Ergogenic Substances: A Monograph

Ergogenic Substances Independent Study Course 16.1.5 Peter A. Huijbregts, PT, MSc, MHSc, DPT, OCS, MTC, CSCS, FAAOMPT, FCAMT University of St Augustine for Health Sciences St Augustine, Florida The Journal of Manual and Manipulative Therapy Forest Grove, Oregon Shelbourne Physiotherapy Clinic Victoria, British Columbia Dynamic Physical Therapy Cadillac, Michigan

Ellen Pong, BA, MOT, DPT University of St Augustine for Health Sciences St Augustine, Florida NovaCare Rehabilitation Milton, Florida

pharmacology

An Independent Study Course Designed for Individual Continuing Education

Pharmacology Mary Ann Wilmarth, PT, DPT, MS, OCS, MTC, Cert MDT—Editor May 2006 Dear Colleague, I am pleased to welcome you to Ergogenic Substances by Peter A. Huijbregts, PT, MSc, MHSc, DPT, OCS, MTC, CSCS, FAAOMPT, FCAMT and Ellen Pong, BA, MOT, DPT. This is the fifth monograph in the Orthopaedic Section Independent Study Course series 16.1, entitled Pharmacology. Dr Peter Huijbregts received his diploma in physical therapy from Hogeschool Eindhoven in The Netherlands, his master of science in manual therapy from Vrije Universiteit Brussel in Belgium, his master of health science in physical therapy from the University of Indianapolis, and his doctor of physical therapy from the University of St Augustine for Health Sciences. He is a physiotherapy consultant for Shelbourne Physiotherapy in Victoria, British Columbia, an educational consultant for Dynamic Physical Therapy in Cadillac, Michigan, as well as an assistant professor of online education for the University of St Augustine. In addition, Dr Huijbregts is the editor-in-chief for the Journal of Manual and Manipulative Therapy, holds numerous certifications, and has published extensively. Dr Ellen Pong received her master’s in occupational therapy as well as her doctor of physical therapy from the University of St Augustine for Health Sciences. In addition, she has a bachelor of arts in journalism and English from Louisiana College. Dr Pong is an online instructor of pharmacology for the University of St Augustine, and is a staff physical and occupational therapist for Novacare in Milton, Florida. Her clinical experience is extensive and covers literally all areas of the body. We are very pleased to have the expertise from both Dr Huijbregts and Dr Pong for this monograph. This monograph describes the mechanism of action, effects on performance, medical indications, side effects, and testing and regulation for the following: anabolic-androgenic steroids, androstenedione, human growth hormone, creatine, beta-hydroxy-beta-methylbutyrate, alcohol, caffeine, amphetamines, and erythropoietin. The information is very straightforward and the case studies give a good indication of how this can be applied in the clinic. The authors touch on the ethical and legal implications for the physical therapist when dealing with clients and any of the above-mentioned ergogenic substances. This is not always a clear situation for physical therapists, but it is something that needs to be addressed. I believe that the detailed information in this monograph will give the reader greater insight into the complexity of ergogenic substances and the delicate balance that is necessary when dealing with clients and this pharmacological topic. Best regards,

Mary Ann Wilmarth, PT, DPT, MS, OCS, MTC, Cert MDT Editor

2920 East Avenue South, Suite 200 | La Crosse, WI 54601 Office 608-788-3982 | Toll Free 877-766-3452 | Fax 608-788-3965

TABLE OF CONTENTS LEARNING OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 ANABOLIC-ANDROGENIC STEROIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 ANDROSTENEDIONE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 HUMAN GROWTH HORMONE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 CREATINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 BETA-HYDROXY-BETA-METHYLBUTYRATE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 ALCOHOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 CAFFEINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 AMPHETAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 ERYTHROPOIETIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 ETHICAL AND LEGAL CONSIDERATIONS FOR THE PHYSICAL THERAPIST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 CASE STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Case Study 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Subjective information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Objective findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Guide to Physical Therapist Practice diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Case Study 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Subjective information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Objective findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Physical therapy diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Physical therapy intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Reevaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Guide to Physical Therapist Practice diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 REVIEW QUESTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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Opinions expressed by the authors are their own and do not necessarily reflect the views of the Orthopaedic Section. The publishers have made every effort to trace the copyright holders for borrowed material. If we have inadvertently overlooked any, we would be willing to correct the situation at the first opportunity. © 2006, Orthopaedic Section, APTA, Inc. Course content is not intended for use by participants outside the scope of their license or regulations. Subsequent use of management is physical therapy only when performed by a PT or a PTA in accordance with Association policies, positions, guidelines, standards, and ethical principals and standards.

Ergogenic Substances

um used unspecified stimulants to combat fatigue, as did medieval knights. To increase their strength and aggression, the berserkers of Norse mythology used a drug derived from mushrooms containing muscarine. For centuries, Andean Indians have chewed coca leaves to increase endurance and stave off mountain sickness.3 In more recent times, Thomas Hicks won the 1904 St Louis Olympic marathon after openly being administered brandy and strychnine as performance-enhancing stimulants several times during the race. In the 1960 Olympics, cyclist Knut Jensen of Denmark collapsed and died during competition as a result of amphetamine use. In the 1967 Tour de France, Tom Simpson of the United Kingdom died of similar causes, and his became the first doping-related death to be televised. In the 1980s, multiple young Dutch professional cyclists died from cardiovascular events linked to erythropoietin use. Anabolic steroid use has become endemic at the Olympics from 1964 onward.3,4 Due to the suspected prevalence of its use in the absence of a validated test for its detection, the 1996 Atlanta Olympics were dubbed the “Growth Hormone Games.”5 Use of ergogenic substances is not limited to high-level athletes nor is it limited to adults. The 1991 National Household Survey on Drug Abuse indicated that over 1 million people in the United States used anabolic steroids, with a lifetime use of 0.9% in men and 0.1% in women. More current estimates have indicated there are as many as 3 million steroid users in the United States. The studies also indicated that 2.7% to 2.9% of young American adults have taken anabolic steroids at least once in their lives. Among adolescents in the United States, 3% to 12% of boys and 0.5% to 2% of girls are using anabolic steroids.6 In a 1998 survey of 224 male high school students, 5% reported the current or past use of human growth hormone.7 In a more recent survey of 1515 high school students, 2.2% admitted to using the then legal but now illicit steroid precursor androstenedione and 7.6% reported using amphetamines.8 Some ergogenic substances are controlled substances, meaning they can only be obtained legally with a physician’s prescription. All controlled and some uncontrolled substances with an ergogenic potential are considered doping and are banned by various sporting organizations. The World Anti-Doping Agency publishes a yearly updated prohibited list9 that includes prohibited methods and prohibited classes of substances (Table 1). However, not all substances used for performanceenhancing purposes are on this list. Creatine and betahydroxy-beta-methylbutyrate are freely available overthe-counter nutritional supplements. Nutritional supplements are regulated in the United States under the 1994 Dietary Supplement Health and Education Act. This act defined supplements as distinct from drugs and food additives, and limited federal control over marketing claims, purity standards, and content labeling.7 In 1996, about half of the United States population reported the use of some supplements. Supple-

Peter A. Huijbregts, PT, MSc, MHSc, DPT, OCS, MTC, CSCS, FAAOMPT, FCAMT University of St Augustine for Health Sciences St Augustine, Fla The Journal of Manual and Manipulative Therapy Forest Grove, Ore Shelbourne Physiotherapy Clinic Victoria, British Columbia Dynamic Physical Therapy Cadillac, Mich Ellen Pong, BA, MOT, DPT University of St Augustine for Health Sciences St Augustine, Fla NovaCare Rehabilitation Milton, Fla LEARNING OBJECTIVES Upon completion of this monograph, the course participant will be able to discuss the following with respect to ergogenic substances: 1. Data on prevalence of use. 2. Mechanisms of action. 3. Effects on performance. 4. Medical indications. 5. Side effects. 6. Testing procedures. 7. Regulations relating to use. 8. Ethical and legal considerations as related to physical therapy practice and patients using or suspected of using the substances discussed. INTRODUCTION Ergogenic substances are products used with the aim of improving athletic performance. One might associate the use of these products solely with high-level amateur or professional sports. Recent allegations of erythropoietin use by 7-time Tour de France winner Lance Armstrong may come to mind.1 The sudden withdrawal of 27 members of the Chinese team before the 2000 Sydney Olympics raised suspicions of a state-run doping program similar to the one uncovered in the former communist German Democratic Republic.2 Another highprofile case involved the 1988 Seoul Olympics 100meter winner, Ben Johnson, who was stripped of his title after testing positive for the anabolic steroid stanozolol.2 However, the use of ergogenic substances is by no means a recent phenomenon. In the ancient Olympic games, athletes experimented with special diets to enhance performance. Charmis of Sparta won the 200-yard race in 668 BC and credited his performance to a diet of dried figs. The champion middle-distance runner Dromeus of Stymphalos ate a diet consisting of only meat. Gladiators in the Roman Colise1

Table 1. 2005 World Anti-Doping Agency Prohibited List

74% of power lifters, boxers, weightlifters, and track and field athletes reporting the use of this nutritional supplement.11 A survey of 1103 middle and high school athletes (10 to 18 years) reported 5.6% using creatine with users from grades 6 to 12.12 With such high prevalence for the use of both illegal and legal ergogenic substances, the physical therapist will at some time provide services to patients using these substances for performance-enhancing or possibly medical purposes. As with any pharmacological substance, the therapist needs to be aware of intended and adverse effects on the patient and the possible interaction of these substances with the physical therapy interventions provided. As many of the substances discussed in this monograph are illegal to use, except on prescription by a physician for medical purposes, and are banned by sporting organizations, the authors also have to discuss legal and ethical implications. The authors of this monograph do not intend to provide a comprehensive discussion of all substances with ergogenic potential but do hope to cover the most common of these products.

Prohibited classes of substances Anabolic agents • Anabolic-androgenic steroids • Other anabolic agents Hormones and related substances • Erythropoietin • Growth hormone, insulin-like growth factor-I, mechano growth factors • Gonadotrophins • Insulin • Corticotrophins β2-agonists Anti-estrogenic agents Diuretics and other masking agents Prohibited methods Enhancement of oxygen transfer • Blood doping • Artificial enhancement of oxygen uptake, transport, or delivery Tampering with samples (intravenous infusions, catheterization, urine substitution)

ANABOLIC-ANDROGENIC STEROIDS Mechanism of Action The main male sexual hormone is called testosterone. From birth until puberty, plasma testosterone concentration is up to 2 nmol/L. In boys, from about the age of 10, testosterone production increases until, after puberty, plasma testosterone levels reach approximately 0.6 mg/dL. In postpubertal women, plasma testosterone levels are about 0.03 mg/dL. Ninety-five percent of the testosterone circulating in the blood is bound to proteins, mainly to sex–hormone-binding globulin and to a lesser extent to albumin. Only 2% to 3% circulates in the form of free testosterone.13,14 Testosterone production in men is about 8 mg/day (with a range of 4 to 10 mg/day15), of which the Leydig cells of the testes produce 90% to 95%. The remainder is produced by the adrenal cortex, which is the only source of testosterone in women.13 Testosterone is a so-called C19 steroid hormone. In the human body, these steroid hormones are derived from cholesterol. The testosterone precursor dehydroandrostenedione (DHEA) is converted to the immediate precursor of testosterone (ie, androstenedione) by the action of the enzyme 3β-hydroxysteroid dehydrogenase. The enzyme 17β-hydroxysteroid dehydrogenase then converts this androstenedione to testosterone. Whenever testosterone is produced, its isomer epitestosterone is also synthesized. The structure of epitestosterone is similar to that of testosterone, with the exception of the orientation of the –H and –OH groups at the 17th carbon atom. In normal men, the ratio of plasma concentrations of testosterone to epitestosterone rarely exceeds 3:1. In 1 of 1000 men, this ratio is 4:1.16 Deviations from this ratio are considered indicative of exogenous supplementation.16 The testes also produce 5α-dihydrotestosterone (DHT), a substance with effects similar to

Gene doping Substances and methods prohibited in competition Stimulants Narcotics Cannabinoids Glucocorticosteroids Substances prohibited in particular sports Alcohol β-blockers Specified substances Ephedrine, L-methylamphetamine, methylephedrine Cannabinoids All inhaled β2-agonists except Clenbuterol Probenecid All glucocorticosteroids All β-blockers Alcohol

ment sales in 1997 amounted to $11.8 billion in the United States, with a predicted growth of 10% to 14% for 2000.10 Supplements do not fall under the jurisdiction of the US Food and Drug Administration (FDA) and, therefore, the FDA has not evaluated claims as to their efficacy and safety.10 Creatine is probably the most popular of ergogenic nutritional supplements, with annual sales over $400 million.7 Recent surveys indicate that 28% to 41% of athletes in the National Collegiate Athletic Association (NCAA) were using creatine, and 29% to 57% of health club members reported using creatine. Creatine use is even higher in power-sport athletes, with 45% to 2

letes taking the substance for ergogenic purposes is skeletal muscle.13,17 Testosterone analogs or synthetic derivatives that might be degraded less rapidly by the body were developed.13,14 Testosterone can be alkylated at the 17-α position to produce oral anabolic steroids or esterified at the 17-β position to form injectable anabolic steroids.14 Table 2 provides an overview of commonly used oral and injectable anabolic-androgenic steroids (AAS). Oral and injected doses are the typical method of delivery in nonelite athletes. Elite athletes also seem to be using transdermal patches, buccal tablets, nasal sprays, gels, and creams as delivery methods.14,17 All AAS possess both anabolic and androgenic activity. When used for performance-enhancing reasons, the androgenic effect is obviously an unwanted side effect, especially in women athletes. The goal for a synthetic testosterone derivative is to minimize these androgenic effects. Testosterone has an anabolic-androgenic ratio of 1:1. This ratio for nandrolone is 10:1 and for stanozolol it is 30:1. However, provided AAS are used for a sufficient period at sufficient doses, they will all have masculinizing effects.6

testosterone, and 2 distinctly less biologically active substances (ie, the testosterone precursor androstenedione and dehydroepiandrosterone).13 Testosterone is lipid-soluble and, therefore, can freely cross cell membranes to produce its main effects by interaction with the cell nucleus. However, interaction with a cell surface receptor has not been ruled out. In some cells, testosterone is first converted by the enzyme 5α-reductase to DHT, which then interacts with the nucleus. In addition to its formation in the testes, as noted above, DHT is formed from testosterone in the liver, brain, prostate, external genitalia, and, to a very minimal extent, skeletal muscle. The enzyme aromatase converts testosterone to estradiol in the liver and the hypothalamus. This estradiol is essential for sexual differentiation of the brain, bone mass consolidation, and epiphyseal closure. Some testosterone is also converted to estradiol in the testes. In addition to its conversion to DHT and estradiol, testosterone is metabolized in the liver to DHT and androstenedione. These substances are then converted by the 3-keto reductive enzymes (3α and 3βketoreductase) to androsterone or 1 of its 2 isomers, epiandrosterone or etiocholanolone, which are all excreted through the kidney in the urine.13 Testosterone is an anabolic-androgenic hormone. Androgenic actions involve development and maintenance of primary and secondary sexual characteristics. In utero, testosterone plays a role in the formation of the internal male genitalia. Dihydrotestosterone has a role in formation of the external genitalia and the prostate. Secondary sexual characteristics in men include musculoskeletal configuration, genital size, psychological changes, and sperm production. Dihydrotestosterone is the hormone responsible for adult secondary hair growth.13 In the young, the anabolic actions of testosterone include stimulation and eventual inhibition of skeletal growth. Anabolic actions also consist of the inhibition of urinary nitrogen loss and stimulation of protein synthesis, mainly in the skeletal muscles, resulting in muscle growth.13 The increase in muscle size and whole body protein synthesis is one of the reasons for the weight gain seen in people using anabolic steroids.14 Anabolic steroids may also have an anticatabolic effect by inhibition of the actions of the glucocorticoids that are released as a result of intense exercise by way of competitive inhibition of the glucocorticoid receptor.16 They also increase the number of red blood cells14 and may have a direct neural action on alpha-motor neurons through androgen receptors.16 In the soft connective tissues, anabolic steroids enhance collagen synthesis. They also exert a direct suppressive effect on osteoclasts with a resultant increase in bone mineral density.6 Testosterone was first chemically synthesized in 1935, but it was soon discovered that when given orally or injected, this newly isolated compound was quickly metabolized in the liver and, thus, inactivated before it could reach the target organ, which in the case of ath-

