streer Journal, October 4, 1988. p. A20.

Couzens, G.S. A serious drug problem. Newsday, November 26, 1988.

p. II, 5.

Cowart, V. Steroids in sports: After four decades, time to return these

genies to the bottle? JAMA 257(4):421-427, 1987a.

Cowart, V. Physician-competitor’s advice to colleagues: Steroid users

respond to education, rehabilitation. JAMA 257(4):427-428, 1987b.

94
Hancock, L. Have body, will travel. Long Island Monthly 2(2):21-23,

1989.

Hecht, A. Anabolic steroids: Pumping trouble. FDA Consumer,

September 1984. pp. 12-15.

Herrmann, M. Steroids: A vague threat. Newsday, October 30, 1988.

pp. 36, 31.

Huapt, H.A., and Rovere, G.D. Anabolic steroids: A review of the

literature. Am J Sports Med 12(6):469-484, 1984.

Jacobson, S. NFL is late in seeing the light. Newsday, November 6, 1988.

pp. 9, 40.

Johnson, B.D.; Goldstein, P.J.; Preble, E.; Schmeidler, J.; Lipton, D.S.;

Spunt, B.J.; and Miller, T. Taking Care of Business: The Economics of

Crime by Heroin Abusers. Lexington: Lexington Books, 1985.

Kahler, K. Steroids ‘mania’ spawning perilous new drug traffic. The

Sunday Star Ledger (Newark), January 8, 1989. pp. 1, 29.

Lee, B.L. Growth drug hitting black market. The Journal, Addiction

Research Foundation 15(9):4, 1985.

Lindesmith, A.R. Opiate Addiction. Evanston: Principia Press, 1947.

Mann, F. Dark side of steroids plagues former boxer. Miami Herald

December 27, 1988. pp. 1D, 4D.

Matza, D. Delinquency and Drift. New York: John Wiley, 1964.

McBride, D., and Clayton, R.C. Methodological issues in the etiology of

drug abuse. J Drug Issues 15(4):509-529, 1985.

Miami Herald Study: 6% of teen boys use steroids. December 23, 1988.

pp. 1A, 7A.

Penn, S. Muscling in. Wall Street Journal, October 4, 1988. pp. Al,

A20.

Phillips, M., and Lohrer, R. High schools are considering steroid tests.

Miami Herald January 14, 1989. pp. 1D, 4D.

Schuckit, M.A. Weight lifter’s folly: The abuse of anabolic steroids.

Drug Abuse and Alc Newsletter 17(8), October, 1988.

Scott, J. Use of steroids by youths widespread, study finds. Los Angeles

Times, December 16, 1988. pp. 1, 45.

Sklarek, H.M.; Mantovani, R.P.; Erens, E.; Heisler, D.; Niederman, M.S.;

and Fein, A.M. AIDS in a bodybuilder using anabolic steroids. N Engl

J Med 311(26):1701, 1984.

Southwick, L. Testimony before U.S. House of Representatives Subcommittee on Crime, May 17, 1990.

STASH Staff. Drugs in Sports. Educational Offprint Series #219. Madison, WI: STASH, Inc., 1978.

Strauss, R.H. Controlling the supply of anabolic steroids. Phys Sports Med

15(5):41, 1987.

Telander, R., and Noden, M. The death of an athlete. Sports Illustrated

70(8):68-78, 1989.

Toufexis, A. Shortcut to the Rambo look. Time Magazine, January 30,

1989. p. 78.

95
Wieberg, S. All quiet on drug-test front—but why? USA Today, December

30, 1988. p. E1.

AUTHOR

Paul J. Goldstein, Ph.D

Deputy Director

Narcotic and Drug Research, Inc.

11 Beach Street

New York, NY 10013

96
Incidence of the Nonmedical Use of

Anabolic-Androgenic Steroids

Charles E. Yesalis, William A. Anderson,

William E. Buckley, and James E. Wright

INTRODUCTION

The use of drugs to enhance physical performance predates the ancient

Greek Olympiads (Strauss and Curry 1987). Throughout history, athletes

have used a variety of drugs as ergogenic aids. These have included alcohol, cocaine, ether, and strychnine (Boje 1939; Wright 1978). Currently

there are over 100 substances banned by the International Olympic Committee (IOC), including over 17 anabolic-androgenic steroids (AS) and related

compounds (United States Olympic Committee 1989).

Only 4 years after testosterone was synthesized, Boje (1939) suggested that

sex hormones, based on their physiologic actions, might enhance physical

performance. It has been rumored, but not documented, that during World

War II a number of German soldiers were given some type of androgen to

increase aggressiveness in combat (Wade 1972).

Several prominent older athletes have indicated that various forms of testosterone were being used by a few bodybuilders in the United States in the

late 1940s and early 1950s (Wright 1978). However, the most often referenced account of the initiation of systematic use of AS in sports credits the

Soviet weightlifting team in the early 1950s. In 1954, at the world weightlifting championships in Vienna, Dr. John Ziegler, the U.S. team physician,

reportedly was told by his Soviet counterpart that the Soviets were taking

testosterone (Goldman 1984; Starr 1981; Todd 1987). Dr. Ziegler returned

to the United States and experimented with testosterone on himself and a

few weightlifters in the York Barbell Club. Dr. Ziegler was concerned,

however, with the androgenic effects of testosterone and, in 1958, when the

Ciba Pharmaceuticals Company released Dianabol (methandrostenolone), he

began experimentation with this new drug. After several of the early AS

users achieved championship status, the efficacy of these drugs apparently

spread by word of mouth during the early 1960s to other strength-intensive

97
sports from field events to football (Starr 1981; Todd 1987). Thereafter,

use of AS apparently diffused to endurance sports such as long-distance

running and swimming; however, this has not been chronicled.

Until the mid-1970s all that was known regarding the incidence of the nonmedical use of AS was based on rumors, anecdotes, and testimonials (Goldman 1984; Wade 1972; Wright 1978). High levels of use were attributed to

such sports as professional football, weightlifting, powerlifting, bodybuilding,

and throwing events in track; even use by high school athletes has been

rumored as early as 1959 (Gilbert 1969; Morris, personal communication,

1989). Although rumors still abound, estimates of the incidence of AS use

are now available, based on the results of drug testing associated with

athletic competition and on the results of systematic surveys.

Drug Tests

Owing to the lack of satisfactory screening techniques, AS were not banned

by the IOC until 1975, and it was not until the 1976 Montreal Games that

testing for these drugs was initiated (Catlin 1987). Testosterone esters were

not added to the banned list until 1982 because of the previous unavailability of testing techniques (Todd 1987). Exogenous testosterone can be detected only by examining the peak height of the testosterone:epitestosterone

ratio (Catlin et al. 1987). Normally the ratio is approximately 1:1; a value

of 6:1 or greater is considered positive.

In 1986, the National Collegiate Athletic Association (NCAA) began testing

for AS at football bowl games and championship events (National Collegiate Athletic Association 1987). The results of these announced drug tests

are shown in table 1. Generally, less than 2 percent of athletes tested positive for AS. In addition, less than 1 percent of athletes tested positive

during announced drug testing in sporting events sponsored by the U.S.

Olympic Committee (USOC) from 1984 to 1988 (Voy, personal communication, 1989). However, when the USOC conducted unannounced drug tests

with no punitive actions at a number of “Olympic Sports” events in the

United States in 1984 and 1985, approximately 50 percent of athletes tested

positive for AS use (Voy, personal communication, 1989). There are two

explanations for this rather large discrepancy: (1) athletes knew when they

would be tested, and (2) the detection time for most AS is relatively short

(i.e., a few days to several weeks). Thus, it seems that to escape detection,

athletes have avoided certain long-lasting injectable steroids, e.g., nandrolone

decanoate (Deca Durabolin), which may have a detection time of up to 6

months or longer, in favor of oral steroids and injectable esters of testosterone (Yesalis et al. 1988). Based on recent IOC pronouncements (deMerode

1988) it seems that some athletes have had themselves tested by laboratories in order to titrate the doses of particular AS to their own biochemistry; thus they know when to stop use prior to official testing during

98
TABLE 1. Anabolic steroid use based on announced drug testing

Year Event Results

Percent

Positive

1976 Olympic Games 8 positives

(Montreal) 275 analyses

1980 Olympic Games 0 positives

(Moscow) 1,500 analyses

1983 Pan American Games 15 positives

(Caracas) 825 analyses

1984 Olympic Games

(Los Angeles)

(10 “sanctioned” positives;

17 positives)*

17 positives

1,510 analyses

1986-

1987

1987

NCAA Championships 26 positives

and Bowl Games 3,360 analyses

U.S. Olympic Festival 6 positives

(Greensboro) 628 analyses

1987- NCAA Championships 9 positives

1988 and Bowl Games 2,385 analyses

1988 Olympic Games

(Seoul)

(10 “sanctioned” positives;

30 positives)

30 positives

1,500 analyses

2.9

0

1.8

1.1

0.8

0.9

0.4

2.0

*For the past two Summer Olympiads, the number of laboratory “positives” has exceeded the number of

athletes sanctioned (Catlin et al. 1987). No satisfactory explanation is available.

competitions. Athletes usually discontinue oral AS 2 to 4 weeks and testosterone esters, which are injectable, 3 to 6 weeks before testing (DiPasquale

1987).1

The results of a recent study by Friedl et al. (1989) cast further doubt on

the sensitivity of drug tests for testosterone esters. Two volunteers were

administered 300 mg of testosterone cypionate per week for 6 weeks. This

dose equals or exceeds that used by many strength athletes during the 1960s

and early 1970s (Wright 1978) and exceeds the dose used by most of

today’s track and endurance athletes.

99
Two other volunteers were administered 100 mg of testosterone cypionate

per week for 6 weeks. At the end of the sixth week, urine samples were

screened and testosterone:epitestosterone ratios were determined. All four

subjects had ratios at or below 4.2:1. Backup samples were tested and

yielded the same results.

Little can be said at present about the effect of purported masking drugs

such as probenecid or the use of designer steroids (substances with minor

structural modifications that shift the gas chromatographic signature of currently existing steroids). Neither the extent of use nor the efficacy of either

strategy in subverting the testing process has been scientifically documented

(DiPasquale 1987).

Finally, the recent negotiations between the United States and the U.S.S.R.

to establish year-round, unannounced random testing for AS bears witness to

the impotence of infrequent, announced testing for these drugs (Cowart

1988; Janofsky 1988).

Surveys

A number of surveys are available that attempted to measure the incidence

or prevalence of AS use among a designated population. These surveys of

AS use are categorized here as (1) high school age (or younger) students,

(2) college students, and (3) athletes not fitting in categories 1 or 2. The

results of these surveys are summarized in tables 2 to 4.

HIGH SCHOOL

Corder et al. (1975) surveyed students in 10 Arizona high schools in 1971

and 1975 and found a prior AS-use rate of less than 1 percent. They did

not report their findings by sex, but 4 percent of athletes in the 1975 survey

reported previous use of AS. In a study of 8th, 10th, and 12th graders in

11 public school districts in Michigan, 3 percent, 2 percent, and 2 percent

of students, respectively, reported previous AS use, while 1 percent of

respondents in each of the grades acknowledged AS use in the prior month

(Newman 1986). The lifetime AS-use rate among seniors was 5 percent for

boys and 1 percent for girls. Of the respondents, 25 percent of males and

7 percent of females believed that an athlete’s performance is safely

improved by AS (Newman 1986).

Polen et al. (1986) surveyed 200 randomly selected students at a Florida

high school with an enrollment of 2,000, and 18 percent of males (but no

females) reported prior AS use. Of 190 varsity football players in 6 high

schools in Oregon, only 1.1 percent admitted AS use (Bosworth et al.

1987).

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TABLE 2. Self-reported anabolic steroid use among high school students

Investigator Site and Subjects Percent Percent

and Year Population (Number) AS use Response

Corder et al. Arizona

1975 10 schools

Arizona

10 schools

Newman 1986 Michigan

11 districts

grade 8

grade 10

grade 12

Polen et al.

1986

Bosworth et al.

1987

Florida

1 school

Oregon

6 schools

varsity football players

Buckley et al.

1988

24 States

46 high schools

12th-grade males

Johnson et al.

1989

Arkansas

6 schools

11th grade

Terney and

McLain 1990

Illinois

1 school

Windsor and

Dumitru 1989

Texas

5 schools

1,393 0.7 NR

1,099

208 athletes

5,029

(—)

(—)

1,426

NR

NR

200

0.7

4

3

3

2

2

(M=5, F=1)

M=18, F=0 NR

190 1.1 NR

3,403 6.6 50

1,775 5.7

(M=11, F=.5)

4.4

(M=6.5, F=2.5)

3.0

(M=5.0, F=1.4)

99.5

2,075 98

901 89

KEY: NR=Not Reported.

In the first nationwide study of AS use, Buckley et al. (1988) found that

6.6 percent of male high school seniors reported having used these drugs.

There was no difference in the level of reported AS use between urban and

rural areas, but there was a small but significant difference by size of

enrollment, with larger high schools reporting higher levels of AS use.

Almost 40 percent of the AS users repotted five or more cycles of use.2 In

addition, of the self-reported AS users, 38 percent initiated use before age

16, 44 percent used more than one steroid at a time, i.e., stacking, and

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TABLE 3. Self-reported anabolic steroid use among college students

Investigator Site and Subjects Percent Percent

and Year Population (Number) AS Use Response

Toohey and

Corder 1981

Dezelsky et al.

1985

Anderson and

McKeag 1985

Anderson and

McKeag, in press

Pope et al.

1988

6 universities 67

intercollegiate (M=17, F=50)

swimmers

5 universities

1970, 1973, 1976,

1980, 1984

11 universities

intercollegiate

athletes

11 universities

intercollegiate

athletes

3 universities

4,171

2,100

2,300

NR

M=5.8, F=0

athletes=15

(1970)

NR

athletes=20

(1976 to 1984)

nonathletes=1

(1984)

football=9

Division I

athletes=5

men’s basketball

and track=4

women’s

swimming=1

7 2

M=6.4, F=1

football=10

Division I and

II athletes=5

Division II

athletes=4

men’s track

and field=5

78

women’s swimming,

track and field,

softball=1

males=1,010

varsity

athletes=147

2 30

9.4

KEY: NR=Not Reported.

38 percent used injectable AS. Over one-third of the AS users did not

intend to participate in interscholastic sports. Approximately 21 percent of

AS users reported that a health professional was their primary source for

these drugs, while the remainder identified “black market” sources, e.g.,

contacts at gyms and academic institutions, mail order, visits to foreign

countries, etc. Only 15 percent of the public and private high schools that

102
TABLE 4. Self-reported anabolic steroid use among athletes

Investigator Site and

and Year Population

Subjects

(Number)

Percent

AS Use

Percent

Response

Ljungqvist 1985 elite Swedish

track and field

athletes

99 31

throwers=75

middle- and long

distance runners=8

69

Frankle et al.

1984

Newman 1987

weightlifters in

3 gymnasiums

elite women

athletes in

more than

15 sports

250 44 NR

271 3 59

Yesalis et al. elite 45 questionnaires 33.3 7 4

1988 powerlifters 20 telephone 5 5

KEY: NR=Not Reported.

participated in this study had no reported AS use. However, in a recent

survey by Swenson of 472 high school head football coaches in Michigan,

only 12 percent admitted that they had at least one player who used AS

prior to 1988 (Duda 1988).

Three more recent studies in Illinois, Texas, and Arkansas confirm Buckley

et al. (1988) findings and show that 5 to 11 percent of high school males

admit having used AS (Johnson et al. 1989; Temey and McLain 1990;

Windsor and Dumitru 1989). These three studies also examined AS use

among high school girls and found that approximately 1 to 2 percent

reported use.

Johnson et al. (in press) surveyed 1,775 male and female 11th-grade students in 6 Arkansas high schools, and the results indicated that 11 percent

of males and 0.5 percent of females had used AS. The most common

reason for AS use was to increase strength (64 percent) and size (50 percent); however, 27 percent of users wanted to improve their physical

appearance.

McLain (1989) surveyed over 2,100 students in a high school (grades 9 to

12) in Illinois and found a total incidence of use of 4.1 percent (6.5 percent

for males and 2.5 percent for females). Incidence of AS use did not vary

significantly by grade. Of reported AS users, 83 percent participated in

sports, and the use rate among all athletes surveyed was 9.4 percent. In

addition, 35 percent of AS users said they obtained the drugs from a physician, while the remainder cited black market sources.

103
In a study of 901 male and female students in 5 Texas high schools, an

overall use rate of 3 percent was reported (5 percent for males and 1.4 percent for females) (Windsor and Dumitru 1989). The AS-use rate among

athletes was greater for males (6.7 percent vs. 1.8 percent) but, surprisingly,

less for females (0.7 percent vs. 2.5 percent). AS use by grade was not

reported. This was the first study to examine use by socioeconomic status

(SES), with high-SES males exhibiting the highest AS-use rates. Once

again, the large majority of users obtained their drugs from black market

sources (85 percent), while only 7 percent obtained them from a physician.

COLLEGE

Of 67 intercollegiate swimmers (male and female) from 6 universities surveyed, only 1 athlete (a male) reported prior use of AS (Toohey and Corder

1981). In a study of nonmedical drug-use behavior of students at five

public universities from 1970 to 1984 by Dezclsky et al. (1985), only 1 percent of nonathlete students reported using AS in 1984. However, the percent of intercollegiate athletes who reported AS use rose from 15 percent in

1970 to 20 percent in 1984. Separate AS-use rates for men and women

were not reported.

Anderson and McKeag (1985) surveyed over 2,100 NCAA men and women

athletes at 11 universities regarding alcohol and drug use. Heaviest AS use

was among football players (9 percent). Other men’s sports not typically

considered to be associated with AS use but that did include AS users were

baseball (3 pcrccnt). basketball (4 percent), track and field (4 percent), and

tennis (4 percent). For women, only one sport reported AS use-women’s

swimming (1 percent). Altogether, 5 percent of Division I athletes, 4 percent of Division II athletes. and 2 percent of Division III athletes reported

AS use.

Athletes who used AS obtained them from several different sources: nonteam physicians (25 percent), teammate (22 percent), friend or relative

(22 percent), other source (22 percent), coach (5 percent), team physician

(5 percent), and pro scout or agent (2 percent).

Anderson and McKeag (in press) replicated their study of NCAA athletes

during the 1988 to 1989 academic year. Data were collected from 2,300

men and women athletes at 11 universities nationwide. Of the original 11

universities. 8 participated in the replication study. In general, AS use had

increased over the past 4 years. For Division I male and female athletes,

reported AS use remained at 5 percent. However, for Division II and Division III athletes, AS use rose to 5 percent and 4 percent, respectively, of all

the athletes surveyed.

Heaviest reported AS users were again football players (10 percent of all

football players surveyed). Anabolic steroid USC also rose for track and

104
field athletes (5 percent) but declined for baseball (2 percent), basketball

(2 percent), and tennis (2 percent). Unlike the 1984 to 1985 study in which

only one women’s sport reported AS use, in the replication study, three

women’s sports reported a small amount of AS use. Track and field, basketball, and swimming all reported 1 percent of the women athletes in those

sports using AS.

The sources for obtaining AS also changed over the past 4 years. The two

largest sources for obtaining AS in the 1988 to 1989 study were teammates

(49 percent) and friends or relatives (29 percent). Additional sources were:

nonteam physicians (10 percent), other sources (6 percent), pro scout or

agent (4 percent), and coach or trainer (2 percent).

For those athletes using AS, 25 percent began use before college, 25 percent initiated use during the first year of college, and 50 percent began after

the first year of college. When asked whether members of their coaching

staff knew that they were using AS, 23 percent of AS users said their

coaches knew, 15 percent were uncertain, and 62 percent did not think

their coaches were aware of their AS use.

Of the 1,010 respondents in a survey of college men at 3 eastern universities, 2 percent acknowledged AS use, while 9.4 percent of the 147 varsity

athletes in the sample reported use of these drugs (Pope et al. 1988). More

than 40 percent of AS users reported personal appearance as their primary

reason for use.

OTHER ATHLETES

Ljungqvist (1975) surveyed elite Swedish male track-and-field athletes and

found 31 percent had used AS. None of the middle- or long-distance runners admitted AS use compared to 75 percent of the throwers.

Weight trainers in three gymnasiums in the Chicago area were questioned

6 years ago, and 44 percent reported prior AS use (Frankle et al. 1984);

however, no details of study methods, including sample selection, were provided. Of a subsample of 50 AS users interviewed in depth, only 44 percent were competing in athletics. AS-use rates by sex were not reported.

The majority of respondents obtained their drugs illegally, but 20 percent

claimed to have received them by prescription.

Elite women athletes in over 15 sports reported a lifetime AS-use rate of

3 percent, but only 1 percent acknowledged using these drugs in the past

year (Newman 1987). The lifetime-use rate was slightly higher for those

over the age of 26 (4 percent) and members of professional teams (5 percent). Of the respondents, 11 percent believed that their performance could

be safely enhanced by AS.

105
Yesalis et al, (1988) surveyed elite powerlifters at a major contest using

both a questionnaire at a major contest and followup telephone interviews.

One-third of the questionnaire respondents admitted prior AS use; however,

55 percent of those interviewed later by telephone conceded use. The

acknowledged AS users (via questionnaire) reported a lifetime average of

eight cycles each. The primary sources of AS for this group were black

market (73 percent) and physician or pharmacist (20 percent).

The extent to which the respondents in the surveys reviewed here honestly

reported their AS use is not known. It is possible that they intentionally

underreported or overreported their AS use. Intentional overreporters could

be characterized as “braggarts,” who overemphasize drug use to present

themselves in a more worldly manner. This is unlikely to be a major

source of bias, however, since virtually all surveys dealing with AS use are

written and anonymous. Reasons for unintentional reporting errors include

the reading levels of the respondents, the reporting timeframes for drug use,

and the complexity of the scales for reporting frequencies and amounts of

drug use.

The respondents may have underreported their drug use to meet more

socially acceptable standards of behavior. The use of AS is in violation of

not only the rules of all sport federations, but also of the traditional ethics

of fair play in sports and would likely meet with the disapproval of family,

friends, and fans. Indeed, even though these surveys guaranteed personal

anonymity, the potential for underreporting could have existed because of

concern for the reputation of their sport, school, or athletic conference. The

difficulty of convincing athletes to be open about steroid use has been

described as “getting only a glimpse of a large, underground subculture”

(Pope and Katz 1988, p. 489). The underreporting of drug use is also undoubtedly due partly, if not largely, to the lack of trust and communication

between members of the athletic and the scientific and medical communities. This, in turn, is a function of poor understanding on the part of

researchers and physicians of the motivation of athletes and vice versa. The

medical community lost much credibility as a result of repeated denials that

steroids enhance performance (American College of Sports Medicine 1977).

Until recently, statements from physicians and scientists dogmatically reported that any weight gained while taking steroids was mainly the result of

fluid retention and that any strength gain was largely psychological (a

placebo effect).

The studies reviewed here had a mean response rate of 73 percent. Thus,

we have no information on individuals who chose not to volunteer, but,

again, it could be hypothesized that those who did not participate were

more likely to be AS users.

On the other hand, the research on the use of self-report methods has

shown them to be valid for documenting recreational drug use, especially

106
for adolescents (McClary and Lubin 1985; Smart and Blair 1978). When

the recreational drug-use rates from self-report studies have been compared

with external methods of documenting drug use (reports by others, blood,

urine samples, etc.), the self-report-use rates have been similar or only

slightly lower than rates derived by the other methods (Ausel et al. 1976;

Bonito et al. 1976; Deaux and Callaghan 1984; Petzel et al. 1973; Stacy

et al. 1985).

On the whole, it is reasonable to infer that the level of AS use as determined by the survey method likely reflects a lower bound and that the level

of underreporting may vary by age, sport, level of competition, and sex.

Adolescents may be more open regarding their AS use than older athletes

whose scholarships or livelihood depend on their participation and success

in sport. Because of the virilizing qualities of AS (Wright 1980; Haupt and

Rovere 1984) women might be more secretive about their AS use than

men.

CONCLUSIONS

1.

2.

3.

4.

5.

6.

7.

8.

The nonmedical use of AS is reported from early adolescence to adulthood. It is believed that, of high school seniors, at least 7 percent of

males on average and 1 percent of females have used AS. Less information is available on the AS-use levels in adult populations.

Significant variation in the incidence of AS use has been reported

among high schools and colleges.

AS use has been reported by both urban- and rural-dwelling adolescents

attending schools of all sizes.

The level of AS use among all groups has likely increased significantly

over the past two decades.

The level of AS use by women appears to be significantly less than that

for men.

Although higher AS-use rates are reported by elite and competitive

athletes, a significant number of recreational athletes appear to be using

AS, probably to improve their appearance.

The results of surveys based on self-reports likely represent a lower

bound of the level of AS use.

The results of announced drug tests at athletic events are a poor indicator of the overall level of AS use.

107
9. Although the black market serves as the primary source of AS, between

one-fifth and one-third of users identify medical professionals as their

source for the drugs.

FOR THE FUTURE

The medical community has identified the nonmedical use of anabolic steroids as a potentially significant health problem (American Academy of

Pediatrics 1988; American College of Sports Medicine 1977; American

College of Sports Medicine 1984; American Medical Association 1988).

However, development of an effective response to this problem requires that

a clearer picture of the magnitude of the problem-the extent of use, characteristics of users, and the real health implications-be obtained. Although

much more information is available now than 5 years ago, further research

is strongly indicated in the following areas:

1. The incidence and prevalence of AS use by males and females and

among competitive and recreational athletes of all ages needs to be

more accurately measured;

2. the dose and frequency of use of AS among high-risk groups needs to

be established;

3. adolescent and adult AS users need to be profiled, and a better understanding of the processes involved in initiating and continuing AS use

needs to be achieved; and, finally,

4. the association of AS use with other illicit drugs or alcohol use needs

to be examined.

FOOTNOTES

1. Athletes view steroids primarily as training drugs. Because the effects

on physiologic capacities and performance linger for a signficant time

after steroids are discontinued, athletes can use them during training and

stop before being tested at the time of competition. Thus, it appears

likely, based on anecdotal information, that steroid users who abstain for

a time continue to have enhanced capacities relative to nonusers.

2. A cycle is an episode of AS use that is usually 6 to 12 weeks or more

in length.

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Voy, R.O., Director, Division of Sports Medicine and Science, U.S. Olympic Committee, Colorado Springs, CO, personal communication, 1989.

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AUTHORS

Charles E. Yesalis, Sc.D.

Professor of Health Policy and Administration

and Excrcisc and Sport Science

College of Health and Human Development

The Pennsylvania State University

115 Henderson Building

University Park, PA 16802

William A. Anderson, Ph.D.

Associate Professor of Medical Education

Michigan State University

East Lansing. MI

111
William E. Buckley, Ph.D.

Assistant Professor of Health Education

The Pennsylvania State University

19 White

University Park, PA 16802

James E. Wright, Ph.D.

Sports Science Consultants

Northridge, CA 91324

112
Androgens: Endocrine Physiology

and Pharmacology

Stephen J. Winters

INTRODUCTION

Androgens are used in clinical medicine primarily to treat hypogonadal

androgen-deficient men. The observation that a lipid extract of the urine of

normal adult men decreased urinary nitrogen excretion in orchidectomized

dogs (Kochakian 1935) followed within a few years by the isolation of

testosterone and the finding that it caused nitrogen retention and muscle

growth in hypogonadal men (Kenyon et al. 1938) has led eugonadal men to

use various androgens to increase muscle growth and strength. Androgens

stimulate many other target tissues in addition to skeletal muscle, however,

and, when androgens are administered in pharmacological dosages, undesirable effects may occur in those tissues. Although all androgens function by

activating seemingly identical intracellular receptors, differences in absorption and metabolism of androgen preparations may lead to unequal actions

on individual target issues. The purpose of this chapter is to compare the

physiology of testosterone with the pharmacological information available

for the testosterone derivatives currently in clinical use. An understanding

of the similarities and differences among these compounds should aid in our

approach to androgen use and misuse (Wilson and Griffin 1980).

TESTOSTERONE PHYSIOLOGY

Testosterone is the principal androgen in males. Approximately 95 percent

of the testosterone in adult men is produced by the Leydig cells of the

testis; the remaining 5 percent is produced directly or indirectly by the

adrenal glands. During early fetal development, the placenta produces human chorionic gonadotropin, which enters the fetal circulation and stimulates

testosterone secretion. Only late in the first trimester does the pituitary

develop. Secretion of the pituitary gonadotropins luteinizing hormone (LH)

and follicle-stimulating hormone (FSH) begins in the second trimester. The

principal stimulus to the fetal gonadotroph, as in the adult, appears to be

gonadotropin releasing hormone (GnRH), which is produced in the anterior

113
hypothalamus. Pituitary gonadotropin secretion declines in late fetal life and

decreases further in the neonate such that, by 2 to 4 months of age, little

testosterone is produced. The ability of administered GnRH to stimulate

LH and FSH release in children suggests that these changes are due to a

decline in GnRH secretion, However, GnRH cannot be studied directly in

humans, since it is present in undetectable amounts, except in the hypothalamus and in hypothalamic-pituitary portal blood. There is presently no

known mechanism to explain the decrease in GnRH secretion during childhood, although studies in nonhuman primates indicate that it also occurs in

castrated animals and is therefore independent of testicular factors (Plant

1980).

