Doping with anabolic androgenic steroids (AAS)

13 Pages·2015·0.41 MB·English

RevEndocrMetabDisord(2015)16:199–211
DOI10.1007/s11154-015-9320-5
Doping with anabolic androgenic steroids (AAS): Adverse effects
on non-reproductive organs and functions
EberhardNieschlag1,2 &ElenaVorona3
Publishedonline:15September2015
#SpringerScience+BusinessMediaNewYork2015
Abstract Since the 1970s anabolic androgenic steroids Keywords Anabolicandrogenicsteroids(AAS) .
(AAS)havebeenabusedateverincreasingratesincompeti- Performanceandappearanceenhancingdrugs(PAED) .
tive athletics, in recreational sports and in bodybuilding. Adverseeffects .Stroke .Cardiomyopathies .Hepatotoxicity.
Exceedingly high doses are often consumed over long pe- Aggression .Depression
riods,inparticularbybodybuilders,causingacuteorchronic
adverse side effects frequently complicated by additional
polypharmacy. This review summarizes side effects on non- 1Introduction
reproductiveorgansandfunctions;effectsonmaleandfemale
reproductionhavebeenrecentlyreviewedinaparallelpaper. Anabolicandrogenicsteroids(AAS)arethemostwidelyused
Among the most striking AAS side effects are increases in performance and appearance enhancing drugs (PAED) in
haematocritandcoagulationcausingthromboembolism,intra- competitive athletics, recreational sports and bodybuilding,
cardiacthrombosisandstrokeaswellasothercardiacdistur- as documented by epidemiologic studies [1] as well as by
bancesincludingarrhythmias,cardiomyopathiesandpossibly positive samples detected in the WADA worldwide anti-
sudden death. 17α-alkylated AAS are liver toxic leading to doping network (www.wada.org) [2]. Worldwide AAS are
cholestasis, peliosis, adenomas and carcinomas. used—or rather abused—for doping with a lifetime
Hyperbilirubinaemia can cause cholemic nephrosis and kid- prevalencerateof6.4 % inmales and 1.6 % infemales, the
ney failure. AAS abuse may induce exaggerated self-confi- highestratebeingencounteredinMiddleEasterncountries,as
dence,recklessbehavior,aggressivenessandpsychoticsymp- discoveredwithinthe programme oftheWorldAntiDoping
toms. AAS withdrawal may be accompanied by depression Agency[3].TheincreasingratesofAASabuseamongadults
andsuicidalintentions.SinceAASabuseisnotoronlyreluc- andinparticularinadolescentsarealarming,asthegrowing
tantlyadmittedphysiciansshouldbeawareofthemultitudeof organism may be even more susceptible to unwanted side
serioussideeffectswhenconfrontedwithunclearsymptoms, effectsthantheadult.AASareobtainedpredominantlyfrom
theblackmarketandthroughtheinternetandpostalservices
[4], but healthcare providers are also involved in the
procurement of AAS to a surprisingly high extent [5] and
some states have even, or have had in the past, secret
* EberhardNieschlag programmes for providing AAS to their elite athletes. As
[email protected] AAS abuse is reaching worldwide epidemic dimensions,
untoward side effects—acute and long-term—become more
1 CentreofReproductiveMedicineandAndrology,Universityof and more evident and a cause for growing concern by the
Münster,Münster,Germany medicalprofession.
2 CenterofExcellenceinGenomicMedicineResearch,King RecentlyaleadingGermannewspaperpublishedalistof73
AbdulazizUniversity,Jeddah,SaudiArabia former GDR athletes—now in their 40s and 50s—suffering
3 CentreofEndocrinology,DiabetologyandRheumatology, fromailmentsattributedtodopingwithAASduringtheiractive
Dortmund,Germany sportscareer[6].Themostprevalentdisordersonthelistwere
200 RevEndocrMetabDisord(2015)16:199–211
musculo-skeletalproblems(44%)anddepressions(35%),but addition, most AAS users also administer other drugs
cases of breast cancer and cardiac dysfunction were also re- simultaneously, often of unknown purity and at unde-
corded. This compilation highlights the problem of assessing fined doses. This makes it very difficult to establish
thesequelaeofdoping,becausethe73athletescontributingto any causal relationship between a specific substance
the list are members of the BDoping Victims’ Association^ andsideeffects,asillustratedbya27-yearoldOlympicathlete
(BDoping-Opfer-Hilfe e.V.^) representing 700 of the about who died in 1987 from toxic multiple organ failure;
10,000 former GDR high-performance athletes involved in upon autopsy102 drugs were identified in her body,
thesystematicgovernmentaldopingprogrammebasedonthe among others, stanozolol, aspirin, diclofenac, metamizol,
AAS oral turinabol (dehydrochlormethyltestosterone) in the codeine and heparin [7]. Retrospective systematic analy-
1970s and 1980s. Thus the 73 of the 700 cases represent a ses are also lacking, as again, former consumers do not
biased selection of former athletes. Furthermore, there is no come forward, especially if they were champions and
controlgroupconsistingofathleteswhowerefreeofanydop- medal winners, except in a few rare cases. Often such
ingsothathealtheffectsofhigh-performanceathletesassuch successful users forget what they were taking and at
can not be disentangled from possible additional sequelae of what doses, or they never knew.