Table 2. Commonly Used Oral and Injectable Anabolicandrogenic Steroids* 17α-Alkylated Derivatives

17β-Esterified Derivatives

Methandrostenolone Methyltestosterone Oxandrolone Oxymetholone Stanozolol Ethylestrenol Fluoxymesterone Danazol

Testosterone esters: blend, cypionate, enanthate, heptylate, propionate Nandrolone esters: decanoate, phenpropionate Boldenone Methenolone Trenbolone Stanozolol Dromostanolone

*Adapted from Evans.6

Physiological replacement levels are common for clinical applications. Participants in strength sports generally use doses that may be 10 to 100 times that of physiological doses, or even more, in an attempt to gain muscle mass and strength.14 In extreme cases, dosages of 1 to 3 grams per day have been reported.6,15 However, because illicit AAS frequently contain falsely labeled contents or even products meant for veterinary use, actual human dosages are hard to establish.18 Steroid users also use cycling (episodes of steroid use lasting 6 to 12 weeks), stacking (use of more than 1 steroid at a time), and pyramiding (moving from a low to a higher dose and then tapering off to a lower dose during a cycle). Steroid users also often stagger different steroids to avoid developing tolerance to a particular steroid and combine steroids with other drugs to combat known side effects.14,15 Effects on Performance Because AAS are illegal for use as an ergogenic aid in healthy subjects, there are very few well-controlled stud3

ies.16 The fact that many of the drugs used by athletes are in fact veterinarian preparations or drugs originating in other countries, both of which are not FDA approved for human use, further (justifiably) thwarts any researcher seeking approval from an institutional review board.19 This probably explains why up until 1987, the American College of Sports Medicine regarded AAS as effective to increase strength (in combination with strength training and proper nutrition) only in some but not all individuals.20 More recent studies using supraphysiologic doses have provided more evidence in support of the anecdotal reports of a positive ergogenic effect. Based on the physiological actions of testosterone discussed above, the authors would expect to see AAS use result in increased strength, greater lean body or muscle mass, enhanced tendon and muscle repair and regeneration, increased bone mineral density, and possibly increased endurance as a result of the increase in the number of circulating erythrocytes. The anticatabolic effects on glucocorticoid action may also play an ergogenic role by allowing for higher training intensity. Over a 6-week period, Friedl et al21 administered 100 or 300 milligrams per week of testosterone enanthate (TE) or 19-nortestosterone decanoate to eugonadal young men. This resulted in insignificant pretest to posttest increases in isokinetic elbow flexor and knee extensor strength, with a trend to greater and more consistent strength gain occurring in the high-dose TE group. The low-dose TE group (considered in this study as a replacement dose) did not increase body weight; the other groups gained, on average, 3 kilograms. Percentage of body fat did not change in any group, but there were significant increases in upper body circumference measurements in the 2 high-dose groups. The authors concluded that androgens at greater than replacement doses increase body mass and may increase strength in normal men but that changes are highly variable. Bhasin et al22 randomized 61 eugonadal men (18 to 35 years) to 5 different groups that received 20 weekly injections of either 25, 50, 125, 300, or 600 milligrams of TE. Endogenous testosterone production was chemically suppressed during the study and the subjects refrained from strength training or moderate to heavy endurance exercise. Fat-free mass and thigh and quadriceps muscle volume increased significantly in the 125, 300, and 600 milligrams per week groups. Leg press strength increased significantly in the 50, 300, and 600 milligrams per week groups; leg power increased significantly in the 300 and 600 milligrams per week groups. All changes were correlated significantly with testosterone levels during treatment. Bhasin et al23 randomly assigned 43 experienced men weightlifters (19 to 40 years) to 1 of 4 groups: placebo without progressive resistance exercise, 10 weekly 600 milligram TE injections without exercise, placebo plus exercise, and TE injections plus exercise. In the no-exercise groups, the men receiving AAS had significantly greater increases over placebo in triceps and quadriceps

cross-sectional area and in bench press and squat 1-repetition maximum (1-RM) loads. The men assigned to the exercise and AAS group had significantly greater increases in fat-free body mass and triceps and quadriceps cross-sectional area than those in both no-exercise groups. The 1-RM load in the bench press increased by 22 ± 2 kg for the bench press and 38 ± 4 kg for the squat exercise in the AAS and exercise group, a significant difference again as compared to the no-exercise groups. The changes in quadriceps cross-sectional area and 1-RM load on the squat were significantly greater in the AAS and exercise group as compared to all other groups. In a cross-sectional study, Alway19 compared the elbow flexors of elite women bodybuilders using AAS (29.7 ± 3.5 years) to those of elite women bodybuilders not using these substances (34.6 ± 2.3 years) and controls (25.6 ± 3.3 years). He found significantly greater cross-sectional area for the biceps, greater hypertrophy of type I and II fibers, a greater amount of concentric work during 25 repetitions of isokinetic elbow flexion, and less percentage fatigue during these 25 repetitions for the AAS users as compared to both other groups. Maximal torque was the same for AAS users and nonusing bodybuilders. The AAS users also had significantly greater whole-body lean body mass and less body fat than the other 2 groups. Blazevich and Giorgi24 compared 12 weeks of placebo to 3.5 mg/kg TE during resistance training for the triceps brachii in healthy men. The 1-RM load for the bench press and the angle of pennation in the triceps muscle increased significantly in the AAS group over the placebo group, suggesting a role for possible AASinduced changes in muscle architecture for the strength gains observed with AAS use. Tamaki et al25 administered nandrolone decanoate (ND) to adult male rats and subjected them to a resistance-training stimulus. Chemical markers of postexercise muscle damage were lower and recovered faster in AAStreated rats, while work capacity and resistance to muscle fatigue were higher as compared to a control group. Beiner et al26 studied the effects of ND on the course of recovery after a contusion injury to the gastrocnemius muscle in rats. They found that AAS compared to corticosteroids resulted in significantly greater force-generating capacity and associated better histological appearance at 14 days and suggested a possible role for AAS in the treatment of muscle injury. Äärimaa et al27 reported on 33 subjects with a surgically repaired rupture of the pectoralis major. They found that the only factor that statistically correlated with a positive outcome was the patient using AAS (cumulative odds ratio = 5.1; 95% confidence interval, 1.1-23.3; P = .033). Triantafillopoulos et al28 subjected human tendons to either ND, loading, ND and loading, or no loading and no ND. The AAS with loading group showed the greatest level of remodeling and the best-organized actin cytoskeleton. Mechanical characteristics (ultimate stress 4

and strain and strain energy density) in the AAS with loading group were significantly greater than in the other 3 groups. In summary, the literature reviewed here supports dose-dependent positive effects of supraphysiologic doses of AAS on measures of strength, fat-free mass, and muscle mass.21,22 Concurrent resistance training further enhances these effects.19,23,24 The literature reviewed also seems to indicate possible positive effects on anaerobic work capacity and resistance to fatigue during this type of exertion.19,25 In vitro research,28 animal research,25,26 and a retrospective case series27 support a positive role for AAS on tendon and muscle repair and regeneration. Strength gain with AAS may partly be due to changes in muscle architecture.

Side Effects The use of AAS has been associated with adverse effects on multiple organ systems. Table 3 provides an Table 3. Side Effects Associated With Anabolicandrogenic Steroid Use6,13,16,18,27,31–34 Cardiovascular

Medical Indications Anabolic-androgenic steroids have been used medically for androgen replacement therapy in hypogonadal men or in men after surgical orchiectomy due to testicular tumors. In young men, they may be given to stimulate sexual development in cases of delayed puberty or to increase growth. Women may receive AAS for a condition known as sexual infantilism, where a young woman fails to secrete estradiol, progesterone, and testosterone. In postmenopausal women, it has been used to restore libido.13 Initial medical use of AAS included attempts to stimulate weight gain in concentration camp survivors after World War II.13,15 Anabolic-androgenic steroids have also been used to increase body weight, muscle mass, and strength in eugonadal patients with secondary wasting syndromes (eg, as a result of human immunodeficiency virus and acquired immunodeficiency syndrome).6,13 Sattler et al29 noted a significant increase in lean body mass in two groups of men with human immunodeficiency virus infection that received 16 weeks of ND injections whether or not they participated in a resistance-training program. However, the AAS with training group increased lean body mass to a significantly greater degree than the group just receiving ND. In large doses, AAS are sometimes used to treat therapy-resistant anemia in men.13 Anabolic-androgenic steroids are also used to augment muscle mass in the elderly and to prevent the agerelated sarcopenia that contributes to frailty and falls.6 They may also have a role in the treatment of osteoporosis.13 Hedström et al30 found significant between-group differences favoring a group of elderly women after hip fracture receiving 1 year of ND, vitamin D, and calcium supplementation over calcium supplementation alone. The group receiving AAS had significantly better Harris hip scores, gait speed, maintenance of muscle volume in the operated leg, increased muscle volume in the nonoperated leg, and less bone mineral density loss than the calcium group. In the future, AAS may also have further orthopaedic indications in the area of muscle and tendon healing.6

Hypertension Left ventricular hypertrophy Impaired diastolic filling Arrhythmia Erythrocytosis Increased blood volume Edema Thrombosis Negative impact on blood lipid profile Atherosclerosis Increased C-reactive protein levels Increased risk of myocardial infarction Increased risk of sudden death

Dermatological Acne Striae Alopecia Hirsutism Reproductive

In men: Hypogonadism Testicular atrophy Reduced sperm count Decreased sperm motility Abnormal sperm morphology Infertility Changed libido Gynaecomastia In women: Hirsutism Increased facial hair Deeper voice Clitoral hypertrophy Oligomenorrhea Amenorrhea Decreased breast size Male-pattern baldness

Psychological

Depression Mania or hypomania Psychosis Aggression Withdrawal symptoms Dependence Suicide and homicide

Gastrointestinal Elevated liver enzymes Hepatic carcinoma Hepatitis A and B Jaundice Orthopaedic

Injection-related intramuscular fibrosis Injection-related dystrophic calcification Needle-stick injury to nerves Tendon rupture Posttraumatic compartment syndrome

Administration- Local infection at the injection site related Bacterial abscess Septic arthritis Septic shock Human immunodeficiency virus infection Hepatitis A and B infection

5

because the slower adapting, less vascular tendons may not be able to keep up with the increase in force-generating capacity caused by the more rapid AAS-induced hypertrophy and strength changes in skeletal muscle.6,28 Skeletally immature AAS users face additional risks. Exogenous testosterone administration, if not under careful medical supervision, can lead to premature closure of the epiphyses with decreased bone growth and development. This side effect persists up to 3 months after discontinuation of the drugs.13 Up to 25% of adolescent AAS users engage in needle sharing, with the associated risk of transmission of blood-borne pathogens such as human immunodeficiency virus and hepatitis B and C.16 Combining AAS with other drugs is also common among adolescent users.14 Simultaneous use of amphetamines and AAS increases the chance of cardiotoxicity. Cocaine-related seizures and heart rate increases are potentiated by AAS.18 Manoharan et al35 described a young bodybuilder in whom AAS combined with bromocriptine, a dopamine agonist with a possible positive effect on body fat content, resulted in bradycardia and syncopal episodes. Perhaps the most bottom-line approach to the adverse effects was the study that indicated that chronic AAS users had a 4.6 times higher risk of mortality than nonusers.6

overview of reported side effects.6,13,16,18,27,31–34 Side effects considered relatively minor are quite common in AAS users.6 Acne affects 40% to 54% of users; testicular atrophy, 40% to 51%; gynaecomastia, 10% to 34%; cutaneous striae, 34%; and reported injection-site pain, 36%. Orally administered rather than injectable AAS may have a more deleterious effect on liver enzymes6 and on blood lipid profiles.29,31 Hartgens et al31 found no effect on blood lipid profiles in men bodybuilders after using injectable ND for 8 weeks. Sattler et al29 similarly found no effect on total cholesterol, low-density lipoprotein cholesterol, low-density lipoprotein phenotype, or fasting triglyceride levels in a study of men with human immunodeficiency virus infection using ND with or without exercise, as described above. In fact, they found transient favorable changes in low-density lipoprotein particle size and high-density lipoprotein cholesterol, triglyceride, and lipoprotein-A levels in both groups. In contrast, Hartgens et al31 did find significant adverse effects on blood lipid profiles in experienced bodybuilders self-administering multidrug regimens including both oral and injectable AAS variants. Both studies29,31 noted an unexpected significant decrease in lipoprotein-A levels. This particle is an independent risk factor for atherogenesis. The hypogonadal state induced in men by the administration of exogenous testosterone derivatives is generally reversible, but it may take 3 to 12 months for endogenous testosterone production and spermatogenesis to resume. Hypogonadism induced by AAS may require hormone treatment. Some of the masculinizing effects noted in Table 3 for women using AAS are permanent (a deeper voice and facial hair growth), and male-pattern baldness may persist even after discontinuation of AAS.6 The psychological effects of AAS are less clear. Placebo-controlled trials have indicated that 5% of users will develop manic or hypomanic reactions, with an increased likelihood of psychiatric effects in subjects with a prior psychiatric history or a history of alcohol or drug abuse.6 Some authors13,17,18 noted that expectations about increased aggression and the influence of personality type in people apt to use these drugs may be the main reason for roid rage. Brower18 found no evidence of dependence in medical users of AAS but noted 165 reports in the medical literature of AAS dependence in nonmedical users. He also warned of the high incidence of homicide and suicide among AAS users and recommended treatment for withdrawal symptoms including psychotherapy and medication. Tendon rupture has been associated with steroid use based on case reports.6 Earlier we discussed the in vitro evidence for the positive effect AAS may have on the mechanical characteristics of tendons.28 Anabolic-androgenic steroids may predispose tendons to failure by altering their crimp pattern and biomechanical properties.28 This results in a stiffer, less elastic tendon, but one with the same ultimate tensile strength.6 It is assumed that tendons are mainly indirectly at greater risk of rupture only

Testing and Regulation Anabolic-androgenic steroids are a Schedule III controlled substance.18 This means that they are legally available only with a physician’s prescription. They are banned and tested for by the International Olympic Committee (IOC) and most United States sporting associations, including the National Basketball Association, the NCAA, and the National Football League.16 Up until recently, Major League Baseball did not test for these drugs. Recent claims by former players and congressional hearings on the topic of steroid use in America’s favorite pastime16 have resulted in a drug-testing program. Testing for AAS suffers from considerable variation in what is considered a normal result. The tests are expensive and a positive result is often contested in court with great financial ramifications. Newer versions of drugs that go undetected with current testing are being developed constantly; currently, the designer AAS tetra-hydrogestrinone is under intense scrutiny. The impact of legal matters on testing is exemplified by what is considered a negative test result. We discussed the normal testosterone-epitestosterone ratio above. According to the IOC Anti-Doping Code, a positive test for exogenous testosterone supplementation in men and women is a test with a ratio ≥6:1. As discussed, a normal ratio for men is 3:1, with only 1 in 1000 men having a ratio of 4:1.16 Table 4 provides the take-home message for AAS. ANDROSTENEDIONE Mechanism of Action Androstenedione is part of a class of androgenic steroids known as prohormones or steroid precursors.36,37 Steroid precursors either are converted directly to testos6

years). They found an increase of whole-day mean (± SE) serum testosterone changes of -2 ± 7%, -4 ± 4%, and 34 ± 14% for the 0, 100, and 300 mg/day groups, respectively. This represented a significant increase only in the 300 versus the 0 mg/day group. They also found an increase of whole day mean (± SE) serum estradiol changes of 4 ± 6%, 42 ± 12%, and 128 ± 24% in these same groups. Both supplementation groups significantly increased serum estradiol levels as compared to the nosupplementation group. The study reported no changes in estrone, luteinizing hormone, and follicle-stimulating hormone levels, but the authors of the study did comment on the large interindividual differences in estrogenic and androgenic responses to androstenedione supplementation. Earnest et al42 administered 200 mg/day of 4androstene-3,17-dione, 200 mg/day of 4-androstene-3 beta,17 beta-diol, or placebo to 8 men (23.8 ± 3 years). They noted a significant increase in total and free serum testosterone only in the androstenedione group for 90 minutes after supplementation. Broeder et al43 provided 50 men (35 to 65 years) with either placebo, 200 mg/day of oral androstenediol, or 200 mg/day of oral androstenedione for 12 weeks while they participated in a high-intensity resistance-training program. Both supplementation groups had significant increases in blood levels of estrone and estradiol. Androstenedione supplementation resulted in a significant increase in total testosterone levels by 16% after 1 month. At 12 weeks, these levels had returned to pretreatment levels, partly due to a down-regulation in endogenous testosterone synthesis as a result of 18% to 33% attenuation in luteinizing hormone levels. Ballantyne et al44 administered 200 mg/day of oral androstenedione or placebo for 2 days to 10 men. On the second day, the subjects performed heavy-resistance exercise. They found no significant between-group differences for serum testosterone levels but a significant increase in luteinizing hormone after supplementation and estradiol levels after exercise in the androstenedione group. Brown et al45 provided placebo or daily doses of 300 mg androstenedione, 150 mg DHEA, 750 mg Tribulus terrestris, 625 mg chrysin, 300 mg indole-3-carbinol, and 540 mg saw palmetto for 6 of 8 weeks with subjects performing resistance exercise 3 days a week for 8 weeks. They noted no change in serum free or total testosterone concentrations in either group but did note significant increases in serum estradiol and estrone levels in the supplementation group. In summary, androstenedione supplementation at 300 mg/day seems to have the potential to increase serum testosterone levels in some individuals but is also associated with an increase in serum estrone and estradiol levels, substances both not known for their ergogenic potential. This estrogen release may be potentiated by resistance exercise. The authors previously discussed the conversion of testosterone by the enzyme aromatase to estradiol in the liver, hypothalamus, and testes. Consid-

