1. Performance Enhancing Drugs in Sports An Overview

2. Disclosures : None 2

3. Overview of Presentation Topics Major types of PEDs and how they work Side effects, methods of testing, evasion Incidence Safety issues with supplements MD/ATC approach to the athlete using PEDs 3

4. Many Ways to Enhance Performance Enhancement Strategy Hormonal methods Medicinal methods Blood doping Nutritional methods Training methods Sub-topics Mechanism Effects and side-effects Permissibility and testing 4

5. Steroidogenesis Steroid synthesis starts with cholesterol Most athletic benefit from testosterone and dihydrotestosterone Glucocorticoids and mineralocorticoids have short- term benefits Estrogens cause side-effects Wikimedia Commons: steroidogenesis

6. Steroidogenesis Testosterone All the same Differs by attached ester Testosterone analogs Testosterone precursors Pathway modifiers Antiestrogens Wikimedia Commons: steroidogenesis

7. Testosterone: Original and Best PED Effects Increases strength & lean muscle mass Reduces fat mass Reduces recovery time Increases RBC mass Types: Testosterone is Testosterone “Types” differ by the attached ester Propionate, enanthate, cypionate, testosterone suspension, sustanon-250, omnadren Molecules that emulate testosterone Dihydrotestosterone Testosterone analogs Testosterone precursors Steroidogenesis pathway modifiers

8. Steroidogenesis Testosterone Testosterone analogs Stanozolol (Winstrol) Nandrolone (Durabolin) Tetrahydrogestrinone (the Clear) Testosterone precursors Pathway modifiers Antiestrogens Wikimedia Commons: steroidogenesis

9. Testosterone Analogs Molecules with similar structure to testosterone Testosterone esters are injected Stanozolol (Winstrol) depot Nandrolone (19-nortestosterone) Enanthate (Primobolan) Cypionate 17α-alkylated androgens are usually taken orally Stanozolol (Winstrol) Selective Androgen Receptor Molecules (SARMs) Andarine most well-known example Designed to have greater anabolic than androgenic effects –No clear evidence any drug is anabolic without being androgenic Designer steroids, designed to evade testing No pharmacologic use, FDA regulation, safety data Poorly characterized, potentially dangerous

10. Marion Jones, Jason Giambi, Barry Bonds 10 Implicated for transactions with Balco (Bay Area Laboratory Co- Operative), which supplied designer androgen tetrahydrogestrinone (the Clear)

11. Testosterone and Analogs Side Effects Suppression of endogenous testosterone and gametogenesis, testicular atrophy Usually recovers in 4 months Gynecomastia Premature physeal closure Left ventricular hypertrophy (data conflicting) Lower HDL, higher LDL (esp 17a-alkylated) Hypertension Changes in concentrations of clotting factors, but unclear clinical import Roid rage in retrospective surveys, but not seen in controlled studies Erythrocytosis Hepatotoxicity Abnormal LFTs, cholestasis, peliosis hepatis. Probably not hepatomas. Water retention Tendon rupture Often biceps and triceps Infections from needle use ? Prostatic hypertrophy / cancer Not seen at replacement doses but not studies at PED doses Side Effects in Women Virilization Hirsutism Clitoromegaly Male pattern baldness Deepening of voice Acne Oligomenorrhea / amenorrhea Muscle dysmorphia 11

12. Detecting Testosterone & Analogs Analogs can be detected directly Testosterone Testosterone glucuronide : epitestosterone glucuronide ratio (T/E ratio) Ratio of 13C to 12C Exogenous testosterone made from plant sterols; have higher 12C Detected with liquid-chromatography mass-spectrometry (LCMS) or gas- chromatography mass-spectrometry (GCMS) 12

13. Steroidogenesis Testosterone Testosterone analogs Testosterone precursors Dehydroepiandrosterone (DHEA) Androstenedione Androstenediol Pathway modifiers Antiestrogens Wikimedia Commons: steroidogenesis

14. Mark McGwire Admitted to using androstenedione in 1998 Same year he hit 70 home runs Androstenedione was legal in MLB until 2004

15. The Andro Project Archives of Internal Med, 2000 RCT of 50 men undergoing 12 weeks of high intensity training Double blind design Branches: Androstenedione Androstenediol Placebo Conclusion: Androstenedione & androstenediol equal to placebo for strength and body composition Did down-regulate testosterone and raise estrogen levels

16. Mark McGwire Admitted to using androstenedione in 1998 In 2010 admitted to using steroids throughout his career

17. Steroidogenesis Testosterone Testosterone analogs Testosterone precursors Pathway modifiers Aromatase inhibitors Exemestane Anastrazole Letrozole 5α-reductase inhibitors Antiestrogens Wikimedia Commons: steroidogenesis