doping.Hence,itremainsextremelydifficulttoassesswhether AnothercriticalquestioniswhethertheinfluencesofAAS
currentdiseasesareorarenotconsequencesofdoping. arethesameinmaleandfemaleathletes.Exceptforthetypical
This example illustrates the general dilemma when sex-dependent effects and side effects [8] it is generally as-
dealing with sequelae of doping on athletes’ health. sumed that AAS act similarly in men and women, but this
This has various reasons. None of the AAS (nor any remainsunclear.Inaddition,thebiologicalandclinicaleffects
other PAED) has ever been approved by regulatory agen- of AAS are dependent on the chemicalstructure of steroids,
cies for the purpose of doping and has therefore never theircapabilitytoundergoaromatizationtoestrogensor5α-
been subjected to any of the usual regulatory scru- reductionto5α-dihydrotestosterone(DHT).Afurtherimpor-
tinization requiring proper toxicology and randomized tantstructuralfeatureis17α-alkylationofthesteroidmolecule
controlled trials (RCT). AAS doses used for doping ex- whichisresponsibleforhepatotoxicity(seeTable1).Forfur-
ceed clinically applied doses five to 20 or even more therdetailsofthemechanismofactionthereaderisreferredto
times, doses which would only be used during drug de- pertinentreviews(e.g.,[9,10]).
velopment in toxicological animal studies but not in clin- WehaverecentlyreviewedtheeffectsofdopingwithAAS
ical trials. As the use of AAS is illicit, it is unimaginable onfemaleandmalereproductivefunctions[8]andnowsum-
to enrol current users in RCTs as they would not admit marizetheadverseeffectsofAASonnon-reproductiveorgans
AAS use and would reject revealing their identity. In andfunctions(Table2).OursummaryofAASsideeffectsis
Table1 Androgenicanabolic
steroids(AAS),theirmajor Aromatization 5α-reduction 17α-alkylation
metabolisationandhepatotoxicity (hepatotoxic)
Testosterone x x –
19-Nortestosterone x x –
Boldenone x x –
Dihydrotestosterone – x –
Mesterolone – x –
Methenolone – x –
Trenbolone – x –
17α-Methyltestosterone – x x
Fluoxymesterone – x x
Dehydrochloromethyl-testosterone – x x
Formebolone – x x
Oxandrolone – x x
Oxymetholone – x x
Stanozolol
Metandione x x x
Clostebol – – –
Drostanelone – – –
RevEndocrMetabDisord(2015)16:199–211 201
Table2 SummaryofsequelaeofdopingwithAAS Table2 (continued)
Skina
Haematopoiesisandcoagulation
Acne
Erythrocytes
Striaedistensae
Haemoglobin Profusesweating
Haematocrit Alopecia
Hirsutism
Polycythaemia
Malereproductivefunctionsa
Hypercoagulability Decreasedtestisvolume
Venousthromboembolism Suppressedspermatogenesis
Arterialthromboembolism Infertility
Lossoflibido
Stroke/Apoplexy
Erectiledysfunction
Musculo-skeletalsystem Gynaecomastia
Prematureepiphysealclosure(inadolescents) Anabolicsteroidinduced
Hypogonadism(ASIH)
Rhabdomyolysis
Femalereproductivefunctionsa
Tendonruptures(?)
Anovulation
Ligamentousinjuries Amenorrhoea
Discherniation Dysmenorrhoea
Infertility
Cardiovascularsystem
Breastatrophy
HDL↓LDL↑,ApoA1↓ Dysphonia
Coronaryheartdisease Deepeningofvoice
Myocardialinfarction
aTheseeffectshavebeendescribedbyNieschlag&Vorona[8]
Hypertension(?)
AbnormalECG(QRS>114ms)
Arrhythmia basedonextrapolationfromeffectsobservedinpatientstreat-
Leftventricularhypertrophy edwithAASandondescriptionsofindividualcasesorgroups
Hypertrophiccardiomyopathy ofcases,mainlyretrospectiveandhardlyevercontrolled.