Table 4. Take-home Message for Androgenic-Anabolic Steroids • Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male sex hormone testosterone. • Supraphysiologic doses of AAS have a proven positive effect on strength, fat-free mass, and muscle mass. Concurrent resistance training further augments these effects. • AAS may have positive effects on anaerobic work capacity, resistance to fatigue during anaerobic exertions, tendon and muscle healing, and bone mineral density. • AAS have proven adverse side effects affecting multiple organ systems. These adverse effects range from minor temporary complications to sudden cardiac death. • The skeletally immature and women athletes using AAS are especially at risk for irreversible adverse effects. • AAS are only legally available on a physician’s prescription. They are banned and tested for by all major sporting organizations and valid tests exist for their detection.

terone or they form androgen-like derivatives (ie, AAS such as nandrolone).36 The class of steroid precursors includes androstenedione, DHEA, 5-androstenedione, 4-androstenediol, 5-androstenediol, 19-norandrost4-enedione, 19-norandrost-5-enediol, and 19-norandrost-4-enediol.36,38,39 In vitro evidence indicates that androstenedione, 5-androstenediol, and possibly 4-androstenediol, all are direct chemical precursors to testosterone.36 As is the case for testosterone, endogenous production of androstenedione peaks in one’s mid-20s and declines after the third decade.37 Women produce some 33% more androstenedione than do men.39 The authors have discussed further details on the metabolism of androstenedione and testosterone earlier in the section on AAS. Steroid precursors have little affinity for androgen receptors and, therefore, little androgenic and anabolic action by themselves.37 The anabolic action of androstenedione is about 10% to 20% that of testosterone.39 Therefore, the hypothesized mechanism of action for androstenedione as an ergogenic substance is that increased levels of this testosterone precursor will lead to increased serum levels of testosterone, with the resultant performance-enhancing effects, as discussed earlier. Before looking at actual effects on performance and body composition, it is very relevant to test this hypothesis by examining the in vivo effect of androstenedione supplementation on blood hormone levels with or without exercise. King et al40 administered 300 mg/day of androstenedione or placebo to 30 eugonadal men (19 to 29 years) and noted no between-group differences in serum free testosterone, luteinizing hormone, or follicle-stimulating hormone blood levels but did note a significantly larger increase in estradiol and estrone levels in the androstenedione group. Leder et al41 administered 0, 100, or 300 mg/day of androstenedione for 7 days to eugonadal men (20 to 40 7

erable interindividual variations in this androgenic and estrogenic response make it hard to make definitive statements on the hypothesized testosterone-related mechanism of action for androstenedione. The testosterone response to androstenedione supplementation may be different in women and hypogonadal men.40 Androstenedione is usually taken as an oral capsule. Doses recommended for performance-enhancing purposes vary from 100 to over 1200 mg/day.38,39 One hypothesis for the discussed lack of efficacy for androstenedione is the significant first-pass hepatic metabolism to which oral supplements are subjected: only 2% of an oral dose is converted to testosterone.46 Androstenedione is also available as a sublingual spray, transdermal patch, percutaneous gel, or oil-based injectable variant.38,39

unpredictable and highly variable effect on multiple serum hormone levels, this should hardly be surprising. Side Effects Without providing evidence, some authors have hypothesized that the adverse effects of androstenedione are likely similar to those of AAS.37,39,41,48 In a case report, Battista et al49 linked bilateral asynchronous Achilles tendon ruptures to the use of androstenediol in a 35-year old bodybuilder. The authors discussed the effects of androstenedione on estrogenic hormones. Increased estrogen levels have been linked with increased cardiovascular risk.39,40 Increased estradiol levels have been linked to breast cancer in women and to pancreatic cancer in men. Increased serum levels of androstenedione have been linked to prostate and pancreatic cancer.40 Increased estrogenic levels may produce feminizing effects in men using androstenedione (eg, gynaecomastia).37,39 Yesalis and Bahrke39 warned about possible adverse hepatic effects of long-term androstenedione use. As for true evidence of adverse action, Beckham and Earnest47 reported no effect of androstenedione supplementation on mood state and noted no reports of changes in libido or acne, which are frequently associated with the use of AAS. King et al40 noted a significant decrease in high-density lipoprotein cholesterol levels in androstenedione users when compared to placebo. Beckham and Earnest47 found no significant effects on lipid profile for androstenedione supplementation but did note a nonsignificant 13% reduction in high-density lipoprotein cholesterol. In his review, Powers37 noted reports of a 12% to 20% reduction in high-density lipoprotein cholesterol. Broeder et al43 reported significant adverse effects on high-density lipoprotein-C cholesterol levels, coronary heart risk disease, and blood lipid ratios.

Effects on Performance Based on its hypothesized mechanism of action for which the lack of evidence was discussed above, androstenedione supplementation would be expected to have the same ergogenic effects as AAS. Beckham et al47 found no significant changes in body composition or body mass in men (44.1 ± 3 years) supplemented with 200 mg/day of androstenedione or placebo for a period of 28 days. In the study discussed earlier, King et al40 found no significant between-group differences with regard to the 1-RM load with knee extension, mean increase in type II fiber cross-sectional area, increase in lean body mass, or decrease in fat mass with exercise and placebo or 300 mg/day supplementation with androstenedione. In the study discussed above, Broeder et al43 found no between-group differences for muscle strength or body composition measures after 12 weeks of resistance training and supplementation with 200 mg/day of androstenedione, androstenediol, or placebo. Similarly, Brown et al45 found no between-group differences in muscle strength gain after 8 weeks of resistance training and supplementation with a combination of 300 mg/day of androstenedione, 150 mg/day of DHEA, and herbal substances, or placebo. In summary, the evidence reviewed above does not support an ergogenic effect of androstenedione supplementation of up to 300 mg/day on parameters of strength or body composition. Powers,37 after a review of the literature, concluded that the available scientific data did not support ergogenic claims for androstenedione supplementation. Yesalis38 commented on the possible role that using inexperienced weightlifters for studies on androstenedione supplementation may have had and hypothesized a possible ergogenic role in more experienced strength athletes.

Testing and Regulation In 1996, androstenedione became available as an over-the-counter nutritional supplement.46 Mark McGwire’s admission that he used androstenedione as a performance-enhancing substance during his 1998 race to break the home run record catapulted sales of this steroid precursor.38 Since October of 2004, androstenedione and other steroid precursors (with the exception of DHEA, estrogens, progestins, and corticosteroids) are classified as Schedule III controlled substances.48 The IOC, the National Football League, and the NCAA have all banned androstenedione. As for testing, ingestion of androstenedione would likely cause athletes to test positive for steroid use, as it results in increased urinary concentrations of androsterone, etiocholanolone, and hydroxylated derivatives of both substances; testosterone; and epitestosterone. These substances will cause an increased testosterone-toepitestosterone ratio and a positive test for AAS.36 The fact

Medical Indications The literature reviewed did not provide indications for the medical use of androstenedione. Considering its 8

(VO2max), hGH levels rise. More intense exercise results in earlier hGH secretion, and intermittent intense exercise supposedly produces the highest hGH levels.5 The effect of aerobic exercise is greater than that of resistance exercise.54 The hGH plasma half-life is only 12 to 45 minutes, and hGH is metabolized in the liver.5 Receptors for hGH are present on every cell in the body. Its most obvious action is stimulation of somatic growth in preadolescents. In children, hGH promotes amino acid uptake and protein synthesis, resulting in length and cross-sectional muscle fiber growth. Bone growth occurs by way of stimulation of cartilage proliferation in the epiphyseal plates. In adults, hGH and IGF-I stimulate osteoclast differentiation and activity, resulting in increased bone remodeling and increased bone mineral density.52 Human growth hormone also has metabolic effects on the homeostatic regulation of fuel storage and usage, but this role is less clear, as is its exact role in adults.5 Determining the unique role of hGH is further complicated because hGH stimulates the mainly hepatic release of 2 further hormonal polypeptides: IGF-I and IGF-II.51 Many of the effects of hGH are thought to be mediated by IGF-I.5,51 Metabolic effects of hGH in the acute phase include increased activity of muscle membrane amino acid transport mechanisms with resultant increased amino acid uptake into the muscle and increased glucose uptake in the muscle and adipose tissue with reduced fat metabolism. Insulin-like growth factor-I mediates the second phase with quite a contrary effect: increased lipolysis in adipose tissue results in increased fatty acid utilization and glucose sparing.5 Lipolysis is also brought about by an hGH-mediated increase in other lipolytic hormones and by increasing responsiveness of the adipocyte to these other hormones. Lipogenesis is decreased by an hGH-mediated inhibition of some key lipogenic enzymes.51 These combined effects of hGH on fat and protein metabolism result overall in a decrease in adipose tissue mass and an increase in lean body mass.5,51 Administration of hGH is by way of intramuscular or subcutaneous injection or by way of an implanted biodegradable microsphere.5,51 Because of possible contamination of human-derived hGH with the prion causing Creutzfeldt-Jacob disease, hGH is now produced synthetically.51,55 A number of pharmaceutical companies have developed recombinant hGH (rhGH) products with the generic name of somatropin. Brand names include Protropin, Nutropin, Nutropin AQ, Norditropin, Genotropin, Humatrope, Serostim, and Saizen.51 In the United Kingdom, the prescribed replacement dose in hGH-deficient children is 0.6 IU/kg body weight per week. People who abuse hGH for performance enhancement may use up to 10 times this dose.5 Stacy et al55 reported that doses used by athletes are often even 20 times those prescribed and range up to 5 mg/day.

that some one-time commercially available supplements in fact contained 19-norandrostenedione or even testosterone further increases the likelihood of a positive test.50 Table 5 provides the take-home message for androstenedione. Table 5. Take-home Message for Androstenedione • The scientific evidence reviewed does not support claims for an ergogenic effect of androstenedione supplementation. • Androstenedione supplementation has shown to increase cardiovascular health risks related to altered blood lipid profiles and elevated estradiol and estrone levels. • Androstenedione is a controlled substance and banned for use by most sporting organizations. Its ingestion will likely result in tests positive for the use of androgenicanabolic steroids.

HUMAN GROWTH HORMONE Mechanism of Action Human growth hormone (hGH), or somatotropin, is a polypeptide hormone released from the somatotroph cells in the anterior pituitary gland.5,51 Secretion is episodic and pulsatile. There are approximately 10 pulses of hGH secretion throughout the day interspersed by 128-minute intervals where serum hGH levels are nearly undetectable.52 The highest levels occur some 60 to 90 minutes after the onset of sleep.5 In young adults, serum concentrations vary from 0.1 to 30 mg/L or higher.53 Endogenous hGH exists in many molecular forms.51,54 The main pituitary molecular weight variant is a 191-amino acid, 22kDa form that represents about 21% of plasma hGH. However, as a result of posttranslational and postsecretory modifications, endogenous hGH has a great molecular heterogeneity with many aggregates and fragments existing in the circulation with possible independent and specific roles.51 Release of hGH is under the control of 2 hypothalamic hormones. Somatostatin inhibits secretion and somatocrinin (or growth hormone-releasing hormone) stimulates secretion.5,51 Estradiol also stimulates hGH release; testosterone has little effect. Drugs that stimulate α2-adrenergic receptors (eg, clonidine) increase hGH secretion; drugs that stimulate β-receptors (eg, salbutamol) decrease secretion.5 Arginine, insulin-induced hypoglycemia, and γ-hydroxybutyrate also increase secretion.5 Serotonin, dopamine, and gamma-aminobutyric acid receptor stimulation all also lead to an increase in hGH release. Cortisol, insulin-like growth factor-I (IGF-I), and hGH itself all inhibit secretion. Secretion is lower in elderly, postmenopausal, and obese individuals.52 The 24-hour serum hGH levels in men and women over age 55 are one third of those of individuals ages 18 to 33.53 Exercise can increase hGH production fivefold to tenfold;55 within 20 minutes of beginning aerobic exercise at 75% to 90% of maximum oxygen consumption 9

increase in fat mass). Rudman et al60 administered 0.03 mg/kg of hGH 3 times a week to 12 men aged 61 to 81 with low plasma IGF-I levels for 6 months and found significant increases in lean body mass and average lumbar vertebral body mass and a decrease in adipose tissue mass when compared to age-matched subjects. Yarasheski et al61 administered placebo or 12.5 to 24 mg/kg/day hGH to healthy, sedentary men aged 67 ± 1 years with low serum IGF-I levels for 16 weeks. Both groups participated in a heavy-resistance program. There were no between-group differences in muscle strength noted, but there was a greater increase in fat-free mass in the hGH group, possibly due to an increase in noncontractile protein synthesis and fluid retention. Yarasheski et al62 also studied the effect of daily administration of 12.5 to 18 mg/kg/day hGH versus placebo during 16 weeks of heavy-resistance training in men aged 67 ± 1 years. They found no between-group differences in whole body, spine, or hip measures of bone mineral density. A review of the effects of hGH supplementation in the subjects over 60 years did not show favorable additional results on muscle mass or strength over resistance training alone.63

Effects on Performance The effects of hGH and IGF-I on fat, protein, and bone metabolism discussed above explain a potential performance-enhancing effect for hGH administration with regard to body composition, strength, and bone mineral density. Potentially serious side effects pose ethical limitations with regard to performing research that involves hGH administration to healthy individuals. Therefore, the research on the performance-enhancing effects of hGH administration in athletes is very limited.55 Deyssig et al56 provided either placebo or 0.09 IU/kg/day of hGH to men who were power athletes (23.4 ± 0.5 years) for a period of 6 weeks. They controlled for simultaneous use of AAS. They showed no significant between-group differences for concentric strength of the biceps and quadriceps muscles or body weight and body fat. Yarasheski et al57 administered a placebo injection or 40 mg/kg/day of rhGH to young men (21 to 34 years) participating in heavy-resistance exercise for 12 weeks. The study showed no between-group differences in muscle strength, muscle size, or muscle protein synthesis but did show a larger increase in lean body mass in the rhGH group, which was attributed to an increase in noncontractile proteins. Yarasheski et al58 administered 40 mg/kg/day of rhGH to men who were experienced weightlifters (23 ± 2 years) for 14 days and found no increase in the rate of muscle protein synthesis and no decrease in the rate of whole-body protein breakdown, indicating no effect of short-term hGH supplementation on muscle protein metabolism in this specific group.