Figure 1 is a diagram of the interrelationships between the hypothalamus,

pituitary, and testes. GnRH secretion occurs primarily from the anterior

hypothalamus in the region of the arcuate nucleus where it appears to be

coupled to discharges of excitatory neurons. Numerous hormones and

neurotransmitters have been found to influence GnRH release under different conditions. GnRH stimulates the synthesis, glycosylation, and release of

LH and FSH (Clayton 1987). LH and FSH stimulate Leydig cells and

Sertoli cells within seminiferous tubules, respectively. Gonadotropin secretion is also negatively regulated by Leydig cell steroids (Plant 1986) and by

inhibin, a glycoprotein produced by Sertoli cells.

GnRH secretion reawakens at the time of puberty. LH and FSH levels

increase and testis growth commences. Testosterone levels begin to rise at

age 12 and reach adult levels at approximately age 16. Gonadotropin

secretion exhibits a striking diurnal rhythm in early puberty with elevated

levels of LH and testosterone at night (Boyar et al. 1972). In adult men, it

is more difficult to demonstrate a diurnal rhythm for LH, although testosterone levels are highest at about 8 a.m. and are about 35 percent lower in the

late afternoon to early evening (Spratt et al. 1988). Direct analysis of

GnRH in hypothalamic blood in experimental animals and the tracking of

GnRH secretion by measuring moment-to-moment changes in circulating LH

concentrations indicate that GnRH secretion is episodic and that LH pulses

generally follow GnRH secretory episodes. LH pulses in adult men appear

to occur every 60 to 100 minutes. The estimate of frequency depends upon

the blood-sampling protocol and the method used to analyze hormonesecretory events. This mode of intermittent secretion is needed for pituitary

gonadotrophs to function normally (Belchetz et al. 1978). Unlike the situation in many lower animals, including nonhuman primates, striking fluctuations in testosterone levels are not observed in the peripheral blood in men,

although a pulsatile pattern of testosterone release can be identified in

spermatic vein blood (Winters and Troen 1986).

Although there is no male climacteric comparable to the dramatic hormonal

changes that occur in women, aging is associated with a series of endocrine

changes in men. Serum testosterone levels decline and LH and FSH levels

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FIGURE 1. Interrelationships between the hypothalamus, pituitary,

and testes

rise, indicating testicular damage. Responses to GnRH are also altered,

revealing an additional abnormality of the hypothalamic-pituitary unit

(Winters and Troen 1982). Androgen negative feedback is increased, and

there is a blunting of the normal diurnal rhythm in testosterone secretion.

Impotence is common in older men, as is a decrease in skeletal and muscle

mass. Finally, sperm production declines (Neaves et al. 1984). It is sometimes difficult, however, to separate changes due to aging from changes

resulting from illness and medications taken by older adults or from social

changes.

TESTOSTERONE BIOSYNTHESIS, TRANSPORT, AND

METABOLISM

Testosterone is a steroid hormone with 19 carbons synthesized from cholesterol (Miller 1988) through a pathway summarized in figure 2. The

major portion of precursor cholesterol in humans is produced in Leydig

cells from acetate and is stored in lipid droplets. There is no evidence for

the delivery of circulating cholesterol bound to lipoproteins to the testis via

the low-density lipoprotein (LDL) receptor. Cholesterol is converted in

115
mitochondria to pregnenolone, which is in turn transported to the endoplasmic reticulum and its surrounding cytoplasm (microsomes). Pregnenolone is

converted to testosterone in three steps: hydroxylation and C17-20

side-chain cleavage, which are catalyzed by the same enzyme, and reduction

of the 17-keto group. Two possible pathways exist for the synthesis of testosterone from pregnenolone; one is through hydroxypregnenolone to

dehydroepiandrosterone (the delta-5 pathway) and the second is through progesterone, hydroxy progesterone, and androstenedione (the delta-4 pathway). Incubation of human testicular microsomes with radiolabeled pregnenolone and examination of the products formed suggest that the delta-5

pathway predominates in man (Yanaihara and Troen 1972). Most of the

testosterone produced is released immediately into the circulation. The

normal production rate of testosterone in adult men is about 6 mg per day.

Circulating testosterone is bound tightly by a serum glycoprotein of hepatic

origin, sex-hormone-binding globulin (SHBG), and weakly by albumin.

Approximately 1 to 2 percent of the circulating testosterone is thought to be

unbound. The binding to albumin is of such low affinity, however, that this

pool is believed to be functionally equivalent to unbound testosterone. Testosterone is thought to enter target cells by simple diffusion (figure 3). The

50 percent of the circulating testosterone in normal men that is bound

tightly to SHBG probably does not enter cells, although some evidence to

the contrary has been presented. Changes in the concentrations of SHBG

will therefore influence the measured total testosterone level as well as the

proportion of the testosterone in serum that can enter target cells.

Figure 4 is a diagram outlining the metabolism of testosterone. Testosterone is metabolized by the liver to the 17 keto-steroids androsterone and

etiocholanolone, which are excreted in urine. The total 17 keto-steroids

in the urine of normal adult men is 5 to 25 mg over 24 hours. Testosterone derivatives constitute a small percentage of the total urinary 17 ketosteroids, which also include the metabolites of androstenedione and dehydroepiandrosterone produced by the adrenal cortex. Testosterone is metabolized

to a series of 3, 15, and 16 hydroxylated polar compounds, which are

excreted in the urine, and is conjugated to sulfuric and glucuronic acids,

which are excreted in the urine and bile. A small amount (<250 μg per

day) of testosterone is excreted unmetabolized in the urine. Testosterone is

bioconverted in certain target tissues to the active compounds -dihydrotestosterone (DHT) and estradiol, as discussed below.

TESTOSTERONE ACTION ON TARGET CELLS

Testosterone influences the function of its target cells by binding to a highaffinity intracellular receptor protein (figure 3). Complementary DNA sequences to androgen receptors have been recently obtained (Lubahn et al.

1988), facilitating the study of the structure and biological actions of

the receptor. The androgen receptor is a protein of approximately

116
FIGURE 2. Pathways of testosterone biosynthesis in the human

120 kilodaltons coded in humans by genes located on the X-chromosome.

Based upon physicochemical and kinetic properties, the androgen receptor

appears to be identical in all androgen target cells. However, the concentration of receptors in target tissues varies widely. Evidence to date suggests

that, by binding to the receptor, testosterone dissociates the active monomer

from a larger inactive protein. The receptor is thus activated and capable

117
SCHEMATIC DIAGRAM OF

ANDROGEN ACTION AT ITS TARGET CELLS

FIGURE 3. Schematic model of androgen action in target cells

PATHWAYS FOR THE METABOLISM

OF TESTOSTERONE

FIGURE 4. The metabolic pathways for testosterone

of binding to nucleotide sequences known as the hormone-response element.

Nuclear binding increases RNA and protein synthesis and, in some tissues,

DNA synthesis. Upstream promoter elements at the 5’ flanking region bind

intracellular proteins that regulate the rate of transcription. These intracellular events appear to be similar to those for the other steroid hormones

118
including glucocorticoids, mineralocorticoids, estrogens, progestins, thyronines, and vitamin D (Carson-Jurica et al. 1990).

Androgens probably influence the action of most cells (Mooradian et al.

1987). A list of selected androgen target tissues and the biological actions

of androgens on these cells is presented in table 1. Classically, the actions

of testosterone have been divided into those that are androgenic, i.e., promoting the development and maintenance of male secondary sex characteristics (virilizing), and anabolic, i.e., assimilating nutritive matter into living

substances (muscle promoting). However, the limitations of this classification are evident upon inspection of the many actions of testosterone that are

neither androgenic nor anabolic.

TABLE 1. Functions of androgens in various target tissues

Target Tissue Function of Androgen

Testes

Sex-Accessory Glands

prostate, seminal vesicles,

epididymis, penis

Skin, Hair, Sebaceous Glands

Muscle

skeletal

cardiac

smooth

Central Nervous System

Hypothalamus/Pituitary

Liver

Kidney

Larynx

Hemapoietic Organs

Immune System

Salivary Glands

Breast

Bone

Spermatogenesis

Growth and secretions

Hair growth, secretions

Hypertrophy

Increase contractility

Libido

GnRH, LH, and FSH secretion

Enzymes and secreted proteins

Enzymes

Growth

Erythropoiesis

Lymphoid involution

Pheromones

Inhibit glandular development

Promote mineralization

In certain target tissues, such as prostate, seminal vesicles, and pubic skin,

testosterone is irreversibly and nearly completely metabolized to DHT, and

it is DHT that primarily binds to the androgen receptor. In other target

tissues, such as kidney, testis, and skeletal muscle, which contain little

119
reductase, testosterone interacts with the receptor directly. Although

there is no clear explanation for the presence of testosterone reductase in

only certain androgen target tissues, the significance of testosterone

reductase is underscored by the existence of a clinical syndrome of

ambiguous external genitalia in patients who lack normal testosterone

reductase activity (Peterson et al. 1977). DHT is 2.5 to 10 times more

potent than testosterone in bioassays and binds with two to three times

higher affinity (KD=0.25 to 0.50 nM) to the androgen receptor than does

testosterone (KD=0.4 to 1.0 nM). In this way, reduction appears to

locally amplify the actions of testosterone in selected target tissues.

Because DHT is present in the circulation of adult men in levels (30 to

80 ng/dl) about one tenth those of testosterone, circulating DHT has little

influence on target tissues compared to testosterone.

Not only is little DHT produced by skeletal muscle, but DHT is also further

metabolized to the weak androgen andrcstane diol by the cytosolic

enzyme -hydroxysteroid oxidoreductase (Warrenski and Almon 1983).

This bioconversion limits the action of DHT in skeletal muscle as well as

the action of other androgens metabolized by this enzyme. By contrast, the

action of reduced androgens is sustained in prostate, which contains

considerable reductase and little -hydroxysteroid oxidoreductase activity. In this way, target tissue metabolism modifies the actions of

androgens unequally among target tissues. This concept is schematically

represented in figure 5.

Estradiol is a second product of testosterone with biological activity. Approximately one-fourth of the estradiol produced in men is secreted directly

by the testes, and the remainder is produced from circulating testosterone in

liver and fat cells (MacDonald et al. 1979). The physiological actions of

estrogens in men are largely unknown. Estrogens increase the synthesis of

several hepatic proteins, including SHBG, thyroid-binding globulin, and lipoproteins; estradiol may be important in mediating some aspects of male

sexual behavior (Pardridge et al. 1982). Estrogen administration or

increased estrogen secretion by a tumor of the adrenal gland or testis suppresses gonadotropin and testosterone secretion, producing hypogonadism

and feminization.

CLINICAL EFFECTS OF ANDROGENS

Male sexual differentiation occurs during the first trimester of fetal life.

The urogenital sinus and external genitalia develop identically in both sexes

by the eighth week of gestation and have the capacity to differentiate into

either male or female structures. Testosterone induces differentiation of the

internal (Wolffian) ducts. The urethral folds fuse to form a phallic urethra,

the labialscrotal swellings fuse to form a scrotum, and the prostate and

bulbourethral glands form as outgrowths of the urogenital sinus. Descent of

the testes into the scrotum occurs during the third trimester. There is

120
FIGURE 5. A comparison of the relative androgen receptor-binding affinities and intracellular metabolism of testosterone, DHT, and

androstane diol in rat prostate and

skeletal muscle

NOTE: Relative binding affinity was studied using (

3H)methyltrienolone as the radiolabeled ligand

and setting the EC50 of nonlabeled methyltrienolone equal to 1.0.

SOURCE: Data from Saartok et al. 1984.

accumulating evidence that behavioral masculinization also begins during

fetal life.

Thereafter, the reproductive system is relatively quiescent until puberty, at

which time testosterone secretion increases, and a complex series of physical and behavioral changes produce the adult male phenotype. The testes

grow to adult size between ages 11 and 16, and the production of sperm

commences (Nielsen et al. 1986). The scrotum darkens and becomes rugated. Beard and body hair growth are stimulated, and sebaceous gland development occurs, increasing the production of sebum producing an adult body

odor and acne. The phallus enlarges. Growth and development of the

prostate and seminal vesicles permit the production of semen. The larynx

enlarges, the vocal cords thicken, and the voice deepens. Adult sexual

121
behavior begins. There is an increase in the linear growth rate known as

the adolescent growth spurt. Accelerated growth is maintained for about 2

years and is accompanied by skeletal maturation. Fusion of epiphyseal

growth plates usually occurs by age 17, terminating longitudinal growth.

Skeletal muscles grow, and there is an increase in total body water, indicating a relative decline in body fat.

In adult men, testosterone sustains these secondary sex characteristics and

increases male sexual behavior. Testosterone stimulates erectile potency,

although the details of its interaction with the neural and vascular mechanisms for this effect are uncertain. Testosterone is also an important spermatogenic hormone, which affects both Sertoli and myoid cells within the

seminiferous tubule. Androgens influence bone metabolism, since androgen

deficiency is associated with osteoporosis (Greenspan et al. 1986). Finally,

androgens stimulate erythropoiesis by increasing renal erythropoietin production and by directly affecting bone marrow cells; androgen-deficient men are

frequently mildly anemic.

CLINICAL USE OF ANDROGENS

Androgens are used in clinical medicine to treat adult men with androgen

deficiency owing to either an abnormality of the testes or of the hypothalamus-pituitary axis (Wilson and Griffin 1980). The goal of therapy is to

restore libido and potency and to stimulate the expression of secondary sex

characteristics. Because of etythropoietic actions, androgens have been used

in patients with the anemia of chronic renal failure (Neff et al. 1981) and in

patients with aplastic anemia. Androgens are used to prevent attacks of

hereditary angioneurotic edema because androgens stimulate the production

of an inhibitor of the activated first component of complement, which is

deficient in these individuals (Gelfand et al. 1976). Patients with insufficient protein synthesis and excessive protein breakdown, such as those with

malignancies, bums, major trauma, and chronic illnesses such as AIDS,

have also been treated with androgens.

In women, androgens have been used in the treatment of osteoporosis, endometriosis, fibrocystic disease of the breast, and breast cancer. In the pediatric population, androgens are used in boys with congenital micropenis.

Most boys born with a small phallus will have hypogonadism as adults. A

much more common problem in pediatric endocrinology is the young teenager with short stature and delayed puberty. Some of these short children

have a disturbance in pituitary hormone secretion or systemic illness, whereas others are normal short children. Androgens are given to these teenagers

to stimulate linear growth and to accelerate the clinical features of puberty.

The use of androgens in children and women is limited, however, by the

undesirable side effects of virilization.

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ANDROGEN PREPARATIONS

The structures of androgens currently used in clinical medicine are diagrammed in figure 6. Natural testosterone taken orally or injected intramuscularly is rapidly cleared by the liver and is therefore ineffective clinically.

Esterification of testosterone at the 17-hydroxyl position produces compounds with increased lipid solubility. These derivatives, administered by

intramuscular injection in oil, represent the most commonly prescribed

androgens today. The solubility and rate of absorption of these compounds

varies depending upon the fatty acid chain. After they leave the depot, the

esters are rapidly metabolized to free steroid, which interacts with target

tissues. The testosterone released is also available for bioconversion to

DHT and estradiol.

FIGURE 6. Androgens used orally and parenterally

Testosterone esters in clinical use in the United States are propionate, cypionate (Depo-testosterone, Virilon IM), and enanthate (Delatestryl, Testaval).

Testosterone propionate at a dose of 50 mg sustains physiologic testosterone

levels for 36 to 48 hours (Fujioka et al. 1986). Because of its short duration of action, this ester is of limited clinical usefulness. Doses of 200 mg

of testosterone enanthate (Snyder and Lawrence 1980) or cypionate (Nankin

123
et al. 1986) maintain normal serum testosterone levels for 10 to 14 days.

These doses generally produce supraphysiological levels of both testosterone

and estradiol for 1 to 3 days. The increase in estradiol levels may produce

gynecomastia in some testosterone-treated men. Both the peak and trough

levels are monitored in treated patients because the hormone levels produced

and the clinical responses vary among individuals. Long-acting testosterone

esters are well tolerated by patients and in replacement dosages are free of

side effects. Because the hormone profiles produced do not mimic physiological levels, alternative delivery systems including transdermal, buccal, and

longer acting injectable formulations are currently under study.

Several testosterone derivatives are available for oral use. Most are alkylated at the position, as this change produces compounds that are more

slowly metabolized by the liver. Oral testosterone derivatives available in

the United States include methyltestosterone (Android, Metandren, Oreton

methyl, Testred, Virilon), fluoxymesterone (Halotestin), and danazol (Danacrine). Stanozolol (Stromba, Winstral) is not licensed in the United States

for clinical use but is used in veterinary medicine. These androgens are not

metabolized to testosterone, but rather interact directly with the androgen

receptor. These steroids are also neither metabolized to estradiol nor to

DHT. Since they tend to bind less tightly to the receptor than does testosterone (Saartok et al. 1984), they tend to be less biologically active. In

sufficient dosages, however, they inhibit LH, FSH, and testosterone secretion (Vigersky et al. 1976; Small et al. 1984). The -alkylated androgens

elevate serum levels of haptoglobin, orosomucoid, and plasminogen (Barbosa

et al. 1971) and reduce the circulating concentrations of SHBG and thereby

total testosterone, thyroid-binding globulin and thereby total 1-thyroxine

levels, and vitamin-D-binding globulin and 25 hydroxy vitamin D levels.

17-Alpha methylated androgens also reduce HDL cholesterol and increase

LDL cholesterol (Haffner et al. 1983).

Manufacturers’ recommendations indicate that oral androgens can be given

in a single daily dose or three to four times per day. Recommended doses

do not generally produce complete androgenization in hypogonadal men,

however, perhaps because these compounds bind weakly to androgen receptors and cannot be metabolized to DHT. Further, the absence of convenient

assays for these compounds in serum together with the difficulty associated

with determining the appropriate end point for assessing bioactivity limits

their clinical usefulness. Finally, 17-alkyl androgens are associated with

idiosyncratic liver disease. Accordingly, oral androgens are generally

reserved for patients who do not tolerate intramuscular injections, such as

children and those with bleeding disorders. Testosterone undecanoate

(Sustanon), available in Europe, has a long aliphatic side chain resulting in

its adsorption into lymphatics bypassing the liver. The ester linkage is

broken, and unconjugated testosterone is present in the circulation. This

androgen must be given three times daily (Gooren 1986).

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Deletion of the 19 methyl group of testosterone produces 19-nortestosterone.

This change increases the growth-promoting effect on the levator ani muscle

relative to that of seminal vesicles (Hershberger et al. 1953). This has been

termed the anabolic-androgenic index. Like DHT, 19-nortestosterone is

more planar than testosterone, increasing its receptor-binding affinity. However, it binds with similar affinity to androgen receptors in skeletal muscle

and in prostate (Saartok et al. 1984). 19-Nortestosterone is not converted to

DHT in tissues containing reductase but instead is converted to

dihydro-19-nortestosterone, a compound that binds less tightly to androgen

receptors than does DHT (Bergink et al. 1985). Together, these factors

could explain the diminished effect of 19-nortestosterone relative to testosterone on androgen target tissues containing reductase (e.g., seminal

vesicles) together with a greater effect than testosterone on tissues containing little or none of this enzyme, e.g., levator ani and skeletal muscle (Toth

et al. 1982). Further, 19-nortestosterone has limited affinity for serum

SHBG. Therefore, a greater fraction of circulating 19-nortestosterone than

testosterone would be available to all androgen target tissues according to

the free-hormone hypothesis.

Of the 19-nortestosterone derivatives, only nandrolone decanoate (DecaDurabolin) and nandrolone phenylpropionate are licensed for clinical use in

the United States. The dimethyl derivative dimethyl nortestosterone

(mibolerone) binds more tightly to androgen receptors than does 19-nortestosterone and is used in animals. A radioimmunoassay for nandrolone has

been developed (Wijnand et al. 1985). Peak levels of 2.0 to 6.5 ng/ml are

produced by 12 hours and decline by 50 percent over 7 days after intramuscular injections of 100 to 200 mg of the decanoate ester. The hexoxyphenylpropionate ester has a longer circulating half-life of 21 days (Belkien

et al. 1985). Nandrolone derivatives are frequently used by athletes for

their anabolic properties. Other androgen target tissues are also influenced

by nandrolone, however, when it is taken in sufficient dosage. Nandrolone

hexoxyphenylpropionate was given to normal men at a dose of 100 mg

twice weekly for 10 weeks. Testis size declined by 50 percent, and all

men became azoospermic. These changes were reversed within 16 to 30

weeks of discontinuing treatment (Schurmeyer et al. 1984). There are a

few case reports, however, suggesting that recovery of gonadotropin secretion may be incomplete with prolonged high-dose treatment. Nandrolone

may also adversely affect the testis directly, as a profound decrease in

serum total and free testosterone levels unassociated with a decline in serum

LH concentrations has also been reported (Bijlsme et al. 1982).

Oxandrolone (Anavar) was also developed in an effort to dissociate androgenie from anabolic actions. This compound is methylated, slowing its

hepatic metabolism, and is modified in the A ring with the substitution of

an oxygen for carbon in position 2. Data in rats indicated that this drug

had less than 5 percent of the activity of testosterone propionate to stimulate prostate, seminal vesicle, and levator ani growth when both drugs were

125
administered intramuscularly in oil. However, oxandrolone was only 50 to

70 percent as active as methyltestmterone in stimulating seminal vesicle and

prostate growth but 110 percent as active in increasing levator ani weight

when each was given orally (Lennon and Saunders 1964). Differences in

absorption and distribution kinetics as well as the availability of testosterone

but not oxandrolone or methyltestosterone for reduction may have influenced these results. Oral oxandrolone has been used to increase linear

growth in short children. Although mean height velocity is often initially

accelerated, there is no convincing evidence that ultimate height is increased

(Marti-Henneberg and Niirianen 1975). As with other anabolic steroids, the

clinical use of this compound has not resulted in selected effects on growth.

At a dose of 0.1 mg/kg per day, this drug has antigonadotropic actions in

children, as testis growth in treated teenagers was reduced compared to an

untreated control group (Marti-Henneberg and Niirianen 1975). At a dose

of 5 mg per day, oxandrolone had a greater antigonadotropic effect in adult

men than did 10 mg of methyltestosterone, based upon suppression of urinary 17-ketosteroid excretion (Fox et al. 1962).

Oxymetholone has also been used to stimulate linear growth in children

with similar results. A recent study has verified that intramuscular testosterone enanthate in low doses will also accelerate short-term growth velocity

without compromising final adult height (Richman and Hirsch 1988). Methandrostenolone (Dianabol) is another androgen commonly taken for its anabolic properties. The manufacture of methandrostenolone has recently been

discontinued in the United States.

CONCLUSION

Testosterone probably affects most cells in the body. However, it is sexual

behavior, phenotypic changes, and bone mineral metabolism that are most

evidently adversely influenced by androgen deficiency. Androgen treatment

of hypogonadal men can restore these abnormalities to normal and is currently most effectively accomplished with long-acting parenteral esters of

testosterone.

The availability of preparations with selective actions of testosterone, such

as the stimulation of linear growth in children, the restoration of muscle

mass in catabolic patients, or the induction of Cl inhibitor in women with

hereditary angioedema, would represent an important pharmacological

advance. However, such compounds are not presently available. Although

the various androgens in clinical use, including those reported to have

enhanced anabolic action compared to testosterone, stimulate identical androgen receptors in all target tissues, differences exist in plasma transport,

hepatic clearance, and target-tissue metabolism among these compounds. In

particular, tissue distribution of reductase appears to be important in

explaining differences in dose-response curves among androgen target

tissues. Further studies of intracellular androgen metabolism are needed to

126
better understand the many actions and controversies surrounding the efficacy and safety of androgen treatment for conditions other than androgen

deficiency.

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ACKNOWLEDGMENTS

This work supported in part by U.S. Public Health Service grant

R01 HD 19546 from the National Institutes of Health. Philip Troen,

M.D., provided helpful suggestions in the development of this chapter.

AUTHOR

Stephen J. Winters, M.D.

Associate Professor of Medicine

Division of Endocrinology

University of Pittsburgh School of Medicine

Montefiore Hospital

3459 Fifth Avenue

Pittsburgh, PA 15213

130
The Androgen-Induced Phenotype

C. Wayne Bardin, James F. Catterall, and Olli A. Jänne

INTRODUCTION

Early studies on the action of testosterone emphasized that this steroid

influences almost every organ in the body. Actions on reproductive tracts

were called androgenic, while those on other organs were termed anabolic

(Mainwaring 1977; Kochakian 1984). These designations were the first

attempt to characterize the diverse effects of testosterone and other steroids

with similar structures (Bardin and Catterall 1981). Androgen receptors

were initially identified in prostate, seminal vesicle, and other reproductive

tissues. Subsequent studies showing that antiandrogens could compete with

testosterone and its reduced metabolite, -dihydrotestosterone (DHT), for

receptor binding sites clearly associated these receptors with the action of

androgens (Jänne and Bardin 1984). The ultimate proof, however, that androgen receptors were an essential link between the steroid and the

androgen-induced phenotype was the identification of receptor mutants in

the rat and the mouse that were insensitive to many of the effects of testosterone and other androgens (Bardin et al. 1973). Studies on these animals,

and ultimately in men (Keenan et al. 1974) with similar receptor abnormalities, emphasized that both the androgenic and the anabolic effects of testosterone were mediated by the androgen receptor.

In view of the fact that many of the diverse effects of androgens were

mediated via a common receptor protein, it was perplexing that their actions

were so diverse and their effectiveness so varied on tissues. Part of the

reason why some steroids appear to have more androgenic than anabolic

activity relates to their ability to undergo metabolism either to a -reduced

product with enhanced biological potency or to an estrogen that may be

antiandrogenic (Bardin and Catterall 1981). Thus, in reproductive tissues

and skin, testosterone is metabolized by -reductase to DHT, which is five

times more potent than testosterone, whereas there is very little -reductase activity in most nonreproductive tissues, and testosterone per se is the

active intracellular androgen. In addition, testosterone in some tissues can

be aromatized to estrogens, which can, in turn, either oppose the action of

androgen or exert anabolic effects via estrogen receptors (Bardin and

131
Catterall 1981). These observations suggest that part of the differential

effects of one androgen on multiple tissues or of multiple androgens on the

same tissue result from tissue- and steroid-specific differences in androgen

metabolism.

Testosterone metabolism cannot, however, explain all of the variable

responses to androgens observed in different tissues. The general concept

of androgen action holds that interaction of testosterone, DHT, or other anabolic steroids with the androgen receptor changes its conformation and

allows it to bind to hormone regulatory elements adjacent to or within

androgen-responsive genes (Beato 1987). Such steroid response elements

are able to interact with other regulatory elements and tissue-specific

factors. Diversity of the receptor-mediated responses will, therefore, be

generated by the nature of the steroid bound to the receptor, the structure of

regulatory DNA motifs that regulate individual genes, and the tissue-specific

factors that are present. All these factors determine whether a gene will be

responsive to androgen in a given tissue and, if so, the magnitude of the

ensuing response. Finally, it will be the variable tissue-specific responses of

multiple genes along with the kinetics of mRNA and protein turnover that

will eventually determine the androgen-dependent phenotype of an

individual.

In the present chapter, a scheme of androgen action will be reviewed that

attempts to illustrate (1) how androgen receptor levels relate to androgen

action; (2) how the androgen-induced phenotype is produced; and (3) why

differential sensitivity of genes is necessary to explain differences in phenotype. These concepts will be reviewed in line with research from our own

and other laboratories. An attempt to refer to all of the relevant articles on

this subject must await a more comprehensive treatise.

Most of the experiments reported here have been conducted using mouse

kidney, as this androgen-responsive tissue has a number of features that

make it particularly amenable to study. These include the facts that testosterone rather than DHT is the active intranuclear androgen; mRNA kinetics

are easily studied, as RNA synthesis is not interrupted by successive rounds

of DNA replication as it is in prostate, in which androgens are mitogenic;

and there are established genetic variants of mice that demonstrate differences in the magnitude of response of individual genes to testosterone and

other hormones (Bardin et al. 1973; Catterall et al. 19%). To study the

androgen-induced events in mouse kidney, a number of genes were cloned

and cDNAs prepared for measurement of mRNA levels. These genes include those coding for kidney androgen-regulated protein (KAP), omithine

decarboxylase (ODC), and ß-glucuronidase (ß-Gluc). Androgens stimulate

accumulation of KAP, ODC, ß-Glut mRNAs, and the rates of synthesis of

the respective proteins in the epithelial cells of the proximal tubule.

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THE RELATION OF ANDROGEN RECEPTOR LEVELS TO

ANDROGEN ACTION

The notion that the amount of androgen receptor in a tissue might determine the magnitude of androgenic response probably arose from the observation that some individuals with receptor defects have reduced receptor

levels associated with an incompletely androgenized phenotype. Such a

conclusion appeared to be supported by observations showing a linear relationship between the dose of testosterone and the amount of occupied

nuclear androgen receptor in responsive tissues (Van Doom et al. 1976).

These results led to the expectation that there would also be a linear relationship between the number of occupied nuclear androgen receptors and the

accumulation of some androgen-induced gene products. Such an expectation

appeared to be fulfilled, provided that receptor levels were related to a

single androgen-induced product. Once multiple responses were examined

in the same cell, then a clear relationship to androgen receptor levels was

not obvious (Pajunen et al. 1982). This is illustrated by the results of an

experiment shown in figure 1, in which a large single dose of testosterone

was administered to mice, and the accumulation of ODC, KAP, and ß-Glut

mRNAs was plotted relative to nuclear androgen receptor levels. ODC

mRNA levels rose rapidly after hormone administration and plateaued at a

high level by 20 hours. KAP mRNA levels also increased rapidly but plateaued at a much lower level. The rise in ß-Glut mRNA was not observed

until 24 hours, and the peak response was observed only after a continuous

administration of androgen for about 3 weeks (Watson and Catterall 1986).