Dilativecardiomyopathy
Heartfailure
Suddencardiacdeath 2Haematopoiesis
Liver
Cholestasis/Hyperbilirubinaemia Stimulation of haematopoiesis (stem cells, reticulocytes,
Steatosis erythrocytes,haemoglobinandhaematocrit)isoneoftheim-
Peliosis portanteffectsoftestosteroneandAASexploitedbyathletes
Adenomas for higher performance. The increase of haemoglobin and
Hepatocellularcarcinoma haematocritduringpubertyinboysresultsfromrisingtestos-
Livercoma terone[11]andthehighertestosteronelevelsremainrespon-
Kidney sibleforthedifferencesbetweeneugonadalmenandwomen
Creatinine↑,cystatinc↑ life-long.Inhealthyandhypogonadalmentestosteronehasa
Glomerulosclerosis linear dose-dependent effect on haematopoiesis. Older men
Cholemicnephrosis andthosewithhigherBMIreactmoresensitivelytotestoster-
Renalfailure one stimulation than younger and leaner men [12, 13]. This
Psycheandbehavior hastobetakenintoaccountwhentreatingpatientswithlate-
Irritability onset hypogonadism [14]. The haematopoietic effect of tes-
Nervousness,unrest tosterone does not require aromatization, as shown in
aromatase-deficient men [15]. DHT has a similar effect on
Aggressiveness
haematopoiesis as testosterone itself, indicating that 5α-
Recklessbehavior
reductiondoesnotimpairthehaematopoieticeffectoftestos-
Self-aggressiveness
terone and other androgens [16]. It remains controversial
AASdependence
whether,inadditiontodirectstimulation,thehaematopoietic
AASwithdrawalsyndrome
effect of testosterone and AAS is also mediated by erythro-
Depression
poietinsothatandrogensmayhavetwopathwaystostimulate
Suicidethoughts
haematopoiesis [17, 18]. Before erythropoietin and its ana-
logues became available for clinical use, testosterone was
202 RevEndocrMetabDisord(2015)16:199–211
widely used for the treatment of aplastic and nephrotic (AR) by inducing hypertrophy of muscle fibres of type I as
anaemia. wellastypeII,andbyanincreaseinthenumberofmyonuclei
Androgensnotonlystimulatehaematopoiesis,butalsoin- and capillaries per fibre [46]. These effects are mediated by
crease2,3-diphosphoglyceratinerythrocyteswhichdecreases stimulationofmuscleproteinsynthesis,oftheGH/IGF-1axis
the haemoglobin-oxygen affinity, thereby facilitating release andmesenchymalmuscleprogenitorcells[45].Aswithother
ofoxygenfromhaemoglobinandenhancedoxygendelivery androgeneffects,musclemassisdeterminedbythepolymor-
to the tissues [9]. Androgens also appear to stimulate phismoftheAR(shorterCAGrepeatsinexon1 areassoci-
granulopoiesis and thrombopoiesis in vitro and in vivo [19, ated with higher muscle mass) under physiologic conditions
20]. [47] and most likelythis alsoplays a role inthe responseto
Testosterone can increase the activity of thromboxanA2- supraphysiological doses of AAS. There are also ethnic dif-
receptors and thrombocyte aggregation and thereby also the ferences in the AR polymorphism as Sub-Saharan Africans
riskofthrombosis.Simultaneouslytheactivityofthefibrino- have shorter CAG repeats than Caucasians and East Asians
lyticsystemrises,inparticularofantithrombinIIIandofpro- [48, 49]. How this may contribute to differences in perfor-
tein S [21, 22]. Levels of plasmin-α2-antiplasmin-complex mance and in response to AAS is not known. Experiments
(PAP, terminal marker of fibrinolysis), of factor XIIc and of in mice suggest that once muscle fibres are exposed to high
antithrombinsanksignificantlyinhypogonadalmenwhore- AASdoses,theyrespondfastertofurthertreatmentevenafter
ceivedtestosteroneundecanoateasdepotinjectionsforsubsti- adrug-freeinterval.Thiscellularmemoryappearstobelocat-
tution [23]. Short-term, low-dose administration of the AAS ed in the myonuclei which do not diminish in number after
oxandrolonetohealthyvolunteersledtoanincreaseinblood cessationofAASintake[50].
coagulation factors and plasminogen, producing a state of Testosterone supports periost formation, radial bone
hypercoagulability[24]. growth and areal bone density. This explains the larger
High doses of ASS as used in doping cause a significant cross-section size of male compared to female bones. The
increaseoferythrocytesundhaemoglobinconcentration[25, action of testosterone on bones is mediated by the AR and
26] which constitutes part of the intended effects as it in- by estrogens converted from testosterone through the
creases oxygen transport. However, increases in the RANKL-OPG-Systembystimulationofosteoblastsandsup-
haematocrit above 52 % may lead to thromboembolism pression of osteoclasts [51, 52]. AAS that cannot be aroma-
(VTE), intracardiac thrombosis and stroke [27–29]. Stroke tizedmaythereforehavelittleeffectonbones.AASgivento
maybeassociatedwithleftventricularthrombusandcardio- athletesinchildhoodoradolescencecauseanaccelerationof
myopathy [30] or with fatal massive myocardial infarction bone maturation. At the end of puberty, activation of endo-
[31](seealsoTable3).TowhatextenttheARpolymorphism chondral bone formation leads to closure of the epiphyseal
thatmodifiestheerythropoiesis-stimulatingeffectoftestoster- growthzoneswithgrowthretardation[28,53,54]sothatearly
one in substituted patients is of influence in athletes is not administration of testosterone or AAS may lead to growth
known[13]. arrestbelowtheexpectedheight.