Side Effects Most of the known side effects of hGH abuse have been obtained from studying medical conditions that result in its excessive production.51 Acromegaly is a condition that results from hGH oversecretion, mainly in middle-aged adults and frequently due to a benign adenoma of the anterior pituitary gland. In prepubertal and adolescent children, hGH oversecretion leads to a medical condition called gigantism. However, in adults, the epiphyses have fused and the affected individual does not grow taller. Instead the internal organs enlarge, the fingers grow, and the skin thickens.5 Acromegaly also causes increases in total body water, calcium, sodium, potassium, and phosphorus content. Oversecretion may cause facial and aural soft tissue swelling; hyperhidrosis; a deeper voice; growth of the ribs, mandible, and frontal bones; bony overgrowth of the frontal sinuses, vertebral bodies, and phalanges; widening of the joint space due to a disproportionate expansion of mechanically dysfunctional cartilage and subsequent premature osteoarthritis; diabetes mellitus with insulin resistance, hyperinsulinemia and impaired glucose tolerance; headache; vision loss; sleep apnea; nerve entrapments; hypertrophic neuropathy; myopathy; menstrual abnormalities; and secretory changes of adreno-corticotropic hormone, thyroid-stimulating hormone, and vasopressin.51,52 Treatment with rhGH has been shown to increase the incidence of leukemia.51 Studies on hGH abuse with the aim of performance enhancement have shown muscle weakness despite increased size, hyperlipidemia, diabetes, arthritis, and impotence. Cardiomegaly is often a cause of death in people abusing hGH. The increased serum levels of free fatty acids due to hGH administration can promote car-

Medical Indications Inadequate pituitary hGH secretion may be the cause of dwarfism, a situation where a child’s rate of growth is below the 90th percentile for the child’s age. Pituitary dwarfism is treated by administering rhGH before the end of puberty, with careful attention to prevention of secondary diabetes or skin hyperplasia.5 Growth failure due to chronic renal insufficiency or Turner syndrome is also treated with hGH administration.55 A further accepted medical use in adults is for the muscle wasting associated with acquired immunodeficiency syndrome.55 Schambelan et al59 randomized 178 subjects infected with human immunodeficiency virus with unintentional weight loss greater than 10% of body weight or body weight less than 90% of the ideal weight into a placebo group and a group receiving 0.1 mg/kg/day hGH for 12 weeks. The study produced significant between-group differences, with a greater decrease in body fat and greater increases in body weight, lean body mass, and work output on a treadmill test to volitional exhaustion in the hGH group. The decrease in hGH levels with age, reported above, has also led to the administration of hGH to affect changes associated with normal aging (ie, a reduction in lean body mass, bone mass, and skin thickness and an 10

diac arrhythmia.54 Metabolic acidemia seems to result in decreased rather than improved exercise performance. Decreased glycogen storage in the muscle and liver due to increased hGH levels make recovery from exercise more difficult.54 The increased protein synthesis with hGH abuse also results in a thickening and coarsening of the skin leading to a condition called elephant epidermis. Other skin effects include increased dermal viscosity and increased incidence of skin nevi.5 The authors already mentioned the chance of contracting Creutzfeldt-Jacob disease from human-derived hGH.5 Stacy et al55 noted that further research on supraphysiologic hGH administration is needed to clarify the prevalence of side effects. Also, we should bear in mind that rhGH is very expensive; the cost of a therapeutically worthwhile yearly dose runs from $30 000 to $50 000.5,51 Evidence indicates that a lot of the illicit hGH is counterfeit, adulterated, or of animal origin, containing other peptide hormones, anabolic steroids, and bovine hGH (which has no effect in humans).5 The risk of injection and of unknown substances combined with the potentially lethal side effects observed in clinical conditions with hGH oversecretion make the abuse of hGH a very dangerous practice.

Table 6. Take-home Message for Human Growth Hormone • In healthy young adults, exogenous human growth hormone (hGH) provides no performance-enhancing effects in the sense of increased strength or muscle mass. • Exogenous hGH may increase lean body mass in healthy young and elderly adults, but this increase is likely due to an increase in noncontractile proteins. • The evidence for an increase in bone mass in healthy elderly subjects is equivocal. • The abuse of hGH as an ergogenic substance has proven potential for serious side effects and disease. • For ergogenic purposes, hGH is a banned substance. However, at this time no valid test exists to detect its abuse.

seminal vesicles, macrophages, retinal photoreceptor cells, kidney, liver, spleen, and lungs of vertebrates.64 About 95% of the body’s creatine pool is located in the skeletal muscles. Approximately 70% of creatine is stored in the muscles in a phosphorylated form, phosphocreatine (PC), and the remaining 30% is free creatine.64,65 Creatine is constantly degraded to creatinine at a rate of about 2 grams per day (for a 70-kilogram person), which then diffuses through the muscle membrane and is excreted through the kidneys in the urine. Creatine is replenished by synthesis in the liver and by way of dietary intake.64 Dietary sources of creatine include pork (5 g/kg), beef (4.5 g/kg), and cold-water fish such as tuna, salmon, and cod (1.5 to 2 g/kg). The denaturing process that occurs with heating degrades some of the creatine, so the content in uncooked food is somewhat higher. Virtually no creatine is present in plant products, and vegans have to rely solely on endogenous production, which results in lower creatine muscle levels as compared to those of nonvegans.65 Endogenous synthesis involves the amino acids arginine, glycine, and methionine. The enzyme glycine amidinotransferase catalyzes the first of 2 reactions, where an amidine group from arginine is transferred to glycine to form ornithine guanidinoacetate. In the second reaction, creatine and S-adenosylhomocysteine are formed from guanidinoacetate and S-adenosylmethionine with the enzyme guanidinoacetate methyltransferase as a catalyst.64,65 The role of creatine in muscle is fourfold. It provides an anaerobic mechanism for resynthesis of muscle adenosine triphosphate (ATP) by way of a reaction that is catalyzed by the enzyme creatine kinase: PC + adenosine diphosphate (ADP) + H+ ↔ ATP + creatine. The anaerobic nature of this resynthesis makes creatine a major source of energy for high-intensity exercise; PC use is maximal in the first second of this type of exertion and decreases over 30 seconds.64 The creatine-PC system also functions as a metabolic buffer by using H+ ions during resynthesis of ATP. This ability to attenuate pH changes in the muscle may delay onset of fatigue.64,65

Testing and Regulation As also noted by Rennie,54 an Internet search for “growth hormone” produces a multitude of Web pages touting the rejuvenating and muscle-building benefits of this substance. This may in part be due to the stance of international regulating sports agencies and the highly publicized search for a valid test to detect hGH abuse.54 The IOC and other sport-governing bodies have banned the use of rhGH.51 Tests have been developed that rely on the immunological differences between endogenous and recombinant hGH, but these tests cannot identify increased endogenous hGH levels that result from the injection of human cadaveric hGH or hGH released by the action of drugs with an effect on pituitary secretion. Another radio-immunoassay test can detect increases in plasma constituents affected by hGH secretion or injection. However, both tests require blood samples, which has legal and religious implications in many countries.5 Increased urinary hGH levels indicative of rhGH abuse return to normal after 24 hours, making timing of a urine test (random versus staged testing) crucial.51 A further confounding factor is the large interindividual variation in hGH levels, especially in trained endurance athletes.5 The possible future development of orally administered hGH-releasing substances further complicates testing.5 At this time, no legally or scientifically valid test exists to detect hGH abuse.51 Table 6 provides the take-home message with regard to hGH. CREATINE Mechanism of Action Creatine (or methyl guanidine-acetic acid) occurs naturally in the skeletal muscles, heart, spermatozoa, brain, 11

In contrast to these negative outcomes, 2 studies have found a significant increase (22.1%) in anaerobic work capacity on the bicycle ergometer critical power test in physically active women (age 22 ± 5years) compared to a placebo after supplementation with 20 g/day for 5 days69 and in men (19.9 ± 1.6 years) after drinking 5.25 g/day of creatine monohydrate without (9.4%) or with 33 grams of dextrose (30.7%).70 A placebo group ingesting 35 g/day of dextrose had no significant changes.70 Supplementation with 0.3 g/kg/day for 5 days and 2.25 g/day for 9 days produced a significant improvement in the 100-meter sprint and a trend for improvement in the 50meter sprint in men and women who were Division III NCAA swimmers (19.3 ± 0.2 years).71 On the other hand, Dawson et al72 found no improvement in 50-meter and 100-meter sprint times for men and women who were junior swimmers (16.4 ± 1.8 years) after supplementation with 20 g/day for 5 days and 5 g/day for 22 days. MacLaren64 concluded that creatine might improve single bouts of intense exercise only when fatigue is present due to previous activity. The role of the creatine-PC system as a cellular and metabolic buffer and its role in ATP resynthesis should affect performance on repeated high-intensity activities. However, one study73 noted no significant betweengroup differences in peak and mean anaerobic power in 3 consecutive bouts of arm and leg Wingate tests in men who were recreational athletes ingesting either 20 g/day of creatine monohydrate or placebo for 6 days. This was confirmed by another study74 that also found no significant between-group differences on a repetitive leg Wingate test in well-trained women subjects (27 ± 6 years) ingesting either 20 g/day of creatine monohydrate or a placebo for 5 days. Edwards et al75 also found no significant between-group differences in performance for moderately active men (21.5 ± 3.6 years) ingesting either a placebo or 20 g/day creatine monohydrate for 6 days on a 20% incline treadmill test at 8 mph preceded by four 15-second bouts of high-intensity running. Stevenson and Dudley76 reported no significant between-group differences on open chain knee extension 5-set performance when comparing resistance-trained subjects ingesting placebo or 20 g/day creatine monohydrate for 7 days. Delecluse et al77 found no effect of supplementation with 0.35 g/kg/day creatine monohydrate versus placebo for 7 days in highly trained sprinters of both sexes on repeated 40-meter sprint times. On the other hand, Warber et al78 noted a significant increase in total repetitions on 5 sets of bench press at 70% of a 1-RM load in men (32 ± 5 years) ingesting 24 g/day of creatine monohydrate for 5 days when compared to placebo. Earnest et al79 also reported a significant effect for time to exhaustion on 2 consecutive about 90-second runs in well-trained men ingesting 20 g/day for 4 days and 10 g/day for 6 days when compared to placebo, mainly due to improvement in the second run. Kirksey et al80 did find significant between-group differences in average peak power, peak power, total work,

Increased levels of ADP inhibit multiple enzymatic functions involved in glycolysis and also the enzymes known as ATPases; PC acts as a cellular buffer by attenuating the ADP concentration changes.64 Finally, creatine is an osmotically active substance, and the increased intracellular water levels due to creatine supplementation have been shown to stimulate muscle protein synthesis.64 Fast glycolytic muscle fibers contain about 30% more creatine than slow oxidative fibers.64 Higher creatine kinase activity in glycolytic fibers leads to a higher rate of PC degradation. Phosphocreatine resynthesis occurs in the muscle mitochondria. This resynthesis is slower in glycolytic than in oxidative fibers due to lower intracellular oxygen and higher H+ concentrations.64 Creatine supplements commercially available are creatine monohydrate and creatine phosphate.65 Both appear to be equally effective.65,66 Most research on creatine supplementation has used short-term (≤14 days) supplementation with 20 to 30 grams of creatine monohydrate in 4 to 6 daily doses of 5 to 6 grams.64,65 This loading phase is followed by a maintenance phase where 2 grams per day is ingested.65 More prolonged low-dose supplementation (3 grams per day over 4 weeks) has been shown to produce muscle creatine levels similar to these higher dose regimens.64 Creatine uptake is enhanced with simultaneous ingestion of simple carbohydrates, probably by stimulating an insulin-dependent creatine transmembrane transport system.64,65 Muscle creatine levels return to normal in about 4 weeks after stopping supplementation.64,65 However, a case report on a competitive bodybuilder67 found that muscle PC levels decreased by only 22% over 30 days after an initial 45% increase after supplementation with 20 g/day for 5 days. In some individuals, the washout period obviously may exceed 30 days, with an accompanying persistent increase in body mass. Effects on Performance Based on the mechanism of action of creatine discussed above, one would expect to see performanceenhancing effects of creatine supplementation mainly with repeated high-intensity activities and body composition. Effects on single bouts of high-intensity exercise and strength measures can also be hypothesized. Creatine supplementation might have an effect on high-intensity aerobic exercise. Single bouts of high-intensity exercise use the creatine-PC system as a major source of anaerobic energy. However, research found no significant change in the maximum number of repetitions with the preacher bench curl in men (19 to 29 years) ingesting 20 g/day creatine monohydrate or creatine phosphate for 3 days followed by 10 g/day for the remainder of 6 weeks when compared to a placebo.66 Research also showed no significant benefit of 0.3 g/kg/day creatine monohydrate for 5 days followed by 0.03 g/kg/day for 32 days in men who were recreational weightlifters (20 to 26 years) over placebo on total lifting volume to failure at 80% of the 1-RM load for bench and incline leg press.68 12

and initial rate of power production in five 10-second maximum cycle ergometer rides in collegiate track and field athletes ingesting 0.3 g/kg/day for 6 weeks as compared to placebo. Cottrell et al81 found that supplementation with 0.3 g/kg/day creatine monohydrate for 7 days was effective in improving recovery from eight 15-second cycling bouts in trained cyclists when the recovery interval was less than 6 minutes long. MacLaren64 noted that creatine supplementation has been shown to result in a 4% to 10% improvement in performance with repeated high-intensity exercises in the sense of cycling, swimming, running, and vertical jumping with the greatest effects in later bouts of exercise. Even studies showing no significant improvement (possibly due to low power) showed 2% to 4% improvements.64 Measures of strength could be considered single bouts of high-intensity exercise. Some studies found no effects of creatine supplementation. Syrotuik et al68 found no significant change in 1-RM load for the bench and incline leg press. Stevenson and Dudley76 found no significant between-group difference on 1-RM for an open chain knee extension exercise. Other studies have shown significant effects for supplementation. Peeters et al66 found significant increases in the 1-RM load for the bench press in the supplement versus placebo group. Brenner et al82 reported significant between-group differences for the bench press 1-RM load, favoring the 20 g/day for 1 week followed by 2 g/day for 4 weeks supplement situation over the placebo situation in female collegiate lacrosse players. Larson-Meyer et al83 found that in female collegiate soccer players, 15 g/day of creatine monohydrate for 1 week followed by 5 g/day for 13 weeks resulted in a significantly higher 1-RM on bench press and squat than ingesting a placebo. Functional measures of strength have also been investigated. Haff et al84 found significant between-group differences in jump-height performance with a countermovement jump when comparing a placebo to 0.3 g/kg/day creatine monohydrate for 6 weeks in male and female track and field athletes. Watsford et al85 noted significant increases in vertical jump and 20-centimeter drop jump height after creatine supplementation with 20 g/day for 7 days and 10 g/day for 21 days in a group of men (23.4 ± 4.9 years), with no change in the placebo group. Kirksey et al80 found improved countermovement vertical jump height and power index in collegiate track and field athletes ingesting 0.3 g/kg/day for 6 weeks as compared to placebo. MacLaren64 noted that reports of the ergogenic effects on strength measures are mixed but that on balance, the evidence for a positive effect is greater than that for no effect. Greater energy storage in the creatine-PC system might be beneficial in high-intensity aerobic exercise. Biwer et al86 provided male and female college soccer players with a placebo or 0.3 g/kg/day of creatine for 6 days. Supplementation did not result in significant effects during a submaximal treadmill run interspersed with high-intensity intervals lasting more than 20 minutes.