Thus, there was dissociation between the slope of the response and the

magnitude of the response (Catterall et al. 1986).

A similar dissociation was also shown in a study that compared serum

testosterone levels, nuclear androgen receptors per cell, and ODC activity in

intact male mice of eight different genetic backgrounds (Melanitou et al.

1987). Even though serum testosterone concentration varied over a tenfold

range, there was no correlation between the steroid levels and the nuclear

androgen receptor concentrations across mouse strains. For example, the

C57BL/6J mice, which had the lowest serum testosterone levels, had the

same nuclear receptor concentrations as RF/J mice, which had the highest

circulating testosterone levels. In spite of this, the renal ODC activity in

RF/J mice was five times higher than that of C57BL/6J animals. Examination of the other six strains confirmed that there was no correlation between

the concentration of nuclear androgen receptors and ODC activity. Another

illustration of how nuclear androgen receptors do not strictly relate to the

biologic response of a given gene is demonstrated by the fact that agents

such as testosterone, medroxyprogesterone acetate, and a nonsteroidal antiandrogen, flutamide, can all occupy similar numbers of androgen receptors

but can, respectively, markedly stimulate, modestly stimulate, or inhibit the

response of an individual gene (Kontula et al. 1985; Bullock 1983).

133
FIGURE 1. Changes in accumulation of mRNAs coding for ODC, KAP, ßGluc, and nuclear androgen receptors (AR,) in mouse

kidney after a single dose of testosterone (10 mg)

NOTE: All values are expressed relative to those of untreated female mice.

134
We infer from these observations that the concentration of occupied androgen receptors in a cell is correlated, at least in some cases, directly with the

response in a single gene product. However, the number of occupied

nuclear receptors cannot be correlated with differential responses of two

genes within the same cell, of one gene in different cell types, of one gene

in the same cell type of animals with different genetic backgrounds, or of

two hormones, such as androgen and progestin, that mediate response on the

same gene via the same receptor.

THE ANDROGEN-INDUCED PHENOTYPE

The phenotype is defined as the manifest characteristics of a cell, organ, or

organism collectively, including all traits that result from heredity and environment. The androgen-induced phenotype would be those characteristics

of an organism that are dependent upon testosterone-induced differentiation

or growth. In an attempt to explain the difference in the phenotype between individual men, investigators have attempted to relate prostate size,

muscle mass, magnitude of aggression, etc., to testosterone levels in blood

or tissue. There are, however, marked variations in phenotype among individuals that are exposed to the same testosterone concentrations and environmental factors. Although these differences have been attributed to

genetic variation, this postulate has been difficult to confirm in humans.

Some verification for such a proposal was derived from responses of various inbred strains of mice to graded doses of androgens. Kidneys of such

animals were removed, and mRNA concentrations for KAP, ODC, and ßGluc were measured. Concentrations of these three mRNAs are representative of an androgen-dependent phenotype for the epithelial cells of renal

proximal tubules. Four androgen phenotypes are illustrated for both A/J

and C57BR/cdJ mice in figure 2. The amounts of three different mRNAs

are shown by Northern blot analysis for the two strains of mice exposed to

four vastly different testosterone levels. These phenotypes are those for

animals exposed to doses of testosterone found in normal females

(~0.4 μg/day), normal males (4 μg/day), 10 times the normal male secretion

rate (40 μg/day), and 50 times the normal male secretion rate (200 μg/day).

The relative amounts of the three mRNAs that comprise the four phenotypes

are strikingly different. Simulated dose-response curves of the three

mRNAs to various doses of testosterone in A/J and C57BR/cdJ mice are

illustrated in figure 3. In this figure, the testosterone production rate is displayed against the percent of the maximal response for the three mRNAs.

The testosterone production rate of normal males is taken as 4 μg/day, emphasizing that, in most species, males produce approximately 10 times more

testosterone than females. A series of vertical lines defines the phenotypes

for a given dose of testosterone as each intersects the three response curves.

For example, in A/J mice the phenotype of renal cells stimulated by the

physiological level of testosterone is characterized by KAP and ß-Gluc

mRNA levels that are 20 percent and 7.5 percent of maximal, and ODC

135
FIGURE 2. Concentrations of ß-Gluc, ODC, and KAP mRNAs in kidneys

of two inbred strains of mice exposed to different doses of

testosterone

KEY: F=intact female mice; M=intact male mice; T-40=female mice treated for 5 days with implants

releasing 40 μg testosterone per day; T-200=female mice treated for 5 days with implants releasing 200 μg testosterone per day.

NOTE: Each sample was analyzed in duplicate, and the filters hybridized successively with cDNAs

specific for each of the three mRNAs.

mRNA levels that are not different from those in the uninduced females.

By contrast, in C57BR/cdJ mice, the male phenotype is characterized by

stimulation of KAP, ODC, and ß-Gluc mRNA accumulation to levels that

are 50 percent, 12 percent, and 5 percent of maximal, respectively. Not

only is the magnitude of the response for each gene different between the

two strains, but the ordering of the dose-response curves for each of the

three genes is dissimilar. Thus, the possible androgen-induced phenotypes

for the mouse kidney can be illustrated by an ordered series of curves that

describe the responses of all the different mRNAs and proteins that increase

in this organ in response to androgens. The fact that each response curve

can be genetically regulated offers tremendous opportunity for diversity.

136
FIGURE 3. Hypothetical dose-response curves for the expression of ßGluc, ODC, and KAP genes in two strains of mice exposed

to different doses of testosterone

NOTE: The vertical line illustrates the situation when testosterone production rate is approximately

that of intact male mice.

When these and other observations are applied to the androgen-induced

phenotype in humans, the following predictions are warranted: (1) clinical

phenotypes are defined by the sum of multiple androgen-induced responses;

(2) differences in phenotype between individuals result from how individual

dose-response curves are ordered as well as from other environmental factors such as exercise; (3) physiological androgen levels do not maximally

express the male phenotype; and (4) the response to androgens in most

species is based upon the log of the steroid dose, and, as a consequence, a

significant change in the phenotype may require a three- to tenfold increase

in the circulating testosterone concentration, depending upon what percent of

the maximal response is already archived by physiological hormone levels.

DIFFERENTIAL SENSITIVITY OF ANDROGEN-RESPONSIVE

GENES

Studies on the mechanism of androgen action now provide insight into the

reasons for the genetic diversity between individuals with different genotypes. Genetic regulation of ß-Gluc, an acid hydrolase present in lysosomes

and endoplasmic reticulum of virtually all tissues, serves as a good example

to illustrate this point. Genetic studies led to the identification of four

137
genes in the ß-Gluc genetic complex (Gus) (Swank et al. 1978). The ß

Gluc structural gene, Gus-s, has five well-characterized alleles that code for

electrophoretic and thermostability variants of the enzyme protein. In addition to Gus-s, three regulatory loci have been described. These have all

been shown to be linked closely to Gus-s. The Gus-t locus regulates the

temporal development of enzyme activity in various tissues. This locus is

unique among the regulators of the Gus complex because it appears to

encode a trans-acting factor. A second regulatory locus of the Gus complex, Gus-u, controls the synthesis of ß-Gluc in all tissues at all stages of

development. This is a cis-acting systemic regulator. Finally, a third

regulatory locus, Gus-r, acts cis to control the response of the structural

gene, Gus-s, to androgens. There are two alleles of Gus-r, and mouse

strains are divided into two haptotypes based on their response to androgens. In strains of mice carrying the Gus-rb

allele, ß-Gluc activity rises

slowly in response to testosterone and reaches a plateau at approximately

3 weeks of treatment. Strains carrying the Gus-raallele exhibit a more

rapid and a much higher maximum response. The responses to androgen

administration of the A/J strain with the Gus-raallele and the C57BL/6J

strain with the Gus-rballele are shown in figure 4.

The nature of the Gus-r locus and its location within the DNA either adjacent to or remote from the structural gene for ß-Gluc is currently being

intensely investigated by several laboratories. Direct cloning of Gus-r will

be difficult, since there is no Gus-r-encoded gene product. It is assumed by

many that the Gus-r locus will be found near the site of initiation of

transcription of the Gus-s gene. If this assumption is correct, then characterization of the Gus-s transcription unit and sequences flanking it will

provide means to identify Gus-r. However, comparison of sequences encompassing about 2,500 nucleotides of DNA flanking the two alleles has

revealed no significant differences (unpublished results). It is also possible

that Gus-r is located within Gus-s, possibly as part of an intervening sequence. It is interesting that the only major difference between the structures of Gus-sa

and Gus-sbis a 206-base pair element in intervening

sequence 4 of Gus-sathat is absent in Gus-sb(D’Amore et al. 1988). The

relationship, if any, between this element and Gus-r function is not known.

Alternatively, Gus-r may represent a tissue- and gene-specific enhancer, possibly acting at a distance from Gus-s. In the latter two cases, characterization of Gus-r is also approachable by cloning and sequencing of Gus-s and

its flanking DNA from mouse strains carrying the Gus-raand Gus-rballeles.

Ultimately, however, a correlation must be made between structural variation

and allelic Gus-r regulatory function.

On the basis of observations on other hormone-responsive genes, it is

assumed, but not proven, that Gus-r is a hormone-response element interacting with the androgen receptor, similar to those that have been identified as

DNA-binding sites for glucocorticoid, progesterone, and estrogen receptors,

which are other members of the receptor gene superfamily. The fact that

138
FIGURE 4. Androgen-related increase in renal ß-Gluc activity in mice

carrying Gus-raand Gus-rbregulatory alleles of the ß-Gluc

gene

there can be multiple hormone regulatory elements for a single steroid

receptor associated with a given gene, that these DNA motifs can regulate

either negatively or positively, and that they can interact with a variety of

tissue-specific transcription factors offers the possibility for variable sensitivity between different hormone-responsive genes in the same individual.

Regulatory elements may also show genetic diversity, as is the case with

the Gus-r locus, which provides one possible explanation for dissimilar

responses to androgens of the same gene in two individuals. This, in turn,

will explain the enormous diversity in phenotype that is observed among

men.

139
REFERENCES

Bardin, C.W.; Bullock, L.P.; Sherins, R.J.; Mowszowicz, I.; and Blackbum,

W.R. Androgen metabolism and mechanism of action in male pseudohermaphroditism: A study of testicular feminization. Recent Prog Horm

Res 29:65-109, 1973.

Bardin, C.W., and Catterall, J.F. Testosterone, a major determinant of

extragenital sexual dimorphism. Science 211:1285-1294, 1981.

Beato, M. Induction of transcription by steroid hormones. Biochim

Biophys AcTa 910:95-102, 1987.

Bullock, L.P. Androgen and progestin stimulation of omithine decarboxylase activity in the mouse kidney. Endocrinology 112:1903-1909, 1983.

Catterall, J.F.; Kontula, K.K.; Watson, C.S.; Seppanen, P.J.; Funkenstein, B.;

Melanitou, E.; Hickok, N.J.; Bardin, C.W.; and Janne, O.A. Regulation

of gene expression by androgens in murine kidney. Recent Prog Horm

Res 42:71-109, 1986.

D’Amore, M.A.; Gallagher, P.M.; Korfhagen, T.R.; and Ganschow, R.E.

Complete sequence and organization of the murine ß-glucuronidase gene.

Biochemistry 27:7131-7140, 1988.

Jänne, O.A., and Bardin, C.W. Androgen and antiandrogen receptor binding. Annu Rev Physiol 46:107-118, 1984.

Keenan, B.S.; Mayer, W.J., III; Hadjian, A.J.; Jones, H.W.; and Migeon,

C.J. Syndrome of androgen insensitivity in man: Absence of

dihydrotestosterone binding protein in skin fibroblasts. J Clin Endocrinol

Metab 38:1143-1146, 1974.

Kochakian, C.D. How It Was. Anabolic Action of Steroids and Remembrances. Birmingham: University of Alabama School of Medicine, 1984.

Kontula, K.K.; Seppanen, P.J.; Van Duyne, P.; Bardin, C.W.; and Jänne,

O.A. Effect of a nonsteroidal antiandrogen, flutamide, on androgen

receptor dynamics and ornithine decarboxylase gene expression in mouse

kidney. Endocrinology 116:226-233, 1985.

Mainwaring, W.I.P. The Mechanism of Action of Androgens. New York:

Springer-Verlag, 1977.

Melanitou, E.; Cohn, D.A.; Bardin, C.W.; and Jänne, O.A. Genetic variation in androgen regulation of omithine decarboxylase gene expression in

inbred strains of mice. Mol Endocrinol 1:266-273, 1987.

Pajunen, A.E.I.; Isomaa, V.V.; Jänne, O.A.; and Bardin, C.W. Androgenic

regulation of omithine decarboxylase activity in mouse kidney and its

relationship to changes in cytosol and nuclear androgen receptor concentrations. J Biol Chem 257:8190-8198, 1982.

Swank, R.T.; Paigen, K.; Davey, R.; Chapman, V.; Labarca, C.; Watson, G.;

Ganshow, R.; Brandt, E.J.; and Novak, E. Genetic regulation of mammalian glucuronidase. Recent Prog Horm Res 34:401-436, 1978.

Van Doom, E.; Craven, S.; and Bruchovsky, N. The relationship between

androgen receptors and the hormonally controlled responses of rat ventral

prostate. Biochem J 160:11-21, 1976.

140
Watson, C.S., and Catterall, J.F, Genetic regulation of androgen-induced

accumulation of mouse renal ß-glucuronidase mRNA. Endocrinology

118:1081-1086, 1986.

ACKNOWLEDGMENT

This work was supported in part by U.S. Public Health Service grant

HD 13541 from the National Institutes of Health.

AUTHORS

C. Wayne Bardin, M.D.

Vice President and Director

James F. Catterall, Ph.D.

Scientist

Olli A. Jänne, M.D., Ph.D.

Senior Scientist and Associate Division Director

Center for Biomedical Research

The Population Council

1230 York Avenue

New York, NY 10021

141
Reappraisal of the Health Risks

Associated With the Use of High

Doses of Oral and Injectable

Androgenic Steroids

Karl E. Friedl

INTRODUCTION

A price is paid for a beard and the presence of functional

testes. Inheritance, ageing, and other factors determine what

the cost will be to the individual. (Hamilton 1948, p. 315)

Many athletes, especially bodybuilders, powerlifters, and football players, are

reported to use androgenic steroids for physical and psychological advantage. The specific benefits and the ethics of such benefits have been heatedly debated. Meanwhile, due to the absence of substantive scientific data

on the health risks, proponents of androgen use by athletes claim an advantageous “benefit-to-risk ratio” (Hatfield 1984). Their opponents make

equally unfounded claims (Miller 1987) with gross exaggerations such as

“six athletes died as a consequence of their steroid use in 1984 alone” (USA

Today 1987, p. 6C). Such overwrought lay reviews predominate by default

because scientists and physicians have had little interest in the medical

problems of athletes who choose to medicate themselves in drug regimens

that defy any scientific rationale. The scare tactics of negative reviews are

unlikely to be effective in discouraging the abuse of androgens by athletes

(Wade 1972), but they do undermine legitimate applications of androgens

and contribute to the paranoia that impedes reliable investigation of androgen abuse.

This chapter reviews the health risks associated with the use of synthetic

androgens by adult men on the basis of primary-source reports of studies

and cases published in the medical literature. Extrapolation of this information to the health risks that may be faced by self-medicating athletes using

very high (“mega”) doses is still tenuous; very high dose androgen may

142
produce effects through other, nonandrogenic, actions, as discussed by Jänne

(this volume).

SUSPECTED RISKS AND THE UNKNOWN DENOMINATORS

Much of the attention lavished by the public press on adverse effects of

androgens is based on case reports generated when significant morbidity or

mortality is involved. The published cases are summarized in table 1.

TABLE 1. Summary of case reports of significant morbidity or mortality in

athletes with associated androgen use

Age Disease Outcome Description of Use Reference

38 BB

26 BB

37 BE

40 BB

27 B B

34 BB

32 BB

22 PL

Wilm’s tumor

Hepatocellular

carcinoma

Death from cancer

with metastases

Hepatocellular Surgical resection

adenoma and recovery

Adenocarcinoma

of prostate

Death from cancer

with metastases

Hepatocellular

adenoma

Death from

hemorrhage

Cerebrovascular

thrombosis

Partial recovery

Cerebrovascular

thrombosis (?)

and cardiomyopathy

Partial recovery

Myocardial

infarction

Death from cancer

with metastases

Recovery

Possibly high-dose

methandrostenolone

Many androgens for

4 years

Oxymetholone

100 mg/d for 5 years

15 cycles of many

androgens in 20 years

Anabolic steroids

for at least 3 years

Cycles of anabolic

steroids for 4 years

Many androgens since

age 16; stopped

4 months before

second cardiovascular

accident

IM and oral androgens

for 6 weeks

Prat et al. 1977

Overly et al. 1984

Goldman 1985

Roberts and Essenhigh

1986

Creagh et al. 1988

Frankle et al. 1988

Mochizuki and Richter

McNutt et al. 1988

KEY: BB=bodybuilder; PL=powerlifter.

Even the rare conditions, such as hepatic adenoma (Pelletier et al. 1984)

and Wilm’s tumor (Scully et al. 1981) have also been observed in adult

men not known to be using any androgens. In some cases, other likely

causes of the disease are present, For example, a 22-year-old elite powerlifter with myocardial infarction weighed 330 pounds and had a serum cholesterol of 596 mg/dl (McNutt et al. 1988). Inexplicably, these cases nearly

all involve bodybuilders.

A common aspect of these athlete case reports is the inadequate description

of their drug use. More to the point, in each of the four cases resulting in

143
death, the use of androgens appeared to be a chance discovery that gave the

case report current relevance. Other athletes with significant morbidity may

conceal their drug use when complications arise. No systematic study of

the medical risks of androgen use by any athletes has ever been conducted,

and even the population of adult athletes at risk remains undefined.

The doses used by athletes range from levels that may make them hypogonadal to the more frequently documented doses that far exceed any

experienced in clinical medicine. For example, replacement doses of testosterone enanthate for a hypogonadal man average 75 to 100 mg per week;

doses of 200 to 250 mg per week have been used in male contraceptive

trials and in the treatment of oligospermia with suppression-rebound therapy;

and doses reportedly used by athletes for a cycle of use lasting 6 weeks or

more have exceeded 1 g per week (Yesalis et al. 1988). Oxymetholone, an

orally active 17-alkylated androgen, is used at high doses of 150 mg per

day in the treatment of life-threatening anemias, and this dose is comparable

to that used by some athletes, with other androgens used in addition (Friedl

and Yesalis 1989). Methandrostenolone, which is estimated to give full

replacement in hypogonadal men at 15 mg a day (Liddle and Burke 1960),

has been administered in doses of 100 mg a day to athletes (Hervey et al.

1975), with doses up to 300 mg a day reportedly used by some athletes for

several years (Freed et al. 1975). Although generally used for short durations of several weeks at a time by bodybuilders (Friedl and Yesalis 1989),

powerlifters have been reported to use high doses of androgens continuously

for up to 7 years (Cohen et al. 1988). A summary of the most frequently

used drugs based on survey reports is presented in table 2.

The wide variety of doses and drug combinations employed by athletes

makes it difficult to pinpoint the agent responsible for an adverse effect.

More reliable information on androgen effects is available from male contraceptive trials that use greater than replacement doses of androgens and from

therapeutic treatment of specific disease such as aplastic anemias with highdose androgen treatment and male hypogonadism with replacement-dose

treatment. Even replacement-dose treatments yield adverse effects because

of nonandrogenic properties of the synthetic steroids, such as 17-alkylated

testosterone, and some of these effects will be common to the androgenabusing athletes.

Two main categories of androgens are considered here: orally active androgens alkylated at the 17-carbon position, which are therefore afforded some

protection against first-pass hepatic clearance, e.g. oxandrolone, oxymetholone, methandrostenolone, and stanozolol, and parenterally administered

nonmethylated androgens with a 17b-ester, e.g., testosterone enanthate and

nandrolone decanoate. A few exceptions to these two principal categories,

such as mesterolone, testosterone undecanoate, and methenolone, so far

appear to be compounds of lesser significance in the epidemiology of

androgen abuse by athletes.

144
TABLE 2. Summary of androgens and associated drugs used by athletes,

or&red by ranked frequency of use within surveys

Androgen

Number of Reported Users

A B C D E F G H I

Total Users 32

Oral Use

Methandrostenolone

Oxandrolone

Stanozolol

Oxymetholone

Ethylestrenol

Methyltestosterone

Methenolone Acetate

Fluoxymesterone

Other

26

19

(5)

5

5

1 1

3

1

3

Parenteral Use

Testosterone Esters

Nandrolone Esters

Methenolone Esters

Stanozolol

14-22

24-30

7

(5)

Testosterone (Aqueous)

Boldenone Undecylenate

Methandriol Dipropionate 1

Other 3

Other (Nonsteroidal)

Chorionic Gonadotropin

Growth Hormone

Diuretics

Thyroid Hormones

Testolactone/Tamoxifen

Others

50

7

5

3

2

1

9

5

1

24 8

16

19

17

3

3

1

1

2

20

8

1

6

7 17

6

5

2

4

7 1

7 6-8

4

22

16

5

16

5

1.5

14

12

8

6

12

8

4

6

5

4

1

?

(2)

1

5

(2)

KEY: A=several U.S. gyms; Strauss et al. 1983.

B=St. Louis—8 powerlifters and 4 bodybuilders; Hurley et al. 1984.

C=Chicago—22 competitive bodybuilders, powerlifters; Frankle et al. 1984.

D=Phoenix—19 bodybuilders, 2 powerlifters, 3 other; Burkett & Falduto 1984.

E=Finland-nationally ranked athletes; Alen & Rahkila 1984.

F=Glasgow, Scotland—bodybuilders; McKillop 1987.

G=Cape Town, South Africa—powerlifters; Cohen et al. 1988.

H=1987 US. Powerlifting Federation Championship; Yesalis et al. 1988.

1=1984 Olympics-positive drug screens; Catlin et al. 1987.

( )=oral or injected use not specified for stanozolol or methenolone, each of which have been

administered by either route by athletes.

x=use indicated but unquantified.

145
17-ALKYLATED ANDROGEN SUPPRESSION OF

HDL-CHOLESTEROL (HDLC)

The single significant adverse effect that has been clearly established for

androgen self-administration by athletes is the alteration in serum lipids,

most dramatically a reduction in serum HDLC. This begins within a few

days after the start of use and generally recovers within approximately a

month after cessation. Figure 1 illustrates this change in a 23-year-old university student who injected testosterone cypionate and ingested stanozolol

in one cycle (left shaded area), quit steroids for several months, and then

began a cycle of oral methandrostenolone and injected nandrolone decanoate

(right shaded area). Sex-hormone-binding globulin (SHBG) changes parallel

FIGURE 1. Serum cholesterol, HDLC, SHBG, and testosterone concentrations during and between two cycles of androgen selfadministration in a 23-year-old university student, an

amateur bodybuilder

the changes in HDLC. The consistency of this decrease in HDLC is evident from a summary of nine different lipid surveys in table 3. Profound

reductions into the single-digit mg/dl concentrations were observed in individuals in several of the studies (Hurley et al. 1984; Costill et al. 1984).

This reduction in HDLC is largely due to a reduction of the HDLC-2

subfraction and the accompanying apolipoprotein AI, as an apparent

146
TABLE 3. Serum lipid measurements with and without androgen selfadministration in athletes (mg/dl±SE)

KEY: BB=bodybuilder; PL=powerlifter; W=wrestler; C=control; flu=fluoxymesterone; m=methenolone;

meth=methandrostenolone; oxan=oxandrolone; oxy=oxymetholone; ND=nandrolone decanoate;

st-V=stanozolol; T?=testosterone ester; TC=testosterone cypionate. Values in parentheses are

from a reference control group.

NOTE: The decline in HDLC with androgen administration is consistent across studies; all used 17-

alkylated androgens with or without injectable androgens. Oral androgens were generally used

alone or in conjunction with injected androgens; duration of use ranged from 4 to 26 weeks.

consequence. of the induction of hepatic triglyceride lipase activity (HTGLA)

(Kantor et al. 1985; Lenders et al. 1988; Applebaum et al. 1987). The substantial reduction in HDLC is generally offset by an increase in low-density

lipoprotein cholesterol (LDLC), with no net alteration in total cholesterol,

although in two reports total cholesterol also increased (Hurley et al. 1984;

Cohen et al. 1986). In each of these nine studies, 17-alkylated androgens

were used by the athletes, with or without the addition of parenteral

androgens.

The altered balance of cholesterol fractions in self-medicating athletes suggests that these individuals are at substantially increased risk for coronary

heart disease. Coronary artery disease tripled in middle-aged men in the

147
Framingham Heart Study with antecedent HDLC measurements of less than

25 mg/dl, compared to the incidence in men starting with a mean level

of 50 mg/dl (Gordon et al. 1977). Other studies have suggested that the

level of apolipoprotein AI, which decreases markedly in the self-medicating

athletes, is an even better discriminator of coronary artery disease (Maciejko

et al. 1983), while serum LDLC and the associated apolipoprotein B appear

to be more important determinants of the production and reversal of vascular lesions (Nessim et al. 1983). In one study, reduced HDLC was the

single factor identified (with normal gonadal steroid levels) that distinguished men at low risk for heart disease who still develop heart disease

(Heller et al. 1983). Whether or not an androgen-induced change in this

risk factor in this group produces a detectable increase in heart disease in

athletes remains to be established. At least while they are still engaged

in athletics, these men tend to be nonsmokers, exercise intensively, and

maintain relatively low body fat, thereby minimizing other risk factors for

heart disease; most of these men also maintain normal total cholesterol

levels. Androgen-induced alteration may actually reduce other risk factors.

For example, the substantial niacinlike reduction in serum lipoprotein a

(Lp(a)), demonstrated with stanozolol administration (Albers et al. 1984),

may signify a reduction in risk of ischemic heart disease (Schriewer et al.

1984) and cerebrovascular disease (Jurgens and Koltringer 1987). The casereported increase in left ventricular mass among strength athletes using

androgens (McKillop et al. 1986) plays an unknown role in heart disease.

To date there is only one published case of heart disease in a young androgen-using athlete (McNutt et al. 1988). As previously described, other predisposing factors were clearly present. Another case that was reportedly

investigated demonstrated a familial risk: a 27-year-old steroid user who

died of heart disease had a father who had died at age 32 of heart disease

(Cowart 1987). The role of other drug use in such cases also needs to be

carefully considered; the bodybuilder depicted in figure 1 eventually admitted to a history of intravenous drug use (unspecified) under questioning by

a physician in connection with a diagnosis of hepatitis. Thus, if an increased incidence of heart disease in androgen-using athletes emerges, it is

likely to be detected only in a properly designed epidemiological study with

careful control of the potential confounders.

The HDLC depression observed so consistently in self-medicating athletes is

not an obligatory consequence of androgen use. It is also not readily apparent that studies with synthetic androgens explain the sex differences in

serum lipids and heart disease (Godsland et al. 1987; Nordoy et al. 1979).

Early studies demonstrating opposing effects of estrogens and androgens on

the HDLC/LDLC ratio were all based on methyltestosterone administration

(Russ et al. 1955; Furman et al. 1958; Oliver and Boyd 1956). Once this

effect of methyltestosterone was ascribed to an androgenic effect, the

premise was reversed, with the suggestion that HDLC depression could

serve as an index of androgenicity (Furman et al. 1957). Thus, it was

148
concluded that 17-alkylated androgens such as methyltestosterone and methylnortestosterone were highly potent androgens, while up to 100 mg per day

sublingual testosterone had little androgenic potency because of nonsignificant decrements in HDLC (Furman et al. 1957). A similar absence of effect on HDLC was discovered for testosterone propionate (Oliver and Boyd

1956), and parenteral administration of androsterone was found to reduce

only the LDLC fraction (Cohen et al. 1971).

Subsequent studies in normolipid subjects have failed to demonstrate a clinically significant reduction in HDLC with androgen ester administration in

doses that are markedly androgenic (table 4). Thus, while 17-alkylated androgens such as stanozolol, oxandrolone (Hazzard et al. 1984), and methyltestosterone reduce HDLC by approximately half, the administration of nandrolone and testosterone esters has little or no effect.

TABLE 4. Serum lipid concentrations before and during androgen

administration in normolipidemic volunteers (mg/dl±SE)

KEY: MeT=methyltestosterone; stan=stanozolol; TC=testosterone cypionate; TE=testosterone enanthate.

NOTE: 17-Alkylated androgen-treated groups show the greatest decreases in HDLC. Mixed sex subjects are indicated with counts of each; Crist et al. (1986) was a crossover design that included placebo; Thompson et al. (1989) was a crossover design.

149
This difference is explained by the induction of HTGLA demonstrated for

methyltestosterone or stanozolol, with no effect on this enzyme by testosterone enanthate in the same studies (Friedl, submitted for publication; Thompson et al. 1989). Induction of HTGLA may be specific to the 17-alkylsubstituted androgens and may not be due to an androgenic effect at all, but

a simpler explanation is that it reflects an alteration in the androgen—estrogen balance in the presence of an androgen that is not readily aromatized to

estrogen, since estrogen has an opposite effect, suppressing HTGLA (Applebaum et al. 1977; Tikkanen et al. 1982). Testosterone enanthate administration results in a large increase in estrogen, while a lesser proportion of

methyltestosterone is aromatized, and only to 17a-methylestradiol, which

appears to be a weak estrogen (Ryan 1963; Dimick et al. 1961; Feenstra

et al. 1983). Further evidence for this role of estrogen comes from a study

with coadministration of the aromatase inhibitor, testolactone, with testosterone enanthate. This suppresses the normally observed increase in estradiol

following administration of the enanthate and produces a modest but significant reduction in HDLC that does not occur with testosterone enanthate

alone (Fried et al. 1990, Friedl et al. 1988).