Athletesoftenstraintheirmusculo-skeletalsystemacutely
andtoanextremeextentoverlongperiods,resultinginahigh
3Musculo-skeletalsystem incidenceofcomplaints,injuriesanddisordersinjoints,ten-
dons, bones and muscles. Individual sport categories have
The main reason for AAS abuse for enhancing performance their specific pattern of injuries. These may become chronic
and appearance in sports and bodybuilding rests in their sothattheformerathletesufferslongafterdiscontinuinghigh-
haematopoietic and musculotrophic effects. Whereas AAS performancesports—andAASabuse.Thereare,however,no
abusehasbeenboomingsincethe1970s,themedicalprofes- appropriate investigationsdocumenting a negativeimpactof
sionremainedconvincedthatthemuscle-buildingeffectwas AASonthemusculo-skeletalsystemanditisevensuspected
rather a placebo than a real effect of AAS, as reflected in a that AAS could possibly prevent more severe damage. It is
review of all relevant publications between 1966 and 1990 also unclear whether the increased bone mass may prevent
[43]. However, research studies so far had only investigated fracturesaslongasAASareconsumedaswellasinlaterlife.
clinical doses, incomparable with the AAS doses used in Atleast,noreportscanbefound thatAAS abusingathletes/
sportsandbodybuilding.Onlysincethelate1990sweretrials bodybuilders have higher or lower rates of osteoporosis (in
withsupraphysiologicaldoses—mainlyoftestosterone—per- advancedage)orbonefractureratesthanBclean^athletes.
formed,andthesignificantincreasesinskeletalmusclemass However, under acute intake of AAS rhabdomyolysis has
and voluntary strength produced by AAS were scientifically beenobserved[55],withacuterenalfailureasapossiblecom-
documented[44,45]. plication (see below under BKidney^). The growth in muscle
Todaythereisgeneralagreementthattheanaboliceffecton massandpowerunderAASappearsnottobeparalleledbyan
skeletal muscle is mediated through the androgen receptor equalincreaseintendonstrengthasAASabusersaresupposed
RevEndocrMetabDisord(2015)16:199–211 203
Pathol.findings FatalDCM+myocarditis Non-fatalDCM Non-fatalDCM Non-fatalDCM+hepatits,familyhistoryforcongestiveheartfailureandearlycardiacdeath Fatalhypoglycemiacardiachypertrophy Fatalmultiorganfailure,cardiachypertrophyandfibrosis FatalMI FatalMI,DCM FatalMI,cardiachyper-trophy Non-fatalMI,familyhistoryofCVD,Hk63%! Non-fatalDCMfatherseveralMIs Non-fatalDCMacuteliverfailure FatalLVapoplexy FatalLVapoplexy Fataldisseminatedmyocarditis Fataldisseminatedmyocarditis
y
dl
n
a
cingdrugs(PAED) Durationofintake 2xweeksfor6weeks,intermittsince3years Severalyrs
n
a
h
n
e
eandappearance Othersubstances Tobaccochewingsince5ys.ThyroxinDiazepamPolypharmacyEphedra80-120mg/dyγ-OHbutyrate–12g/dy Clenbuterol(Insulin?) Ephedrin Coffein Sildenafiloccasionally FurosemidSpironolactoneHydrochloro-thiazid,IgF1
c
n
a
m
or
erf
p
withorwithoutother AAS TestosteroneRetabolilAnasteronPrimobolanSustanonSublingualTP2x/dysince3mths19-Nortestosteroneplus8furtherAAS 200-400mg/weekNandroloneDianabol–2040mg/dy TestosteroneNandroloneStanozololBoldenoneStanozolol TestosteroneNorandrosteroneStanozololEpimethediolMetenoloneTestosteroneNandroloneMetadienoneMesteroloneStackedhigh-doseTim HighdosesT250mgevery5dys AASpoAASim AAS AAS AAS AAS
S
A
A
e
dos ars)
high e(ye
ng Ag 33 29 21 40 31 32 32 35 45 44 41 40 19 22 25 28
si
u
s
e
athlet Sex m m m m m m m m m m m m m m m m
5
2
n
i
atalcardiopathies Typeofsport Bodybuilder Weightlifter Bodybuilder Bodybuilder Bodybuilder Bodybuilder Bodybuilder Bodybuilder Bodybuilder Recreationalweightlifter Competitivebodybuilder BodybuilderBodybuilder Weight-lifter PhysicalexerciseteacherBodybuilder Soccer
n-f
o
n
d
n