MacLaren64 hypothesized a positive effect on aerobic high-intensity activities from 4 to 12 minutes. No effect has yet been found for longer-duration activities. Creatine supplementation may affect body composition. Some of the studies reported above found no effect of creatine supplementation on body weight,69–71,75 whereas others noted increased weight.78 Some reported increased lean body mass,66,80,84 and 1 found no such change.83 Some studies report a decrease in percentage of body fat.78,82 Kutz and Gunter87 found significant increases in body weight and body water content but not in percent of body fat in men (22.9 ± 4.9 years) supplemented with 30 g/day for 2 weeks and 15 g/day for another 2 weeks; they attributed the weight gain to increased water retention. Powers et al88 found a significant between-group difference with increased body mass and total body water content in male and female resistance-trained athletes ingesting 25 g/day for 7 days and 5 g/day for 21 days versus placebo. MacLaren64 reported clear evidence for an increase in muscle mass in studies where creatine supplementation was combined with resistance training. Medical Indications Creatine has been used in the clinical medical setting for inborn deficiencies of creatine metabolism, gyrate atrophy of the choroids and retina, heart disease, neuromuscular disease, and recovery from orthopaedic injury or surgery. Creatine may have a cytoprotective function on cardiac muscle in patients with heart disease. It has also been shown to positively affect blood triglyceride and cholesterol levels.64 Some studies have investigated creatine supplementation in clinical situations. Jacobs et al89 found a significant between-group difference in oxygen uptake and tidal volume with arm ergometry in favor of patients with complete C5 to C7 spinal cord injury ingesting 20 g/day creatine monohydrate for 7 days when compared to placebo. A 5-day protocol of 20 g/day creatine monohydrate did not produce greater total work production with 3 sets of 30 repetitions of isokinetic open chain knee extensions over placebo in individuals with multiple sclerosis.90 Creatine supplementation (10 g/day for 10 days presurgery and 5 g/day for 30 days postsurgery) did not affect recovery from total knee arthroplasty.91 Creatine has had positive effects in animal research into muscular dystrophy and on strength in humans with mitochondrial cytopathies.92 Supplementation at 20 g/day for 5 days did not attenuate or enhance recovery from eccentric-induced muscle injury.93 Side Effects There are some case reports discussing adverse health effects, including death due to renal dysfunction as a result of combined high-dose creatine supplementation and dehydration in athletes.64 However, prolonged (2 to 5 years) low-dose creatine use for clinical reasons has not been documented to result in kidney dysfunction. 13

step in the endogenous production of HMB is the transamination of leucine to α-ketoisocaproate. The cytosolic enzyme α-ketoisocaproate-dioxygenase then catalyzes the production of HMB from α-ketoisocaproate. Normal plasma concentrations of HMB vary from 1 to 4 mmol/L but can increase fivefold to tenfold after ingestion of leucine.95 Beta-hydroxy-β-methylbutyrate production in the body seems mainly controlled by enzyme and α-ketoisocaproate concentrations; on average, a 70-kilogram person will produce 0.2 to 0.4 grams of HMB per day.98 Normally, 5% of leucine oxidation proceeds via the pathway described above.95 However, exercise affects leucine metabolism, with oxidation increasing by a factor of up to 4.8 as a result.96 The mechanism by which HMB brings about its documented positive effects is not totally clear. The hypothesis that HMB works through a testosterone-mediated pathway was discredited by Slater et al,99 who found no change in the testosterone to epitestosterone ratio in healthy men after ingesting 3 grams of HMB per day for 2 weeks. The role of HMB in maintaining muscle membrane integrity is more evident. Beta-hydroxy-β-methylbutyrate is converted in the cytosol and the liver to βhydroxy-β-methylglutarate-Co-A (HMG-CoA), which is then used for cholesterol synthesis. Stressed or damaged cells may be unable to produce HMG-CoA in sufficient quantity to support adequate cholesterol production.95 An increase in cytosolic cholesterol production as a result of an increase in HMB concentrations may be used to maintain muscle cell membrane integrity and thus prevent muscle damage. It may also be used to regenerate damaged muscle membranes, thus speeding recovery.100 Other less substantiated hypotheses as to the mechanism of action of HMB include: • Stimulation of cellular proteinosis with decreased recovery time due to increased collagen and connective tissue synthesis.97 • Regulation of enzymes responsible for muscle breakdown.97 • Stimulation of liver metabolism, with increases in the rate in the Cori cycle resulting in a more effective conversion of lactate to glucose.96 • Stimulation of mitochondrial and cellular protein concentration with a subsequent increase in cellular oxidative capacity and decreased production of lactate.96 • Increased muscle buffer capacity for H+ ions as a result of the increase in muscle protein content96 Beta-hydroxy-β-methylbutyrate supplementation generally comes in the form of orally ingested capsules. Most research has studied a daily dose of 3 grams of HMB per day.

Taking low doses of creatine (3 to 5 g/day) during a maintenance phase together with sufficient volumes of fluid should not pose a problem in an athlete with normal kidney function.64 When considering creatine use, seeking medical advice in case of renal disease is recommended. Anecdotal reports of gastrointestinal upset, muscle cramps, and muscle injuries have not been substantiated by research; in fact, the incidence of gastrointestinal upset was less in creatine users in a study comparing creatine supplementation to a placebo.64 Gastrointestinal upset has been associated with taking dosages above recommended levels.65 Unnithan et al94 noted, based on their review of the literature, that insufficient evidence existed to suggest the use of creatine supplementation for children and adolescents. Metzl et al12 noted that use among adolescents should actively be discouraged until safety can be established and suggest in general a nonpermissive attitude from the medical community toward nutritional supplement use in young athletes. Testing and Regulation Creatine is a natural component of food with a proven significant effect on strength, power, speed, and lean body mass. Determining the level of muscle creatine in the context of drug testing would likely involve the need for expensive (and invasive) muscle biopsy and magnetic resonance imaging.64 An upper limit for maximum total creatine content in muscle of 160 mmol/kg64 has been suggested, but how does one determine whether this is the result of a healthy diet or supplementation? If any, above which level should an athlete be banned from competition? In 1998, the IOC Medical Committee ruled that creatine is a food and not a banned substance.65 Table 7 provides the take-home message for creatine supplementation. Table 7. Take-home Message for Creatine • Creatine supplementation has a proven significant performance-enhancing effect on strength, power, speed, and lean body mass. • With the possible exception of aggravating a pre-existing renal dysfunction with creatine supplementation in combination with insufficient hydration, the use of creatine does not seem to produce clinically significant side effects. • Insufficient evidence exists with regard to efficacy and safety of creatine use in children and adolescents. • Creatine is not considered a banned substance.

BETA-HYDROXY-BETA-METHYLBUTYRATE Mechanism of Action Beta-hydroxy-β-methylbutyrate (HMB) is a metabolite of the branched-chain amino acid leucine.95,96 Betahydroxy-β-methylbutyrate concentrations in the body are maintained both by dietary intake (eg, by eating catfish and grapefruit) and by endogenous production.97 The first

Effects on Performance Based on its hypothesized and more substantiated mechanisms of action, HMB supplementation might be expected to have a direct positive influence on high14

Division I football players involved in a strenuous exercise program. They found no significant between-group differences on the predicted 1-RM load for the bench press, squat, and power clean or with regard to body weight or percentage of body fat. The authors hypothesized that the effects of supplementation might have been decreased due to the state of overtraining associated with the high volume of the exercise program. In summary, the research reviewed here seems to support the hypothesized positive effect of HMB supplementation on preventing muscle damage and delaying the onset of blood lactate accumulation. Effects on measures of strength and body composition are equivocal but seem to indicate a positive ergogenic effect. No data indicate a positive effect on aerobic endurance.

intensity aerobic exercise by way of its possible effect on lactate production and metabolism and on markers of muscle damage as a result of exercise by way of its effect on muscle membrane integrity. Indirectly, HMB supplementation might positively affect measures of both strength and endurance and body composition by decreasing recovery time after strenuous exercise. Nissen et al98 studied the effect of simultaneous resistance training and HMB supplementation in 2 groups. One portion of the study compared men (19 to 29 years) taking 0, 1.5, or 3 grams of HMB per day for 3 weeks while engaging in a resistance-training program 3 times per week. This study found a significant between-group difference favoring the HMB-supplemented groups, with lower plasma creatine phosphokinase levels indicative of muscle damage, decreased proteolysis as measured by urinary 3-methylhistidine levels, and a higher volume measure of total weight lifted. The second portion of the study compared men (19 to 22 years) who did resistance training 6 days per week for 7 weeks while ingesting either 0 or 3 grams of HMB per day and found a significant between-group difference with an increase in fatfree mass in the HMB group. Kreider et al101 supplemented resistance-trained athletes simultaneously engaged in a resistance-training program with 0, 3, or 6 grams of HMB per day for 28 days. The study found no significant between-group differences for fat-free mass, bone-free mass, percentage of body fat, and 1-RM load on the bench press or leg press. Knitter et al100 compared 6 weeks of ingestion of 3 grams of HMB per day to placebo in experienced runners of both sexes. Despite similar performance on a 20kilometer collegiate cross-country run, they found a significant between-group difference in creatine phosphokinase and lactate dehydrogenase postrun blood-level responses, indicating a lesser degree of muscle damage in the supplemented group. Panton et al102 compared placebo to supplementation with 3 grams of HMB per day in men and women (20 to 40 years) engaged in a resistance-training program. The study noted a trend for lower plasma creatine phosphokinase levels in the supplemented group and a significant increase in a volume measure of upper body strength favoring the HMB-supplemented group. There was also a between-group trend for increased fat-free weight and decreased percentage of body fat (P = .08) in the HMB group. Vukovich and Dreifort96 compared ingestion of 3 grams of HMB per day for 2 weeks to ingestion of 3 grams per day of leucine or placebo in competitive masters-level cyclists (34.2 ± 2.6 years). They found a significant between-group difference in the onset of blood lactate accumulation (defined as the oxygen consumption per unit time [VO2] at levels of blood lactate of 2 mmol/L) favoring the HMB-supplemented group. Ransone et al97 compared 4 weeks of supplementation with 3 grams of HMB per day to placebo in NCAA

Medical Indications Lynch92 noted that HMB supplementation in combination with supplementation with the amino acids L-glutamine and L-arginine has been shown to be effective in slowing the course of muscle wasting in patients with acquired immunodeficiency syndrome. However, he also reported that further study is needed to determine the efficacy of HMB supplementation as a medical intervention in patients with neuromuscular disorders.92 Side Effects Nissen et al95 performed a systematic review with regard to safety of HMB supplementation. The reviewed studies researched the effects of ingestion of 3 grams of HMB per day for a period varying from 3 to 8 weeks. Subjects included men and women, both young and old, who took HMB with or without participating in a structured exercise program. Adverse effects were monitored by way of hematological work-up, a test of mood state, and an adverse-effects questionnaire. The review showed no adverse effects on any marker of tissue health or function. Ingestion of HMB resulted in a net decrease as compared to the placebo group in total cholesterol, low-density lipoprotein cholesterol, and systolic blood pressure. There was also a significant decrease in 1 indicator of negative mood with HMB supplementation. The HMB group showed a trend to reporting less loss of appetite and less diarrhea than the placebo group. A higher report of onset of stiff joints in the HMB group was dismissed as an artifact of pretest between-group differences. The authors concluded that HMB was well-tolerated and safe for use as an ergogenic supplement in humans.95 Testing and Regulation Beta-hydroxy-β-methylbutyrate is a natural component of food with a proven positive effect on blood markers of muscle damage and on anaerobic endurance. It is available in over-the-counter nutritional supplements and to date has not been banned by any sporting organization.103 Table 8 provides the take-home message on HMB. A word of caution to the novice (especially the 15

Table 8. Take-home Message for β-hydroxy-β-methylbutyrate

Alcohol is partly eliminated through breath, urine, and sweat (2% to 10%); higher excretion rates occur with higher temperatures and higher blood alcohol levels. However, the liver metabolizes the majority of alcohol (90% to 98%) at a constant rate of 100 mg/kg/h.105,106 The hepatic enzyme alcohol dehydrogenase converts alcohol to acetaldehyde. In turn, this substance is converted by the enzyme aldehyde dehydrogenase to acetic acid. Some 75% of ingested alcohol is released into the circulation as acetic acid and metabolized in the Krebs cycle to carbon dioxide and water. Acetic acid is also activated to acetyl coenzyme A, which is then further metabolized to fatty acids, ketones, amino acids, and steroid compounds.105 The speed of hepatic metabolism is determined by the function of liver enzyme systems. Age, menstrual cycle, heredity, race, liver disease, and experience with alcohol and other drugs may affect the function of these enzyme systems and thus alcohol metabolism and clearance.106 Alcohol is not metabolized by muscle, making it impossible to exercise oneself to sobriety.105 Alcohol causes vasodilation of superficial vessels: using alcohol to warm up in cold environmental circumstances may thus lead to heat loss and hypothermia. Alcohol is also a diuretic and may negatively affect electrolyte balance needed for optimal performance. The anticoagulant properties of alcohol may be a risk factor when combining alcohol use with contact sports. Alcohol also stimulates gastric secretion and appetite.106 The main effects of alcohol are mediated by its actions on the central nervous system. Ingesting alcohol lowers central calcium levels. This decreases the permeability of the axonal membranes to Na+ and K+, generally slowing nerve conduction. Alcohol also blocks release and synthesis of acetylcholine. Decreased activity in the ascending acetylcholinergic reticular pathway decreases cortical arousal and thereby lowers concentration, attention, skilled performance, and eventually short-term memory. Alcohol also inhibits tryptophan hydroxylase. This enzyme is responsible for the synthesis of serotonin. Decreased activity in serotonergic pathways lowers the experience of anxiety in stressful situations. The initial euphoric state when alcohol levels are increasing followed by mood reversal when alcohol levels drop again is related to the effect of alcohol on noradrenergic pathways. Alcohol also stimulates the brain to release dopamine, which improves mood, decreases nociperception, and eventually causes a mild cerebellar ataxia. In addition, alcohol stimulates glucose utilization in the brain, and the subsequent drop in brain glucose levels produces mental fatigue.105 Alcohol has been part of human culture at least since 8000 BC. Alcoholic beverages are produced in the form of beer (4% alcohol by volume), wines (12% to 20%), liqueurs (22% to 50%), and distilled spirits (40% to 50%). A “standard” drink usually contains 16 grams of alcohol.106

• β-hydroxy-β-methylbutyrate (HMB) supplementation has a proven effect on markers of muscle damage and anaerobic performance with equivocal effects on strength and body composition. • The literature reviewed indicates no negative side effects but rather a potentially cardioprotective effect from HMB supplementation. • HMB has not been banned by any sporting organization.

female athlete thinking of using HMB for ergogenic purposes) to avoid confusion between HMB and gammahydroxybutyric acid, abbreviated to GHB; this substance, which was originally developed as an anesthetic agent has been touted as an ergogenic substance and information on its manufacture is still available on the Internet, but it is now classified as a federal Schedule I controlled substance in the United States due to its documented use as a date rape drug.104 The importance of knowing one’s abbreviations is evident in this case. ALCOHOL Mechanism of Action Ethanol or ethyl alcohol is obtained by fermenting sugar. It is part of a group of chemicals called alcohols. Unlike most alcohols, ethanol (further called alcohol) is nontoxic except in large or chronic doses. Small amounts of alcohol (up to 7.5 milligrams total) are produced endogenously from bacterial fermentation in the gut and the action of alcohol dehydrogenase on acetaldehyde derived from pyruvate. Most alcohol is, of course, of exogenous origin.105 Alcohol is absorbed unaltered after ingestion in small amounts in the mouth, more in the stomach, but mostly in the small intestine.105,106 The rate of absorption depends on the type of alcoholic beverage, the speed of consumption, the concentration of alcohol and other chemicals in the beverage, gastric mobility, body weight, stomach contents, and factors influencing gastric emptying (beverage carbonation, emotional state, and condition of the stomach tissues).106 Absorption is quicker when alcohol is drunk on an empty stomach and when the beverage is carbonated and has high alcohol content. Absorption is slower with intense mental concentration, lower body temperature, and when exercising. Blood alcohol levels peak about 45 minutes after ingestion of a single drink. This peak is delayed by 15 minutes when strenuous exercise precedes the drink.105 Alcohol quickly penetrates all biological membranes including the blood-brain barrier, acting as an almost instantaneous central nervous system depressant. Although soluble in fat as well as water, alcohol does not distribute significantly into fatty tissue. This explains why similar quantities affect people with higher fat-free mass less than people with a higher proportion of body fat; women with, on average, a higher proportion of body fat are more affected by alcohol than equal-weight men.106 16

Effects on Performance Considering the effects of alcohol, it is unlikely that this substance has an ergogenic effect on measures of strength and endurance. It does, however, have potential as a performance-enhancing anxiolytic in highly stressful athletic events. In regard to the effects of alcohol on endurance, Borg et al107 studied the effects of 1 g/kg alcohol in fit men on performance during a progressive bicycle ergometer exercise protocol. Each subject served as his own control. Alcohol caused a significant increase in heart rate at an intensity of 50 W and 100 W (8 and 10 beats per minute, respectively). Thereafter, heart rate, systolic blood pressure, blood lactate, or rating of perceived exertion were not significantly affected by alcohol. The authors concluded that a moderate dose of alcohol did not affect exercise capacity. Blomqvist et al108 had healthy men ingest 150 milliliters of alcohol. At submaximal intensities, increased VO2 and increased heart rate resulted in increased cardiac output at equal workloads when compared to the no-alcohol test. Respiratory function was not altered by alcohol use and there were no changes at maximal intensity. The anxiolytic effects of alcohol may be beneficial to the performance of aiming sports such as darts, billiards, pistol shooting, archery, and snooker. Alcohol use in small doses is a common component of archery and darts. Reilly and Halliday109 tested subjects under 4 different conditions: sober, placebo, and 0.02% and 0.05% blood alcohol level. They found no significant effects on measures of isometric strength and muscular endurance but did find significantly dose-dependent slowed reaction time and impaired steadiness with alcohol ingestion. However, electromyographic measures indicated reduced muscle tremor with exercise. A similar study on dart throwing showed negative effects of the lighter alcohol dose on eye-hand coordination but increased balance and higher scores.110 A 0.05% blood alcohol level led to deterioration of performance on all tasks measured. In summary, moderate doses of alcohol do not seem to have a negative effect on endurance activities, but the lack of any ergogenic effect makes alcohol an unlikely choice for a performance-enhancing substance. Small amounts of alcohol may improve performance in some aiming sports.

lower incidence of coronary artery disease and myocardial infarction.105 However, methodological issues make the interpretation of these studies problematic.106 Side Effects Ingestion of alcohol results in both acute and chronic effects. Table 9 summarizes the acute effects of various blood alcohol levels.106 Whereas the effects of lower blood levels may be desirable at times, the effects of the higher levels clearly are not. Alcohol overdose occurs when excessive amounts of alcohol are ingested in a very short time and may result in death. Usually loss of consciousness occurs before overdose, but college and adolescent drinking games every year still result in multiple deaths.106 Relevant to the athletic setting is that postexercise alcohol consumption perturbs blood hemostasis and may increase risk of thrombosis.111 Also relevant is the deleterious effects that the nausea, vomiting, headache, and thirst associated with a hangover can have on athletic performance. Even nondependent binge drinkers without a history of heart disease run the risk of “holiday heart syndrome,” experiencing depressed cardiac function and arrhythmia.106 Table 9. Acute Effects of Different Levels of Alcohol Ingestion* Blood Alcohol Level

Effects

0.02

Sense of warmth and well-being in light and moderate drinkers.