Paradoxically, the reduction in serum lipids by androgens suggested possibilities for clinical use in the treatment of hypertriglyceridemia (Stone 1963;

Sachs and Wolfman 1968; Howard and Furman 1962); this was suggested

by observations that triglycerides tend to be elevated by estrogens and could

be reduced by androgens (Howard and Furman 1962; Kim and Kalkhoff

1975), but the benefit of a reduction in serum triglycerides that occurs in

some patients is offset by the atherogenic shift in HDLC/LDLC produced at

the same time (Hazzard et al. 1984).

Androgens have long been suspected of a role in heart disease because of

gender differences in the disease incidence, but estrogens may be involved.

Serum estrogens are higher and testosterone is reduced in men with coronary artery disease (Chute et al. 1987; Hamalainen 1985) although such

alterations may be secondary to illness and stress (Plymate et al. 1987;

Friedl et al. 1988). Estrogens increase apolipoprotein AI secretion; but at a

substantially higher dose, estrogens also increase apolipoproteins B and E

(Tam et al. 1986). Although male patients treated with estrogens in the

Coronary Drug Project did not show a change in the rate of myocardial

infarction, the risk of venous thromboembolism approximately doubled

(Coronary Drug Project Research Group 1973). The case reports of stroke

in two athletes (Frankle et al. 1988; Mochizuki and Richter 1988) and one

additional case of a young hypogonadal man self-administering very high

doses of testosterone (Nagelberg et al. 1986) are consistent with a role of

estrogen in thrombotic stroke (Collaborative Group for the Study of Stroke

in Young Women 1975). Increased estrogenicity is supported by the occurrence of gynecomastia in some androgen-using athletes, including one of the

athletes with stroke (Frankle et al. 1988); presumably, this is a result of

150
aromatization of high doses of androgen, but it may also result from an

altered hepatic clearance of steroid (Friedl and Yesalis 1989).

Hyperinsulinemia and impaired glucose tolerance has been reported with

methandrostenolone (Woodard et al. 1981; Landon et al. 1962), oxymetholone (Landon et al. 1962) and for athletes self-administering several androgens (Cohen and Hickman 1987). Such an effect may adversely affect

serum HDLC (Stalder et al. 1981), and it has been suggested from epidemiological observations that testosterone increases risk of heart disease through

an effect on insulin (Lichtenstein et al. 1987). Alternatively, it may count

as an additional independent risk factor, additive to the HDLC reduction.

This effect has not been duplicated with androgen esters (Friedl et al. 1989;

Swerdloff et al. 1978; Landon et al. 1963), including injected methenolone

acetate, a 1-methylated androgen (Landon et al. 1963). In one recent

report, a Klinefelter’s patient whom the authors claimed was receiving

parenteral methyltestosterone (250 mg every 3 weeks), developed glucose

intolerance and acanthosis nigricans (Shuttleworth et al. 1987), again supporting the contention that the effect on glucose tolerance is specific to

17-alkylation and is not simply a consequence of the route of androgen

administration.

OTHER SERUM PROTEIN ALTERATIONS RELATED TO

17-ALKYLATION

17-alkylated androgen-induced changes like those observed with HTGLA

have also been obtained for other functionally diverse proteins produced by

the liver (Barbosa et al. 1971a; Barbosa et al. 1971b). Some of these

changes are what make the 17-alkylated androgens clinically useful, such as

the stimulation of complement Cl inhibitor activity and complement C4 in

the treatment of angioedema. On the other hand, hemostatic alterations,

coupled with an increased hematocrit in some athletes (Alen 1985), could

conceivably lead to thromboembolytic disorders including stroke and myocardial infarction, or increased fibrinolytic activity (Feamley and Chakrabarti

1964; Feamley and Chakrabarti 1962) may account for an apparent tendency

for androgen-associated hepatic tumors to rupture. Some of these hemostatic changes may be more structure-related than simply 17-alkyl substitution;

seven different 17-alkylated androgens produced increases in plasminogen

(while no esters did), but only oxymetholone, oxandrolone, and norethandrolone also produced decreases in fibrinogen (Barbosa et al. 1971a). On the

other hand, Kruskemper reported increases in clotting factors with any

methylated androgens, but this did not occur with testosterone propionate

(Kuskemper 1968) while a net increase in fibrinolytic activity is reported in

some patients with either oral androgen administration (Feamley and Chakrabarti 1964) or parenteral testosterone propionate (Feamley and Chakrabarti

1962). Small but statistically significant increases in systolic blood pressure

have been reported with androgen use in athletes (Freed et al. 1975;

Lenders et al. 1988) and these may also represent alterations in hepatic

151
proteins similar to that observed in some susceptible women with oral contraceptive use (Vessey et al. 1976).

SHBG is reduced by both 17-alkylated androgens and the esters, but the

17-alkylated androgens are more potent in this effect (Stone 1963), perhaps

reflecting the difference in androgen-estrogen balance produced with these

two classes of androgens (Ruokonen et al. 1985; Belgorosky and Rivorola

1985; Chetkowski et al. 1986). The physiological significance of a reduction in SHBG and the consequent increase in free and albumin-bound testosterone is uncertain, as many of the synthetic androgens have a reduced

binding affinity (Saartok et al. 1984) and would be little affected; alternatively, the SHBG-bound steroid may be important for some actions (Reese

et al. 1988).

The mechanism of this regulation is more complex than simply a change in

the rate of protein secretion by hepatocytes, because, in vitro, androgens and

estrogens both stimulate SHBG (Lee et al. 1987). As suggested by studies

of thyroxine-binding globulin (Ain and Refetoff 1988), an increase in the

androgen-estrogen ratio may result in secretion of a less glycosylated form

of the binding protein, with a reduced circulation half-time. In this way,

thryoxine-binding globulin levels are reduced by oral or sublingual methyltestosterone, while sublingual testosterone propionate and injected nandrolone phenylpropionate have no effect (Barbosa et al. 1971b), again suggesting a structural specificity, in this case perhaps related to the ability to

aromatize to potent estrogen.

The moderate increases in serum aspartate aminotransferase (AST, SGOT)

and alanine aminotransferase (ALT, SGPT) activities noted in androgenusing athletes (Alen 1985) may reflect hepatocellular necrosis or, less likely,

cholestasis, but the elevation has been reported to be a transient phenomenon even with continued use (Wynn et al. 1961; Petera et al. 1962). For

example, Petera et al. (1962) found that methyltestosterone (30 mg per day)

produced a peak rise in both SGOT and SGPT levels after approximately

10 to 12 days administration to 40 patients, and, with continued therapy, the

levels declined again. No such enzyme rise occurred if patients were treated with testosterone propionate (25 mg per day) either by oral or parenteral

routes of administration. Kruskemper (1968) also found increased serum

transaminase levels only with 17-alkylated androgens and no increase with

testosterone propionate or even with an orally administered 1-methylated

androgen. The pathological significance of this transient increase is

unknown.

CHOLESTATIC JAUNDICE: DISRUPTION OF

MICROFILAMENTS?

In 1952, Lloyd-Thomas and Sherlock used methyltestosterone to treat pruritis associated with obstructive jaundice and found that the jaundice

152
deepened in five of their seven cases (Lloyd-Thomas and Sherlock 1952).

This, and several cases of jaundice in hypogonadal men replaced with methyltestostetone (Werner 1947; Werner et al. 1950), led to the association of

cholestatic jaundice with 17-alkylated androgen administration; subsequent

cases were reported primarily for patients treated with methyltestosterone

(Brick and Kyle 1952; Bonner and Homburger 1952; Wood 1952; Almaden

and Ross 1954; Kaplan 1956; Koszalka 1957) and norethandrolone (Dunning

1958; Schaffner et al. 1959; Shaw and Gold 1960; Gordon et al. 1960;

Gilbert et al. 1963) but also with stanozolol (Evely et al. 1987), methylnot-testosterone (Peters et al. 1958), and methandrostenolone (Wynn et al.

1961). Foss and Simpson (1959) summarized 42 case reports in 1959, and

cases reiterating this association continue to appear in the literature 30 years

later (Lucey and Moseley 1987).

One case of jaundice with testosterone enanthate administration occurred

during pregnancy (Gill et al. 1986), making this connection with androgen

esters uncertain, since the same form of cholestatic jaundice is an established consequence of pregnancy for some women (Svanborg and Ohlsson

1959). However, recurrent jaundice of pregnancy has been attributed to an

abnormal response to high circulating levels of estrogen in subjects with a

familial history (Reyes et al. 1981), and this effect is conceivably enhanced

by the addition of a readily aromatizable androgen.

Androgen-related cholestasis ranges in frequency from very few patients

with even histological evidence of disease (Cicardi et al. 1983; Westaby

et al. 1977; Kory et al. 1959) to 17.3 percent of patients evolving an overt

jaundice (Pecking et al. 1980). This form of cholestatic drug reaction

generally lacks histological features of inflammation and necrosis and is

characterized by a bland accumulation of bile in cells and canaliculi (Foss

and Simpson 1959). Recovery typically occurs within several weeks after

drug cessation, and jaundice does not necessarily recur in these patients

with reinstitution of treatment (Werner et al. 1950; Pecking et al. 1980).

Death is a highly unlikely consequence: the reports of death with cholestatic jaundice that have been attributed to 17-alkylated androgen administration (summarized in table 5) have all occurred in elderly or very ill

patients, including two patients with metastatic carcinomas and at least one

suspected of suffering from severe viral hepatitis; in four of these cases, the

medication was continued until the death of the patient because it was not

recognized as a potential agent of the cholestasis.

Intrahepatic cholestasis can be produced with norethandrolone infusion in

rats, and the primary defect appears to be a disruption of microfilaments

similar to the action produced with cytochalasin B (Phillips et al. 1978).

This suggests that reduced bile transport and hepatocyte structural changes

that lead to cholestasis are mediated through this single mechanism. Reduced transport may be an early marker of hepatic dysfunction, since it

153
TABLE 5. Summary of case reports of deaths attributed to androgeninduced cholestatic jaundice by the authors or later

reviewers

Age/Sex Disorder Treated

Androgen Used/

Dose/Exposure

Cause of

Death Reference

60 M

62 M

43 M

57 F

74 M

“to improve healing methyland protein anabolism” testosterooe(sl)

(metastatic disease) 30 mg/d, 10 weeks

“therapeutic trial”

(metastatic disease

and angina, treated with

I-131-induced myxedema)

methylnortestosterone

6 to 25 mg/d,

for 18 weeks

corticosteroid-induced

osteoporosis

norethandrolone

30 mg/d, 23 weeks

anorexia

(result of ‘pancreatic

insufficiency”)

norethandrolone

20 mg/d, 42 weeks

osteoporosis and

hemiplegia

norethandrolone

30 mg/d, 30 weeks

‘obstructive

jaundice”

Koszalka 1957

? ?

(histology:

“resolving

jaundice”)

Peters et al. 1958

cholestasis

and peliosis

Gordon et al. 1960

*severe viral Gordon et al. 1960

hepatitis” with

cholestasis

and peliosis

sepsis and

intrahepatic

cholestasis

Gilbert et al. 1963

appears to precede cholestasis and jaundice. Thus, in one anemia study,

254 patients were randomized to one of four oral androgens (norethandrolone, methandrostenolone, oxymetholone, and the 6-methylated methenolone); 35 percent of patients had signs of abnormal liver function, including

reduced bromosulfophthalein (BSP) uptake, but only 17.3 percent had overt

jaundice (Pecking et al. 1980). Similarly, Kory et al. (1959) noted abnormal BSP retention in 74 percent of 47 patients treated with norethandrolone

(25 or 50 mg a day), but liver biopsies from seven of the patients with

poor BSP retention times yielded normal tissue, with only one demonstrating a minimal bile stasis and focal necrosis.

Hypercholesterolemia is also a marker of cholestasis, and there may be a

relation to hypercholesteremia, which has been reported for some androgenusing athletes (Cohen et al. 1988).

PELIOSIS HEPATIS: AN UNKNOWN ETIOLOGY

Peliosis hepatis is a potentially life-threatening hepatic lesion characterized

by a spectrum of microscopic to grossly visible blood-filled cysts in the

liver, with or without endothelial lining (Kalra et al. 1976). Originally

recognized as a very rare disease associated with fatal pulmonary tuberculosis (Zak 1950), Burger and Marcuse (1952) proposed a relationship between

peliosis hepatis and androgen treatment in 1952 with a case report. Since

then, more than 70 cases have been reported in association with androgen

154
administration (Gordon et al. 1960; Kintzen and Silny 1960; Bernstein et al.

1971; Port et al. 1971; Bagheri and Boyer 1974; Ogg and Cattell 197.5;

Kew et al. 1976; Paradinas et al. 1977; Nadell and Kosek 1977; Groos

et al. 1974; Taxy 1978; Wakabayashi et al. 1984; Nuzzo et al. 1985;

Karasawa et al. 1979; Bird et al. 1979), and this has included cases of

splenic peliosis (Taxy 1978; Slater et al. 1981; Fouquette and Lefebvre

1976). Wakabayashi et al. (1984) performed autopsies on 47 patients with

aplastic anemia and found peliosis in 7 of 19 patients who had been treated

with oxymetholone or methenolone and in only 1 of 28 patients not treated

with androgens. In an American series of patients with wasting disorders,

Karasawa et al. (1979) found that of nine postmortem peliosis cases, five of

the patients had received androgens. In the Westaby series (Westaby et al.

1977) of 60 transsexual women and impotent men treated with MeT (150

mg per day) for up to 5 years, 9 patients had sinusoidal dilatation and 3

patients had cyst formation, suggestive of potential prepeliotic lesions.

Although the patients in this series were free of symptoms, a later case

report described peliosis hepatis and liver tumor rupture requiring emergency surgery in one of the transsexuals following 7 years of continuous

androgen treatment. In a 3-to-5-year followup of many of the patients from

this series and others on various androgens, Lowdell and Murray-Lyon

(1985) found hepatic abnormalities (based on liver scans and colloid uptake)

only in the patients still using methyltestosterone, with resolution of abnormalities in those who had stopped using methyltestosterone, and essentially

normal livers in those using sublingual or parenteral steroids.

Most reported cases of androgen-associated peliosis involve patients treated

with 17-alkylated androgens including fluoxymesterone (Kintzen and Silny

1960; Nuzzo et al. 1985), norethandrolone (Gordon et al. 1960; Ogg and

Cattell 1975) oxymetholone (Nadell and Kosek 1977; Groos et al. 1974),

methenolone (Wakabayashi 1974), and methyltestosterone (Bird et al. 1979).

Peliosis is not clearly associated with androgen esters; however, Turani

et al. (1983) reported peliotic lesions in postmortem study of a series of six

chronic renal failure patients who received only androgen esters for an average of more than 3 years. Saheb (1980) found no peliosis in postmortem

examinations of 52 dialysis patients, but these patients had a much shorter

exposure to testosterone enanthate (up to 250 mg a week for 5 months).

Peliosis may not be readily diagnosed by standard laboratory studies and is

usually discovered either as occult disease in postmortem examination or,

rarely, as a result of symptomatic hemorrhage. At least five patients died

from internal hemorrhage resulting from their peliosis (Bagheri and Boyer

1974; Nadell and Kosek 1977; Taxy 1978), but internal hemorrhage is also

a frequent cause of death in severe anemias. In nine other cases, death

from hepatic failure was attributed to the existing peliosis (Gordon et al.

1960; Bernstein et al. 1971; Bagheri and Boyer 1974; Nadell and Kosek

1977); in several of these cases, metastatic disease and severe cholestasis

may have been more directly responsible for patient death. One case of

155
histologically diagnosed peliosis hepatis was followed after androgen withdrawal, and complete recovery was observed (Nadell and Kosek 1977).

Peliosis has also been observed in a woman treated with tamoxifen (Loomus

et al. 1983), a drug that is also used by some androgen-abusing athletes in

an attempt to prevent the side effect of gynecomastia (Friedl and Yesalis

1989). Although this represents only a single case, it is unusual, since this

is such a rare disorder, and it may indicate a role of an androgenic-estrogenic component in this disorder.

Paradinas et al. (1977) have proposed a mechanism that may explain occurrence of cholestasis and peliosis hepatis through a single pathogenic mechanism. Based on microscopic evaluation of biopsy material from the

Westaby series of patients treated with methyltestosterone, they propose that

17-alkylated androgens specifically produce hepatocyte hyperplasia; the

enlarged hepatocytes then encroach on the hepatic venous system, occluding

vessels and perhaps also blocking bile canaliculi to produce cholestasis or

peliotic sinusoids.

ANDROGEN-ASSOCIATED TUMORS: A PECULIAR FORM OF

HEPATOCELLULAR CARCINOMA

Just as with heart disease, a male predominance of hepatocellular carcinoma

has led to a suspected involvement of androgen, and this has been supported by animal studies with castration and androgen replacement (Vesselinovitch and Mihailovich 1967). Since the first suggestion of a relation

between androgen treatment and hepatic tumors (Bernstein et al. 1971), at

least 91 cases of androgen-associated tumors have been reported in the

medical literature. Most of these cases were identified by collecting all

reports indexed in five DIALOG data bases: Biosis (for 1969), Cancerlit

(for 1963), Embase (for 1974), Medline (for 1966), and Scisearch (for

1974); additional cases were gleaned from bibliographies of identified

reports.

Of the 91 cases, 48 were discarded because they were not histologically

demonstrated or because they were demonstrated to be patients with

Fanconi’s anemia. Hereditary anemias such as Fanconi’s syndrome carry an

increased incidence of malignant neoplasia (Schaison et al. 1983), and there

may be a predisposition to the development of hepatic tumors in this group

(Cattan et al. 1974a; Cattan et al. 1974b), with such tumors emerging more

frequently when lives are extended by androgen therapy.

For the 43 remaining cases, the diagnoses were reportedly established

through microscopic evaluation of tumor material obtained through biopsy,

surgical resection, or at postmortem examination. This included 28 cases

recognized antemortem (or through death as a direct consequence of the

disease) (table 6). Another eight cases represented occult disease, detected

156
TABLE 6. Summary of case reports of histologically diagnosed hepatic tumors associated with androgen

administration

Year Age al

Diag- Diag- Diagnosed nosis nosis FP

Androgens Used

Dose Duration Reason Used

Means of

Discovery

Treatment

of Tumor Survival References/Case

Death Due to Hepatic Failure or Tumor Rupture

(76) 17M HCA oxy 50 68 m apl anemia

76 50M CLC oxy 100-300 24 m anemia

79 71M HCC - oxy 5O;ND 100 36 m nephrectomy

83 26M HCC + (several) 48 m athlete

88 27M HCA - unspecified 36 m athlete

Successful Treatment and/or Regression of Hepatic Tumor

61 44M

67 33M

70 40M

HCC

HCC -

HCC -

MeT 50 11 yr

MeT 50+TP 12 8 yr

MeT 50 72 m

cryptorchid

cryptorchid

hypopituitar

hemoperitoneum

pain

pain

malaise/anorexia

hemoperitoneum

pain

pain/anorexia

pain/fever

71 18F

71 6F

72 25M

73 68M

74 33M

75 19M

75 30F

75

(75)

19M

29M

HCC -

HCC -

HCC -

HCC -

HCC -

HCA -

HCA +

HCA

HCC -

oxy 150-250

oxy 30-100

MeT 50

MeT ?

oxy 150

28 m

41 m

60 m

30 yr

64 m

oxy ?

MeT 150

36 m

37 m

meth 65

MeT 25-60

36 m

11 yr

apl anemia

apl anemia

hypogonadism

impotence

par noct hem

par noct hem

transsexual

par noct hem

craniopharyng

laporotomy

pain

pain/fever

pain

pain

hemoperitoneum

pain/anorexia

hemoperitoneum

hemoperitoneum

M

M

1b,2,4 R

1b M? R

1b,2 R

1

1 R

4 R

?,2,4

1 R

?,2

1,2

?,2

1,2

*0 Lesna et al. 1976

*4wk Stromeyer et al. 1979

*1m Zevin et al. 1981

*3 m Overly et al. 1984

*0 m Creagh et al. 1988

22 yr

66 m

14 yr

*8m

*8 m

48 m

10 yr

18 m

Drew 1984

Farrell et al. 1975/3

Farrell et al. 1975;

McCaughan et al. 1985/2

Johnson et al. 1972/2

Johnson et al. 1972/1

Goodman and Laden 1977

Ziegenfuss and Carabasi 1973

Farrell et al. 1975;

McCaughan et al. 1985/1

Bruguera 1975

Westaby et al. 1977;

Coombes et al. 1977

Hernandez-Nieto et al. 1977

Boyd and Mark 1977
TABLE 6. (continued)

Year Age at

Diag- Diag- Diagnosed nosis nosis FP

Androgens Used

Dose Duration Reason Used

Means of Treatment

Discovery of Tumor Survival References/Case

(77) 7M HCC - oxy ? 60 m sider anemia ? ?,2

78 51M HCC - MeT 150 20 yr hypogonadism hemoperitoneum 1,2,3 R

78 28M HCA - MeT 40

78 58M HCA - MeT 50

(78) 39F HCA - MeT 150

79 16M HCC - oxy 75

(82) 49M HCA - MeT 50

82 29M HCA - oxy 150-300

(83) 68M CLC ND 100

83 32M HCA - TE 25O/2wk

85 37M HCA oxy 100

10 yr

10 yr

84 m

72 m

25 yr

44 m

24 m

1 1 yr

60 m

hypogonadism

hypogonadism

transsexual

apl anemia

hypopituitar

apl anemia

gen weakness

Alports synd

athlete

hemoperitoneum

pain

hemoperitoneum

pain/fever

hemoperitoneum

pain/fever

hemoperitoneum

Iiv funct tests

pain/vomiting

1 R

1

?,2

1,2 R

1,3

1b,2 R

?,2

1

?,2

Ishak 1979/2

24 m Cocks 1981;

Westaby et al. 1983

48 m Westaby et al. 1983/1

l 24 m Westaby et al. 1983/2

Bird et al. 1979

6 m Treuner et al. 1980

42 m Lewis et al. 1986

3 m Lyon et al. 1984

Turani et al. 1983/11

6 m Carrasco et al. 1985

Goldman 1985

*Death reported.

KEY: HCA=hepatocellular adenoma; HCC=hepatocellular carcinoma; CLC=cholangiocarciooma (or mixed with HCC); FP=alpha fetoprotein within normal limits (-)

or above normal limits (+). Androgens orally administered in mg/day: MeT=methyl testosterone, oxy=oxymetholone, meth=methandrostenolone; androgens

injected in mg/week: ND=nandrolone decanoate, TE=testosterone enanthate. Apl=aplastic, sider=siderdk+stic, par noct hem=paroxysmal nocturnal hematuria.

Pain usually described as right upper quadrant or epigastric; hemoperitoneum in all cases, severe abdominal pain. l=withdrawn from androgen 1b=withdrawn >l year after diagnosis or androgen reinstated, 2=partial or complete tumor excision, 3=tumor dearterialization 4=chemotherapy (usually 5-FU).

R=apparent regression of tumor. M=metastatic; survival=known survival after diagnosis.

NOTE: Not listed in table are four cases of hepatic angiosarcoma, three cases of focal nodular hyperplasia, and eight cases of occult disease discovered in

postmortem examination.
only in postmortem examinations and unrelated to the cause of death

(Turani et al. 1983; Ishak 1979; Sale and Lerner 1977; Chandra et al. 1984;

Bakker et al. 1976; Sugiyama et al. 1982; Meadows et al. 1974). The remaining cases were minority diagnoses of nonepithelial tumors: four hepatic angiosarcomas (Falk et al. 1979) and three focal nodular hyperplasias

(Kessler et al. 1976; Sweeney and Evans 1976; Alberti-Flor et al. 1984).

The earliest known case with an androgen association (Drew 1984) typifies

the liver tumors that have been described. In 1961, hepatocellular carcinoma (HCC) was diagnosed in a 44-year-old man presenting with a right

upper quadrant abdominal mass. The multinodular tumor was partially resected, and he was given treatments of 5-fluorouracil. This patient was

alive 22 years later with no complaints of liver dysfunction.

The androgen-associated tumors do not behave as cancers, although they

may present with cytological characteristics of HCC (Sweeney and Evans

1975; Anthony 1975; Johnson 1975); in some cases, this has led authors to

construct incongruous diagnoses such as “benign” HCC or “malignant”

adenoma (Goldman 1985). In another case, the authors concluded that they

had nodules with both HCC and hepatocellular adenoma (HCA), which suggested the possibility that HCA can transform into HCC (Boyd and Mark

1977). That these are benign tumors is indicated by the long survival following diagnosis, the absence of metastases, and the absence of elevated

alpha fetoprotein (FP) production. Nearly all of the reported cases are also

negative for serum hepatitis surface antigen and lack evidence of an associated cirrhosis, which is found with many of the more typical HCC cases,

in the absence of known exogenous androgen exposure (Peters 1976). That

they are androgen related is supported by the finding that tumor regression

occurred in more than half of the cases with followup observation following

androgen withdrawal, with no other treatment (or only partial tumor excision). Although regarded as a subgroup of HCC, cholangiocarcinoma, by

itself or in association with HCC, was associated with a much poorer prognosis compared to the other androgen-related tumors; two of these three

tumors demonstrated malignant behavior.

The associated drug was largely determined by the condition being treated.

The median time of androgen exposure before diagnosis was 5 years, with a

range of latency between 2 and 30 years. All patients with severe anemias

had exposure to oxymetholone, usually at a dose of at least 100 mg a day,

and all androgen-deficient patients received methyltestosterone, usually at a

dose of 50 mg per day. Only two cases were associated with exclusive use

of androgen esters, and Carrasco et al. (1984) were unable to demonstrate

the androgen dependence in their patient (Carrasco et al. 1985). Whether or

not methyltestosterone and oxymetholone are the still preferred drugs is

uncertain, as drug production figures are not readily forthcoming from the

producers; however, the superiority of parenteral androgens in the treatment

of anemia has been promoted (Neff et al. 1981), and the use of

159
methyltestosterone for replacement therapy has fallen into disfavor

(Nieschlag 1982). On the other hand, methyltestosterone is manufactured

by 14 of the 28 legitimate U.S. androgen manufacturers, and, for 12 of

these companies, this is the only androgen produced (Food and Drug

Administration, personal communication). Anemia patients, of which

androgen-deficient patients may be a part, may be more predisposed to

tumor formation, and they are already at greater risk through transfusional

hemosiderosis (Steinherz et al. 1976); however, these are also the two main

groups of patients who would receive the majority of legitimate androgen

treatments and are probably not overrepresented.

The three most recent case reports comprise all the reports of liver tumors

in androgen-using athletes. These include one who died from a metastatic

carcinoma (Overly et al. 1984), one who died from internal hemorrhage following the rupture of an adenoma (Creagh et al. 1988) and another who

apparently survived following surgical resection of an adenoma (Goldman

1985). In the case reported by Overly et al. (1984), the features are typical

of the better known malignant HCC, including high serum levels of FP

synthesized by the carcinoma, and the aggressive biological behavior of the

tumor with metastasis and short time to death. The median survival time

for this disease may be as short as 1 month, with very few patients

expected to live beyond 1 year (Lai et al. 1979); in contrast, most patients

with androgen-associated tumors survive following successful treatment or

with only withdrawal of androgen treatment. The Overly case (Overly

et al. 1984) also included cholangiole involvement, seen in only two other

patients in these cases (one of which also metastasized). Thus, this cancer

case does not bear the characteristics that are typical of the androgenassociated tumors.

These reports are selective for the more extreme and symptomatic cases and

for current issues, e.g., steroid-using athletes. This may explain why 10 of

these cases were diagnosed after internal hemorrhage brought the case to

medical attention (24 of 28 presented with acute abdominal pain). The

majority of tumors may remain undetected because they do not rupture and

the patients remain unsymptomatic. Cases of such occult disease have been

described from careful postmortem examinations of androgen-treated patients

(Turani et al. 1983; Ishak 1979; Sale and Lerner 1977; Chandra et al. 1984;

Bakker et al. 1976; Sugiyama et al. 1982; Meadows et al. 1974). On the

other hand, in 31 cases of HCA in males collected from the literature by

Pelletier et al. (1984), all three associated with androgen use ruptured. It

could be suggested that 17-alkylation does not produce more tumors than

the androgen esters but simply increases the likelihood of discovery through

rupture. Turani et al. (1983) have described tumors and peliosis associated

with nonalkylated androgens in a mostly postmortem series; however, this

still remains an isolated finding. The high rate of adenoma rupture and

hemorrhage in women using oral contraception, compared to women with

HCA not using oral contraceptives, is particularly associated with the use of

160
17-alkyl-substituted progestagens with some androgenic activity (Klatskin

1977). This data suggests a structural specificity; although this too could

reflect selective reporting.

In our series, peliosis was not consistently present with the tumors (it was

described in half of the cases), and it has been suggested that necrotic

lesions described as peliosis may be more representative of the vascular

ectasia frequently seen with tumors (Peters 1976). As an example, in the

case of the athlete who died following tumor rupture (Creagh et al. 1988)

the liver surrounding the adenomas was described as hyperplastic with

ectatic sinusoids but was apparently devoid of peliotic cysts.