Table3Fatala Reference SchollertandBendixen[32] Ferreraetal.[33] Vogtetal.[34] ClarkandSchofield[35] Kistler[36] Stergiopoulosetal.[37] AhlgrimandGuglin[38] Bispoetal.[39] Fantonetal.[40]
204 RevEndocrMetabDisord(2015)16:199–211
s,
u
s b
Pathol.findings FatalcoronarythrombosiandDCM FatalLVhypertrophy Non-fatalCM,LVthromstroke FatalDCM FatalDCM,endocardialthrombosis FatalDCM,pulmonaryinfarction Fataleosinophilicmyocarditis FatalmassiveMIandischaemicstroke Fatalsuddencardiacarrythmia Hke,hematocrit
at
n
o
pri
o
pr
T
P
e T
k s
Durationofinta Since3years 7years Severalyrs Severalyrs Forsince2year Tar,testosterone,
ul
c
ntri
stances macy leftve
Othersub Polyphar EphedrinTadalafil LVarction,
nf
i
al
AAS AAS AAS Nandroloneim,2x/week AAS++ StanozololBoldenoneDromostanoloneMetelononeTrenboloneAAS++ Testosterone19-Nortesto-sterone MethandienoneMethanolone(Dosesnotspecified)9differentAASforlast12mths(metandienone,mestanolon,stanozolol) MIculardisease,myocardi
s
a
v
o
di
ears) Dcar
y V
( C
e
Ag 54 48 39 32 31 32 25 37 20 hy,
at
p
o
y
m
Sex m m m m m m m m f dio
ar
c
e
v
ati
Typeofsport Marathon Marathon Bodybuilder Bodybuilder Bodybuilder Cyclist Bodybuilder Fitnessathlete FitnessathleteProstituteDrugdealer DCMmale,dil
e
f
f
e,
Table3(continued) Reference Youssefetal.[30] Montiscietal.[41] Shamlouletal.[31] Thiblinetal.[42] Abbreviations:mmal
RevEndocrMetabDisord(2015)16:199–211 205
to experience a higher rate of tendon ruptures [56]. This im- AAScanoftencauseconcentricleftventricularmyocardial
pressionisbasedonsingleobservationsandacontrolledinves- hypertrophy whose extent seems to be dose-related [73, 74]
tigationisnotavailable.Infact,aself-reportedsurveyof2552 andmayalsodependontheARpolymorphismasinnormal
formerUSfootballplayersrevealedthattherewasnoassocia- men:shorterCAGrepeatsareassociatedwithhighermaximal
tionbetweenAASabuseandtendonaswellasmuscleinjuries, left ventricular wall thickness [75]. It has been shown that
while a higher rate of disc herniations, knee ligamentous and AASexertalong-standinghypertrophiceffectonthemyocar-
meniscal,elbow,spineandfoot/ankleinjurieswasreportedin dium.Therearenosignificantdifferencesbetweencurrentand
AASabusers.However,theauthorscautionagainstcausalcon- previousAASabusers[34,76,77].Anaffecteddiastolicfunc-
clusions since the players often took AAS after an injury for tionoftheleftventricleservesasacriterionfordifferentiation
fasterrecoveryandthesurveydoesnotprovideclueswhenthe between physiologic, training-induced hypertrophy and a
AAS were taken [57]. Frequent intramuscular injections of pathologicmyocardium[63,71,78].
AAS may lead to local reactions such as myositis ossificans, Theathlete’sheartischaracterizedbymoderateproportional
aformofheterotopicossification[58]. myocardial hypertrophy without functional limitations.
Pathologic left ventricular myocardial hypertrophy, developing
under AAS intake is often associated with a reduction of the
4Cardiovascularsystem ejectionfractionoftheleftventricle,aswellasarestricteddia-
stolicfunctionoftheaffectedheartchamber,probablycausedby
During the last two decades testosterone has undergone a increasingmyocardialfibrosis[79].Theseconddiagnosticcrite-
metamorphosisfromariskfactorforcardiovasculardiseases rionisthethicknessoftheleftventricularmyocardiumseenon
toacardio-protectiveagent[59–61].However,thisappliesto echocardiography.Aheartchamberwallthicknessofmorethan
testosterone inthe physiological range and tosubstitution in 13 mm is suspicious of pathologic myocardial hypertrophy or
hypogonadalmen.Thisiscertainlydifferentwhenexcessive AASmisuse[63,73].Aleftventricularhypertrophycanpersist
AASdosesareapplied. onechocardiographyseveralyearsafterAASwithdrawal[68].