0.04

Slight impairment of motor skills. Feeling relaxed, energetic, and happy.

0.05

Lightheadedness and lowered inhibitions. Slightly affected coordination.

0.06

Ability to make decisions regarding personal abilities affected.

0.08

Increased reaction time and impaired coordination. Heavy pulse and slowed respiration. May have numbness in lips, cheeks, and extremities.

0.10

Staggering, fuzzy speech. Judgment and memory affected. Legally drunk in most states.

0.15

Medical Indications Alcohol has been used in medicine as an antiseptic, an anesthetic, and a sedative. It is still used for sedation in liquid medications (eg, cough syrups).106 The use of alcohol as an anesthetic was stopped when the medical community realized that it was too dangerous to use in the large quantities needed for that purpose.105 Another medical use is during detoxification in a person with alcohol dependence.106 Cross-sectional studies have shown an association of light drinking with lower blood pressure, an increase in high-density lipoprotein cholesterol, and a

Definite impairment of balance and movement.

0.20

Slurred speech, double vision, and difficulty standing and walking.

0.30

Confusion and stupor. May lose consciousness.

0.40

Usually unconscious. Skin is sweaty and clammy.

0.45

Circulation and respiration are depressed or stopped.

0.50

Near death.

*Adapted from Stainback and Jansevics-Cohen.106

17

tered coffee contains more caffeine than percolated coffee and longer brewing increases caffeine content of tea. Caffeine is also added to many soft drinks and is available in over-the-counter cold and headache medications.114 Orally administered caffeine is absorbed by nearly 100%. It can be detected in the blood within 5 minutes from ingestion. Caffeine occurs in the blood mainly unbound; only 15% to 17% binds to plasma proteins. Peak plasma concentrations usually occur after 30 to 60 minutes with a range of 15 to 20 minutes due to interindividual variations in gastric emptying. Caffeine is water and lipid soluble and, therefore, diffuses rapidly from the plasma into all body tissues including the brain.114 Normally, the half-life of caffeine in the body is 3 to 6 hours.114,115 However, clearance is nonlinear so that higher doses are metabolized more slowly.115 Caffeine is broken down in the liver by the hepatic cytochrome P450 1A2 enzyme to theophylline (4%), theobromine (12%), and paraxanthine (84%).114,115 These metabolites have potencies similar to caffeine and contribute to the systemic effects.115 The P450 enzyme system also metabolizes selective serotonin selective reuptake inhibitors and the steroids in oral contraceptives. The use of oral contraceptive agents, selective serotonin reuptake inhibitor antidepressants, and alcohol reduces caffeine metabolism, thus raising plasma levels.114 High-intensity exercise slows elimination of caffeine, more markedly in women than in men.114 Cigarette smoking stimulates P450 activity and thereby enhances clearance of caffeine.115 Multiple mechanisms have been proposed to explain the ergogenic effects of caffeine.115,116 Caffeine inhibits the 5’-nucleotidase enzymes, and the resultant decreased conversion of adenosinemonophosphate (AMP) to adenosine may play a role in protecting exercising tissues from ischaemia.114 In vitro, caffeine also enhances calcium release from the sarcoplasmic reticulum. However, similar concentrations in vivo would be toxic to humans, making this mechanism unlikely.115,116 A third mechanism involves the caffeine-mediated inhibition of the cyclic nucleotide phosphodiesterase enzymes. Inhibition of these enzymes increases the activity of intracellular second messengers, including cyclic-AMP.114,115 Increased cyclic-AMP levels stimulate release of catecholamines (epinephrine and norepinephrine). The “glycogen-sparing” hypothesis suggests that these increased catecholamine levels may stimulate lipolysis, and promoting the release of free fatty acids may save glycogen stores for later use during prolonged exercise, thus delaying fatigue.115–118 Research shows inconsistent support for this mechanism, with reports of glycogen sparing only in the first 15 minutes of exercise at about 80% VO2max.119 The majority of the effects of caffeine seem mediated by a competitive antagonism for adenosine receptors. Activation of these receptors depresses neurotransmission, epinephrine and dopamine release, and lipolysis, and

Chronic alcohol abuse results in adverse health effects in multiple body systems. Probably the most telling outcome measure is that life expectancy of an alcoholic is 15 years less than that of a nondependent individual. Mortality rates among alcoholics are 2.5 to 3.3 times higher due to accidents, suicide, homicide, and other health issues.106 Alcoholic liver disease is the most common cause of liver disease in the Western world. Of all deaths attributed to liver disease, 75% are related to liver cirrhosis. In the United States, cirrhosis is the fourth leading cause of death in people aged 25 to 64.112 Cancer also occurs more frequently in cirrhotic livers. Women who drink alcohol regularly are more susceptible to breast cancer. Years of alcohol abuse can cause cardiomyopathy, generalized skeletal myopathy, pancreatitis, and cancer of the larynx and pharynx. Alcohol dependency can result in alcoholic psychosis.105 Alcoholism can also lead to encephalopathy and cerebellar degeneration.113 Alcohol easily crosses the placenta, and even 1 to 2 drinks a day can result in fetal growth retardation. More than 4 to 5 drinks a day during pregnancy may result in fetal alcohol syndrome with mental retardation, microcephaly, growth deficiencies, and facial abnormalities.106 Testing and Regulation In most countries, law restricts the use of alcohol by minors. In some countries in the Middle East, there are strict religious edicts against the use of alcohol.106 Alcohol is prohibited in several sports (eg, modern pentathlon, fencing, and shooting).105 The NCAA has banned alcohol from rifle-shooting competitions.106 In other sports such as darts, snooker, and billiards, the use of alcohol is still very much an accepted part of competition.105 Table 10 contains the take-home message for alcohol. Table 10. Take-home Message for Alcohol • Alcohol has no proven ergogenic properties in the sense of increased strength or endurance. • In low doses, it may confer an advantage in aiming sports. • Alcohol in large or chronic doses is toxic with adverse health effects in multiple organ systems. Law and religion limit or prohibit the use of alcohol. • Alcohol is prohibited in modern pentathlon, shooting, and fencing.

CAFFEINE Mechanism of Action Caffeine (1,3,7-trimethylxanthine) is a member of the methylxantine group, which also includes theophylline, paraxanthine, and theobromine. Caffeine occurs naturally in more than 60 plants, including coffee, tea, cocoa, and guarana.114,115 Caffeine content of foods and beverages depends to a large extent on processing method; fil18

increases glycogenolysis and muscular glucose uptake.114,115 Stimulation of A2 receptors causes peripheral and cerebral vasodilation, and A3 receptor stimulation inhibits eosinophil migration.114 Even at physiologic levels, caffeine, theophylline, and theobromine are strong competitive antagonists of the adenosine A1 and A2 receptors; caffeine is also a weak antagonist of the A3 receptor. Chronic caffeine ingestion increases the number of adenosine receptors, thus providing a plausible explanation for the observed tolerance to caffeine.115 Table 11 summarizes the widespread systemic effects of caffeine.114

effects on peak torque, power, and endurance with isokinetic knee flexion and extension. Plaskett and Cafarelli117 administered 6 mg/kg of caffeine or a placebo to men (22.6 ± 0.6 years) not using caffeine. They found a significant increase in endurance measures (17 ± 5.25%) during repeated isometric contractions at 50% of maximum voluntary capacity and a significant increase in maximum voluntary capacity (5 ± 2%) in the caffeine condition. However, these changes were not the result of simultaneously monitored contractile characteristics. Rather, the authors showed a decrease in force sensation with caffeine, and they attributed the observed ergogenic effects to alterations in muscle sensory processes due to caffeine ingestion. Greer et al123 administered placebo or 6 mg/kg caffeine to recreationally active men (29.1 ± 2.7 years) and found no effect on peak and average power output during 4 consecutive 30-second Wingate sprint cycling tests. As for effects on aerobic endurance, Hunter et al124 administered 6 mg/kg of caffeine and 0.33 mg/kg top-up doses every 15 minutes or placebo to trained male cyclists during a 100-kilometer trial ride with several high-intensity intervals. They found no significant between-group differences in total time, interval performance, average power, and electromyographic measures. Cole et al125 provided 6 mg/kg of caffeine or placebo to 10 subjects. They noted a significant increase in average total work for the caffeine group only on a 30-minute cycling test involving periods with ratings of perceived exertion varying from 9 to 15 on the Borg rating of perceived exertion scale. Birnbaum and Herbst120 administered 7 mg/kg of caffeine or placebo to male and female collegiate cross-country runners. Subsequent treadmill runs at 70% VO2max resulted in significant between-group differences in tidal volume, alveolar ventilation, and rating of perceived exertion favoring the caffeine group. Bell and McLellan126 had caffeine users and nonusers (32 ± 7 years) ingest 5 mg/kg of caffeine or placebo and then measured time to exhaustion 1, 3, and 6 hours after ingestion on a bicycle test at 80% VO2max. They found significant between-group differences favoring the caffeine group at all times for nonusers and at 1 and 3 hours for caffeine users and noted that the ergogenic effects of caffeine were greater in the absence of habituation. In summary, caffeine may have an effect on maximal isometric force and submaximal isometric endurance but seems to lack an effect on dynamic measures of strength and muscular endurance. Research supports an ergogenic effect on moderate-intensity to high-intensity activities lasting 90 to 120 minutes.115 These effects appear to be smaller in habituated caffeine users, but responses are again potentiated after 4 days of caffeine withdrawal.117 The evidence for caffeine as an ergogenic substance in female athletes is limited.119

Table 11. Effects of Caffeine • Increased gastric acid and pepsin secretion. • Increased heart rate, stroke volume, cardiac output, and resting blood pressure. • Increased lipolysis. • Increased skeletal muscle contractility. • Increased oxygen consumption and metabolic rate. • Increased urinary output. • Potentiation of the antinociceptive action of nonsteroidal anti-inflammatory drugs. • Mild independent antinociceptive action. • Increased vigilance and attention. • Decreased deterioration of cognitive performance with fatigue. • Effects on mood ranging from increased vigor and euphoria to dysphoria and anxiety.

Caffeine for ergogenic purposes is sold in the form of tablets, as a powder contained in gelatin capsules, and as suppositories.114,119,120 Athletes have also used caffeinated beverages as a source of caffeine. Caffeine is absorbed more slowly from soft drinks than it is from tea or coffee. Pure caffeine may have greater ergogenic effects than equivalent amounts of caffeine from coffee, which may also contain antiergogenic compounds.114,119 Effects on Performance It is difficult to hypothesize as to the expected ergogenic effects of caffeine due to the multiple peripheral and central mechanisms proposed for its action. The direct effect on muscle calcium kinetics would indicate an effect on strength and muscular endurance. The mechanisms of action involving alterations in substrate utilization and central excitation would seem to indicate a possible effect on prolonged aerobic activities. As for strength and endurance effects, Jacobson and Edwards121 administered placebo, 300 milligrams, or 600 milligrams of caffeine to men and women with similar caffeine-consumption histories. They found no significant effects for peak torque and muscular endurance on isokinetic tests of the knee flexors and extensor muscles. Bond et al122 administered 5 mg/kg of caffeine or placebo to male collegiate track athletes and found no significant

Medical Indications The potentiation of the analgesic effect of nonsteroidal anti-inflammatory drugs in combination with 19

and methylphenidate.114,128 Methylphenidate is probably best known as the drug Ritalin, which is used in the treatment of attention-deficit/hyperactivity disorder.128 Methamphetamine and its derivative methamphetamine hydrochloride are illicit street drugs with high addiction and abuse potential.129 Amphetamine or phenyl isopropylamine was first synthesized in 1887 and first introduced as a drug by the name of Benzedrine in 1920.114,128 Amphetamines are mainly absorbed from the small intestine and reach peak plasma levels 1 to 2 hours after administration. Complete absorption occurs within 2.5 to 4 hours and is increased by simultaneous intake of food.114 Some 20% binds to plasma proteins.128 Amphetamines are cleared from the body by renal filtration with an elimination half-life of 10 to 13 hours.114,128 Most amphetamine is excreted unaltered, but a small portion is excreted in the form of its main metabolites, p-hydroxyephedrine and p-hydroxyamphetamine. These metabolites have a pharmacological action similar to that of the parent substance.114 There are multiple suggested mechanisms of action for amphetamines. Amphetamines may increase presynaptic release of the neurotransmitters norepinephrine, dopamine, and serotonin. Amphetamine-mediated inhibition of monoamine oxidase activity decreases the breakdown of serotonin and dopamine. Amphetamines also decrease dopamine and norepinephrine reuptake.114,128,130–132 Increased release and decreased reuptake and metabolism result in increased synaptic neurotransmitter concentrations with resultant increased local nerve-impulse transmission. George114 also noted a possible direct effect on the neurotransmitter receptors. The main effect of amphetamines seems mediated by activation of noradrenergic pathways.114 Amphetamines have an agonist activity on α1, α2, and, to a lesser extent, β1 noradrenergic receptors.130 Stimulation of α1-receptors on vascular smooth muscle produces muscle contraction and resultant vasoconstriction. Other effects have been identified on spinal cord interneurons whose disinhibition produces increased motor neuron excitability. Stimulation of the β1-receptors, located mostly on the myocardium, results in increased heart rate and cardiac output.130 Overall effects are summarized as increasing blood pressure and heart rate, as well as glycogen and fatty acid metabolism.133,134 Amphetamines can be taken orally as a tablet, inhaled as a nasal spray, or injected.114,128 Methamphetamine hydrochloride crystals are inhaled by smoking, albeit hardly for ergogenic reasons.129

the independent antinociceptive properties of caffeine has led to the inclusion of caffeine in a number of pharmacological preparations, including over-the counter headache and cold medications.114,116 Birnbaum and Herbst120 suggested a possible role for caffeine in athletes with exercise-induced asthma. Side Effects Caffeine results in mood effects generally perceived as positive with doses of up to 100 to 200 milligrams. Doses greater than 400 milligrams cause lowered mood and anxiety. Mild side effects of caffeine use can include nervousness, irritability, insomnia, and gastrointestinal upset. Severe adverse effects include peptic ulcers, delirium, coma, and seizures. Doses greater than 200 mg/kg have been associated with supraventricular arrhythmias. The main chronic side effect of caffeine use is elevation of serum cholesterol levels. Caffeine intoxication may simulate an anxiety attack with nausea, insomnia, nervousness, and jitteriness. Caffeinism is a medical syndrome involving anxiety, mood changes, sleep disruption, psychophysiological changes, and withdrawal symptoms. Caffeine withdrawal can result in headaches, muscular twitching, decreased mood states, insomnia, and irritability.114,127 Testing and Regulation In the context of athletic competition, caffeine is a controlled and restricted substance. The IOC considers postcompetition urinary levels exceeding 12 mg/mL indicative of illegal use of this substance for ergogenic purposes.117,118 The NCAA uses an upper limit of 15 mg/mL. Generally, ingestion of 9 mg/kg causes the athlete to achieve urinary levels of 12 mg/mL.118 Caffeine is regulated under the Dietary Supplement Health and Education Act and as such content and dose of caffeine supplements is not evaluated or certified.115 Table 12 contains the take-home message for caffeine. Table 12. Take-home Message for Caffeine • Caffeine has a proven ergogenic effect on activities requiring aerobic endurance. • Caffeine may have some effect on muscular endurance during submaximal tasks. • At ergogenic doses, the potential for serious adverse effects is small. • Insufficient evidence exists on the ergogenic effects in women athletes. • Caffeine is a restricted substance in athletic competition, but it has proven ergogenic effects well below legal limits.