The occurrence of androgen-related tumors appears to be considerably higher than the rate of hepatic tumors associated with female oral contraceptive

steroids; within 5 years of the first case report associating oral contraceptives with liver tumors, at least 117 cases had been documented in the literature, with perhaps 100 more claimed; 92 percent of these were benign

tumors, for which fewer than 400 cases had been reported in women since

1937 (Klatskin 1977). Oral-contraceptive-related tumors are rare relative to

the size of the population at risk; at least 30 million women are estimated

to be currently using contraceptive steroids in the United States alone. The

prevalence of androgen use, even with inclusion of androgen abusers, is not

reasonably expected to come close to this, nor is exposure during the past

30 years likely to rival oral contraceptive exposures. In patients with severe

anemia surviving 2 years with androgen treatment, the incidence was 2 benign tumors in 137 patients (Pecking et al. 1980; Joint Group for the Study

of Aplastic and Refractory Anemias 1981); previously, Hemandez-Nieto

et al. (1977) reported tumor rupture in a patient from the larger sample of

429 patients originally enrolled in this same series (3 patients out of 429),

although many of these patients have had a shorter exposure to androgens.

In the Westaby study of 60 female-to-male transsexuals and impotent men

treated with high-dose methyltestosterone (Westaby et al. 1977; Coombes

et al. 1977). only one HCA was detected, although Bird et al. (1979) later

reported a case with tumor rupture in another transsexual from the same

series (2 patients out of 60). Thus, the incidence of hepatic tumors may be

estimated to be 1 to 3 percent within 2 to 8 years of exposure of greaterthan-replacement doses of 17-alkylated androgen; occult disease undoubtedly

drives this incidence higher.

Hepatic angiosarcoma has also been associated with androgen use in one

retrospective epidemiological study. In a review of 168 cases of histologically confirmed cases of hepatic angiosarcoma, 4 cases with some previous androgen exposure (3.1 percent) were identified from a review of

medical records (Falk et al. 1979). The connection with androgen exposure

remains unconfirmed, with no new androgen-associated cases reported since

the latest of the four case deaths in 1974, and at least one of those four

patients was exposed to isoniazid, another proposed agent of hepatic

161
angiosarcoma (Daneshmend and Bradfield 1979). Three cases of focal

nodular hyperplasia (Kessler et al. 1976; Sweeney and Evans 1987; AlbertiFlor 1974) have also been reported in patients with androgen exposure, in

two cases with only 3 and 6 months of androgen exposure, thus leaving the

role of androgen open to question.

Androgens do not appear to be in themselves mutagenic but may enhance

effects of carcinogens and promote tumor formation (Lesna and Taylor

1986; Anderson and Rossof 1979). In animal studies, doses of androgenic

steroids (AS) 400 to 600 times the equivalent human dose are given over

most of the life span of the animal. These steroids cause liver growth

(hyperplasia and hypertrophy) without tumors and are not mutagenic in the

Ames test (lngerowski et al. 1981). In mice, nandrolone decanoate

(600 mg/kg a week for 6 weeks) did not produce liver tumors, but if it

followed exposure to dimethylnitrosamine, which is known to produce liver

cancer in rodents, the expected tumor formation was markedly enhanced

(Lesna and Taylor 1986).

ANDROGENS AS POTENTIAL CONTRACEPTIVES: REVERSIBLE

INFERTILITY

Androgen treatment in normal men will produce oligo- or azoospermia

through suppression of gonadotropins, and most, if not all, will be rendered

infertile after weeks or months of continuous high-dose exposure (Swerdloff

et al. 1978; Mauss et al. 1975; Matsumoto 1988). Since the major portion

of the testis is composed of seminiferous tubules and developing germ cells,

this reduction in the population of developing germ cells decreases testicular

size by a measurable 15 to 35 percent (Lichtenstein et al. 1987; Palacios

et al. 1981). Since the normal cycle of sperm development from spermatogonia to mature spermatid in the testis takes 64 days, it is not surprising

that the recovery with cessation of steroid may take 6 months or more for

some men; some androgens with long half-times will have an even more

extended effect. There are no documented cases of irreversible sterility

occurring in healthy men with initially normal sperm count as a result of

As use.

High-dose AS use has been used in the opposite sense as well, in an attempt to restore fertility in men with low sperm count through a well recognized but poorly understood rebound that occurs following several months

of high-dose AS sperm suppression (Rowley and Heller 1972; Chamy and

Gordon 1978). Up to 60 percent of patients with below normal spermatogenic activity but otherwise normal seminiferous epithelia show at least a

temporary improvement in their sperm counts, and, in some patients, this is

a permanent improvement. Norethandrolone, testosterone esters, and mesterolone have all been used in rebound therapy and appear to improve

pregnancy success rates. Nevertheless, there has been no study of the

162
reproductive axis in men who previously used high doses of androgens for

several years.

CONCLUSION

From the evidence of studies of androgen administration, it is not readily

apparent that significant adverse health effects can be attributed to androgens as a general class; however, the 17-alkyl-substituted androgens have

certain established consequences, all involving the liver. The 17-alkylated

androgens produce a consistent and substantial reduction in HDLC/LDLC

fractions, possibly increasing the risk of heart disease, although this outcome

remains to be demonstrated in androgen users. Cholestatic jaundice has

been observed in frequencies ranging from none to 17 percent in various

categories of 17-alkylated-androgen-treated patients, but is readily reversed

when androgen treatment is stopped. Peliosis hepatis clearly occurs in association with 17-alkylated androgen use, but with unknown frequency. Hepatic tumors are rare in men but occur with a frequency as high as 1 to

3 percent with 17-alkylated-androgen treatment with a latency of 2 to

30 years, Nearly half of these discovered tumors rupture, although a yet

larger proportion of benign disease may remain undetected. In two cases,

including one of a self-medicating bodybuilder, rupture proved fatal. In the

absence of effects reported in association with 17-alkylated androgens, there

would be few reports of androgen adverse effects, even though the clinical

use of injected androgen esters appears to be widespread.

Several case reports involving death or significant illness in athletes who

were thought to be self-administering androgens suggest the possibility of

other adverse effects that have not been commonly associated with androgen

doses in the clinical range. Foremost among these reports are several cases

of stroke reported in two bodybuilders and a third in a hypogonadal man

with unsupervised high-dose androgen self-administration. Previously unobserved adverse consequences may emerge from extraordinarily high-dose

androgen actions through effects related to crossover interactions with nonandrogenic receptors and to the unusually high serum levels of some metabolites, including estrogens. These effects may become apparent only with

prospective study of androgen abusers.

What these findings mean to current efforts to reduce the abuse of androgens by athletes is that some aspects of a standard smoking-cessation type

educational approach may not be useful, since there are few direct health

consequences, other than cosmetic effects such as acne (Strauss and Pochi

1963; Kiraly et al. 1988) and gynecomastia (Friedl and Yesalis 1989), that

can be used to dissuade these athletes from androgen use. There are also

certain problems with athletes discovering that the injectable esters may

carry less health risk than the orally active 17-alkylated androgens if this

causes more athletes to shift to the abuse of injectable androgens. This

introduces all the risks associated with self-injection by nonmedically trained

163
individuals using materials that are largely procured through unreliable black

market sources, ranging from localized sepsis (Rastad et al. 1985) to hepatitis and AIDS (Sklarek et al. 1984). This may also lead to much higher

dose administration of these more potent and longer lasting compounds, and

such use may introduce a new set of adverse actions not previously

encountered.

Thus, the question remains open: Hamilton (1948) suggested that there was

a price to pay for virilization, and studies of androgen administration in

men are not yet adequate to determine if additional androgen exacts a higher price in health consequences. Clearly, 17-alkyl substitution in an androgen introduces properties producing health risks that should not be ascribed

to androgenic actions. It may be speculated that more serious side effects

such as stroke may occur at very high doses, even with androgen esters,

through estrogenic metabolites or by actions of nonphysiological receptor

binding.

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176
AUTHOR

Karl E. Friedl, Ph.D.

Captain, Medical Service Corps

Exercise Physiology Division

U.S. Army Research Institute of Environmental Medicine

Natick, MA 01760-5007

177
Androgen Interaction Through

Multiple Steroid Receptors

Olli A. Jänne

INTRODUCTION

Under normal physiological conditions, different classes of steroid hormones

initiate distinct actions via binding to their cognate receptor proteins. The

specificity of the ensuing biological response relies on several characteristics

inherent to the steroid-receptor interaction. First, the steroid-binding specificity of all steroid receptors is relatively strict in that these proteins associate with their cognate physiological steroids with affinities that are usually

at least one order of magnitude higher than those for other classes of steroids (Ojasoo and Raynaud 1978). Second, the binding affinity of a given

receptor is commensurate with the concentration of its physiological ligand

such that the circulating steroid levels are generally close to those required

for the half-maximal saturation of the receptor’s binding site (Jänne et al.

1978b). Third, steroid metabolism that occurs under physiological conditions does not generate metabolites that are biologically more potent than

the parent compound, in cases other than the conversion of testosterone to

dihydrotestcsterone. Finally, the concentration of a receptor within a

given target cell is in line with its hormonal responsiveness; the formation

of biologically active receptor-steroid complexes is dictated by the law of

mass action, a low receptor content permits formation of functionally insufficient amounts of receptor-steroid complexes under physiological ligand

concentrations (Jänne and Bardin 1984).

Two main reasons account for deviations from this strict specificity in

steroid action: first, a change from a physiological to a pharmacological

ligand concentration and, second, modulation of the structure of the steroid

in question. In the case of male sex steroids, both natural and synthetic

androgens can potentially interact with several separate receptor systems,

including those for androgens, estrogens, progestins, and glucocorticoids. In

most instances, the interaction of androgens with receptors other than the

androgen receptor leads to the expression of the biological action characteristic of the receptor rather than of the androgen; however, this interaction

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sometimes results in the inhibition of the receptor’s function (Samuels and

Tomkins 1970). To illustrate some of these observations, results on the

interaction of androgens with the uterine progesterone receptors are first

reviewed in this chapter.

BINDING OF ANDROGENS TO THE PROGESTERONE RECEPTOR

Table 1 summarizes the relative binding affinities of physiological and

synthetic androgens to human and rabbit progestin receptors (Jänne et al.

1978a). All androgens tested, including testosterone and -dihydrotestosterone, competed with progesterone for binding to its receptor. In general,

19-nortestosterone derivatives appear to bind to the progestin receptor better

than derivatives of testosterone do (table 1). Two of the androgens,

ethyl-19-nortestosterone and -dimethyl-19-nortestosterone (figure l),

bound to the progestin receptor with affinities similar to or higher than that

of the cognate ligand progesterone. Many of the compounds listed in table

1 have been shown in different bioassays to be more potent androgens than

testosterone or -dihydrotestosterone; in addition, several of them (figure

1) are commonly abused by athletes (Wilson 1988). These and other

studies (Kontula et al. 1975; Ojasoo and Raynaud 1978) have indicated that

most of the structural modifications in the androgens that render them biologically more active (addition of double bonds or hydrophobic substituents,

removal of the 19-methyl group) are very similar to the modifications of the

progestational molecules required for their improved receptor-binding affinity

and biological potency.

TABLE 1. Relative binding activity of physiological and synthetic androgens to the cytosolic progesterone receptors from human and

rabbit uteri

Steroid

Relative Binding Affinity*

Human Receptor Rabbit Receptor

Progesterone 100.0 100.0

Testosterone 1.6 1.6

Dihydrotestosterone 3.3 3.3

19-Nortestosterone 8.9 11.8

-Methyl-19-nortestosterone 15.5 19.6

Methyltestosterone 4.6 3.4

-Ethyl-19-nortestosterone 130.0 70.1

-Dimethyltestosterone 8.6 6.4

-Dimethyl-19-nortestosterone 148.0 176.0

*The relative binding affinity was determined according to Kontula et al. (1975).

SOURCE Based on data in Jänne et al. 1978a.

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FIGURE 1. Structures of some synthetic androgens known to elicit

biological responses via multiple steroid receptors

PROGESTATIONAL ACTIVITY OF ANDROGENS

To determine whether the binding of androgens to cytosolic progestin receptor had biological consequences, the ability of these proteins to induce

uteroglobin, a progesterone-regulated protein in rabbit uterus, was studied

(Jänne et al. 1983; Kopu 1981). As illustrated in figure 2, all the androgens induce uteroglobin secretion in vivo when administered to rabbits, and

the extent of this induction is in good agreement with their ability to interact in vitro with the rabbit and human progesterone receptors (table 1). It

is of particular note that even the two physiological androgens, testosterone

and -dihydrotestosterone, elicit a significant increase in uteroglobin secretion (Jänne et al. 1978a). This response is 1 percent to 3 percent of that

brought about by progesterone, when the response is calculated on the

molar basis of the steroid administered and, therefore, commensurate with

the binding affinity of these androgens to the uterine progestin receptor.

Additional studies showed that testosterone and progesterone had similar

180
slopes in their dose-response curves (Jänne et al. 1978a), suggesting that

their actions are mediated by a common mechanism.

FIGURE 2. Comparison of the relative progestin receptor-binding activity

in vitro to the progestational activity (induction of

uteroglobin secretion) in vivo of various androgens

NOTE: The values are expressed relative to progesterone, which was set at 100 in each case. The

dashed line shows the situation when x=y.

SOURCE: Adapted from Jänne et al. 1978a.

Although the above data strongly suggested that uterine androgen and estrogen receptors were not involved in the androgenic regulation of uteroglobin

gene expression, additional studies were carried out to substantiate this

181
postulate. In particular, it was important to rule out the participation of the

estrogen receptor, since physiological androgens at pharmacological doses

are known to interact with this receptor protein (Zava and McGuire 1978;

McGuire 1978; Rochefort and Garcia 1979), and since uteroglobin secretion

is also stimulated by estradiol to some extent (Jänne et al. 1983). Concomitant administration of antiandrogens such as flutamide or RU 23908

with natural and synthetic androgens was unable to inhibit androgen-induced

uteroglobin secretion or accumulation of progesterone receptors in rabbit

uterine nuclei (Jänne et al. 1978a; Jänne et al. 1983; Kopu 1981). These

data make it very unlikely that androgen receptors are involved, as these

nonsteroidal antiandrogens specifically prevent androgen-receptor-mediated

events (Liao et al. 1974; Raynaud et al. 1979; Kontula et al. 1985). Simultaneous administration of -dihydrotestosterone and estradiol to rabbits

resulted in an estrogen dose-dependent inhibition of uteroglobin secretion

and accumulation of uteroglobin mRNA in uterine cells (Kopu 1981; Jänne

et al. 1983). This effect was very similar to that observed during a combined administration of progesterone with estradiol (Hemminki et al. 1980)

and strongly suggests that androgens and progesterone mediate their actions

via the same effector molecule, the progesterone receptor, the function of

which is prevented by high doses of estradiol.

The results from these studies illustrate that androgens can modulate endometrial functions through interacting with the uterine progesterone receptor.

Physiological androgens are able to do so only when administered at

pharmacological doses, as the affinity of these steroids for the progestin

receptor is almost two orders of magnitude lower than that of progesterone.

By contrast, many synthetic androgens interact with the progestin receptor

with a much higher affinity, and some of them ethyl-l9-nortestosterone

and -dimethyl-19-nortestosterone) can be biologically as potent as

progesterone itself. It is of particular note that the rabbit and human progesterone receptors have almost identical steroid-binding specificities

(Smith et al. 1974; Kontula et al. 1975; Jänne et al. 1978b); consequently,

physiological and synthetic androgens are expected to interfere with the

human progesterone-receptor-mediated functions in a manner similar to

rabbit uteroglobin gene expression. This interaction does not have to be

limited to the uterine tissue, but androgens are expected to interfere with

human hypothalamic and pituitary progestin receptors and thus influence

gonadotropin release. In this context, it is worth noting that progesterone

receptors in different experimental animals have dissimilar ligand-binding

specificities (Jänne et al. 1978b), and, therefore, some synthetic androgens

may not be able to interact with progestin receptors in all species. This

appears to be particularly true for steroids carrying substituents in the

D-ring.

182
INTERACTION OF ANDROGENS WITH ESTROGEN AND

GLUCOCORTICOID RECEPTORS

Pharmacological doses of androgens have been shown to elicit hypertrophy

with morphological changes similar to those brought about by estrogens in

immature rat uterus (Lerner et al. 1966). These experiments utilized aromatizable androgens; therefore, the possibility that the estrogenlike effects of

androgens were due to conversion of androgens to estrogens could not be

ruled out. The fact that large pharmacological doses of androgens are

required for the uterotrophic response to occur suggests that this effect is

not mediated by the androgen receptor. By using pharmacological doses of

a nonaromatizable androgen, -dihydrotestosterone, Rochefort and Garcia

(1979) showed that stimulation of estrogen-specific responses, such as

increased protein synthesis and stimulation of the estrogen-induced protein,

occurred in immature rat uteri. These responses correlated well with the

amount of estrogen receptor translocated to uterine nuclei following

dihydrotestosterone administration. Another estrogen-regulated event, the

synthesis of progestrone receptor, has also been shown to be stimulated by

pharmacological concentrations of -dihydrotestosterone in cultured human

breast cancer cells (Zava and McGuire 1978). Since the above effects are

specifically inhibited by concomitant administration of antiestrogens, it is

very likely that they result from the interaction of androgens with the estrogen receptor. However, it is not known whether it is -dihydrotestosterone or its reduced metabolites (androstanediols) that bind to the estrogen

receptor, since the reduced metabolites have been shown to have higher

binding affinity for the estrogen receptor than the parent compound

(Poortman et al. 1977).

The estrogenic activity of synthetic androgens appears to be similar to that

of the natural androgens (Ojasoo and Raynaud 1978) in that estrogenic

effects may be observed only after administration of large doses of these

steroids. In view of the above results, it is evident that administration of

androgens (natural and synthetic) at very high doses can lead to estrogenic

responses in estrogen target tissues. However, aromatization of testosterone

derivatives to estrogens and the resulting increase in the circulating estradiol

concentrations may be by far more important for the development of feminizing side effects observed during androgen abuse (Wilson 1988).

Physiological and synthetic androgens interact with the glucocorticoid receptor with affinities far below those of natural or synthetic glucocorticoids

(Samuels and Tomkins 1970; Rousseau and Schmit 1977; Ojasoo and

Raynaud 1978). At pharmacological steroid concentrations, this interaction

has significant biological consequences in that potent androgens such as

testosterone and -methyltestosterone are antiglucocorticoids (Samuels and

Tomkins 1970). In accordance with studies performed using cultured cells,

Mayer and Rosen (1975) found that pharmacological doses of androgens act

in vivo in rat muscle cells to block the catabolic effects of glucocorticoids.

183
Although the detailed mechanisms for this antiglucocorticoid action of

androgens are not fully understood, recent studies have indicated that

methyltestosterone competes with glucocorticoids for binding to the 10S

cytosolic receptor but does not promote dissociation of the oligomer, and

thus inhibits agonist-mediated nuclear actions of the glucocorticoid receptor

protein (Raaka et al. 1989).

CONCLUSION

A large body of evidence indicates that all of the potent naturally occurring

steroids of each class have relatively short half-lives in blood, have diminished biological activity after ‘oral administration, and are inactivated in the

enterohepatic circulation. To produce steroids that are orally active and that

could be infrequently administered has required modifications of naturally

occurring steroid structures. While these alterations have retained the

desired biological activity, they have also enhanced the ability of synthetic

steroids to interact with multiple receptors and thus exert more than one

biological activity, especially when the synthetic steroids are taken at high

doses. These phenomena are particularly well illustrated by the spectrum of

biological actions exhibited by synthetic androgens. The examples presented

in this chapter, androgen action via multiple receptors, describe the phenomenon of hormone action via the “wrong” receptor. It should be reiterated,

however, that these effects are observed only with large doses of hormone

and occur only very seldom, when the amount of androgen administered is

just sufficient to stimulate the male reproductive tract. As a consequence,

administration of naturally occurring or synthetic androgens at doses 10 to

100 times higher than those used in treatment of hypogonadal patients, as is

the case in self-administration of androgens by athletes (Wilson 1988), will

certainly produce biological effects that are not observed at physiological

dose levels.

REFERENCES

Hemminki, S.M.; Kopu, H.T.; Torkkeli, T.K.; and Jänne, O.A. Further

studies on the role of estradiol in the induction of progesterone-regulated

uteroglobin synthesis in the rabbit uterus. Mol Cell Endocrinol 17:71-80,

1980.

Jänne, O.A., and Bardin, C.W. Androgen and antiandrogen receptor binding. Annu Rev Physiol 46:107-118, 1984.

Jänne, O.; Hemminik, S.; Isomaa, V.; Kokko, E.; Torkkeli, H.; Torkkeli, T.;

and Vierikko, P. Progestational activity of natural and synthetic androgens. Int J Androl (Suppl) 2:162-174, 1978a.

Jänne, O.; Kontula, K.; Vihko, R.; Feil, P.D.; and Bardin, C.W. Progesterone receptors and regulation of progestin action in mammalian tissues.

Med Biol 56:225-248. 1978b.

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Kontula, K.; Jänne, O.; Vihko, R.; de Jager, E.; de Visser, J.; and Zeelen,

F. Progesterone-binding proteins: In vitro binding and biological activity

of different steroidal ligands. Acta Endrocrinol 78:574-592, 1975.

Kontula, K.K.; Seppänen, P.J.; Van Duyne, P.; Bardin, C.W.; and Jänne,

O.A. Effect of a nonsteroidal antiandrogen, flutamide, on androgen

receptor dynamics and omithine decarboxylase gene expression in mouse

kidney. Endocrinology 116:226-233, 1985.

Kopu, H. Dihydrotestosterone-induced uteroglobin synthesis in rabbit

uterus is not inhibited by antiandrogen administration but is prevented by

estradiol. Biochim Biophys Acta 654:293-296, 1981.

Lemer, L.J.; Hilf, R.; Turkeimer, A.R.; Michel, I.; and Engel, S.L. Effects

of hormone antagonists on morphological and biochemical changes

induced by hormonal steroids in the immature rat uterus. Endocrinology

78:111-124, 1966.

Liao, S.; Howell, D.K.; and Chang, T.M. Action of a non-steroidal antiandrogen, flutamide, on the receptor binding and nuclear retention of

dihydrotestosterone in rat ventral prostate. Endocrinology 94:532-540,

1974.

Mayer, M., and Rosen, F. Interaction of anabolic steroids with glucocorticoid receptor sites in rat muscle cytosol. Am J Physiol 229:1381-

1386, 1975.

Ojasoo, T., and Raynaud, J.-P. Unique steroid congeners for receptor

studies. Cancer Res 38:4186-4198, 1978.

Poortman, J.; Vroegindewey-Jie, D.; Thijssen, J.H.H.; and Schwarz, F.

Relative binding affinity of androstane and C-19-norandrostane steroids

for the estradiol-receptor in human myometrial and mammary cancer

tissue. Mol Cell Endocrinol 8:27-34, 1977.

Raaka, B.M.; Finnerty, M.; and Samuels H.H. The glucocorticoid antagonist -methyltestosterone binds to the 10S glucocorticoid receptor and

blocks agonist-mediated dissociation of the 10S oligomer to the 4S deoxyribonucleic acid-binding subunit. Mol Endocrinol 3:332-341, 1989.

Raynaud, J.-P.; Bonne, C.; Bouton, M.-M.; Lagace, L.; and Labrie, F.

Action of a non-steroidal antiandrogen, RU 23908, in peripheral and

central tissues. J Steroid Biochem 11:93-99, 1979.

Rochefort, H., and Garcia, M. Effect of androgens mediated by the oestrogen receptor in uterus. In: Klopper, A.; Lerner, L.; van der Molen, H.J.;

and Sciarra, F., eds. Research on Steroids, Vol. VIII. New York:

Academic Press, 1979. pp. 323-325.

Rousseau, G.G., and Schmit, J.-P. Structure activity relationships for glucocorticoids. I: Determination of receptor binding and biological activity.

J Steroid Biochem 8:911-919, 1977.

Samuels, H.H., and Tomkins, G.M. Relation of steroid structure to enzyme

induction in hepatoma tissue culture cells. J Mol Biol 52:57-74, 1970.

Smith, H.E.; Smith, R.G.; Toft, D.O.; Neergaard, J.R.; Burrows, E.P.; and

O’Malley, B.W. Binding of steroids to progesterone receptor proteins in

chick oviduct and human uterus. J Biol Chem 249:5924-5932, 1974.

Wilson, J.D. Androgen abuse by athletes. Endocr Rev 9:181-199, 1988.

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Zava, D.T., and McGuire, W.L. Androgen action through estrogen receptor

in a human breast cancer cell line. Endocrinology 103:624-631, 1978.

ACKNOWLEDGMENT

This work was supported in part by U.S. Public Health Service grants

HD 13541 and DK 37692 from the National Institutes of Health.

AUTHOR

Olli A. Jänne, M.D., Ph.D.

Senior Scientist and Associate Division Director

Center for Biomedical Research

The Population Council

1230 York Avenue

New York, NY 10021

186
Anabolic-Androgenic Steroids

Profoundly Affect Growth at

Puberty in Boys

Alan D. Rogol, Paul M. Martha, Jr., and

Robert M. Blizzard

INTRODUCTION

Growth at puberty in man (Tanner and Davies 1985) and some animals

(Eden 1979) is clearly sexually dimorphic. It has long been surmised that

these alterations in linear growth are subserved by augmented gonadal

steroid hormone secretion. More recent data (Parker et al. 1984, Link et al.

1986; Mauras et al. 1987; Stanhope et al. 1988) point toward the necessity

of increased circulating concentrations of insulinlike growth factor I (IGF-I)

(also called somatomedin C); which themselves depend upon augmented

growth hormone (GH) secretion. It is the purpose of this chapter to review

the evidence for IGF-I and GH secretion during puberty in children whether

this process occurs spontaneously or is induced by exogenous gonadal

steroid hormone therapy. Although many investigators have contributed to

this field, we shall choose most of the specific examples from our own

work.

IGF-I

IGF-I levels increase as pubertal development advances in boys and girls

(Luna et al. 1982; Rosenfield and Furlanetto 1985). Parker and coworkers

(1984) administered testosterone propionate (25 mg intramuscularly (IM)

daily for 7 days) to six prepubertal GH-deficient boys. None had increased

circulating levels of IGF-I (baseline 0.2 U/ml; after testosterone 0.25 U/ml),

although administration of testosterone enanthate markedly increased IGF-I

levels in GH-sufficient boys (baseline 0.6 U/ml; after testosterone 1.9 U/ml).

GH treatment (0.05 U/kg per day) or the combination of GH and testosterone increased circulating IGF-I levels to 0.84 and 0.87 U/ml, respectively.

These data show that testosterone elevates IGF-I concentrations in prepubertal boys who can secrete GH but not in those deemed GH deficient by

187
classical growth and pharmacological testing criteria. This effect of androgen is considered due to the stimulation of pituitary GH secretion (see

below). Thus, at puberty, physiological concentrations of testosterone may

be responsible for the pubertal IGF-I increase in adolescent boys; however,

since IGF-I levels decline after maximal growth velocity, factors other than

androgenic-anabolic steroid hormones must also play a role.

GROWTH HORMONE

To further define the role of anabolic-androgenic steroid hormones in mediating the rise in IGF-I levels at puberty, we investigated 15 prepubertal

boys, ages 10 to 16.4 years, who had been referred to the Pediatric Endocrinology Clinic at the University of Virginia Health Sciences Center for

evaluation of short stature or delayed sexual development (Link et al. 1986).

Each subject’s genital development was stage I (prepubertal) or II (very

early pubertal) based on the method of Tanner (Marshall and Tanner 1970).

GH concentrations were determined every 20 minutes for 24 hours both

before and after treatment with anabolic-androgenic steroids. Following the

baseline study, 10 boys received oxandrolone (Anavartm), 0.1 mg/kg per day

for 2 months, and 5 boys received testosterone propionate (7.5 mg IM daily

for 7 days) followed by testosterone enanthate (100 mg IM monthly for 3

months). The second GH secretion test occurred within 3 to 5 days after

the third testosterone enanthate injection. The boys receiving oxandrolone

were restudied after a similar therapeutic interval, slightly more than 60

days following the first test.

Although all boys had an increase in their growth rates during treatment,

those receiving testosterone grew twice as fast as the boys in the oxandrolone-treated group (1.2±0.2 cm per month vs. 0.6±0.07 cm per month).

Mean increments above the basal growth rate (approximately 0.4 cm per

month) were 0.84±0.13 cm per month and 0.22±0.12 cm per month,

p=0.002. Mean IGF-I levels before and during therapy are shown in

table 1.

TABLE 1. IGF-I concentrations before and during treatment

IGF-I (U/ml)

Pre-Rx 2 months on Rx

Oxandrolone treatment 0.70±0.2

Testosterone treatment 0.82±0.46

NOTE: Measurements reflect the mean ± standard deviation.

0.84±0.45

2.3±0.4

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There was no significant change in the mean IGF-I concentration in the

oxandrolone-treated group (mean change, 0.14±0.4 U/ml; p=.31). However,

there was a marked increase of 1.52±0.6 U/ml in the mean IGF-I concentration of the testosterone-treated group (p=.007). To determine if the increase

in IGF-I concentration in the testosterone-treated group was mediated by

altered GH secretion, we calculated the grand mean of 24-hour GH levels

obtained from a pool made from equal aliquots from each of the 72

samples withdrawn from the boys in each group. The results are shown in

table 2.

TABLE 2. Mean GH concentration before and during treatment with

oxandrolone or testosterone

Mean GH concentration

(ng/ml)

Pre-Rx 2 months on Rx

Oxandrolone treatment

Testosterone treatment

3.4±1.5 3.1±1.6

2.3±1.8 6.4±2.4

NOTE: Measurements reflect the mean ± standard deviation.

There was no significant change in the mean GH level before or during

therapy (mean change, -0.25±6 ng/ml; p=.22) in the oxandrolone-treated

group. However, in the testosterone-treated group, there was a threefold

increase in mean GH concentration (range two- to twelvefold) during treatment with a mean increase of 4.1±1.2 ng/mI (p=.001) (Link et al. 1986).