High doses of AAS, especially in cases of simultaneous InacardiacMagneticResonanceImaging(MRI)assistedstudy
consumption of several different preparations, can cause re- notonlyanincreaseoftheLVwallmass,butalsomajorvolumes
ductionoftheHDL(high-densitylipoprotein)fractionofcho- ofbothheartventriclesweredescribed[79].Myocardialscarring
lesterolandincreaseofLDL(low-density-lipoprotein)choles- with severe left ventricular hypertrophy can occur in patients
terol[62–65],aswellasadecreaseofapolipoproteinA1[66]. withnormalcoronaryarteriesafterAASabuse[80],potentially
Theseeffectsonlipoproteinlevelscanbenotedapproximately due to an apoptotic testosterone effect on cardiomyocytes, as
2 months after the beginning of ASS abuse. Only several shownincellculturestudies[81].
monthsafterdiscontinuationofAASadministrationdoesthe Evenifthemyocardialhypertrophyshouldregress,impaired
lipid status return to normal [67]. After long-standing, high- diastolicfunctionoftheleftventricleandthedecreasedinotropic
dose AAS abuse atherosclerosis and consequential coronary capacity of the myocardium may persist [10]. In case of acute
heartdisease,cerebralvesseldiseaseorperipheralarterialob- advancedheartfailure due to AAS abuse amaximalimprove-
structivediseasecandevelop. ment in left ventricular ejection fraction was reached within
Whether AAS abuse causes arterial hypertension has not 6monthsafterdiscontinuationofASSintakeandthebeginning
beendefinitelyclarified.InsomecasesAASabuseledtoan oftreatmentwithangiotensinconvertingenzyme(ACE)inhibi-
elevationofbloodpressure[68],whichcanpersistupto1year tors and beta-blockers. In severe cases a left ventricular assist
afterdiscontinuationofdrugintake[69].SomeAASinhigh deviceandahearttransplantationwererequired[82].
doses cause water retention which may be associated with UncontrolledAASabusebyapparentlyhealthyyoungath-
highbloodpressure. letes can cause a significantly increased incidence of cardiac
Long-termAASabusershaveanalteredelectrophysiolog- death.Thisconcernsmainlypowerliftersandbodybuilderstak-
ical capacity of the myocardium with a significantly higher ing very high AAS doses, often in combination with other
incidenceofabnormalpost-exerciseelectrocardiograms(e.g., drugs. In his dissertation Kistler [36] describes effects of
extensionofQRS-complex>114ms, arrhythmias,including AAS-abuseonthehumanorganism,basedonautopsydataof
atrialfibrillation,ventricularfibrillation,ventriculartachycar- tenyoungbodybuilders(meanage33.7years)whotookcom-
dia,supraventricularandventricularectopicbeats)compared binationsofAASandotherdrugstoenhanceappearanceand
withcontrols[68,70].Comparedtonon-AASabusers,chron- performance (Table 3). In four cases the cause of death was
ic consumption of supraphysiological AAS doses by body- acute cardiac dysfunction. In all ten cases the mean heart
buildersincreasedinter-atrialandintra-atrialelectromechani- weightof517gwassignificantlyhigherthanthemeanphys-
caldelay,aswellasprolongedrepolarizationdispersionwith iologicalheartweight.Furthermore,inallcaseschronicische-
significantlyincreasedTp-einterval,Tp-e/QTratioandTp-e/ micchangesofthemyocardiumwerefoundhistologically.Itis
QTcratio-[71,72]. also notable that in almost all cases arteriosclerosis of the
206 RevEndocrMetabDisord(2015)16:199–211
coronary vessels and atheromatosis of the arteria carotis and AASinhighdoses,amongthesestanozololandoxymetholone.
aorta were found, despite the relatively young age of the After stopping AAS intake the sonographically detected ade-
athletes. nomas disappeared slowly and without surgical intervention
Somecasesofdilativecardiomyopathy(DCM)havebeen despiteconsiderableinitialsize.
described in young bodybuilders during intake of AAS Othercasestakeamoreseverecourse,whentheadenomas
(Table3).Inallcasestherewasuncontrolledhigh-doseAAS turn into liver carcinomas [93] and the AAS abusers die in
abuse, particularly in combination with other drugs [32, 34, livercoma,unlesstheyhaveachanceforcurativesurgeryor
35](Table3).Incaseswithageneticdispositionfordilative liver transplantation. This is illustrated by two recently pub-
cardiomyopathy using AAS it becomes specifically difficult lishedcases:a39-yearoldprofessionalbodybuilderhadtaken
to disentangle causal relationships (e.g., [83]). It has been 11(!)AASinhighdosesforthelast5years,amongthemfour
suggested that up to 50 % of DCM cases show a familial 17α-alkylated steroids. A sizable hepatocellular carcinoma
accumulation and diverse genetic background [84]. In most could be removed by laparoscopic surgery and the patient
cases the inheritance is autosomal-dominant, rarely X- had survived for at least 2 years when the publication ap-
chromosomalorautosomal-recessive.Becausetheprobability peared [94]. The second case is a 29- year old bodybuilder
ofmanifestationandgeneexpressionhaveahighvariability, who had taken cycles offive AAS including stanozolol and
some other predictive and environmental factors (e.g., viral methandienoneathighdosesover2years.Inaddition,heself-
infections or stress) can also be responsible for the develop- administered diuretics (aldosterone antagonists and thiazide
mentofcardiomyopathy[85]. forbettermuscleprofiling)aswellashumangrowthhormone,
insulinandtamoxifen.Hedevelopedahepatocellularcarcino-
maandwassavedbylivertransplantation;theexplantedliver
5Liver showed a mass of 8 kg (<2 kg normal), the tissue was AR
positive. At the time of publication he had survived for
Changes of liver structure and function have been described, 27months[95].Thelattercasealsodemonstratesthedifficul-
mainly in cases of chronic abuse of the 17α-alkylated AAS, ty in establishing a possible causal relationship between the
e.g., methyltestosterone, methandrostenolone, oxandrolone, liver carcinoma and a specific hormone/agent consumed by
oxymetholone,stanozolol[10,86].(Table2)Becauseoftheir thebodybuilder.Thispolypharmacyraisesthesameproblem
livertoxicity17α-alkylatedandrogenicsteroidshavebeencon- aswithotherdiseaseentitiesdiagnosedinAASabusers.