Effects on Performance Amphetamines are commonly called uppers because they produce euphoria, false self-confidence, and selfassertion or aggression in addition to masking fatigue.134–136 The decreased sense of fatigue and increased self-confidence are among the effects that have prompted abuse by athletes, even to the point of playing with an injury.132

AMPHETAMINES Mechanism of Action Amphetamines are a group of structurally related drugs also called phenethylamines that includes dextroamphetamine, methamphetamine, phenmetrazine, 20

Other athletes such as ballet dancers, wrestlers, and gymnasts have used the appetite-suppressant dopaminergic effects to maintain a low body weight.136 Amphetamines do not increase intellectual performance unless fatigue and boredom have degraded performance. Amphetamines do increase short-term learning of new tasks. Amphetamines also cause a small distortion of time perception that may interfere with motor planning.114 Earliest studies produced conflicting results regarding amphetamine effects on aerobic and anaerobic performance. A landmark double-blind comparison of weightlifting performance, swimming, and running demonstrated performance improvement in all 3 areas, with the largest increase of 3% to 4% in weightlifting.137 Swimming performance improved the least. Another study138 prior to 1970 measured amphetamine effects on swimming and running, and contradicted those results with findings of either neutral or negative results in untrained individuals. Similar studies on aerobic performance were repeated recently and the effects were not found, possibly because the Controlled Substances Act of 1970 made amphetamines illegal for ergogenic purposes.139 Later work concluded that subjects given amphetamines were able to maintain exercise longer under anaerobic conditions.140 Significant improvements were noted in strength, acceleration, and aerobic power. Notable is the finding that lactic acid and exercise endurance increased during maximal exercise while VO2 was not affected, supporting the premise that amphetamines mask, rather than delay, fatigue.140 In summary, the current view is that amphetamine use does not enhance athletic performance directly; however, a 1% to 2% increase in short-term power activities may be produced due to enhanced confidence and aggression.132

reduced appetite, insomnia, headaches, convulsions, hallucinations, confusion, delirium, sweating, palpitations, pupil dilation, rapid breathing, tremors, muscle and joint pain, and paranoia.114,141 Initially, amphetamine use results in an increased sex drive, but prolonged use frequently reduces the libido and may cause erectile dysfunction.114,128 Amphetamine use can cause death from cerebral hemorrhages, myocardial infarctions, and arrhythmias.141 Amphetamines cause a redistribution of blood away from the skin, thus limiting the normal cooling of blood. The resultant heat stroke has claimed the lives of multiple cyclists during grueling road races.114 Chronic amphetamine use by adolescents may result in growth retardation.114 Chronic effects may also include reversible hearing loss; tremors; nerve damage; vascular disorders; liver, kidney, and lung damage; immune system depression; restlessness; and altered sleep patterns.128,141,142 Behavioral side effects include anxiety, depression, mood swings, aggressive outbursts, panic attacks, and paranoia.131,143–145 The euphoric effects and the indifference, slowness in reasoning, and irresponsible behavior associated with amphetamine use may affect judgment needed in sports.114 Amphetamine withdrawal can cause depression. Chronic high-dose amphetamine use can cause persistent personality changes including amphetamine psychosis. This disorder resembles paranoid schizophrenia but with a preponderance of paranoid and tactile hallucinations.114 There is also mounting evidence that heavy amphetamine abuse both initiates and maintains chronic schizophrenia.146 Testing and Regulation In the United States and internationally, amphetamines are Schedule II controlled substances.128,130 The IOC and the NCAA have banned all amphetamines. Major League Baseball does not explicitly ban amphetamines, but testing for minor league contracts does include these drugs among the banned substances.136 Amphetamines are readily detected in the urine. Amphetamines are abused more as performance drugs than as training drugs, so detection is most likely when drug testing is performed during competition.136 The screening test is performed by immunoassay. This is an antibody-based testing method used for initial screening of specimens. The immunoassay is sensitive to drug groups, as opposed to individual specific drugs. False positives can occur due to the presence of other related drugs. Immunoassays can be performed in a laboratory or on-site with an instant-type test. If the immunoassay is positive, a gas chromatography/mass spectrometry (GC/MS) test will be done. The GC/MS test is very specific. It is based on the physical and chemical properties of the specific drug or metabolite to be measured. A positive result indicates the use of a drug containing methamphetamine, amphetamine, or a drug that is metabolized to these substances. A GC/MS confirmation

Medical Indications Amphetamines were originally used as nasal decongestants and later as stimulants to increase alertness in air force servicemen during prolonged missions.114,128 Until recently, amphetamines were prescribed to treat narcolepsy, but now their only medical use is in the treatment of attention-deficit/hyperactivity disorder.114 Medical use of amphetamines for weight loss is still approved in some countries but is discouraged in the United States due to the high abuse potential.128,130 Side Effects Amphetamines cause a number of side effects as a result of their noradrenergic receptor activity130: • α1: Increased blood pressure, headache, reflex bradycardia, chest pain, dyspnea, nervousness • α2: Dizziness, drowsiness, dry mouth, dyspnea, bradycardia, syncopal episodes • β1: Chest pain, cardiac arrhythmia, dyspnea Side effects may be classified as acute or chronic. Acute effects may include tachycardia, hypertension, 21

ninefold.149,150,153 Cobalt, thyroid hormone, adrenal corticosteroids, growth hormone, and stimulation of peripheral chemoreceptors all increase EPO production.150 Excessive tissue oxygen tension brings about a reduction of produced EPO and consequently red blood cells.152 Erythropoietin stimulates proliferation of late burstforming unit erythroid cells and controls the maturation rate of colony-forming unit erythroid cells by way of a receptor-mediated effect.150 Specifically, binding of EPO to an erythroid progenitor cell-surface receptor that includes a p66 chain dimerizes this p66 protein.151,153 Erythropoietin-receptor binding also engages a regulator of inflammatory and immune genes, additionally inducing survival proteins and cell proliferation.151,154 Other hematopoietic growth factors can mature cells, have overlapping capabilities to affect progenitor cells of several blood cell lines, and also affect cells outside the hematopoietic system, but EPO is specific for erythroid progenitor cells and has little effect on other cells.152 This specificity of EPO makes it a valuable pharmacological tool.155 Additional effects of EPO include hematocritindependent and vasoconstriction-dependent hypertension, increased endothelin production, tissue renin upregulation, stimulation of angiogenesis, and proliferation of endothelial and vascular smooth cells.151,154 Erythropoietin was originally prepared by concentration and purification of urine from patients exhibiting high EPO levels, such as those suffering from aplastic anemia and similar pathologies. This made EPO expensive and thus hardly accessible for medical and ergogenic purposes.152,156–158 Identification and characterization of the gene for EPO on chromosome 7 has allowed for the larger scale production of recombinant human EPO (rHu-EPO).150 In 2001, the FDA approved darbepoietin-α, or novel erythropoiesis stimulating protein (NESP).150 Novel erythropoiesis stimulating protein contains 3 additional N-linked carbohydrate chains and has an approximately threefold longer serum half-life, 10 times the potency of EPO, and can, therefore, be administered less frequently to obtain the same response as EPO.150,151,159,160 The normal therapy with rHu-EPO for the treatment of anemia is 20 to 240 IU/kg 2 to 3 times per week by injection, in some populations, for the lifetime of the patient.159 Dosages used by athletes to improve sports performance have been higher than described above but vary due to dose response. A recent study demonstrated that regular low doses of rHu-EPO may produce readings of hematocrit that fall within the allowable threshold for regulated sports participation while still providing enhanced aerobic performance.161 Erythropoietin and NESP are administered by injection either subcutaneously or intravenously. Erythropoietin-stimulated erythropoiesis highly increases the demand for ferrous iron in the production of hemoglobin and necessitates simultaneous iron injections.150

is considered to be the “gold standard” in the drug-testing industry as it is said to be 100% accurate.147 Amphetamines can be detected from 2 to 4 days after use by GC/MS technology.136 Table 13 contains the take-home message for amphetamines. Table 13. Take-home Message for Amphetamines • Amphetamines may mask fatigue and increase anaerobic performance, possibly due to enhanced confidence and increased aggression in healthy subjects. • Serious physical and behavioral side effects including death can result both acutely and chronically. • Amphetamines are Schedule II controlled substances. • Accurate screening and substance-specific tests are available and are used.

ERYTHROPOIETIN Mechanism of Action The erythrocyte, or red blood cell, is the most common cell type in the blood. It is responsible for delivery of oxygen to tissue beds. A mature red blood cell is stuffed full of hemoglobin and contains almost none of the normal cell organelles, with the nucleus, endoplasmic reticulum, mitochondria, and ribosomes extruded from the cell during development.148 As a result, the red blood cell cannot grow or divide; the lifespan of human erythrocytes is limited to about 120 days. Worn-out red blood cells are phagocytosed and digested by macrophages in the liver and spleen to avoid cellular debris that would attract the attention of inflammatory cells.148 The only way to make more erythrocytes is by stimulation of erythropoiesis in the hemopoietically active bone marrow.149 Erythropoiesis involves differentiation from totipotential hematopoietic stem cells to pluripotential myeloid stem cells. Cytokines stimulate the further maturation into unipotential or committed precursor cells, including burst-forming unit erythroid cells. Under the influence of interleukin-3, granulocyte-macrophage colony-stimulating factor, and erythroid-promoting factor, burst-forming unit erythroid cells mature into colony-forming unit erythroid cells. The colony-forming unit erythroid cells that eventually give rise to the erythrocytes are the first cells sensitive to erythropoietin (EPO).150 Erythropoietin is a glycoprotein hormone that consists of 165 amino acids with a molecular mass of 18 kDa and a 30 kDa carbohydrate component.150 In the fetus, it is produced by hepatocytes; in the adult, 90% is produced by peritubular cells in the kidneys and 10% by the liver.150–152 Normal serum concentration is approximately 20mU or 10pmol. These concentrations vary throughout the day and are greatest around midnight. Erythropoietin half-life is 6 to 9 hours and it is inactivated in the liver.150 Erythropoiesis normally proceeds at a low basal level to replace old red blood cells.149 Hypoxia, or lack of oxygen, increases production of the hormone and can increase red blood cell production as much as sixfold to 22

Medical Indications Erythropoietin is administered medically to replenish the body’s supply of this hormone and correct anemia.159,169–171 Replacement of EPO alone, however, does not suffice for full erythropoiesis to occur properly. For example, this therapy is not fully effective in patients with iron-processing deficiency or patients who have problems with other aspects of erythropoiesis that are not controlled by EPO.172 The FDA has also approved rHu-EPO for use in patients with chronic renal failure, lympho-proliferative diseases, myelodysplasia, myelofibrosis, and aplastic anemia, and for patients after bone marrow transplantation.151,169 It is also indicated for use in patients scheduled to undergo elective, noncardiac, nonvascular surgery.159 In addition, the drug has been used in premature infants during the first 2 weeks of life, although this has been controversial due to the questions remaining regarding administration timing and dosing regimen.173 Current research is studying use of rHu-EPO as a multifunctional tissue-protective cytokine for vascular protection after acute ischemic stroke.154,174

Effects on Performance Sports events lasting more than 1 minute depend predominantly on aerobic energy production. Therefore, performance will be limited by the ability to deliver oxygen to the working muscles. Limiting factors in oxygen uptake and delivery are cardiac output and oxygen-carrying capacity of the blood. The latter is determined by hemoglobin content. Increased total body hemoglobin levels may allow for increased endurance performance. Several methods have been used to augment hemoglobin content, some permitted (altitude training, hypobaric oxygen tents) and others not permitted (blood doping, blood substitutes, hemoglobin modifiers, plasma expanders, actovegin, EPO and its derivatives). Based on its mechanism of action, the authors would expect to see positive effects of EPO use on aerobic performance.150 Use of rHu-EPO has been shown to positively affect an athlete’s VO2max,162–165 increasing it by an additional 7% over altitude training, along with a 9% increase in cycling time to exhaustion after 4 weeks of use. Earlier studies provided support that rHu-EPO increased VO2max and sport performance such as running.151 Prolonged low doses of rHu-EPO, rather than the original higher dosages, were tested later for their effect on hematocrit levels with submaximal and maximal exercise, confirming the ability of the drug to maintain elevated hematocrit levels 4 weeks after the final injection.166 Berglund and Ekblom167 administered 20 to 40 IU/kg of rHu-EPO 3 times a week for 6 weeks to 15 healthy men and found a significant pretest to posttest decrease in heart rate during submaximal (200 W) bicycle ergometer exercise. Birkeland et al163 administered placebo or 181 to 232 IU/kg/wk of rHu-EPO for 4 weeks to male athletes. There was a significant 7% pretest to posttest increase in VO2max in the EPO group but no change in the placebo group. Connes et al164 administered rHu-EPO for 4 weeks to 16 endurance-trained athletes and found both an acceleration of the response of VO2 to submaximal exercise and an increase in maximal exercise capacity at VO2max during cycling exercise. Wilkerson et al168 hypothesized that 4 weeks of rHuEPO treatment would produce a significant increase in hemoglobin concentration and arterial blood oxygencarrying capacity, which would then increase VO2 during ramp incremental exercise and speed VO2 kinetics during a maximal-intensity step exercise. Although treatment resulted in a 7% increase in both hemoglobin and VO2 peak, they found no significant effect on VO2 kinetics at any level of exercise. In summary, EPO appears to positively affect submaximal and maximal endurance performance. Not surprisingly, EPO abuse has been documented among crosscountry skiers, cyclists, middle-distance runners, and rowers.150