The increases in IGF-I concentrations and growth rates in the testosteronetreated boys reflect the biological relevance of the increase in the mean

daily GH concentrations. Similar elevations in IGF-I levels occur during

spontaneous puberty in boys (Parker et al. 1984; Link et al. 1986) and

further support this effect of augmented testosterone secretion as a mechanism for the pubertal growth spurt. By contrast, as noted above, a rise in

serum testosterone level without an increase in GH concentrations does not

increase the circulating levels of IGF-I.

If there is but one androgen receptor, why is the anabolic-androgenic steroid

oxandrolone ineffective in augmenting GH secretion, although it clearly

increases the growth rate of prepubertal boys? Oxandrolone may act directly at the bony epiphysis to augment growth or possibly enhance the bioactivity of the existing circulating GH. We are unaware of data to distinguish

either of these mechanisms or others. Perhaps effects of testosterone are

mediated after aromatization to 17-ß estradiol, since oxandrolone cannot be

aromatized to a biologically effective estrogen. Studies in adults that

demonstrate that circulating concentrations of 17-ß estradiol (total or free)

189
are correlated with higher mean GH concentrations indirectly support this

hypothesis (Blizzard et al. 1974; Ho et al. 1987). Alternatively, the dose of

oxandrolone did not equal that of testosterone in anabolic potency; a greater

dose of oxandrolone might show the same effect as the doses of testosterone employed in these studies.

CROSS-SECTIONAL STUDY OF HORMONAL CHANGES AT

PUBERTY

To more fully investigate the augmented GH secretion linked to anabolicandrogenic steroids, Mauras and colleagues studied the specific characteristics of pulsatile GH release responsible for the altered mean GH levels

previously noted. Serum GH profiles were analyzed for 10 pre- and early

pubertal boys and compared to those from 5 boys late in their pubertal

development (Mauras et al. 1987). Using a conservative objective pulse

detection method, CLUSTER (Veldhuis and Johnson 1986), the investigators

noted markedly augmented circulating levels of GH (and IGF-I) in the late

pubertal boys compared to the pre- and early pubertal boys (table 3).

TABLE 3. Cluster analysis of the GH concentration series and circulating

IGF-I levels

Mean GH

(ng/ml)

CLUSTER Analysis

IGF-I Number of Amplitude

(U/ml) pulses/24 hrs (ng/ml)

Prepubertal boys* 2.7±0.5 0.92±0.10

Late pubertal boys* 5.4±0.7 1.78±0.24

NOTE: Measurements reflect the mean ± standard deviation.

SOURCE: Mauras et al. 1987.

5.5±0.4 8.6±1.7

5.4±0.5 17.1±2.6

These data demonstrate significant augmentation of total GH secretion at the

more advanced stages of sexual development. This increase is due entirely

to the increased amplitude of the individual GH secretory bursts, since there

was no alteration in the frequency of pulsatile GH release. Similar data,

i.e., augmented pulse amplitude without change in frequency, were generated

upon reanalysis of the previous study in which prepubertal boys were given

testosterone treatment (Mauras et al. 1987). The underlying mechanism of

altered GH release, whether attributed to an increased sensitivity of the

pituitary somatotrophs, the stimulatory effects of GH-releasing hormone,

increased amplitude of GH-releasing hormone secretory pulses, decreased

inhibitory tone of somatostatin upon the pituitary, or a combination, cannot

be determined from these studies. To more fully define altered GH

190
secretion during puberty, Martha and colleagues (1989) performed an extensive study of the mode of pulsatile release of GH in healthy male volunteers of normal stature whose ages and physical development spanned the

entire pubertal range, defined as follows: prepubertal (PRE)=Tanner

(Marshall and Tanner 1970) stage I physical development; early puberty

(EARLY)=pubertal, but pubic hair development no greater than Tanner stage

II; late pubertal (LATE)=Tanner stage III or IV pubic hair and hand epiphyses open; postpubertal (POST)=chronological age <=18 years, but hand epiphyses fully closed; and adult (ADULT)=healthy young men.

Testosterone

Serum testosterone concentrations increased with advancing sexual development (table 4).

TABLE 4. Morning mean (±SE) testosterone concentrations (nmol/L) of

study subjects

PRE EARLY LATE POST ADULT

<0.87 4.8±1.25 14.7±l.14 17.1±1.1 21.3±1.6

Since testosterone levels did not fall in the POST and ADULT groups as

did the GH values (see below), serum concentrations did not correlate

positively with any of the assessed GH pulse properties or serum IGF-I

concentrations. No significant correlations were obtained between the serum

testosterone level and the mean number of pulses per 24 hours (r=0.09,

p=0.58).

Growth Hormone

Some specific properties of the pulsatile pattern of GH release are shown in

table 5.

The size of the serum GH pulses was clearly greater in the late pubertal

group, whether assessed as the mean sum of the GH pulse areas (p<0.001),

the mean pulse area (p=0.004) or mean GH pulse amplitude (p=0.001).

However, as distinguished from many other GH pulse characteristics, the

mean number of detectable GH pulses per 24 hours was not distinguishable

from the values for any of the other study groups. Figure 1 illustrates the

values for the average GH pulse amplitude (panel B) and average number

of pulses per 24 hours (panel C) for the study groups. Note the similarity

and dissimilarity of panels B and C, respectively, to the profile of the 24-

hour mean concentration of GH illustrated in panel A. Plasma values for

191
TABLE 5. Properties of pulsatile GH release

PRE EARLY LATE! POST ADULT

24-hour mean concen- 6.7±1.0 4.7±0.7 13.8±2.4 4.4±0.9 3.9±0.5

tration (μg/L)

Mean pulse area 648±66 615±87 1,288±215a

714±216 614±91

(μg/Lxmin)

Mean pulse ampli- 14.4±1.3 12.8±1.3 22.4±2.8 14.7±39 10.3±1.3

tude (μg/L)

Sum GH pulse incre- 104±10.7a,b 80±0.8a,b 142±18.0a,b 82.0±23a,b 48.73±60c

ments (μg/L)

Number of pulses 8.8±0.7b7.0±0.5a7.8±0.6a,b 6.6±0.6a

6.1±0.5

per 24 hours

NOTE: GH pulse properties were determined using the CLUSTER algorithm (Veldhuis and Johnson

1986). All values are mean ± SE Any two values in the same row that either lack a superscript or are designated by identical superscripts do not differ statistically; otherwise values

are distinguishable statistically from one another (p<0.05).

SOURCE: Table based on data after Martha et al. 1989.

IGF-I mirror the mean GH concentrations (data not shown) and correlate

positively with the 24-hour mean GH concentration (r=0.48; p<0.001), the

mean and sum of GH pulse areas (r=0.39, p=0.002 and r=0.47, p<0.001, respectively), and the mean and sum of GH pulse increments (r=0.42,

p<0.001 and r=0.48, p<0.001, respectively). By contrast, there was no

correlation of plasma IGF-I concentration and 24-hour frequency of GH

pulses (r=.17, p<.2). However, when the analyses were repeated including

only those values from subjects whose hand epiphyses remained open,

several strong correlations emerged (Martha et al. 1989). Morning serum

testosterone concentrations from only the PRE, EARLY, and LATE pubertal

boys correlated positively with plasma IGF-I concentration (r=0.68,

p<0.001), 24-hour mean GH concentration (r=0.47, p<0.001), and the mean

and sum of GH pulse increments (r=0.58, p<0.001 and r=0.47, p<0.001,

respectively).

The results of this cross-sectional study indicate that, along with a rise

in plasma IGF-I concentrations, mean circulating levels of GH increase

during puberty in normally growing boys around the time of the expected

midpubertal growth spurt. The levels of testosterone rise continuously

during the ascending portion of the GH and IGF-I increases. This and

other studies (Link et al. 1986; Mauras et al. 1987; Stanhope et al. 1988;

Liu et al. 1987) strongly suggest a central role for the gonadal hormone

environment, particularly circulating androgen concentrations, in mediating

the pulse amplitude changes. However, circulating testosterone concentrations cannot be the sole determinant of the pubertal increase in GH pulse

192
FIGURE 1. Summary of mean and pulsatile properties of GH release in

pubertal boys

NOTE: Panel A illustrates the mean ±SE 24-hour integrated concentrations of GH for the five study

groups. Panel B presents the mean (±SE) area under the GH concentration vs. time curve for

individual GH pulses as identified by the CLUSTER pulse detection algorithm. Panel C

shows the number of growth hormone pulses (mean±SE) as detected by the CLUSTER algorithm in the 24-hour GH concentration profiles for subjects in the five study groups. In each

panel, any two vertical bars not identified by the same letter represent statistically different

values (p<0.05) bars sharing a common letter represent statistically indistinguishable values

(p<0.05).

193
amplitude in man, since this pulse parameter decreased in postpubertal boys

and young men whose circulating testosterone levels continued to rise.

At all the pubertal stages it is apparent that there is a strong interaction

between anabolic-androgenic steroid hormones and GH secretion. What the

precise molecular mechanisms are cannot be determined from these results.

Further research into the aromatization products (estrogens) and opioid

peptide pathways involved may produce new insights, as there is good evidence that the former (Ho et al. 1987) and the latter hormonal products are

involved in hypothalamic feedback mechanisms (Veldhuis et al. 1984; Borer

et al. 1986).

REFERENCES

Blizzard, R.M.; Thompson, R.G.; Baghdassarian, A.; Kowarski, A.; Migeon,

G.J.; and Rodriguez, A. The interrelationships of steroids, growth

hormone, and other hormones on pubertal growth. In: Grumbach, M.M.;

Gilman, G.D.; and Mayer, F.E., eds. The Control of the Onset of

Puberty. New York: Wiley and Sons, 1974. 342 pp.

Borer, K.T.; Nicoski, D.R.; and Owens, V. Alteration of pulsatile growth

hormone secretion by growth-inducing exercise: Involvement of

endogenous opiates and somatostatin. Endocrinology 118:844-850, 1986.

Eden S. Age- and sex-related differences in episodic growth hormone

secretion in the rat. Endocrinology 105:555-560, 1979.

Ho, K.Y.; Evans, W.S.; Blizzard, R.M.; Veldhuis, J.D.; Merriam, G.R.;

Samojlik, E.; Furlanetto, R.; Rogol, A.D.; Kaiser, D.L.; and Thorner,

M.O. Effects of sex and age on the 24-hr secretory profile of GH

secretion in man: Importance of endogenous estradiol concentrations.

J Clin Endocrinol Metab 64:151-58, 1987.

Link, K.; Blizzard, R.M.; Evans, W.S.; Kaiser, D.L.; Parker, M.W.; and

Rogol, A.D. The effect of androgens on the pulsatile release and the

twenty-four hour mean concentration of growth hormone in peripubertal

males. J Clin Endocrinol Metab 62:159-164, 1986.

Liu, L.; Merriam, G.R.; and Sherins, R.G. Chronic sex steroid exposure

increases mean plasma growth hormone concentration and pulse amplitude

in men with isolated hypogonadotropic hypogonadism. J Clin Endocrinol

Metab 64:651-656, 1987.

Luna, A.M.; Wilson, D.M.; Wibbelsman, C.J.; Brown, R.C.; Nagashima,

R.J.; Hintz, R.L.; and Rosenfeld, R.G. Somatomedins in adolescence: A

cross-section study of the effect of puberty on plasma insulin-like growth

factor I and II levels. J Clin Endocrinol Metab 57:268-271, 1982.

Marshall, W.A., and Tanner, J.M. Variation in the pattern of pubertal

changes in boys. Arch Dis Child 45:13-23, 1970.

Martha, P.M.; Rogol, A.D.; Veldhuis, J.D.; Kerrigan, J.R.; Goodman, D.W.;

and Blizard, R.M. Alterations in the pulsatile properties of circulating

growth hormone concentrations during puberty in boys. J Clin Endocrinol Metab 69:563-570, 1989.

194
Mauras, N.; Blizzard, R.M.; Link, K.; Johnson, M.L.; Rogol, A.D.; and

Veldhuis, J.D. Augmentation of growth hormone secretion during

puberty; evidence for a pulse amplitude-modulated phenomenon. J Clin

Endocrinol Metab 64:596-601, 1987.

Parker, M.W.; Johanson, A.J.; Rogol, A.D.; Kaiser, D.L.; and Blizzard,

R.M. Effect of testosterone on somatomedin C concentrations in

prepubertal boys. J Clin Endocrinol Metab 58:87-90, 1984.

Rosenfield, R.L., and Furlanetto, R. Physiologic testosterone or estradiol

induction of puberty increases plasma somatomedin C. J Pediat 107:415-

417, 1985.

Stanhope, R.; Pringle, P.J.; and Brook, C.G.D. The mechanism of the

adolescent growth spurt induced by low dose pulsatile GnRH treatment.

Clin Endocrinology 28:83-91, 1988.

Tanner, J.M., and Davies, P.W. Clinical longitudinal standards for height

and height velocity for North American children. J Pediatr 107:317-329,

1985.

Veldhuis, J.D., and Johnson, M.L. Cluster analysis: A simple, versatile,

and robust algorithm for endocrine pulse detection. Am J Physiol

250:E486-E493, 1986.

Veldhuis, J.D.; Rogol, A.D.; Samojlik, E.; and Ertel, N.H. Role of

endogenous opiates in the expression of negative feedback actions of

androgen and estrogen on pulsatile properties of luteinizing hormone

secretion in man. J Clin Endocrinol Metab 59:580-586, 1984.

ACKNOWLEDGMENTS

Sandra Jackson and her nursing staff at the University of Virginia General

Clincial Research Center provided expert patient care. Miss Ginger Bauler,

Catherine Kern, and Beth Epstein of the Core Radiological Assay

Laboratory performed most of the immunoassays. Data handling and

analysis employed the CLINFO system. This work was supported in part

by U.S. Public Health Service grant RR 00897 from the National Institutes

of Health to the University of Virginia Clinical Research Center.

AUTHORS

Alan D. Rogol, M.D., Ph.D.

Department of Pediatrics and

Department of Pharmacology

Paul M. Martha, Jr., M.D.

Department of Pediatrics

Robert M. Blizzard, M.D.

Department of Pediatrics

University of Virginia Health Sciences Center

Building MR-4, Room 3037

Charlottesville, VA 22908

195
Indications of Psychological

Dependence Among AnabolicAndrogenic Steroid Abusers1

C.E. Yesalis, J.R. Vicary, W.E. Buckley, A.L. Streit,

D.L. Katz, and J.E. Wright

INTRODUCTION

Although a great deal of attention has been paid in recent years to adolescent drug use and abuse, it has been only recently that the phenomenon of

teen use of anabolic-androgenic steroids (AS) has been documented on a

national scale (Buckley et al. 1988). The nonmedical use of AS among

adolescents has become an issue for concern because of the potentially

harmful physical and psychological outcomes (Haupt and Rovere 1984;

Herrmann and Beach 1976; Pope and Katz 1988; Wilson 1988; Wright

1980; Yesalis et al. 1989). Most of the short-term physiologic effects in

adult males are transitory (Haupt and Rovere 1984; Wright 1980; Yesalis

et al. 1989), but several studies suggest that the biophysical consequences

for adolescent males could be more serious (Rosefeld et al. 1982; Strauss

1987; Blether et al. 1984; Wilson et al. 1988). Furthermore, the psychological effects of AS have not been welt documented, and it is in this area

that indications of dependence may be evidenced. Taylor (1987) suggests

habituation among AS users, although his position appears to be based on

user testimonials.

Although AS have been used in the treatment of depression and other mental health disorders (Danziger and Blank 1942; Vogel et al. 1985), serum

testosterone levels have also been linked to aggressive behavior with evidence derived from both the literature on animals (Adams 1983; Bouissou

1983) and humans (Ehrenkrantz et al. 1974; Olweus et al. 1980; Perskey

et al. 1971; Scaramella and Brown 1978; Susman et al. 1987). Use of AS

has been associated with self-reported changes in mood, behavior, and

somatic perceptions (Heller 1959; Strauss et al. 1983; Wright, unpublished;

Bahrke et al., in press[a]). AS have been shown to elicit electroencephalographic changes similar to those seen with amphetamines and tricyclic

196
antidepressants (Itil et al. 1974; Itil 1976). Case reports of hypomania

(Freinhar and Alvarez 1985), schizophrenic, and psychotic episodes have

been noted among AS users (Annitto and Layman 1980; Pope and Katz

1987; Pope and Katz 1988), but objective measures (i.e., blind studies) of

hostility have not been documented (Bahrke et al., in press[b]).

Other psychological effects of use, that is, increased confidence, euphoria,

and enhanced libido (Wright 1980; Haupt and Rovere 1984; Rahrke et al.,

in press [b]), are powerful reinforcers in their own right. However, these

effects, like the physical outcomes, diminish when use is discontinued

(Wright 1978; Wright 1982) and may in fact turn into frank depression

(Pope and Katz 1988). Such reductions may be associated, therefore, more

with a psychological than a physical motivation for continued cyclical use

of the drugs. It is possible that the psychological or affective outcomes act

as secondary reinforcers, equally as powerful as the primary physical ones.

Several findings from our national study of AS use among adolescent male

high school seniors are suggestive of psychological dependence. In this

chapter, data from that survey are discussed in relation to psychological

rewards of use and the potential for dependence to develop. In particular,

the relationships between age of initiation of use, frequency of use, methods

of administration, unwillingness to discontinue use, and perceptions of

strength, health, and peer use are examined.

BACKGROUND

Current research indicates that, by their senior year in high school, 58 percent of teenagers have tried an illicit drug and that male adolescents are

more likely to use illicit drugs (Johnston et al. 1987). It also appears that

the development of drug-use patterns, including acquisition and habit formation, for various substances is most likely to occur between 11 and 24 years

of age (Pandina et al. 1984). The outcomes of use behaviors, from initiation of use through possible dependence on drugs, are of concern for both

their physical and psychological consequences. Adolescence is an age

period during which a number of major developmental tasks are addressed

(Adelson 1980). While each of these is of importance and potentially

affected by drug use, two are of particular relevance to AS use, namely,

(1) development and maintenance of physical health care behaviors and

(2) development of self-identity, self-esteem, and psychological well-being.

To understand adolescent AS use in a developmental context, it is useful to

identify parallels with other teen drug use. Research has shown a variety

of factors associated with teen drug use, several of which may be similar to

those related to AS use. Recreational drugs, both licit and illicit, generally

are expected to provide pleasurable effects for the user, with mood-altering

capabilities most valued (Johnston et al. 1987). Although AS do not

197
provide immediate euphoric effects, the physical and psychological outcomes

have the potential to affect social status and peer perceptions as well as

mood and self-image. Not uncommonly, problems in personal, family,

school, and peer domains are identified as causative or contributing to drug

use, along with the interactions between these and other contexts, e.g.,

sociocultural (Huba et al. 1980). Clearly personal and peer values and

expectations need to be identified to understand adolescent AS use.

The physiological addictiveness of AS is not known but has been suggested

by anecdotal reports of withdrawal symptoms by users (Goldstein, this

volume), and two cases of apparent dependence on AS have recently been

reported (Brower et al. 1989; Tennant et al. 1988). Although studies to

document endogenous opiate levels following AS administration have not

been conducted, the potential for physiological dependence on these drugs is

strengthened by numerous reports demonstrating the role of opiate peptides

in the mediation of sex steroid effects on the central nervous system (particularly hypothalamic hormone secretion) (Bhanot and Wilkinson 1983;

Cicero et al. 1979; Ieiri et al. 1979; Mauras et al. 1986; Van Vugt et al.

1982; Veldhuis et al. 1983; Veldhuis et al. 1985; Veldhuis et al. 1984).

Drug treatment programs recognize that physical dependence on most drugs

can be relatively easily reduced, but eliminating psychological dependence is

more difficult, although necessary for total recovery. Several psychological

attitudes associated with AS use among adolescents parallel those associated

with drug dependence in general. One such attitude is a tendency to overlook, disbelieve, or argue against the physical risks of drug use and to perceive the benefits as outweighing the risks.

Drug use continues, at various levels, as long as the perceived benefits,

often real as well, outweigh the perceived and equally real problems associated with use. Research also indicates that a general tendency to take risks

is associated with the development of drug abuse (Crowley 1988).

Adolescent substance users usually overestimate the prevalence and acceptability of use by their peers (Sherman et al. 1983; Chassin et al. 1985). A

strong predictor of an individual’s use of drugs is reported use by a friend

or admired other (Hansen et al. 1987), although it is not always clear

whether drug-related friendships follow or precede use. Although many of

the problems associated with teen drug use generally are not present with

users of AS, there may be some parallel psychological factors related to

their use and potential for psychological dependence.

METHODS

Participants for this investigation were 12th-grade male students in both private and public high schools. A sample of schools was drawn from an

available nationwide pool of 150 high schools, known to the researchers

198
because these schools employed certified athletic trainers who had recently

participated in a sports epidemiology survey (Powell 1987). Only 10 percent of high schools nationwide employ certified athletic trainers. However,

there is no evidence to suggest that adolescent AS users who attend high

schools with an athletic trainer behave differently than AS users in academic settings without athletic trainers.

The high schools were stratified into eight categories based on general

demographic characteristics: (1) urban and rural locale, using the Metropolitan Statistical Area (MSA) designation; (2) large (more than 700 students) and small (fewer than 700 students) enrollment based on school

records 1 month prior to survey administration; and (3) sunbelt and nonsunbelt locale. Sunbelt locale was defined as schools in States that were contiguous and bordered any ocean body or Mexico, from Virginia south and

west to Texas, Arizona, New Mexico, and California. These strata were selected based upon anecdotal accounts that the rate of AS use is higher

among students in large, urban schools in sunbelt States.

The 150 schools were stratified according to the above three characteristics.

This produced eight separate categories or “cells” of schools. A random

sample, proportional to the national distribution of schools on these characteristics, was drawn from each of these cells, yielding a total of 67 schools

the researchers then contacted for the study. The exceptions to this random

subsampling were the categories of sunbelt schools with enrollment of less

than 700 and rural sunbelt schools with enrollment of more than 700; for

these categories, all available schools were used because of the small numbers in the original pool. Based on these characteristics, the schools in our

sample are representative of secondary schools across the nation on the

stratification characteristics. The schools were treated as clusters of potential respondents, and all male seniors were invited to participate.

The athletic trainer at each school was contacted individually by phone by

the principal investigators. The study was described to him or her, and

only eight athletic trainers (12 percent) declined to participate. The majority expressed great interest in the study and were eager to help out. In

total, 46 of the 67 schools contacted completed the study protocol for a

return rate of 68.7 percent. There were 3,403 (50.3 percent) students who

participated in the study out of a potential 6,765 male senior students who

were eligible from the participating institutions.

An anonymous 23-item questionnaire, generated by the researchers, was employed to collect the data. The majority of athletic trainers, acting as onsite

coordinators, had suggested using homeroom teachers to administer the surveys, as this would include the greatest number of students and provide the

most routine form of administration. The athletic trainers circulated the surveys to the homeroom teachers, along with the list of the project’s administration instructions. The homeroom teachers administered the surveys to all

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male seniors present that day, after having given them each a copy of the

survey’s purpose and description and having read it aloud to them. This

setting provided a standardized testing environment and was used for all

survey completion. The students’ confidentiality was further maintained by

having the homeroom teachers seal the collection envelope prior to returning

it to the athletic trainer, who then forwarded all responses directly to the

researchers for scoring and tabulation.

The tabular analysis involved simple frequency counts and percentages. The

chi-square statistic was used to test for significant differences between

groups at a level of .05. Additional detail regarding the methodology is

reported elsewhere (Buckley et al. 1988).

RESULTS

AS drug use was determined by a yes or no response to the question:

“Have you ever used anabolic steroids?” Using the school as the analysis

unit, the mean rate of AS use was 6.34 (4.61) percent; with the student as

the analysis unit, a mean use rate of 6.64 percent (226/3,403) was derived.

The results indicated significant variation of AS use among the participating

schools, with respondents from seven schools (15 percent) reporting no AS

use.

Use levels among respondents included 40 percent of users reporting five or

more episodes (i.e., cycles) of use, 44 percent reporting using more than

one AS at the same time (i.e., “stacking”), and 38 percent reporting use of

injectable AS.

The AS users in this study perceived significant strength and health benefits

from their AS use. The majority of adolescent AS users perceive their relative strength to be greater than average and assess their health as very good

or excellent (table 1); their self-perceptions of strenglh and health were generally more extreme than those of nonusers (Buckley et al. 1988). The data

also indicated that approximately 40 percent of AS users do not want AS

use in sports stopped, even if they were assured their competitors were not

using the drugs (25 percent of AS users hold this opinion strongly).

Self-reported users were presented with health-risk scenarios related to the

use of AS. Again approximately one out of four stated their intentions to

continue use regardless of dire health consequences such as liver cancer,

heart attack, or sterility. Thus a clear picture of a “hard core” group of AS

users who appear to have no intention of discontinuing use emerges. The

characteristics of this hard-core group in terms of episodes of use and age

at first use are of special interest. Specifically, adolescents who have completed more cycles and who initiated AS use at a younger age are more

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TABLE 1. AS users’ perceptions and behaviors (n=226*)

Frequency Percent

1. Use of injectable AS

Yes

No

80 38.3

129 61.7

2. Use of more than one AS at one time

(“stacking”)

Yes

No

93 43.7

120 56.1

3. Personal strength perceptions

Greater than average

Average

Less than average

126 57.3

67 30.9

1 3 5.9

4. Personal health perceptions

Excellent

Very good

Good

Fair

Poor

89 39.7

71 31.7

39 17.4

14 6.3

1 1 4.9

5. I would like to see the use of AS to

improve performance in sports stopped.

Strongly agree

Agree

Undecided

Disagree

Strongly disagree

38 17.0

25 11.2

71 31.7

35 15.6

55 24.6

6. I would stop using AS if I were absolutely

convinced my fellow competitors no longer

used them.

Definitely yes 37 17.0

Probably yes 28 12.8

Unsure 69 31.7

Probably no 33 15.1

Definitely no 51 23.4

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TABLE 1. (continued)

Frequency Percent

7. I would stop using AS if it was proven

beyond doubt that they would . . .

a. lead to permanent sterility

Definitely yes

Probably yes

Unsure

Probably no

Definitely no

b. greatly increase my risk of liver cancer

Definitely yes

Probably yes

Unsure

Probably no

Definitely no

c. greatly influence my risk of a heart

attack before age 40

Definitely yes

Probably yes

Unsure

Probably no

Definitely no

69 31.4

48 21.8

46 20.9

2 1 9.5

36 16.4

69 31.1

59 26.6

40 18.0

26 11.7

28 12.6

69 31.5

60 27.4

39 17.8

21 9.6

30 13.7

*Instances where the number of respondents does not equal 226 is due to nonresponse or an answer of

“don’t know.”

likely to exhibit those behaviors, perceptions, and opinions that are consistent with habituation.

The data in tables 2 and 3 show that the number of episodes of use (i.e.,

cycles) is significantly and positively correlated with use of injectable AS

and with stacking. Likewise “heavy users” (those who reported using five

or more cycles) were more likely to assess their strength as being above

average, although the relationship approached but did not reach statistical

significance (p=.06) (table 4); 86 percent of the heavy users selected the

highest category for both their health and their strength (data not shown).

Adolescents who reported more than one episode of AS use were much

more apt to perceive their health as being excellent than were one-time

users (table 5). However, the multi-cycle users (i.e., more than one cycle)

were also more likely to have assessed their health as poor (12.5 percent vs.

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TABLE 2. Use of injectable AS

Number of Cycles Yes (%) No (%)

1 2.7 97.3

2-4 28.6 71.4

5 65.4 34.6

NOTE: p<.0001; was calculated from the number of adolescents in each cell). Percents

are presented for ease of interpretation.

TABLE 3. Stacking

Number of Cycles

1

2-4

5

Yes (%) No (%)

17.9 82.1

35.9 64.1

65.4 34.6

NOTE: p<.0001; =28.33.

TABLE 4. Strength perception

Number

of Cycles

Greater Than

Average

(%)

Average

(%)

Less Than

Average

(%)

1 48.9 46.2 2.6

2-4 59.1 32.2 6.5

5 61.2 22.4 7.1

NOTE: p=.06; 11.92.

0 percent), and roughly 73 percent of all users who perceived their health

as poor were heavy users.

When AS users were asked if they wanted to see the use of these drugs

stopped in competitive sports or if they themselves were willing to stop use

if everyone else did, the opinions of the heavy users were once again significantly different from other users and were consistent with addictive attitudes (tables 6 and 7). This group of heavy users is also dramatically more

203
TABLE 5. Health status perception

Number

of Cycles

Excellent Very Good Good

(%) (%) (%)

Fair

(%)

Poor

(%)

1 24.4 41.5 26.8 7.3 0

2-4 45.4 35.1 12.4 4.1 3.1

5 41.2 22.3 18.8 8.2 9.4

NOTE: p=.02; 18.22.

TABLE 6. Wish AS use to be stopped

Strongly

Number Agree

of Cycles (%)

1 12.5

2-4 21.4

5 14.1

NOTE: p<.0001; 7.64.

Agree

(%)

22.5

13.3

3.5

Strongly

Undecided Disagree Disagree

(%) (%) (%)

35.0 17.5 12.5

37.8 18.4 9.2

22.3 11.8 48.2

TABLE 7. Willingness to stop if all will

Number Definitely Probably Undecided Probably Definitely

of Cycles Yes (%) Yes (%) (%) No (%) No (%)

1 25.6 7.7 38.5 10.3 17.9

2-4 14.4 20.6 33.0 21.7 10.3

5 16.1 6.2 27.2 8.6 42.0

NOTE: p<.0001; 36.57.

likely to report intentions to continue use regardless of long-term health

consequences (table 8).