sideredobsoleteforclinicalusefordecades(atleastinEurope)
[86],butcontinuetobeavailableillegallyfordopingpurposes.
They may even be hiddenundeclared indietaryfoodsupple- 6Kidney
ments, as revealed by two cases of severe hepatotoxicity fol-
lowingconsumptionofthesupplementBCelticDragon^ con- TestosteroneandotherAAShavebeenusedinthepastforover
taining2α-17α-dimethyl-etiocholan-3-one,17β-ol[87]. 25yearsforanaemiatreatmentinpatientswithchronickidney
AAS play a key role in the development of steatosis insufficiencybeforeerythropoietinbecameavailableforclini-
hepatis, inhibiting the normal process of steroid metabolism caluse.Thedosesusedwereinthenormalclinicalrangeand
andleadingtocholesterolstorage[10].Anincreaseoftrans- farbelowthoseinAASabuse.Thegeneralconditionandthe
aminases(aspartateaminotransferaseASTandalanineamino- serum parameters of the malnourished patients with chronic
transferaseALT)ismostlyreversibleandseveralweeksafter renalfailureimprovedduetoreductionofcatabolism[96].
discontinuationofAASnormalrangesareachieved[65,88]. Renaldisordershavebeendescribedmostlyafterlong-term
As a direct toxic effect on hepatocytes with ultrastructural AASuseandrangefromaslightincreaseofserumcreatinineto
celldamage, oxidativestressleadingtoincreased ROS (reac- acuterenalfailureasacomplicationofrhabdomyolysisorliver
tiveoxygenspecies)productioncouldplayaroleinthehepa- damage.Inadditiontocreatinine,cystatincandcystatincclear-
totoxicity of 17α-alkylated AAS. Hepatotoxicity caused by anceshouldbeusedtoassessrenalfunctioninathletesasele-
AASischaracterizedbyhighbilirubinlevelsandcausespro- vated creatinine may be due to higher muscle mass and not
nounced jaundice, but only moderately increased AST and necessarily a sign of renal function impairment. AAS-induced
ALT[89].Changesoftenobservedareintrahepaticcholestasis, kidneydamagemayoccurasaconsequenceofliverdamageand
peliosishepatis(lacunarblood-filledcavities,whichcomefrom toxicbilirubinconcentrations,knownasbileacidnephropathyor
centralveinsorfromfocalnecrosisofhepatocytes)andprolif- cholemicnephrosis[97].Kidneyscanalsobeaffectedaspartof
erativechangesoftheliverstructuresuchasfocal-nodularhy- amultipleorgandysfunctionsyndrome[98,99].
perplasiaandliveradenomas[53,86,90–92].Theappearance Histologicallyfocalsegmentalglomerulosclerosiswithtu-
ofadenomasmaybenotedasearlyas6monthsoraslongas15 bularatrophyandinterstitialfibrosiscanbefoundwithlong-
and more years of AAS abuse, as described in two cases by termabuse[10].Mildformsofrenaldysfunctionwitheleva-
Socas et al. [92]. Both bodybuilders had taken five different tionofserumcreatinineandcystatincclearance,bloodurine
RevEndocrMetabDisord(2015)16:199–211 207
nitrogenanduricacidwithoutsclerotic/fibroticmorphological As with other drug addictions (amphetamines, hallucino-
changesoftenreturntonormalrangesafterdiscontinuationof gens, narcotics) AAS abuse may lead to neurotoxicity and
AAS [10]. It has been hypothesized that the inter-individual causeencephalopathy,asevidencedbyanalteredmentalstate
differencesconcerningthegradeofsideeffectsdependonthe withmemorylossandcognitiveproblems[107,108].