Side Effects A phase-3 multicenter clinical trial of the use of rHuEPO in 333 patients on hemodialysis with uncomplicated anemia demonstrated the following side effects: myalgia, iron deficiency, hypertension, and seizures.175 Use of rHu-EPO as a performance-enhancing drug has the potential to increase blood viscosity and produce potentially fatal thrombosis.176 In plain terms, rHu-EPO and NESP have the potential to increase red blood cell numbers, leading to thicker blood; when coupled with dehydration during sports performance, this may result in blood clots, thrombosis, and eventually heart attacks.176,177 During 1987 to 1990, soon after rHu-EPO became available, 18 young Belgian and Dutch high-level competitive cyclists died suddenly of heart attacks. No definitive link between the deaths and rHu-EPO use was established, but it was speculated that misuse of the drug was responsible.177 Between 2003 and 2004, an additional 8 cyclists died of sudden heart attacks, with similar suspicions raised.178 The need for simultaneous injections with ferritin has the added possible adverse effect of iron overload, with iron deposition in various tissues and organs leading to organ failure including liver cirrhosis. Increased ferritin levels (as detected in elite competitive cyclists) also increase the risk of hepatic carcinoma.150 Testing and Regulation Many competitive sports organizations including the IOC, International Cycling Union, and International Skiing Federation have banned the use of EPO and NESP.165 Unfortunately, there are problems with direct detection in the blood or urine due to a short half-life (rHu-EPO) and a structure similar to endogenous EPO. Also, performance elevation outlasts detectable drug presence in the 23

ments.184 Other ethical considerations are less specific to the profession but concern society as a whole. Currently, society and sporting organizations condemn on ethical grounds the use of banned ergogenic substances as providing an unfair advantage in competition. However, a prominent commitment for all health care providers is the prevention of adverse health outcomes. Perhaps for a health care provider, the question of whether a substance is in fact truly ergogenic and whether an athlete is using said substance should be less relevant than the question of whether the use of said substance could adversely affect the athlete’s health.185 Monitoring the athlete’s health by setting standards for physiological parameters with or without the use of ergogenic aids would not only level the playing field but also provide strict control against athlete morbidity and even mortality. For example, permitting the use of relatively cheap EPO, but at the same time setting safe upper limits for hematocrit for sports participation, might allow athletes that cannot afford legal methods of elevating red blood cell count (eg, altitude training and hypobaric oxygen tents) to safely compete with those athletes that do have the required financial backing.185 Revising doping regulations based on this paradigm would allow society to concentrate limited resources on the truly dangerous methods and substances. This position would seem most consistent with principle 4.1 (A) of the APTA Guide for Professional Conduct,183 which requires the therapist to act in the client’s best interests, but obviously this issue requires discussion at the societal level. One ethical question specific to the profession relates to the role of the physical therapist in providing a patient with education and advice regarding the use of ergogenic substances. These substances are no different from other pharmacological or nutritional substances used by the patient in that the physical therapist needs to be aware of intended and adverse effects on the patient and the possible interaction of these substances with the physical therapy interventions provided. Ahrendt10 suggested that the physician confronted with this situation should make sure to be knowledgeable about the topic and then provide the patient with detailed information about what is known and not known with regard to a specific product based on current research with an indepth discussion of the potential adverse effects. The information in this monograph should allow a physical therapist to do just that. Providing patient education is consistent with principle 8.1 (A) of the APTA Guide for Professional Conduct,183 which indicates that the therapist has the responsibility to provide the patient with accurate and relevant information related to the patient’s condition and plan of care. However, providing a patient with a specific plan of care that includes nutritional and pharmaceutical interventions is not part of the physical therapy scope of practice. In principle 11.1, the Guide for Professional Conduct183 discusses the need for consultation and referral to health care professionals with

body.179 Studies have focused on indirect markers of increased erythropoiesis, such as serum levels of soluble transferrin receptor, reticulocyte concentrations, and hematocrit levels, to detect presence or previous use of the drug. In 1997, the International Cycling Union enacted a provision that prevented athletic participation for a 2-week period without formal suspension based on blood hematocrit levels greater than 50% for men and 47% for women. A normal average hematocrit level for cyclists is 43%.165 Serum levels of soluble transferrin receptor may be used as an indirect marker up to 1 week after administration of rHu-EPO. However, performance effects far outlast this time period.163,165 Chemiluminescent immunodetection of EPO in urine after isoelectric focusing has similar time limitations of use.180 One author181 noted that for the most accurate detection in sports testing, the physiological effects of EPO or NESP that last beyond drug use should be measured and factored together with the indirect blood markers. The IOC currently uses a combination of blood and urine tests, but their validity has been questioned successfully in a court of law.150 Table 14 contains the take-home message on EPO. Table 14. Take-home Message for Erythropoietin • Erythropoietin increases maximum oxygen consumption. Effects far outlast use, as elevated hematocrit levels are maintained up to 4 weeks after injection. • Side effects from use to enhance sports performance include increased blood viscosity and potentially fatal thrombosis. • The need for simultaneous ferritin injection increases the chance of iron deposition disorder with multiorgan failure. • Testing involves a combination of blood and urine samples, but test validity has been questioned successfully.

ETHICAL AND LEGAL CONSIDERATIONS FOR THE PHYSICAL THERAPIST As discussed in the introduction to this monograph, some ergogenic substances are controlled substances, and the only legal way to obtain and use these substances is when prescribed by a medical physician. All controlled and some uncontrolled ergogenic substances are considered doping and banned by various sporting organizations. This means that the physical therapist confronted with a patient who reports using illicit or banned substances has to deal with various legal and ethical considerations. With regard to these ethical considerations, members of the American Physical Therapy Association (APTA) are bound by oath by 2 documents that describe ethical professional conduct: the APTA Code of Ethics182 and the APTA Guide for Professional Conduct.183 Some state legislatures have adopted these documents as part of the physical therapy state practice act, adding a legal dimension to ethical conduct as described in these docu24

activities (Section 961). This would certainly seem to impact therapist decisions based solely on ethical guidelines regarding patient confidentiality. Legal enforcement of ethical guidelines incorporated in state practice acts suffers from unclear definitions184 but adds another level of complexity to decision making. The authors of this monograph suggest that therapists with questions on these issues seek legal counsel. The topic of ergogenic substance use by patients in physical therapy raises many unanswered ethical and legal concerns. The authors of this monograph do not have all of the answers; seeking the assistance of the state physical therapy licensing board or legal counsel may be required. Further discussion within society as a whole and within our professional organization in particular is clearly needed in order to provide additional guidelines for clinicians.

specialized knowledge and skills (ie, in this scenario, a physician or nutritionist). Another ethical problem arises from the fact that many of the substances discussed in this monograph are illegal to use if they are not on prescription by a physician for medical purposes. What is the ethical responsibility of the therapist who has knowledge of the fact that the patient is engaging in illegal behavior by having procured and used controlled substances without a physician’s prescription? Principles 1.1 (A) and 2.3 (A) describing the need to respect the patient’s choices and the need for confidentiality would seem to apply.183 However, when it becomes clear to the therapist that the patient is not only using but also trafficking these substances and selling them to other users or if the therapist becomes aware of the mode of supply for the patient, the therapist’s ethical responsibilities with regard to the health status in the community at large, described in principle 10.2 (B),183 would seem to supersede the principles related to the individual mentioned earlier, and the law enforcement community should be contacted. The APTA Ethics and Judicial Committee is meant to provide more clarity on these 2 issues in a March 2006 meeting. There are many additional ethical questions related to patients abusing certain illegal ergogenic substances that have the ability to cloud patient judgement.186 An impaired response to our therapy intervention potentially puts the patient at risk for injury. But how do we determine if the patient is under the influence of a substance that may affect judgment? If the patient does not voluntarily report relevant substance abuse, then the therapist has no way to detect, for example, the use of alcohol, amphetamines, other stimulants, or AAS, which may all potentially impair response to treatment. Do we proceed with treatment or do we deny treatment? Do we have the patient sign a release of liability form and proceed with treatment, putting the patient at risk for iatrogenic injury? Do we report the reason we denied treatment and put the patient at risk of losing insurance coverage? And if we do decide that patient judgment is impaired, can we allow patients to leave the clinic in their vehicle, endangering both themselves and others on the road? For any specific ethical questions, the APTA suggests that you refer to your state board (personal communication, APTA executive office, February 2006). There are, of course, also legal considerations. As noted by Bennett,184 a therapist may have an ethical duty to perform a certain action, but if no law mandates such action, the therapist has no legal obligation. Conversely, if a therapist has an obligation under law to perform a certain action, then that law is binding even if there is no corresponding documented ethical obligation. Federal legislation dealing with controlled substances187 contains provisions for requiring testimony from witnesses (Section 884) and for fining and imprisoning people who fail to notify authorities of their knowledge of drug trafficking

CASE STUDIES Case Study 1 Subjective information Annika is a 24-year-old right-hand dominant Olympic-level competitive rower. Her current level of training is very high in anticipation of an Olympic qualifying meet and includes both an increased volume and intensity of work on the water, on the rowing ergometer, and in the weight room. Over the last 3 weeks she has noted a general fatigue and discomfort in the right arm during but even more so after a workout. Overhead activities also bring on these symptoms. She has also noted some intermittent purple discoloration of the right hand and paresthesia in the ulnar forearm and hand, especially upon awakening and with exertion. Her previous and concurrent medical history is unremarkable as is her family history except for an inherited coagulopathy involving factor V Leiden. Annika reports using oral contraceptives but no other medications. As she is a direct access patient, she has had no further diagnostic tests done and, in fact, has not seen a physician for this current complaint. Annika reports being in overall good general health. Objective findings • Observation: The patient has a mesomorphic build with a moderate forward head posture and rightsided elevated shoulder girdle. The right arm is notably cyanotic. • The superficial veins of the arm are dilated and there is general nonpitting edema of the right arm. • Palpation reveals tenderness along the right axillary vein in the medial bicipital sulcus. • Active range of motion: Cervical and upper extremity range of motion are bilateral within normal limits except for shoulder flexion and abduction right, which are pain free but limited by 15° as compared to the right. 25

•

Elevated arm stress (Roos) test produces right arm discomfort, discoloration, venous distension, and ulnar distribution paresthesia within 30 seconds. These findings are all symptomatic of subclavian and axillary vein deep venous thrombosis.188 On further questioning and after discussion of patient confidentiality requirements in physical therapy, Annika hesitantly reports using rHu-EPO in an attempt to increase her athletic performance. She is referred to the emergency department of the local hospital with the clinical suspicion of upper extremity deep venous thrombosis. A right subclavian vein thrombus is subsequently diagnosed by contrast venography, and treatment with anticoagulants is immediately initiated.

pain. His previous medical history includes multiple tendinopathies in the shoulders, knees, and ankles. A family history is positive for myocardial infarction and cerebrovascular accidents. John denies any medication use. A systems review yields no remarkable findings. John reports being in good health but has lately been a bit fatigued, which he blames on a high training volume. Objective findings • Observation: The patient has a very muscular mesomorphic build with rounded shoulders and a forward head posture. Generalized acne and multiple striae are noted, as is a seemingly increased carrying angle for the left elbow. • Active range of motion: Range is similar bilaterally for the wrist and elbow with the exception of decreased forearm supination and decreased wrist radial deviation left versus right. • Manual muscle tests of the wrist and elbow are 5/5 bilaterally with pain noted on wrist extension, forearm supination, and elbow flexion with pronation left. • Neurodynamic tests for a radial nerve distribution are negative bilaterally. • Varus stress test on the left causes lateral elbow pain, and excursion is decreased compared to the right elbow. • Passive accessory motion tests in the wrist and elbow are normal bilaterally with the exception of decreased lateral glide of the left forearm. • Palpation reveals tenderness over the extensor carpi radialis brevis tendon on the left but with no local swelling or increased temperature.

Guide to Physical Therapist Practice diagnosis The diagnosis according to the Guide to Physical Therapist Practice189 is: • Practice pattern 6A: Primary prevention/risk reduction cardiovascular/pulmonary disorders. • Practice pattern 4D: Impaired joint mobility, motor function, muscle performance, and range of motion associated with connective tissue dysfunction. • Practice pattern 5F: Impaired peripheral nerve integrity and muscle performance associated with peripheral nerve injury. Discussion One of the major adverse effects of EPO is the increased risk for thrombosis. Oral contraceptive use (especially of so-called third-generation contraceptives containing desogestrel or gestodene) has been associated with an increased relative risk for venous thromboembolism.190 The relative risk for upper extremity deep venous thrombosis is increased in women with factor V Leiden coagulopathy when combined with oral contraceptive use.191 Repetitive mechanical insult to the subclavian vein in the thoracic outlet in combination with the inherited coagulopathy and medication-induced hypercoagulability increases the likelihood of upper extremity deep venous thrombosis as the reason for the current complaints.

Physical therapy diagnosis The physical therapy diagnosis is: tendinopathy of the left extensor carpi radialis brevis and abducted ulna syndrome on the left. Physical therapy intervention John was educated as to the physical therapy diagnosis, prognosis, and proposed treatment plan. Treatment was initiated with a varus-type (Stoddard) grade V manipulation to the left elbow and deep transverse friction massage to affect changes associated with degenerative tendinopathy in the extensor carpi radialis brevis tendon. This was followed with grade IV-IV+ lateral glides of the left forearm at the elbow to affect the hypothesized humero-ulnar positional fault. Ice was applied after manipulation to decrease any possible excessive inflammatory response. John was educated regarding a modified workout technique, extensor carpi radialis brevis stretches, and careful eccentric strengthening of the wrist extensor muscles.

Case Study 2 Subjective information John is a 32-year-old amateur competitive bodybuilder. His workout routine consists of 5 days per week of high-intensity resistance training. He does not care much for aerobic exercise and limits aerobic activities to a 10-minute to 15-minute warm-up before his workout. For 5 weeks now, he has noted progressive left lateral elbow pain. The pain started after he was trying some pliometric push-ups in an attempt to increase his bench press performance. During one of the impacts with the arms outstretched during this exercise he felt something “shift” in his elbow. The pain now limits him with activities involving gripping, forearm rotation, and elbow flexion, especially with the forearm pronated. He notes no sensory abnormalities but has loss of strength due to

Reevaluation John was treated with the above program 3 times over 3 weeks and noted a decrease in the elbow pain. During 26

a conversation with the therapist about ergogenic nutritional supplements, John mentions his prolonged use of different regimens of oral and injectable AAS since taking up bodybuilding some 10 years ago. When the therapist decides to introduce John to a more varied workout regimen by introducing an upper body ergometer exercise in the treatment plan at the third visit, John has to stop this new exercise after 5 minutes because of chest and left supraclavicular pain. The pain subsides rapidly after stopping the exercise. John reports that over the last few months, similar pains have made him cut back on his aerobic exercise. Further questioning reveals that John has failed to mention progressive fatigue, shortness of breath, and palpitations during the previous systems review. The therapist refers John to his physician with a request for evaluation of the cardiovascular system. An exercise stress test and coronary arteriography show coronary artery disease. Blood tests showed greatly increased levels of triglycerides and low-density lipoprotein cholesterol. John is subsequently treated with a coronary stent implant and medically managed with diet and cholesterol-lowering medication.

Guide to Physical Therapist Practice diagnosis The Guide to Physical Therapist Practice189 diagnosis is: • Practice pattern 4D: Impaired joint mobility, motor function, muscle performance, and range of motion associated with connective tissue dysfunction. • Practice pattern 6A: Primary prevention/risk reduction cardiovascular/pulmonary disorders. Discussion Anabolic-androgenic steroids, and specifically oral steroids, have a negative impact on blood lipid profiles. Elevated serum cholesterol is an independent risk factor for arteriosclerosis and coronary artery disease, as is a positive family history.192 Arteriolar sclerosis is one form of arteriosclerosis; in tendons, this may lead to hypovascular and hyperthermic damage resulting in tendinopathy.193 The previous medical history of multiple tendinopathies may have been an early warning sign of systemic arteriosclerotic disease but has also been linked to steroid use.193

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NOTES

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Orthopaedic Section Independent Study Course 16.1.5 Ergogenic Substances REVIEW QUESTIONS 6. Which of the following statements regarding alcohol use is true? a. alcohol is useful to warm up when exercising in cold weather. b. all alcohol in the body is from external sources. c. exercise burns alcohol, leading to sobriety. d. percentage of body fat affects tolerance to alcohol.

1. In the United States, over-the-counter nutritional supplements: a. are regulated by the Dietary Supplement Health and Education Act. b. are strictly controlled with regard to marketing claims and content labeling. c. fall under the jurisdiction of the Food and Drug Administration. d. have been tested and regulated for safety and efficacy.

7. Fetal alcohol syndrome may include: a. facial abnormalities. b. growth deficiency. c. microcephaly. d. all of the above.

2. Which of the following effects is reversible in women using anabolic-androgenic steroids? a. deeper voice. b. increased facial hair. c. male-pattern baldness. d. oligomenorrhea.

8. Which of the following speeds up the elimination of caffeine? a. alcohol use. b. cigarette smoking. c. high-intensity exercise. d. oral contraceptive use.

3. Use of androstenedione leads to the most significant dose-dependent increases in the serum concentrations of: a. estradiol. b. follicle-stimulating hormone. c. luteinizing hormone. d. testosterone.

9. Caffeine withdrawal can result in: a. headache. b. irritability. c. muscular twitching. d. all of the above.

4. Which ergogenic substance has no deleterious effects on blood lipid profiles: a. androstenedione. b. beta-hydroxy-beta-methylbutyrate. c. growth hormone. d. injected anabolic-androgenic steroids.

10. Amphetamines have been abused by athletes to: a. increase hematocrit levels. b. increase muscle mass. c. decrease muscle damage. d. maintain a low body weight.

5. The cellular role of creatine is: a. a cellular buffer to excessive adenosine diphosphate concentrations. b. increasing transmembrane osmotic gradient. c. resynthesis of muscle adenosine triphosphate. d. all of the above.

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

a d a b d d d b d d

ANSWERS