Health Consequences of Performance Health Consequences of Performance Enhancing DrugsEnhancing Drugs

Shalender Bhasin, MDShalender Bhasin, MDDirector, Boston Claude D. Pepper Older Americans Director, Boston Claude D. Pepper Older Americans Independence CenterIndependence CenterDirector, Research Program in Men’s Health: Aging and Director, Research Program in Men’s Health: Aging and Metabolism Metabolism Brigham and Women’s HospitalBrigham and Women’s HospitalHarvard Medical SchoolHarvard Medical School

The Endocrine Society’s Expert Panel:Scientific Statement on Health Consequences of PED Use

Dr. Shalender Bhasin

Dr. Harrison Pope Dr. Ruth Woods Dr. Fred Nyberg

Dr. Alan Rogol Dr. Larry Bowers Dr. Jag Khalsa

Historical Evolution of PED Use Historical Evolution of PED Use by Athletesby Athletes

1950s1950s Russian weight lifters use AAS Russian weight lifters use AAS 19521952 Olympics, John Ziegler learns of Olympics, John Ziegler learns of

their use and tries dianaboltheir use and tries dianabol 19681968 IOC introduces first testing IOC introduces first testing 1980s 1980s First edition of “Steroid First edition of “Steroid

handbook”handbook” 19901990 US Congress passes Controlled US Congress passes Controlled

Substances ActSubstances Act 19991999 WADA established WADA established 20032003 World anti-doping code adopted World anti-doping code adopted 20122012 Lance Armstrong stripped of titles Lance Armstrong stripped of titles

Stepanov 1952

Ziegler at York Club

Pope et al, Endocr Rev 2013 in press

How Can We Explain the Androgen Use by Elite Athletes, especially Endurance Athletes and Sprinters?

Motivational effects Androgens promote recovery Androgens decrease reaction time and promote

hand-eye coordination Increased O2 delivery:

– Increase in hemoglobin and hematocrit– Increase in 2, 3 BPG– Increased capillarity– Effects on mitochondrial biogenesis and

quality

Guo et al, Aging Cell 2013; Pope et al, 2013

The State-Sponsored Program of The State-Sponsored Program of Doping in the Former GDR in Doping in the Former GDR in 1970s1970s

The development of a centralized drug distribution The development of a centralized drug distribution and documentation programand documentation program

Establishment of a monitoring programEstablishment of a monitoring program Organization of systematic research into new doping Organization of systematic research into new doping

products and avoidance of detectionproducts and avoidance of detection A comprehensive educational program which trained A comprehensive educational program which trained

coaches and physicians about dopingcoaches and physicians about doping Classification of the doping program as a state secretClassification of the doping program as a state secret

Franke and Beredonk 1997; Ungerleider 2001Franke and Beredonk 1997; Ungerleider 2001

High gold medal count

Two Distinct Populations of PED Users

Athletes Use PEDs to gain competitive advantage in sports

The type of PED used varies with the nature of athletic eventUse often limited to the period of athletic careerFocus of intense detection efforts

Non-athlete Weightlifters Use PEDs mostly to improve personal appearance – look leaner and more muscularUse mostly AAS

Long term continuous use

Largely invisible

Pope et al, Endocr Rev 2013 in press

Categories and Prevalence of PED Use

AAS use uncommon before age of adolescence

About 1/5 of all AAS users have started use by age 18-19

Median age: 23 years > 90% by age 35 Prevalence of lifetime use: about

5% or 3 million persons

Categories of PEDs– Lean mass

builders– Stimulants and

tranquilizers– Painkillers– Diuretics– Blood boosters– Masking drugs

Pope et al, Endocr Rev 2013 in press

The PEDs Used by Athletes and Non-athlete Weightlifters

Pope Survey:Substances identified

in recreational weightlifters

Pattern of abuse:– IM route used by >80%– Large doses: 50% >500 mg TE, 25% >1000 mg TE– Stacking and cycling– Accessory drugs

WADA Survey

Why has PED Use by Non-athlete Weightlifters Remained Hidden as a Public

Health Problem?

The public views AAS use largely as a cheating problem among elite athletes.– Most AAS users are not athletes at all

AAS users do not trust physicians; 56% of AAS users had never disclosed their AAS use to their physician (Pope et al 2004).

Unlike alcohol, heroin, and cocaine users, AAS users do not come to the ER.

AAS use became widespread only in the early 1980s.