geneticallyprogrammedfunctionoftheuridinediphosphate- AASwithdrawalmayalsobeaccompaniedbydepression
glucuronosyltransferase (UGT) enzymes, which provide ordepressivesymptomssuchasdepressedmood,lossofin-
glucuronidationofsteroids,thefirstphaseofthedeactivation terest,lossoflibido,sleepdisturbancesandsuicidalintentions
and elimination pathway of AAS [100]. In-vivo measure of [1,10].InsomeformerAASabusersdepression,anxietyand
the UGT 1B17-activity revealed that low UGT2B17 ac- melancholy may persistfor manyyears ata rateabove non-
tivity, as a result of a UGT 2B17-deletion, was strongly abusers, as a 30-year follow-up among 683 Swedish power
associated with lower body-mass-index (BMI) in males, sport athletes revealed [109]. As many as 30 % of AAS
probably as a consequence of higher serum testosterone abusersmaydevelopAASdependence,oftencombinedwith
concentrations [101]. alcoholandotherdrugaddictions[88,110–112].Atleastthree
etiologic mechanisms may lead to AAS dependence: body
imagedisorderssuchasBmuscledysmorphia^,anexperience
ofdysphoryordepressionafterattemptingtodiscontinuemis-
7Psycheandbehaviour use, and possible hedonic effects of AAS [110]. A survey
among10,365Swedishmenshoweda5timeshigherrateof
Anumberofstudieshaveshown thatAASabusers may de- conviction for violent crime in AAS abusers than in non-
velopmaniacorhypomaniacbehaviourcharacterizedbyirri- abusers, however, this rate was not higher than in other
tability, aggressiveness, exaggerated self-confidence, hyper- polysubstanceabusers,indicatingthatthepredisposedperson-
activity and psychotic symptoms (for review 1). This is pri- alitymaybemoreimportantthanAAS abuse assuch[112].
marilythecasewhenveryhighAASdosesintherangeofor Amongforensicinvestigationsinthecauseofdeathamong34
equivalentto500to1000mgtestosteroneenanthateperweek AAS abusers there were 9 victims of homicide and 11 had
areconsumed.Asananonymousself-administeredquestion- committedsuicide,highlightingthehighincidenceofaggres-
naire revealed, 60 % of the 500 bodybuilders and athletes sivebehaviourordepression[113].
surveyedindeedadministeredsuchdoses—oftenincombina-
tionwithfurtherdrugs[102].
Although the ignorance about deleterious side effects of 8Conclusion
AAS and other PAEDs is often surprising, it is common
knowledgethatanyeffectivedrugsalsohavenegativeeffects, The foregoing description of the multiple adverse medical
especiallywhentakenathighdoses overprolonged periods. consequences of doping with AAS—some reversible, some
Thustheathleteistornbetweenthedesireforrecordachieve- irreversible—causing chronic illness and even death—dem-
mentsandthefearofunwantedsideeffectsofAAS.Henceit onstratesthedangersarisingfromabuseofveryeffectivesub-
islikelythatpersonssubjectingthemselvestosuchdangerous stances. The physician needs to be aware of these defects
regimensare already predisposed toirrationalactions before whenconfrontedwiththeafflictedpatientwhowillnotoronly
AASabuse[103].Dissatisfactionwiththebody(e.g.,muscle reluctantlyconfesstohisdopingpractice.Inordertobeaware
dysmorphia and dysphoria) seems to be common in males of the multiple hormones and drugs used for doping the an-
using AAS [104], similar to males with eating disorders. nually updated WADA BProhibited List^ (www.wada-ama.
Bothgroupshaveseriouspsychiatricsymptomssuchasanx- org)shouldbeconsultedasareference.
iety, depression, obsessive-compulsive behaviour and inter- Knowing the deleterious side effects the medical profes-
personalsensitivityandmaybesuicidal,butdifferregarding sion,togetherwithsportsorganizations,shouldnotonlytreat,
self-image:theeatingdisordergrouphadlowerscoresforself- but also warn and teach especially young athletes about the
emancipationand activeself-love andhigherscoresfor self- possiblemedicalconsequences[1, 114].Hence,WADAand
blame and self-hate than former AAS abusers. There are no itsworldwidenetworkofdopingcontrolshasnotonlythetask
differencesbetweenthesetwogroupsconcerningpsychiatric topreventcheatingandguaranteefairplayandequalchances
symptoms[105].Among17,200USadolescentboyslifetime in competitive sports, but also to protect athletes from self-
prevalenceforAASabusewas5timeshigher(21vs.4%)in inflictedhealthproblemsarisingfromAASabuse.Inorderto
the 635 homosexual than in the heterosexual boys. The ho- fulfilthistaskconstantrenewalofthemethodologyfordetect-
mosexual adolescents showed a higher incidence of depres- inglowdosesofAASandnewsubstancesisrequired[115].
sive symptoms/suicidality, substance use and victimization, While the health risks may be reduced by new forms of
but it could not be clarified whether these symptoms were micro-doping, new forms of detecting fraud by the athlete
precursorsoroutcomesofAASabuse[106]. need to be implemented [116] and existing technology
208 RevEndocrMetabDisord(2015)16:199–211
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