The data were examined to determine if the length of cycles (measured in

weeks) were associated with the number of cycles. As expected, the heavy

users of AS repotted longer cycles (table 9).

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TABLE 8. Health risk

Number Definitely Probably Undecided Probably Definitely

of Cycles Yes (%) Yes (%) (%) No (%) No (%)

Sterility*

1

2-4

5

50.0 30.0 17.5 2.5 0

29.9 32.0 23.7 10.3 4.1

24.4 4.9 19.5 12.2 39.0

Cancer**

1

2-4

5

35.0 32.5 22.5 10.0 0

34.0 33.0 17.5 12.4 3.1

26.2 15.5 16.7 11.9 29.8

Heart Attack***

1 35.9 33.3 23.1 5.1 .6

2-4 37.5 33.3 15.6 10.4 3.1

5 22.9 16.9 18.1 10.9 31.3

*p<.0001;

**p<.0001;

***p<.0001

TABLE 9. Length of cycles

Number 6 Weeks 6-9 Weeks 10-12 Weeks >13 Weeks

of Cycles (%) (%) (%) (%)

1 47.5

2-4 41.2

5 37.2

NOTE: p<.0001; 6.28.

45.0 7.5 0

36.1 18.6 4.1

19.2 15.4 28.2

Lastly, reported users and nonusers were asked to estimate the number of

their fellow senior students whom they think have used AS. In keeping

with the perceptions of users of other illicit drugs (Johnston et al. 1987),

AS users noted a significantly greater prevalence of use than did nonusers,

and these perceptions of peer AS use were significantly and positively related to the number of cycles the respondent reported using. That is, 74 percent of nonusers reported peer AS use in the 0-to-10 category, while only

37 percent of users did so. Once more, acknowledged heavy users stood

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TABLE 10. Peer-use perceptions

AS Users Nonusers

(%) (%)

How many students in your senior class

do you think have ever used AS?

0

1 to 10

10 to 20

21 to 40

over 40

5.8 25.25

31.3 48.75

22.8 16.07

10.7 6.41

29.5 3.52

NOTE: p<.0001;

apart and perceived a greater prevalence of use among their peers; while

29.4 percent of all users believed peer AS use was in the over-40 cateogry,

60.2 percent of the 5-or-more-cycle users perceived this level of peer use

(table 11). Whether this difference between heavy user, light user, and nonuser perceptions of peer use was a rationalization of use behavior on the

part of the heavy users or the result of insider knowledge was tested by

applying the survey’s approximate 7-percent-use rate to the total number of

male seniors enrolled at each high school. This estimate of expected users

at each school was then compared to the estimates given by the heavy

users at each school. Almost without exception, the nonusers’ estimate of

peer AS use was closer to the expected number calculated from the 7-percent-use rate than was the heavy users’. Heavy users often estimated more

than twice the expected number of users. This could suggest that, as the

intensity of AS use increases, users start to rationalize their use and engage

in denial and projection as a way to justify their behavior (Semeonoff

1976). On the other hand, the high estimates on the part of users could

indicate a significant underreporting of AS use in our survey. Alternatively,

the heavy users may tend to associate to a greater extent with other AS

users, a situation that could influence their perception of total use.

Finally the variables listed in tables 1 through 11 were cross-tabulated with

age at time of first use of AS. Not surprisingly, the perceptions of adolescents who initiated their AS use before they were 16 years old were virtually identical in direction and magnitude to those of the heavy user group

described above (data not displayed). More important, only 9.5 percent of

those students who reported initiating use at age 15 or less reported having

used only one cycle; 63 percent of these early starters reported having used

more than five cycles.

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TABLE 11. Peer-use perceptions

Number 0 l-10 11-20 21-40 40+

of Cycles (%) (%) (%) (%) (%)

1 9.8 43.8 19.5 14.6 7.3

2-4 6.1 38.4 30.3 12.1 13.1

>=5 3.6 14.5 14.5 7.2 60.2

NOTE: p<.0001;

DISCUSSION

Data from our national survey suggest that the admitted use of AS is currently much higher in our male adolescent population than was reported

over a decade ago (Corder et al. 1975). It is particularly significant that

approximately one-quarter of AS users in the study reported behaviors, perceptions, and opinions that are consistent with psychological dependence, in

terms of their unwillingness to stop use, their perceptions of risks and benefits of use, and their rationalization of use. The dismissal of health risks,

real or perceived, is consistent with other adolescent drug use behaviors as

well (Johnston et al. 1987). This hard core group was comprised primarily

of adolescents who initiated their AS use at a younger age and who reported a greater number of episodes of use. This is also consistent with outcome research that suggests that earlier and heavier substance users are

more likely to have problems associated with use (Brunswick and Boyle

1979; O’Donnell and Clayton 1979).

It is widely recognized that a drug’s chemical structure alone does not predict the addictive effect the substance will have on a person. Both individual needs and expectations, for example, have a powerful effect on behavior

following administration of a drug (Hansen 1988). These psychological

components especially are responsible for possible addictive outcomes. It is

interesting to note the similarities in attitudes of heavier AS users with

those of other drug-dependent young people, for whom the reinforcement

strength of positive affective outcomes is a powerful motivator to continue

use. For AS users, feeling good about oneself can result from increased

self-esteem and positive peer admiration that may be precipitated by improved appearance and performance. These outcomes are strong reinforcers,

as are the altered mood states that have often been reported with higher

levels of AS use, e.g., increased self-confidence, feelings of euphoria and of

well-being, sometimes to the point of true grandiosity with hypomania or

frank mania (Pope and Katz 1988). Such psychological effects may be as

strong in their own right as the physical benefits of use.

207
Several of the findings deserve additional comment. The use of injectable

AS indicates an increased level of commitment to this drug behavior for

two reasons: (1) few people other than addicts enjoy injections, and

(2) since insulin needles are not usually used for these injections, black

market, larger gauge needles (larger than 20 gauge) must be obtained. The

use of injectable AS could therefore lead to additional health problems associated with reusing or sharing needles, such as AIDS and hepatitis. One

case of AIDS in a bodybuilder who shared needles for AS injection has

already been noted (Sklarek et al. 1984). More recently, a Florida man’s

positive test for HlV was attributed to infected hypodermic needles used for

injection of AS (U.S. Olympic Committee 1988). On the other hand, the

orally active 17 -alkylated AS appears to have the greatest potential for

direct health risk due to their hepatotoxiclty and their ability to alter lipid

states (Haupt and Rovere 1984; Wilson 1988; Wright 1980; Yesalis et al.

1989).

The fact that AS users perceive their physical strength and health status to

be better than that of their nonuser peers does not bode well for intervention strategies. Feeling good and looking good can be psychologically

addicting and are obviously not incentives for terminating AS use. It

should be noted, however, that AS users were also twice as likely as nonusers to report their health as fair or poor (11.2 percent vs. 5.8 percent,

p<.0001). This is an inordinately high figure for this age group, four times

above the national average (U.S. Department of Health and Human Services

1987). It is not known whether this is a function of extremely high expectations of performance or of actual health problems; 70 percent of users

who reported using AS to treat injury reported their health as excellent.

The group with the lowest health perceptions were actually those who reported using AS because of peer pressure; 25 percent of these users reported their health as fair or poor. The potential for deleterious health effects

among adolescent AS users cannot be overlooked.

What can be done to deal with this problem? Clearly the data indicate that

at least a major intervention effort should be directed at early adolescents

(junior high students). Programs aiming at youth should determine whether

AS prevention is best included in general drug abuse prevention material or

should be addressed separately in health and gym classes. Parents, teachers,

coaches, and other school officials should also be included in educational

programs. They should be made aware of the signs and symptoms associated with recreational drug use in general, and with AS use in particular, e.g.,

secretive behavior, mood swings, sudden and dramatic weight gain (especially lean mass gain), edema, or gynecomastia (Crawshaw 1985). In addition,

unfamiliar pills and paraphernalia such as vials and needles in an adolescent’s possession should raise suspicion.

Moreover, all geographic areas should be included, as the study did not

detect, contrary to anecdotal reports, any significant differences in use rates

208
between rural and urban or sunbelt and nonsunbelt areas. The only significant difference was between large and small schools; a slightly higher

use rate was found among large schools. Surprisingly, the heaviest use, that

is, the greatest concentration of 5-or-more-cycle users, was found to be in

rural nonsunbelt schools, both large and small. It was also found that AS

use is not just a high school football problem but that it exists in wrestling,

track and field, baseball, and basketball as well (Buckley et al. 1988).

Interestingly, high school students participating in sports also use significantly more beer than do nonathletes (Swisher and Hu 1983). Further,

users who did not play sports reported using AS for appearance more often

than did sports players; sports participants reported using AS to improve

athletic performance most often (Buckley et al. 1988). This suggests that

prevention campaigns might have to employ different strategies to address

each motivation.

Given the apparent dramatic growth in the use of AS among young adults,

despite significant informational and drug-testing programs, it is difficult to

be optimistic (Cowart 1987; Yesalis and Friedl 1988). However, better educational efforts can be developed, as can other approaches that address the

appearance and performance needs of young people.

For this to be accomplished, further research is necessary. First, it will be

important to determine the extent of physical or psychological dependence

among adolescent AS users, and what, if any, other substances they are

using concurrently, e.g. alcohol, marijuana. Studies may begin to identify

those young people at greatest risk for developing dependence and ascertain

if there are factors similar to those seen in other addictions. It may be

possible to build on other drug abuse prevention strategies found to be

successful (Hansen et al. 1988), but modified specifically for AS-using

teens. Prevention should aim at students both before they begin use and

while they are at the experimental-use phase.

We cannot rely on drug testing alone as a deterrent. Announced drug testing at competitive events has had no documented effect on AS use rates

(Yesalis et al. 1988). Moreover, drug testing is currently facing legal challenges and is prohibitively expensive at the college and international level,

let alone at the high school level (Cowart 1988). In addition, our seeming

inability to control the import, distribution, and sale of cocaine does not

generate confidence in law enforcement as a potential solution to the problem. To be successful, enforcement of any sort, whether through regulations or testing, must involve schools, coaches, and parents to a much

greater degree.

CONCLUSION

The most important strategy, although idealistic, would be to place amateur

sports and physical appearance in a more reasonable perspective in society

209
in general, and in each school and community. Our societal fixation with

winning and with body image, often shown in parental as well as peer

pressures on teens and on teams, help motivate-or pressure-our children

(Yesalis and Friedl 1988). Their response in using anabolic-androgenic

steroids, often with implied if not tacit adult approval, should alarm but not

surprise us.

FOOTNOTES

1. This chapter was adapted from material contained in “Anabolic Steroid

Use: Indications of Habituation Among Adolescents” J Drug Education 19(2):103-116, 1989.

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AUTHORS

C.E. Yesalis, Sc.D.

Professor of Health Policy and Administration

and Exercise and Sport Science

J.R. Vicary, Ph.D.

Associate Professor of Health Education

W.E. Buckley, Ph.D.

Assistant Professor of Health Education

A.L. Streit, M.H.A.

The Pennsylvania State University

115 Henderson Building

University Park, PA 16802

David L. Katz, M.D.

Lecturer on Psychiatry

Harvard Medical School

McLean Hospital

Belmont, MA 02178

and

101 North Carolina Avenue, S.E., #203

Washington, DC 20003

J.E. Wright, Ph.D.

Sports Science Consultants

Northridge, CA 91324

214
Anabolic-Androgenic SteroidInduced Mental Status Changes

David L. Katz and Harrison G. Pope, Jr.

INTRODUCTION

Testosterone and its analogs, the anabolic-androgenic steroids, have been

widely used in athletics for over 35 years, and it appears that their use has

continued to escalate recently. Unfortunately, most of the research available

on these drugs has involved subjects being administered modest doses in

laboratory settings, rather than the large doses used illicitly by actual athletes in the field. As a result, there are limited data available on the medical and psychiatric effects of these drugs under the conditions that they are

most commonly used.

Despite the difficulty of studying illicit steroid use, it is critical to acquire

further data in this area. One reason for this is that steroid use appears to

be increasingly prevalent among young men in the United States. Pope and

colleagues (1988), in a mailed questionnaire survey, found that 1.7 percent

of male college seniors at three institutions reported using anabolic steroids.

Since only about a third of the questionnaires were returned in this study, it

is likely that this 1.7-percent figure represents an underestimate and, possibly, a substantial underestimate of the true prevalence of steroid use.

Buckley et al. (1988) reported that 6.6 percent of 12th-grade male students

had used anabolic steroids. Taylor (1987) estimated that 1 million Americans have used or are using anabolic steroids for physique enhancement.

Lombardo (this volume) and others have commented that anabolic steroids

have now become virtually mandatory for competition bodybuilders and line

positions in professional and college football. These drugs are even becoming increasingly popular among college, high school, and junior high school

students who simply want to look better. Indeed, in the survey of Pope

et al. (1988), nearly half of the respondents who admitted to steroid use

cited personal appearance as one of their reasons for using these drugs. In

short, anabolic steroid use appears to be a widespread phenomenon, and the

medical and psychiatric side effects of these drugs therefore have major

public health significance.

215
Although the medical side effects of anabolic steroids have been fairly

extensively documented (Haupt and Rovere 1984), there are few studies

available regarding the psychiatric effects of anabolic steroids. This is perhaps curious, given the large amount of common lore among bodybuilders

and athletes themselves, who have often considered changes of mood, temperament, and personality to be among the most characteristic effects of

these drugs.

PSYCHIATRIC EFFECTS OF STEROIDS

Among the few studies discussing psychiatric effects of steroids, there are

several that have investigated subjects receiving replacement doses of steroids for the treatment of hypogonadism. Among these studies, those of

Davidson et al. (1979), Salmimies et al. (1981), and O’Carroll and Bancroft

(1984) did not report significant mood changes in subjects receiving anabolic steroids as opposed to those receiving placebo. By contrast, similar

studies of hypogonadal males, such as those of Luisi and Franchi (1980)

Skakkebaek et al. (1981), and O’Carroll et al. (1985) did find significant

changes in certain aspects of mood and behavior, including increased

energy, aggressiveness, tenseness, and irritability, in subjects receiving steroids. These equivocal results, however, must be viewed with recognition of

the fact that they were conducted with physiologic doses of testosterone or

synthetic androgens and thus represent a degree of steroid exposure far

lower than that of eugonadal athletes using very large doses of anabolic

steroids.

In an extensive review, Haupt and Rovere (1984) summarized the findings

of 25 well-documented studies of athletes taking anabolic steroids. In this

review, it was noted that 32 percent of athletes who were studied for mood

changes did report such effects. Perhaps the most common of these was

increased aggressiveness. However, the population in these studies was taking an average of only 15 mg of methandrostenolone per day, a dose that is

much lower than that usually taken by athletes (Katz and Pope 1988). It

should be noted that the above studies involved male subjects or male athletes. In the one available study that exclusively examined women, Strauss

and colleagues (1985) found that 80 percent of 10 elite women athletes

reported increased aggressiveness in association with steroid exposure.

Turning to the psychiatric literature, a few reports, generally anecdotal, have

documented psychiatric changes from anabolic steroids. Wilson et al.

(1974) described an attempt to add methyltestosterone to imipramine in

treating five men suffering from unipolar depression. Four of the five men

developed paranoid delusions, agitation, and severe anxiety in association

with methyltestosterone treatment. These symptoms remitted promptly when

the drug was discontinued. In another report, Annitto and Layman (1980)

described a 17-year-old weightlifter who became psychotic with cognitive

dysfunction, paranoia, auditory hallucinations, and depression. However,

216
this individual did not develop psychotic symptoms until about 6 months

after his first steroid exposure, making it more difficult to be certain that

steroids were a necessary etiologic factor in his symptoms. In another

report, Freinhar and Alvarez (1985) described a 27-year-old bodybuilder

who developed irritability, decreased desire and need for sleep, increased

energy, racing thoughts, and continuous euphoria within 2 days of starting a

regimen of anabolic steroids. These symptoms disappeared when he discontinued use of steroids and reappeared when steroids were resumed.

AN ASSESSMENT OF PSYCHIATRIC SYMPTOMS AMONG

ATHLETE ANABOLIC STEROID USERS

We became interested in the effects of anabolic steroids when we encountered two patients at McLean Hospital in Belmont, MA, both of whom had

experienced prominent psychotic symptoms in association with steroid use.

These patients have been described previously (Pope and Katz 1988); both

had extensive neuroendocrine, medical, psychosocial, psychological, and laboratory workups that revealed no obvious etiology for their symptoms other

than their steroid exposure. Neither patient, for example, had ever suffered

any psychiatric disorder prior to steroid use. The first, a middle-aged white

male, had received methyltestosterone, 15 mg twice per day, from his local

physician for the treatment of impotence. Within 14 days of beginning

treatment, he developed major depression, associated with psychotic features

such as auditory and visual hallucinations and delusions of reference. The

other patient, a 22-year-old construction worker, had taken two courses,

each 8 weeks in length, of 15 mg orally per day of methandrostenolone.

Although he did not develop any acute psychotic symptoms with methandrostenolone exposure, he developed a syndrome of depression and anxiety following the termination of the second course. Then, some months later, he

abruptly developed psychotic symptoms including religious and paranoid

delusions, immediately after a brief re-exposure to steroids. Both patients

experienced a remission of their affective and psychotic symptoms after

withdrawal of anabolic steroids and a few weeks in the hospital. Now,

after 3 to 4 years followup, both patients have remained asymptomatic without psychiatric medication; both have remained abstinent from steroids.

On the basis of this experience, we decided to conduct an interview study

to assess the prevalence of psychiatric symptoms among athletes using anabolic steroids. To recruit these subjects, advertisements were sent to gymnasiums in the Boston, MA, and Santa Monica, CA, areas, offering $25 for

a confidential interview of anyone who had used at least one cycle (course)

of steroids. A total of 41 subjects (39 men and 2 women) were recruited.

They ranged in age from 17 to 51 years (mean 26.1 years). Their use of

steroids had ranged from a single cycle to as many as 30 cycles. The average lifetime exposure to steroids in the sample was 45.1±51.5 weeks.

(Total range of lifetime exposure was from 8 to 240 weeks.)

217
All subjects were interviewed, beginning with a history of anabolic steroids

used, including the names of drugs, dosages, and duration. Changes in

body weight and athletic ability (for example, changes in the bench press or

squat) were recorded for the times before and after steroid use. Medical

history on and off anabolic steroids was also included. The subjects were

next administered the Structured Clinical Interview for DSM-III-R (SCID)

(American Psychiatric Association 1980; Spitzer et al. 1987). This interview has been subjected to a large multicenter test-retest reliability study

(Spitzer et al., unpublished data) in which our center, the Laboratories for

Psychiatric Research at McLean Hospital, was involved.

In administering the SCID, the questions were asked two times. First, they

were posed for the period during which the subject was taking anabolic

steroids, referred to as the on-steroid period, and then they were asked

again for the period when the subjects were off steroids. The on-steroid

period was defined as the period when the subject was actually taking steroids and the 6-month period after steroid exposure (the latter to allow for

possible withdrawal effects, such as depression, following the discontinuation of steroid use). The frequency of various psychiatric syndromes in

the subjects during the on-steroid period was then compared with the

frequency of the same syndromes during the off-steroid period, thus using

each subject as his own control.

The findings, which have been presented in our earlier report (Pope and

Katz 1988), indicated that affective and psychotic symptoms were significantly more prevalent during the periods of anabolic steroid exposure than

during the off-steroid periods. Indeed, about one-third of the subjects

developed either a full manic syndrome or a syndrome closely approaching

DSM-III-R criteria for a manic syndrome (referred to as subthreshold

manic on the SCID). In addition, 5 of the 41 users were found to meet

DSM-III-R criteria (American Psychiatric Association 1987) for psychotic

symptoms, 4 experienced delusions of various types and another experienced

auditory hallucinations. In all cases, the psychotic symptoms disappeared

promptly when steroids were discontinued.

It should be noted that DSM-III-R contains an exclusion criterion that

states that a manic episode cannot be diagnosed as such if it is drug

induced. Thus, these athletes would be technically diagnosed as having an

organic affective syndrome under DSM-III-R. However, the symptoms

described by the athletes closely resembled those of naturally occurring

manic episodes, differing primarily in the fact that most subjects displayed a

particularly prominent component of aggressiveness and irritability. As a

result, the exclusion criterion has not been used for the purposes of the

diagnoses quoted above.

Some case descriptions will illustrate the severity of these symptoms and

how they affected the users. One young male bodybuilder bought an old

218
car for $25 and deliberately drove it into a tree at 35 miles per hour, while

a friend videotaped him. He reported feeling invincible. Another bodybuilder, who began using methadrostenolone, bought an expensive automobile that he could not afford. After stopping methandrostenolone, he

realized he could not make the car payments and sold the car. Some

months later, he began a new cycle of methandrostenolone and impulsively

bought another, more expensive car. A third subject on anabolic steroids

was driving down Santa Monica Boulevard and became incensed that the

driver in front of him had left his right turn signal flashing without making

the turn. At the next stoplight, he jumped out of his car, ran up to the

driver in front of him, screamed at him for leaving the signal on, and then

pulled a road sign out of the dirt and smashed it through the driver’s

window. As these examples vividly illustrate, affective and psychotic

symptoms, particularly increased aggressiveness and impaired judgment,

were significantly more common during and immediately after anabolic

steroid use than at all other times of the subjects’ lives.

THE EFFECT OF ANABOLIC STEROID USE ON PUBLIC HEALTH

What are the public health consequences of this phenomenon? It appears

that there may be a greater number of cases of anabolic-steroid-induced

psychiatric illness in this country than has been assumed previously, and

these effects may pose a danger not only for steroid users themselves, but

also for the public at large. The public danger posed by steroids is illustrated by our experience following publication of the initial study. We

began to receive telephone calls from lawyers and district attorneys around

the country, describing clients who had committed various violent crimes,

including several homicides, apparently while under the influence of anabolic steroids. We have now followed up on a number of these individuals

charged with criminal activity, and one case description follows.

Mr. X, a 23-year-old single male, began bodybuilding for personal pleasure

at age 18. Over the next 3 years, he became increasingly involved with the

gym and other bodybuilders and spent more and more of his spare time in

the weight room. At age 21, he decided to enter a local bodybuilding contest and, in preparation for this event, began a 5-month cycle of methandrostenolone, oxymetholone, and testosterone cypionate. He took the three

anabolic steroids simultaneously. After a brief lapse of 3 weeks, during

which he worked out while taking no drugs, he resumed the same drugs for

another 25 weeks. During the last 9 weeks of this second cycle, he

ingested oxymetholone, 250 mg per day, and testosterone cypionate,

800 mg per week.

A review of Mr. X’s history prior to steroid exposure revealed no evidence

of any affective disorder, psychotic illness or symptomatology, anxiety disorder, or eating disorder. Social drinking (two to eight beers over a weekend) was reported as having occurred during a few brief periods of his

219
years in high school. He also reported other times in which he and several

others would collectively consume about 1 g of cocaine intranasally (again,

only on weekends). He met no DSM-III-R criteria for antisocial personality disorder either prior to or after age 15. His history was negative for

violence, and he denied having ideation of committing violent acts. There

was no known history of psychiatric illness in his family. In fad, Mr. X’s

father was a minister, and Mr. X himself had joined the youth ministry and

was known as an energetic, active member. Mr. X had worked part time

throughout high school, helping with various construction jobs and, after

completing a 2-year trade school program, began full-time employment on a

construction crew. He was known to be very social, with many friends,

and was described as a caring, kindly, religious man.

During his anabolic steroid use, Mr. X noted severe mood changes. Where

he had been respectful and obedient prior to his cycles, he now had many

arguments with his parents and his temper was shortened incredibly. He

remembers “challenging others for no apparent reason,” He recalls, and

others confirm, that on more than one occasion he tore chunks of aluminum

out of cans with his teeth to intimidate bystanders. He also ripped telephones out of the wall on impulse. At this time, he met DSM-III-R criteria for a manic episode (except for the previously mentioned technicality

that his affective state was apparently caused by a known substance) with

decreased desire and need for sleep, explosive temper, extremely reckless

behaviors with a high potential for dangerous and undesirable consequences,

continued irritability, and grandiosity that reached delusional proportions.

While out one weekend evening with some friends during the second course

of anabolic steroids, the group stopped at a small market. While in the

parking lot, Mr. X, without known or observed provocation, suddenly

wrapped his arms around the telephone booth, tore it from its base, and

threw it across the lot. The group left immediately and soon thereafter saw

a hitchhiker on the road. Mr. X told the driver to stop. After the hitchhiker, a stranger to all present, entered the vehicle, Mr. X instructed the

driver to drive to a remote spot in the woods. Once there, without instigation, Mr. X beat the victim repeatedly, tied him between two poles,

smashed a wooden board over his back, and kicked him. The hitchhiker

was found dead the next morning.

Mr. X was arrested and imprisoned. Shortly after his incarceration and the

consequent abrupt discontinuation of his steroids, it was noted that he

returned to his previous mild-mannered personality. Reports of him during

19 months of imprisonment consistently described him as shy, cooperative,

quiet, and still upset and stunned by his behavior and the events of that

evening. Our interview with him and reports from his parents and others

are in agreement with this impression.

220
Given these dramatic psychiatric changes that apparently may be induced by

steroids in susceptible individuals, what is the mechanism by which steroids

produce these effects? One possibility is that anabolic steroids may have

corticosteroidlike properties. It has been well documented that some individuals taking corticosteroids have suffered psychiatric side effects, including

psychotic symptoms (Lewis and Smith 1983). Alin et al. (1984) observed

that athletes ingesting large doses of anabolic steroids had decreased levels

of adrenocorticotropic hormone. This observation would favor the hypothesis that anabolic steroids might mimic some of the biologic activities of

corticosteroids. However, the mechanism by which corticosteroids, in turn,

cause psychotic symptoms is still unknown.

CONCLUSION

In recent years, increased research has focused on neurochemical aspects of

aggression, particularly in animal models. Many substances and most

known neurotransmitter systems have been implicated at one time or

another. Eichelman (1987), in a review of the available literature, pointed

out that the noradrenergic, serotonergic, GABAergic, dopaminergic, and

acetylcholine systems have all been studied to some extent in this connection. In the review, the author suggests that research on the noradrenergic

and serotonergic systems shows particular consistency of findings between

animal and human studies. Svare (this volume) describes his research on

androgen-induced aggression, particularly in mice, and suggests that dihydrotestosterone and andrastenedione (an aromatized androgen) may act synergistically to promote aggression. In short, research in this area remains highly

preliminary, and much further work will be required to elucidate the psychiatric mechanism of action of anabolic-androgenic steroids.

A substantial number of studies have documented the medical side effects

of anabolic steroids. However, psychiatric side effects, though apparently

common, are little explored. Preliminary research findings indicate that

major affective symptoms, particularly increased aggression, irritability, and

impairment of judgment, and even psychotic symptoms may occur in some

individuals who use anabolic steroids. Such changes in mental status may

have profound implications both for the individual and for society at large.

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AUTHORS

David L. Katz, M.D.

Lecturer on Psychiatry

Harvard Medical School

McLean Hospital

Belmont, MA 02178

and

101 North Carolina Avenue, S.E., #203

Washington, DC 20003

Harrison G. Pope, Jr., M.D.

Associate Professor of Psychiatry

Harvard Medical School

Chief, Biological Psychiatry Laboratory

Laboratories for Psychiatric Research

McLean Hospital

Belmont, MA 02178

223
Anabolic Steroids and Behavior:

A Preclinical Research Prospectus

Bruce B. Svare

INTRODUCTION

Steroid hormones secreted by the testes have been long implicated in reproductive physiology and behavior, and a substantial body of literature exists

attesting to their prominent role in these functions (Svare 1983; Leshner

1978). The apparent abuse of these hormones by growing numbers of our

society may have derived, in part, from our understanding (and misunderstanding in some cases) of the reputed effects and presumed benefit of steroid hormones. The purpose of this chapter is twofold. First, I will review

some of the information derived from preclinical research on androgenic

steroids and behavior. In particular, androgenic modulation of aggression

will be considered. Second, because preclinical research utilizing appropriate animal models will be critical for understanding the causes and consequences of anabolic steroid abuse in humans, I will provide a preclinical

research prospectus for future work in this area.

Behavioral side effects of anabolic steroid abuse are little studied but apparently not uncommon. In their review of the literature, Haupt and Rovere

(1984) found that 34 percent (52 out of 155) of athletes studied in 13

investigations reported subjective side effects following anabolic steroid

administration. Roughly 30 percent repotted increased libido and aggressive

behavior (Johnson et al. 1972; Stamford and Moffatt 1974; Strauss et al.

1982). More serious side effects, including psychiatric syndromes, also

have been reported following anabolic steroid administration. In one recent

study (Pope and Katz 1988), interviews of 41 bodybuilders and football

players who had used steroids revealed that 22 percent displayed full affective syndrome and 12 percent displayed psychotic symptoms. Psychiatric

syndromes were absent when anabolic steroid use was terminated.

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THE ROLE OF ANABOLIC STEROIDS IN ACTIVATING

AGGRESSIVE BEHAVIOR

In the past year, two reports in the popular press (Chaikin 1988; Telander

and Noden 1989) have documented extreme behavioral alterations following

heavy anabolic steroid abuse in two football players (one in high school and

one in college). In both individuals, dramatic physiological and behavioral

effects were reported. In addition to focusing widespread national attention

on steroid abuse for the first time, the above articles have a common thread

running through them in that both individuals reported dramatic increases in

violence (e.g., “roid rages”) and general aggressive behavior.