Roots of Academic Dogma and Roots of Academic Dogma and ControversyControversy

Problems of Study Design in Clinical TrialsProblems of Study Design in Clinical TrialsUse of relatively low PED dosesUse of relatively low PED dosesBlinding and randomizationBlinding and randomizationInclusion of competitive athletesInclusion of competitive athletesFailure to control protein and energy intake, and Failure to control protein and energy intake, and exercise stimulusexercise stimulusMethodological limitationsMethodological limitations

Wilson 1988; Bhasin et al 1996, 2003, 2005, 2008, 2013

Contradictory Position Statements

Effects of A Supraphysiologic Dose of Effects of A Supraphysiologic Dose of Testosterone on Fat–Free Mass in Healthy MenTestosterone on Fat–Free Mass in Healthy MenC

han

ge in

Fat

Fre

e M

ass

(K

g)

6 -

4 -

2 -

0 -

Placebo Testosterone Placebo TestosteroneNo Exercise Exercise

0.80.7 3.21.4 1.90.6 6.10.6Bhasin S, Storer TW, et al, N Engl J Med

1996;335:1-7

New Challenges in Detection of Designer New Challenges in Detection of Designer SteroidsSteroids

Synthesis and distribution of novel androgens thatSynthesis and distribution of novel androgens that– have no medicinal propertieshave no medicinal properties– have not been previously tested, andhave not been previously tested, and– which are produced solely for abuse.which are produced solely for abuse.

Precursor Molecules:Precursor Molecules:– Converted to active compounds in bodyConverted to active compounds in body– Based on modifications of structures or novel Based on modifications of structures or novel

structuresstructures Detection and regulation a challenge for Detection and regulation a challenge for

regulatory agenciesregulatory agencies

BALCO, Barry Bonds, and THG: 73 Home Runs and BALCO, Barry Bonds, and THG: 73 Home Runs and the “’Clear’ and the ‘Cream’ for my arthritis and the “’Clear’ and the ‘Cream’ for my arthritis and fatigue”fatigue”

BALCO’s Victor Conte

Bonds’ Trainer Greg Anderson

Barry Bonds

Don Catlin of UCLA

THG Binds AR, Upregulates AR and MyoD, Stimulates MHC+ Myotubes, and Increases

Muscle Mass

control DHT THG 1nM THG 5nM THG 30 nM0

50

100

150

200

** ** p < 0.01*** p < 0.001

******

MHC

+Ar

ea/fi

eld(µ

m2

x 10

3 )

control DHT THG 1nM THG 5nM THG 30 nM0

50

100

150

200

** ** p < 0.01*** p < 0.001

******

MHC

+Ar

ea/fi

eld(µ

m2

x 10

3 )

AR

MyoD

MHC-II

Con

trol

+1nM

TH

G

+5nM

TH

G

+10n

M T

HG

+30n

M T

HG

AR

MyoD

MHC-II

AR

MyoD

MHC-II

Con

trol

+1nM

TH

G

+5nM

TH

G

+10n

M T

HG

+30n

M T

HG

Jasuja et al Endocrinology 2005

Ligand Binding Domain [nM]0.1 1 10 100

FLuo

resc

ence

Pol

ariz

atio

n (m

P)

220

240

260

280

0100

200

225

250

Fat

Free

Mas

s (g

)

Difficulties in Accurately Assessing Difficulties in Accurately Assessing Adverse Effects Associated with PED Adverse Effects Associated with PED AbuseAbuse

Surreptitious nature of abuse Based on self report of abuse Variability in types of drugs, dose, frequency,

and duration of PED use, and age at initiation Accessory drugs High risk behaviors

Therefore, randomized trials of PEDs at the high doses used by athletes and non-athlete weightlifters will never be ethically permissible.

Adverse Effects of AAS AbuseAdverse Effects of AAS Abuse Suicidal, homicidal, and sudden unexplained deathsSuicidal, homicidal, and sudden unexplained deaths Prolonged suppression of HPT axisProlonged suppression of HPT axis Mood and psychiatric disordersMood and psychiatric disorders Cardiovascular and metabolic adverse effectsCardiovascular and metabolic adverse effects Liver toxicity with 17-alpha alkylated, oral androgensLiver toxicity with 17-alpha alkylated, oral androgens Gynecomastia (bitch tits)Gynecomastia (bitch tits) Risks associated with IM injections: abscesses, HIVRisks associated with IM injections: abscesses, HIV Risks associated with the use of accessory drugsRisks associated with the use of accessory drugs Risks associated with excessive muscle hypertrophyRisks associated with excessive muscle hypertrophy Growth retardation in childrenGrowth retardation in children

Choong, Lakshman, Bhasin 2008; Greene et al 2005; Pope and Katz 1994

Suicidal, homicidal, and sudden unexplained deaths

Case reports of sudden coronary and CV deaths Parssinen et al. (2000)

– 62 power lifters who achieved top 5 positions in weight lifting and age-matched control during 1977-1982 period