18. Steroidogenesis Testosterone Testosterone analogs Testosterone precursors Pathway modifiers Aromatase inhibitors 5α-reductase inhibitors Dutasteride Finasteride (Propecia) Antiestrogens Wikimedia Commons: steroidogenesis

19. Steroidogenesis Testosterone Testosterone analogs Testosterone precursors Pathway modifiers Antiestrogens SERMs Tamoxifen Clomiphene Wikimedia Commons: steroidogenesis

20. Non-Steroidal Hormonal PEDs Human Chorionic Gonadotropin (HCG) Function Agonizes luteinizing hormone receptors of Leydig cells Stimulates testosterone production Often used in testosterone supplementation off-cycle to prevent rapid muscle loss May kick-start endogenous testosterone production Recommended not to prescribe for that purpose, since a banned substance in itself Detection Urine test can quantify HCG In females also detects pregnancy In males also detects certain types of cancers

21. Manny Ramirez Suspended for 100 games in April 2011 while on the LA Dodgers for HCG usage

22. Growth Hormone Use Benefits Increases muscle mass Decreases fat mass Increases fat metabolism To reduce atrophy in testosterone off- cycle Liked for difficulty of detection Thought to promote cartilage Insignificant benefit for strength Usually taken every other day in ~6 month cycles with 3-6 months off Usually taken in cocktails Increases IGF-1 production Side-Effects Insulin resistance, hyperglycemia, diabetes Sodium retention, hypertension, cardiomegaly Physeal closure (in pediatrics) Myopathy Carpal tunnel syndrome Theoretical risk of Acromegaly Cancers including prostate 22

23. Growth Hormone Detection Requires blood tests because <0.1% secreted in urine IGF-1 levels N-terminal extension peptide of procollagen type III levels (P-III-P) Ratio of growth hormone isoforms Recombinant HGH is 23 kDa Pituitary secretes many isoforms of different weights Difficult to detect

24. Erythropoietin Aka: EPO, epoietin, darbepoietin, Procrit Stimulates hematopoiesis Increases hematocrit Thus increases v ̇ O2max Side effects: Increased blood viscosity 24

25. Team US Postal Service George Hincapie, Lance Armstrong (front) Implicated in EPO use by testimony of cyclists, not failed tests Armstrong stripped of 7 Tour de France titles From 1996-2010 only one Tour de France winner kept his medal (Carlos Sastre, 2008)

26. Fausto Coppi Won Tour de France in 1949 and 1952 "Yes, and those who claim otherwise, it's not worth talking to them about cycling."

27. Non-Hormonal Methods Stimulants Caffeine (legal) Herbals Red Bull, 5 Hour Energy, other drinks Amphetamines ADHD drugs Decongestants Methylhexanamine (DMAA) Ephedra (ma huang) Old fashioned Strychnine Nicotinyl alcohol Catecholamine modifiers β-blockers/agonists α-blockers/agonists Diuretics Weight loss, test evasion Analgesics All types Ketorolac big in NFL Superman effect Thermogenics 2,4-dinitrophenol (no antidote) Masking drugs

28. Cat and Mouse Athletes may attempt to defeat urine drug testing by Diluting urine with diuretics and high fluid intake Putting proteases in urethra to hydrolize proteins / peptides Drugs that induce endogenous production of anabolic hormones Exogenous epitestosterone Whizzinator

29. Athlete’s Perspective Often learn about PEDs from Other athletes Trainers / Coaches Magazines Internet Advertisements Not necessarily forthcoming about use Goals often not just being healthy 29

30. Where Athletes Get PEDs Sources Online Prescription Foreign Domestic black market labs BALCO, Biogenesis being high profile examples Veterinary In supplements sold over the counter 30

31. Dangerous Drugs at Vitamin Stores USA Today, 7/25/2013, “Sports supplement designer has history of risky products” Craze sold at GNC, Walmart, Amazon, Bodybuilding.com among others USADA tests revealed it contains several amphetamines not on the label New supplement Craze on USADA high risk supplement list 2012 Bodybuilding.com “Supplement of the Year” Founder, Matt Cahill, investigated & jailed for previous supplements containing dinitrophenol (1990s) and 2 designer steroids (2000s) Dinitrophenol supplement Caused blindness, deaths Banned for human use in 1930s for causing blindness Designer steroids Posed as landscaping company to purchase pesticide from China Never tested on humans Sold as sports supplement Caused hepatic failure, death Amy Eichner of USADA: players like Matt Cahill are ubiquitous in supplement industry 31

32. Incidence of Doping, NCAA Report NCAA 2009 Substance Use Report “Anonymous” survey of 20,474 athletes from stratified random sample of all NCAA schools Results indicated Very low incidence of PED use Declining rates of PED use Questionable validity 32