Changes in behavior, especially those related to aggression, may be a desirable outcome of anabolic steroid abuse for many individuals. In the same

way in which anabolics are used by some athletes to promote strength and

performance, they also may be used to enhance combativeness, especially in

sports such as football where violence and aggressiveness are the norm. If

the above reports of elevated aggressive behavior following anabolic steroid

abuse are true, then they apparently confirm what we already know to be

the case in laboratory animals; that is, androgenic steroid hormones promote

aggressive behavior, and they do so with great effectiveness.

It is important to note that, although other hormones secreted from other

endocrine glands have at one time or another been implicated in aggression

(Svare 1983), androgenic steroid hormones, in particular testosterone, have

been repeatedly implicated in the aggressive behavior of a wide variety of

mammalian species (Svare 1983). Also, although testosterone is the steroid

hormone most involved in aggression, it is also involved in many other

behaviors including copulatory behavior, activity, food intake and body

weight gain, learning, and sensation and perception (table 1). The data in

these areas are no less persuasive than that in the area of steroid hormone

involvement in aggressive behavior (Leshner 1978; Svare and Kinsley

1987). In fact, much of it parallels what will be reviewed here for aggression. In this review, attention is focused on aggressive behavior because it

seems the most relevant in view of what is strongly suspected to be the

case in humans. Namely, that one important outcome of anabolic steroid

abuse in humans is the facilitation of aggressive behavior.

The two best known forms of testosterone-modulated aggressive behavior in

laboratory animals are intermale aggression and infanticide. Intermale

aggression is the fighting behavior exhibited by male rodents toward one

another in the establishment of dominance-subordinance hierarchies (Scott

1966). Mice have been most frequently studied in this context because they

display an easily quantifiable repertoire of aggressive responses that reliably

occur when two adult males confront each other for the first time. The

topography of this type of aggression in male mice consists of a series of

initial anogenital investigations, followed by episodes of rough grooming.

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TABLE 1. Androgenic steroid hormones are known to infIuence many

different behavioral responses in laboratory animals

Behavioral Response Representative Citations

Aggression Edwards (1968)

Svare et al. (1974)

Copulation Beach and Holz-Tucker (1949)

Phoenix et al. (1959)

Activity Richter (1922)

Broida and Svare (1984)

Food Intake and

Body Weight Gain

Bell and Zucker (1971)

Slob et al. (1973)

Learning Beatty and Beatty (1970)

Chambers (1976)

Parental Care Gandelman and Vom Saal (1975)

Samuels et al. (1981)

Sensation and Perception Wade and Zucker (1969)

Pietras and Moulton (1974)

After several minutes, the behavior escalates into attacks (severe biting and

wrestling), with retaliation by each upon the other. The attacks are usually

directed at the back and flank area of the male and will continue until one

animal assumes a submissive posture.

Infanticide is the killing behavior that male rodents exhibit when they encounter conspecific neonates for the first time. Because postpartum females

typically resume cycling once young are removed, it is thought that infanticidal behavior functions to enhance the reproductive success of strange

males that encroach upon the nest site of lactating females (Hrdy 1979).

Thus, it is to the competitive advantage of the male to eliminate the offspring of others. Mice have been studied most extensively for the biobehavioral factors governing this response. Killing of neonates by males

typically consists of a short (less than 2 minutes) attack latency followed by

bites to the head, neck, and flank area. Pups frequently are eaten after the

initial attack.

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Sex Differences

Male mice typically exhibit the aggressive behaviors outlined above, while

females do not, and this sex difference, like many others, is controlled by

the presence or absence of testosterone during certain critical developmental

periods. A model describing these events is referred to as the “organization-activation” model of sexually differentiated behavior. The effects of

perinatal hormone exposure during early critical periods of sexual differentiation are called “organizational” effects and are separate and distinct from

the so-called “activational” effects that are seen during pubertal and adult

life (Phoenix et al. 1959; Grady et al. 1965). Organizational effects of testosterone permanently bias an organism in a masculine fashion as well as

defeminize it. They promote aggressive behavior if they are present during

early life, while their absence results in an organism that is less responsive

to the aggression-activating effects of pubertal and adult testosterone.

In 1968, Edwards reported that male mice were relatively nonaggressive if

they were castrated during early life and then were given activational testosterone injections during adult life. He also showed that genetic female mice

would become as aggressive as normal males if they were given testosterone both during the early organizational period as well as during the activational period. This finding, as well as many others of a similar nature

(Svare and Gandelman 1975), led to the view that females were innately

less aggressive than males, primarily because they lacked the underlying

neural architecture that was provided by testosterone during early life.

Sex differences in neural architecture have been reported in rodents. For

example, male and female rats differ with respect to the size and number of

neurons in certain hypothalamic areas, most prominently in the preoptic area

(Gorski et al. 1978; Jacobson and Gorski 1981), as well as in the structure

of the dendrites in this brain area (Greenough et al. 1977; Raisman and

Field 1973). These sex differences can be reversed by neonatal castration

in the male and by neonatal testosterone administration in the female (Raisman and Field 1973). In spite of the above-mentioned morphological sex

differences, the current view concerning testosterone action on aggression is

that females are simply less sensitive to the aggression-promoting quality of

adult testosterone exposure, not that they are refractory or insensitive to the

steroid (Gandelman 1980).

It is the activational effects of testosterone and other steroid hormones that

are of greatest interest to those examining anabolic steroid abuse. Table 2

summarizes the four critical variables involved in modulating the activational effects of androgens on aggressive behavior. Briefly, they are sex; dose,

duration, and route of administration; type of androgen; and genotype. Each

of these factors is illustrated by research from my own as well as other

laboratories.

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TABLE 2. Primary variables modulating the aggression promoting quality

of androgenic steroids

Primary Variables Representative Citations

1. Sex (i.e., perinatal androgen environment) Edwards (1968)

Barkley and Goldman (1977)

Vom Saal et al. (1976a)

Svare and Gandelman (1975)

2. Dose, duration, and route of administration Svare et al. (1974)

Owen et al. (1974)

Svare (1979)

Vom Saal et al. (1976b)

3. Type of androgen (i.e., aromatizable or

reduced)

Luttge and Hall (1973a)

Svare (1979)

Finney and Ecpino (1976)

Luttge et al. (1974)

4. Genotype Selmanoff et al. (1977)

Luttge and Hall (1973b)

Svare et al. (1984)

Simon and Whalen (1986)

There is little doubt that pubertal and adult exposure to testosterone activates aggressive behavior in mice. In males, the development of intermale

aggressive behavior and infanticide corresponds to the increase in circulating

testosterone around the time of puberty (McKinney and Desjardins 1973;

Gandelman 1973). Castration in adulthood reduces these behaviors, while

testosterone administration restores it (Beeman 1947; Gandelman and vom

Saal 1975). The postcastration decline in intermale aggression is modulated

by previous fighting and copulatory experience; male mice with considerable

pregonadectomy fighting or sexual experience persist in their aggressive

behavior following castration much longer than naive animals (Schecter and

Gandelman 1981; Palmer et al. 1984).

Female mice also exhibit aggressive behaviors following adult (activational)

testosterone administration but generally are less sensitive to the steroid than

are males (Svare et al. 1974; Barkley and Goldman 1977). For example, in

one study (Barkley and Goldman 1977), female mice were subcutaneously

implanted with either a 0.3- or 10-mg silastic implant of testosterone.

Three weeks following exposure to the implant, the 10-mg testosterone implant produced levels of intermale aggression in the females almost identical

to that of normal males, while the 0.3-mg steroid implant, which restored

aggression in castrated males, produced little aggression. Testosterone also

is capable of promoting infanticidal behavior in female mice. For example,

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some studies show that virtually 100 percent of female mice will switch

from parenting to killing following the administration of daily injections of

500 μg testosterone propionate (TP) a day for 20 days (Samuels et al. 1981;

Svare et al. 1984).

Why females are less responsive to the aggression-activating effects of testosterone is not well understood. However, in addition to the aforementioned sex differences in the morphology of the brain (Raisman and Field

1973), the weaker response is probably related to qualitative and quantitative

differences between the sexes in steroid uptake and binding and in the distribution of steroid receptors in central neural tissue (Whitsett et al. 1972).

The dose of testosterone exposure is also a critical variable in the effectiveness of the steroid in activating aggressive behaviors, with high doses more

effective than low doses. For example, research conducted in my laboratory

a number of years ago documented dose-response relationships between testosterone exposure and the stimulation of intermale aggressive behavior and

infanticide in female mice. In one study (Svare et al. 1974), adult female

mice were injected daily for 42 days with 10, 200, or 500 μg TP, the

results showed that 20, 50, and 80 percent of the animals, respectively,

exhibited aggressive behavior. In another study (Svare 1979), adult female

mice were injected daily for 6 days with 125, 250, 500, or 1,000 μg of testosterone; the results showed that 5, 35, 35, and 75 percent of the animals,

respectively, exhibited infanticide. Similar findings in castrated male mice

have been reported by a number of different researchers (Brain 1983).

Dose, Duration, and Route of Administration

The effectiveness of testosterone in stimulating aggressive behavior also is

influenced by the duration of testosterone exposure. Simply put, the greater

the duration of testosterone exposure, the greater the probability that aggressive behavior appears. In work conducted in my laboratory (vom Saal

et al. 1976a; vom Saal et al. 1976b), castrated male mice were given daily

subcutaneous injections of TP (500 μg) and were assessed every other day

for 44 days for intermale aggressive behavior. Roughly 10 percent of the

animals fought following 4 injections, 50 percent exhibited aggression following 10 injections, and 100 percent fought following 40 injections. Similar findings for testosterone arousal of infanticide have been reported;

58 percent of females exhibit killing behavior following 5 injections of

500 μg TP, 79 percent exhibit the behavior following 15 injections, and

100 percent kill young following 25 injections (Samuels et al. 1981).

The route of testosterone administration also is an important variable in

determining the effectiveness of the steroid in activating aggressive behavior. Intracranial testosterone implants (10 μg TP) promoted intermale

aggressive behavior in almost 100 percent of castrated male mice within

about 8 days (Owen et al. 1974). In comparison, castrated males receiving

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daily subcutaneous injections (500 μg TP) of the steroid required 40 days of

treatment before 100 percent of animals fought (vom Saal et al. 1976a; vom

Saal et al. 1976b), while castrates receiving subcutaneously implanted silastic capsules of testosterone (0.3 mg) required 28 days of steroid exposure

before 100 percent of the animals exhibited aggressive behavior (Barkley

and Goldman 1977). Clearly, these differences can probably be overridden

by dosage variables. However, the important point is that the rapidity with

which testosterone gets to neural tissue determines the steroid’s behavioral

effectiveness in promoting aggression. It is appropriate to assume that testosterone works on neural tissue very rapidly upon intracranial administration, while absorption and uptake of the hormone into the brain following

subcutaneous injection or implant requires more time.

Data on intracranial testosterone administration is also helpful in understanding just where in the brain testosterone acts to promote aggressive behavior.

Intracranial septal and preoptic area testosterone implants promoted intermale aggressive behavior in castrated male mice, while implants in other

brain areas (amygdala, olfactory bulbs, cortex, and medial reticular formation) were ineffective (Owen et al. 1974). These findings support other

data in both mice and rats showing that these areas are rich in androgen

receptors and that they selectively concentrate testosterone (Luttge 1983).

Although similar experiments have not as yet been conducted for infanticide, it is strongly suspected that the same brain sites also will be found to

mediate testosterone’s effects on this form of aggressive behavior.

Type of Androgen

Another important variable determining the effectiveness of androgenic steroids in promoting aggressive behaviors is whether or not the steroids are of

the aromatizable or -reduced variety. In central tissue, testosterone is

metabolically converted to other steroids. On the one hand, testosterone can

be reduced enzymatically to dihydrotestosterone, while, on the other hand, it

can be aromatized to estrogen. Some reports suggest that aromatization of

testosterone to estrogen may be important for the stimulation of aggressive

behaviors. For example, in mice, estrogen and androstenedione (an aromatizable steroid), but not androstandione (a nonaromatizable androgen), have

been found to maintain fighting behavior in castrated males and to stimulate

infanticide in females (Luttge 1972; Luttge and Hall 1973a; Svare 1979).

Also, administration of antiandrogens does not block testosterone-maintained

intermale aggression (Clark and Nowell 1980), although systemic administration of aromatase blockers does attenuate testosterone-maintained fighting

(Bowden and Brain 1978). In contrast, other reports suggest that the reduction of testosterone to dihydrotestosterone may be more important for maintaining intermale aggressive behavior. This follows from findings showing

that dihydrotestosterone alone can maintain intermale aggression and infanticide (Schecter et al. 1981; Svare 1979) and that antiestrogens are ineffective

in suppressing testosterone-maintained intermale fighting behavior (Simon

230
et al. 1981). Several reports indicate that the combined treatment of dihydrotestosterone and estrogen is effective in stimulating intern-tale aggression and infanticide (Finney and Erpino 1976; Svare 1979), suggesting of

course that both aromatization and reduction may be important for maintaining aggressive behaviors in mice.

Genotype

A variable of major significance in determining testosterone’s effectiveness

in promoting aggressive behavior is genotype, and there are many research

reports attesting to this fact. For example, castrated CF-1 male mice are

responsive to the intermale aggression-promoting properties of either androgens or estrogens, castrated CFW males are sensitive only to estrogenic hormones, and CD-l males fight only in response to relatively high doses of

androgens and are insensitive to estrogens (Simon and Whalen 1986). Also,

with respect to intermale aggression, castrated C57BL/10 males are responsive to both hyper- and hypophysiological silastic implants of testosterone;

castrated DBA/2 males show reduced aggression in response to a hypophysiological implant and increased aggression scores to hyperphysiological

implants (Selmanoff et al. 1977). Finally, male and female mice of the

C57BL/6 and DBA/2 strains are differentially sensitive to the infanticidepromoting property of adult testosterone exposure. In contrast to DBA/2

animals, more C57BL/6 animals respond to the hormone by exhibiting killing behavior, and the latter require fewer testosterone injections to exhibit

infanticide in comparison to the former (Svare et al. 1984). Strain differences in the morphology of androgen-sensitive hypothalamic brain areas

have been detected (Robinson et al. 1985), suggesting that genetic variation

in the propensity to respond to the aggression-activating effects of testosterone may be neural in origin.

Other than the few anecdotal reports of anabolic steroid promotion of

human rage and violence, systematic research examining androgenic steroid

hormone involvement in human aggressive behavior is very limited and generally only correlative in nature. Studying normal male volunteers, Persky

et al. (1971) reported a positive relationship between circulating levels of

testosterone and measures of hostility, aggressive behavior, and social dominance, but Brown and Davis (1975) showed no relationship. In a widely

cited study, Kreuz and Rose (1972) found that prisoners with histories of

violent crime during adolescence tended to have significantly higher levels

of plasma testosterone compared to prisoners without the same adolescent

histories. In another widely cited study, Ehrenkranz et al. (1974) measured

circulating testosterone levels in prison convicts separated into three different categories. One group consisted of men that were socially dominant

(they had asserted themselves into prestigious jobs in the inmate hierarchy)

but nonaggressive, a second group consisted of prisoners that were chronically aggressive (continued acts of aggression and threats while in prison),

and a third group consisted of convicts that were neither dominant nor

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aggressive. The socially dominant but unaggressive group and the chronically aggressive group, although not differing from each other in plasma testosterone levels, exhibited significantly higher levels of the hormone than

did the nondominant, unaggressive group. Finally, castrated sex criminals

with records of violent are are less likely to commit these acts in the

future (LeMaire 1956), and antiandrogen treatment, e.g., medroxyprogesterone, of aggressive individuals and sex offenders is known to make these

individuals placid (Bell 1978; Money 1980; Laschet 1972; Blumer and

Migeon 1975; O’Connor and Baker 1983).

The foregoing selective survey indicates that androgenic steroids promote

species-typical aggression in laboratory animals. The survey also suggests

that some forms of human dominating and aggressive behaviors also may

be modulated by steroid hormones, though more research is clearly needed

to strengthen this statement. The important question at this point is how

might this information be useful for understanding the causes and consequences of anabolic steroid abuse in humans? A preclinical research agenda

for this growing problem clearly emerges from the data reviewed here as

well as from other findings in the field of behavioral endocrinology. A

prospectus for future research is elucidated in the remainder of this chapter

(table 3).

TABLE 3. Key questions for future preclinical research on the causes and

consequences of anabolic steroid abuse

Question Test

1. Do the commonly abused anabolic Animal models of steroid-facilitated

steroids promote aggressive behavior aggression (and other androgen-

(and other androgen-dependent behaviors) dependent behaviors).

in laboratory animals?

2. Do the commonly abused anaolic

steroids produce physical dependence?

Signs of physical dependence such

as withdrawal symptoms (the abstinence syndrome) following the termination of chronic treatment;

reversal of withdrawal symptoms

following steroid administration.

3. Do the commonly abused anabolic

steroids produce behavioral

dependence?

Signs of behavioral dependence

such as the production of pleasurable “subjective” states, with such

states having the potential to control

behavior.

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PROSPECTUS FOR FUTURE RESEARCH

First, we need to know whether or not and to what extent the commonly

abused anabolic steroids do in fact promote aggressive behavior as well as

other androgen-dependent behaviors. This can easily be done by exploring

the effects of anabolic steroids in the context of the aforementioned animal

models of species-typical aggressive behaviors.

An important question pertaining to the recommendation raised above is

why anabolic steroids have not already been extensively studied in laboratory animals for their potential behavioral effects (Svare 1988)? In 1983, I

edited what many considered to be an authoritative volume summarizing the

current state of knowledge on hormones and aggressive behavior. The

book, entitled Hormones and Aggressive Behavior, included an exhaustive

analysis of hormone involvement in the aggressive behavior of many vertebrate and invertebrate species from humans to insects. However, an analysis of the contents of the book reveals that it does not contain a single

reference to the aggression-promoting effects of anabolic steroids in either

humans or subhumans. This was not a case of oversight or omission; there

simply was no data base to draw upon. The fact that we continue to know

so little about anabolic steroids and aggressive behavior is partly a reflection

of the relative newness of the problem of anabolic steroid abuse. However,

at least two other factors have contributed to our relative ignorance in this

area. First, the original goal in making anabolics was to promote the

tissue-building effects of testosterone without its androgenic (masculinizing)

qualities. Thus, drug companies that created anabolic steroids probably

have focused primarily upon morphological changes in their screening and

testing procedures and have given scant attention to potential behavioral

effects. Second, basic researchers considering behavioral endpoints generally have not been interested in studying the effects of the synthetic (anabolic) versions of testosterone but rather have focused their interests on the

so-called naturally produced (masculinizing) androgens. In view of the fact

that anabolics were created so as to provide a hormone that would promote

the tissue-building effects of testosterone without its masculinizing (androgenic) qualities, it makes sense then that behavioral endocrinologists were

simply not interested in studying hormones that were thought to be devoid

of behavioral (masculinizing) properties to begin with.

Significantly, we now know that none of the anabolic steroids available are

completely free of androgenic (masculinizing) properties (Gilman et al.

1985), and abusers routinely self-administer extremely large doses of the

hormone (or hormones) for long periods of time (Katz and Pope 1988;

Haupt and Rovere 1984). Thus, increasingly it appears that anabolicsteroid-induced behavioral change, especially alteration in aggression and

violence, may be one of the more reliable outcomes of this form of drug

abuse (Katz and Pope 1988).

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Second, we need to know more about the similarity (or lack thereof) of

anabolic steroids to other drugs of abuse, in terms of physical dependence.

It is clear that anabolic steroids can produce a form of psychological dependence in that abusers like their appearance much in the same way that an

anorexic likes his or her appearance. But, we must also ask whether or not

anabolic steroid abusers continue to use these hormones because they also

enjoy the physiological and psychological effects produced by their use, in

the same way in which an addict craves the pleasurable effects of heroin or

cocaine.

Preclinical research with laboratory animals is critical to answering the

above question. First, we must know whether anabolic steroids (indeed,

steroids in general) produce physical dependence. That is, when injected

acutely, as well as chronically, do anabolics produce predictable changes in

physiological and behavioral parameters typically seen with other drugs of

abuse? For example, changes in activity, sleep cycles, circadian rhythms,

meal patterns, core temperature changes, stereotypies, reflexive changes, etc.

Second, when anabolics are removed, do they produce an abstinence syndrome in animals in which distinct behavioral changes are detected? Is it

also possible to produce reversal of the abstinence syndrome by readministration of anabolics? These questions are not difficult ones to answer, since

behavioral pharmacologists have already laid the groundwork in this area.

AU one needs to do is to employ anabolic steroids in some of the commonly used screening tests that scientists typically have employed in the past

for other drugs of abuse.

A more difficult but potentially fruitful research question concerns whether

or not anabolic steroids produce subjective states in the same way that other

drugs of abuse do. Clinical work and anecdotal reports indicate that it is

virtually impossible to conduct double-blind studies with anabolic steroids,

since human subjects report that they know when they are and when they

are not being administered the steroid (Haupt and Rovere 1984). This suggests that anabolic steroids are capable of producing a subjectively discriminable state in human beings.

The problem of subjective states is one that strikes to the very heart of the

field of behavioral endocrinology. Scientists have for years speculated as to

whether or not hormones produced states that could in fact serve as internal

cues for the organism. Determining the presence of a subjective state cannot be done by using the techniques typically employed by behavioral endocrinologists. However, it can be elucidated with the aid of an approach

commonly used by the behavioral pharmacologist. The approach is a very

simple one. If a substance produces a subjective state, then that state must

be regarded as a stimulus. The stimulus, under appropriate conditions,

should then serve to control a given behavior. To be specific, the stimulus

could also serve a discriminative function, and, theoretically, it could be

either negative or positive in its ultimate effects upon behavior. This

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approach to the assessment of the stimulus properties of pharmacological

agents in general and drugs of abuse in particular has been used very successfully by workers in the field of behavioral pharmacology (Thompson

and Shuster 1964; Phillips and LePiane 1982).

Research in my laboratory has started to use the above approach to examine

the extent to which steroid hormones can produce negative and positive subjective states that can control behavior. In one series of studies (Miele

et al. 1988) we utilized the steroid hormone estradiol benzoate as an

unconditioned stimulus in a conditioned taste aversion paradigm. Simply

put, conditioned taste aversion learning involves coupling a novel highly

preferred taste such as sugar water with a stimulus that is unpleasant to an

organism. Typically, an intraperitoneal injection of lithium chloride is used

because it temporarily makes animals ill, but any drug can be used to

examine whether or not it too has negative consequences for the animal.

Following this pairing, animals usually avoid the formerly preferred substance because it has been associated with the negative effects of the lithium chloride.

We conducted experiments with mice in which we paired saccharin exposure with an injection of very low doses of estradiol benzoate. The doses

of the hormones were ones that produced activation of hormone-dependent

behavior in mice such as female sexual responding (Iordosis reflex). Even

though there were no observable signs of illness in the animals, they avoided the saccharin on subsequent days and instead drank mostly water when

given a two-bottle preference test with saccharin in one bottle and water in

the other. The higher the dose of estradiol benzoate, the greater the aversion, and males seemed to be more affected than females. The important

result of this work is that the steroid apparently produced a negative subjective state that, to our knowledge, first demonstrated the use of a steroid hormone as an unconditioned stimulus. It is significant to note that other

drugs of abuse are effective unconditioned stimuli when used in a conditioned taste aversion paradigm (Horowitz and Whitney 1975).

Of equal interest is the possibility that steroid hormones also may have

pleasurable (rewarding) consequences for the organism. Thus, organisms

may seek out situations that are associated with the hormone or may actively work to gain access to administration of the hormone. Clearly, a finding

like this would have dramatic implications for classification of steroid hormones as potential drugs of abuse.

Although the investigation is in the preliminary stages at the present time,

we have started to explore this possibility in our laboratory by using an

apparatus called a place-preference chamber. The chamber has a middle or

start area and two sides that can be entered through small doors. One side

is white, while the other side is black. Mice are placed in either the white

or black side on the first day approximately 90 minutes following a single

235
subcutaneous injection of a steroid hormone. This corresponds to the time

at which the steroid is probably peaking in plasma. The door is shut, and

the animal remains there for 30 minutes. The next day the animal is placed

in the center portion of the box, both doors are opened, and the animal can

freely explore either side for 30 minutes. The amount of time spent on

either side is automatically recorded. If the animal prefers the “state” of

steroid hormone exposure and associates that state with contextual cues

(white or black), then it should spend most of its time on the side that it

had been exposed to when it received the steroid hormone. Place-preference tests have been successfully used by behavioral pharmacologists to

explore the potential hedonic value of drugs of abuse (Phillips and LePiane

1982).

Finally, utilization of operant conditioning techniques is another obvious

approach to examining the potential rewarding effects of anabolic steroids.

Operant conditioning has been used with great success in establishing that

certain drugs of abuse have powerful pleasurable consequences for the

organism (Thompson and Schuster 1964). In this situation, an animal must

depress a bar to receive an injection of a drug. If the drug in question is

reinforcing, then the animal should readily learn to depress the bar to

receive the drug. We have not begun pilot work in this area at present

because of anticipated problems associated with steroid solubility and with

temporal delay between response and reinforcer. For example, injected steroids take time before absorption, circulation, and behavioral and physiological effects, and it is well known from the operant conditioning literature

that delays between response and reinforcer cannot be too long or learning

will not proceed. For these reasons, it would seem that the aforementioned

classical-conditioning-oriented place-preference tests would be more

productive.

CONCLUSION

Anabolic steroid hormone abuse is a growing problem for increasing segments of our society. Such abuse is associated with adverse effects upon

behavior including increased incidence of violence, aggression, and psychiatric syndromes such as psychotic reactions. Androgenic steroid hormones

are known to promote aggressive behavior in laboratory animals, but systematic studies examining the aggression-promoting quality of anabolic steroid hormones have not been conducted. Moreover, the extent to which

anabolic steroids are similar to other common drugs of abuse has not been

explored. In particular, research examining signs of physical and psychological dependence as well as the hedonic (rewarding) value of these substances has not been conducted. Therefore, preclinical research using

animal models will be necessary for determining the causes and consequences of anabolic steroids abuse in humans.

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AUTHOR

Bruce Svare, Ph.D.

Professor of Psychology

State University of New York at Albany

1400 Washington Avenue

Albany, NY 12222

241
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74 NEUROBIOLOGY OF BEHAVIORAL CONTROL IN DRUG ABUSE.

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80 NEEDLE SHARING AMONG INTRAVENOUS DRUG ABUSERS:

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86 COMPULSORY TREATMENT OF DRUG ABUSE: RESEARCH AND

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88 MECHANISMS OF COCAINE ABUSE AND TOXICITY. Doris H.

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90 PROBLEMS OF DRUG DEPENDENCE, 1988. PROCEEDINGS OF

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PROBLEMS OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

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91 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION

DATA. Steven W. Gost, Ph.D., and J. Michael Walsh, Ph.D., eds.

GPO Stock #017-024-01384-6 $10 NTIS PB #90-147257/AS $39

92 TESTING FOR ABUSE LIABILITY OF DRUGS IN HUMANS.

Marian W. Fischman, Ph.D., and Nancy K. Mello, Ph.D., eds.

GPO Stock #017-024-01379-0 $12 NTIS PB #90-148933/AS $45

93 AIDS AND INTRAVENOUS DRUG USE: FUTURE DIRECTIONS FOR

COMMUNITY-BASED PREVENTION RESEARCH. C.G. Leukefeld, D.S.W.;

R.J. Battjes, D.S.W.; and Z. Amsel, Ph.D., eds.

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94 PHARMACOLOGY AND TOXICOLOGY OF AMPHETAMINE AND

RELATED DESIGNER DRUGS. Khursheed Asghar, Ph.D., and Errol

De Sousa, Ph.D., eds.

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IN PRESS:

95 PROBLEMS OF DRUG DEPENDENCE, 1989. PROCEEDINGS OF

THE 51ST ANNUAL SCIENTIFIC MEETING. THE COMMITTEE ON

PROBLEMS OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

96 DRUGS OF ABUSE: CHEMISTRY, PHARMACOLOGY, IMMUNOLOGY, AND AIDS. Phuong Thi Kim Pham, Ph.D., and Kenner Rice, Ph.D.,

eds.

97 NEUROBIOLOGY OF DRUG ABUSE: LEARNING AND MEMORY.

Lynda Erinoff, ed.

98 THE COLLECTION AND INTERPRETATION OF DATA FROM

HIDDEN POPULATIONS. Elizabeth Y. Lambert, M.S., ed.

248
99 RESEARCH FINDINGS ON SMOKING OF ABUSED SUBSTANCES.

C. Nora Chiang, Ph.D., and Richard L. Hawks, Ph.D., eds.

100 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION

DATA. VOL. II. Steven W. Gost, Ph.D., and J. Michael Walsh, Ph.D., eds.

101 RESIDUAL EFFECTS OF ABUSED DRUGS ON BEHAVIOR. John W.

Spencer, Ph.D., and John J. Boren, Ph.D., eds.

102 ANABOLIC STEROID ABUSE. Geraline C. Lin, Ph.D., Lynda Erinoff,

Ph.D., eds.

103 DRUGS AND VIOLENCE: CAUSES, CORRELATES, AND CONSEQUENCES. Mario De La Rosa, Ph.D.; Elizabeth Y. Lambert, M.S.; and

Bernard Gropper, Ph.D., eds.

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US GOVERNMENT PRINTING OFFICE 1990 - 2 8 6 - 0 0 0 / 2 1 2 4 0
DHHS Publication No. (ADM) 91-1720

Alcohol, Drug Abuse. and Mental Health Administration

Printed 1990