– 13% of power lifters and 3% of controls died– RR 4.6, median age of death 24.5 years

Thiblin et al. (2000)– Cause of death among 34 androgen users– 32% suicides, 26% homicides, 35% “accidental”

Petersson et al. (2006)– Retrospective review of patient records– Higher standardized mortality among steroid users than non-users

Mood and Behavior Disorders High frequency of mania, hypomania, and major depression

(Pope and Katz)– Mania and hypomania more frequently during use– Depression more frequently after withdrawal

Anecdotal reports of “roid rage” 5 Placebo controlled studies in eugonadal men report

inconsistent changes in anger or aggression scores – Self-reporting “paper pencil” instruments lack sensitivity– Pre-existing psychopathology or personality disorder

» Higher frequency of use among doormen, bouncers, or those convicted of weapons offence

Tricker 1997; Su 1993; Daly 2003; Yates 1999; Pope 2000 Tricker 1997; Su 1993; Daly 2003; Yates 1999; Pope 2000

Prolonged Suppression of Hypothalamic-Pituitary-Testicular Axis

Universal suppression of HPT axis– Infertility

Prolonged period of testicular suppression upon discontinuation of androgen use– Symptoms of androgen deficiency– Increased risk of relapsing AAS use or of using other

psychoactive drugs Unproven use of hCG, clomiphene and aromatase

inhibitors to promote recovery

Androgen Abuse and Cardiovascular RiskStrong evidence:

– Proatherogenic dyslipidemia, particularly with oral 17-alpha alkylated, oral androgens

» Decrease HDLC» Increase LDLC

Weak or inconclusive evidence: – Increased LV mass: impairment of both systolic and

diastolic function (Dickerman, 1996; De Piccolli, 1991; Urhausen, 2004)

– Increased risk of thrombosis– Vasospasm through vascular NO

Melchert and Welder Med Sci Sports Med 1995;27:1252; Bhasin et al, 2008

Measure AAS Users (n=12)AAS Nonusers

(n=7)P*

Systolic function parameters

LV ejection fraction, %

50.6 (48.4, 53.6) 59.1 (58.0, 61.7) 0.003

Longitudinal strain, %

16.9 (14.0, 19.0) 21.0 (20.2, 21.9) 0.004

Radial strain, % 38.3 (28.5, 43.7) 50.1 (44.3, 61.8) 0.02

Diastolic Function

E-wave, cm/s 64.0 (55.5, 78.5) 77.0 (67.0, 86.0) 0.05

A-wave, cm/s 61.5 (55.3, 65.8) 43.0 (36.0, 54.0) 0.02

E/A ratio 0.93 (0.88, 1.39) 1.80 (1.48, 2.00) 0.003

Early peak tissue velocity, cm/s

7.4 (6.8, 7.9) 9.9 (8.3, 10.5) 0.005

LV Systolic and Diastolic Dysfunction Among AAS Users

Baggish et al, Circulation: Heart Failure 2010; 3: 472-476

Adverse Effects of rhGH and Erythropoietin

rhGH Edema Excessive sweating Myalgias and

arthralgias Carpal tunnel syndrome Diabetes Hypertension Cardiomyopathy Increased frequency of

neoplasms Arthropathy

Erythropoietin Increased risk of

thrombosis, cardiovascular events, and stroke

Implicated in the deaths of 18 European professional bicycle racers (1987-81)

Meta-analyses of RCTs in cancer and ESRD:– increased risk of death,

thromboembolic events, CV events

The Endocrine Society’s Scientific Statement

PED use is associated with serious health consequences including the increased risk of death, as well as cardiovascular, psychiatric, metabolic, endocrine, neurologic, infectious, hepatic, renal, and musculoskeletal disorders.

PED abuse is an important public health problem that has largely remained subterranean so far.

Vast majority of PED users are not athletes, but rather non-athlete weigt lifters who use PEDs to look lean and muscular.– Singular attention on doping in sports has detracted attention from the larger

public health problem of long-term PED use by non-athlete weightlifters. – The current focus on detecting and punishing elite athletes has had limited

impact on PED abuse by non-athlete weightlifters

Pope et al, Endocr Rev 2013 in press

The Endocrine Society’s Scientific Statement: Unmet Needs and

Opportunities Observation studies, implemented by establishing a registry,

are needed to monitor long term health consequences of PEDs, and may be the only feasible method of collecting scientifically meaningful outcome data.

RCTs of interventions to facilitate recovery of HPT axis in men whose endogenous axis is suppressed by long term AAS use

Mechanisms by which PEDs improve physical performance and contribute to adverse health effects need examination.

Innovative approaches to enhance public awareness of the serious health consequences of PEDs.

Pope et al, Endocr Rev 2013 in press

Questions?