33. NCAA Report Overall doping reported as rare, decreasing Similar across divisions I, II, III 33

34. Different Results with a Different Survey Method NY Times reported unpublished study of >2000 track & field athletes Anonymously asked: “Have you knowingly violated anti-doping regulations by using a prohibited substance or method in the past 12 months?” Used “randomized response” so athletes knew response was anonymous Yes from 29% of athletes at 2011 world championships Yes from 45% of athletes at Pan-Arab Games <2% of WADA drug tests in 2010 were positive WADA told researchers not to publish their data Sport governing bodies, national organizations, teams often have no incentive or disincentive to catch dopers 34

35. Signs of Use Behavioral Secretive actions High dietary supplement interest / use Physique or diet obsession Other high-risk behaviors Cavalier attitude about supplements Using the lingo: “stacks,” “cycles,” names of PEDs Physical Rapid performance gains Rapid size / muscularity increases Hypermuscularity Tendinopathies, ruptures Virilization (more females) Acne 35

36. Role of the Clinician / Trainer What the clinician should know More than the athlete Can be difficult Some basic rules about legality of the substance Athlete is responsible for substances / medications taken Prescriber liability minimal if prescribing substance for medical purposes Prescriber liability high if for performance enhancement Possession of many anabolic PEDs is a felony There is no legal obligation to report Support the health of the patient, monitor: Lipids, BP, LFTs, lytes, renal function, coags, Hct, TSH… Don’t say it doesn’t work. May lose credibility. 36

37. 37 Elite Natural Bodybuilder: Rob Riches: 5’10, 180 lbs Elite Professional Bodybuilder: Jay Cutler: 5’9, 310 lbs Natural bodybuilding restricts certain PEDs Professional bodybuilding does not restrict PED use Probably not effective to council that steroids do not work

38. Dealing with the Suspected Athlete For high school ATCs (4) Advantage in knowing athletes, rapport Avoid unfounded scare tactics Acknowledge short-term benefits Segue to health, moral, ethical, legal aspects Discuss risks of tainted products Support healthy behavior Offer good information Do not compliment performance boosts, appearance Comment on acne, slowed growth in height, jaundiced appearance Pre-emptive education, discussion ATLAS Athletes Training & Learning to Avoid Steroids ATHENA Athletes Targeting Healthy Exercise & Nutrition Alternatives 38

39. References 1.Antidoping agency delays publication of research: NY Times http://www.nytimes.com/2013/08/23/sports/research-finds-wide-doping-study-withheld.html?_r=0 2.Broeder et al. The Andro Project: physiological and hormonal influences of androstenedione supplementation in men 35 to 65 years old participating in a high- intensity resistance training program. Arch Intern Med. 2000 Nov 13;160(20):3093-104. PubMed PMID: 11074738. 3.Antidoping agency delays publication of research: NY Times http://www.nytimes.com/2013/08/23/sports/research-finds-wide-doping-study-withheld.html?_r=0http://www.nytimes.com/2013/08/23/sports/research-finds-wide-doping-study-withheld.html?_r=0 4.Kersey RD, Elliot DL, Goldberg L, Kanayama G, Leone JE, Pavlovich M, Pope HG Jr; National Athletic Trainers' Association. National Athletic Trainers‘ Association position statement: anabolic-androgenic steroids. J Athl Train. 2012 Sep-Oct;47(5):567-88. doi: 10.4085/1062-6050-47.5.08. PubMed PMID: 23068595; PubMed Central PMCID: PMC3465038. 5.MLB bans use of androstenedione: MLB.com http://mlb.mlb.com/content/printer_friendly/mlb/y2004/m06/d29/c783595.jsphttp://mlb.mlb.com/content/printer_friendly/mlb/y2004/m06/d29/c783595.jsp 6.National Study of Substance Use Trends Among NCAA College Student-Athletes, 2009: http://www.ncaa.org/sites/default/files/13.%20Substance%20Use%20Report%202009.pdf 7.Steroid.com: useful to know what the athletes know, or think they know, about PEDs 8.Steroids Loom Large Over Programs: Associated Press, 12/20/2012: http://espn.go.com/college-football/story/_/id/8765531/steroids-loom-major-college-football-report- says 9.US Anti-Doping Agency High Risk Dietary Supplement List: http://www.usada.org/supplement411/high-risk-list 10.USA Today, “Sports supplement designer has history of risky products” http://www.usatoday.com/story/news/nation/2013/07/25/bodybuilding-supplement-designer- matt-cahill-usa-today-investigation/2568815/ 11.World Anti-Doping Agency prohibited drugs list: http://www.wada-ama.org/en/World-Anti-Doping-Program/Sports-and-Anti-Doping-Organizations/International- Standards/Prohibited-List/ 12.Up To Date: “Non-Hormonal Performance Enhancing Drugs,” “Perforance Enhancing Drugs” 13.Antonio & Stout. “Sports Supplement Encyclopedia” Nutricia Institute of Sports Science, 2001 39