Medical consequences of doping with anabolic androgenic steroids

12 Pages·2015·0.26 MB·English

ENieschlagandEVorona Testosterone,AASand 173:2 R47–R58
Review
reproductivefunction
MECHANISMS IN ENDOCRINOLOGY
Medical consequences of doping with anabolic
androgenic steroids: effects on reproductive
functions
Correspondence
EberhardNieschlag1,2andElenaVorona3
shouldbeaddressed
1CentreofReproductiveMedicineandAndrology,UniversityofMu¨nster,48129Mu¨nster,Germany,2Centerof toENieschlag
ExcellenceinGenomicMedicineResearch,KingAbdulazizUniversity,Jeddah,SaudiArabiaand3Centreof Email
Endocrinology,DiabetologyandRheumatology,Dortmund,Germany eberhard.nieschlag@
ukmuenster.de
Abstract
Anabolicandrogenicsteroids(AASs)areappearanceandperformance-enhancingdrugs(APEDs)usedincompetitive
y
g athletics,inrecreationalsports,andbybody-builders.ThegloballifetimeprevalenceofAASsabuseis6.4%formales
o
ol and1.6%forwomen.ManyAASs,oftenobtainedfromtheinternetanddubioussources,havenotundergoneproper
n
cri testingandareconsumedatextremelyhighdosesandinirrationalcombinations,alsoalongwithotherdrugs.Controlled
o
nd clinicaltrialsinvestigatingundesiredsideeffectsarelackingbecauseethicalrestrictionspreventexposingvolunteersto
E
f potentiallytoxicregimens,obscuringacausalrelationshipbetweenAASsabuseandpossiblesequelae.Becauseofthe
o
al negativefeedbackintheregulationofthehypothalamic–pituitary–gonadalaxis,inmenAASscausereversiblesuppressionof
n
ur spermatogenesis,testicularatrophy,infertility,anderectiledysfunction(anabolicsteroid-inducedhypogonadism).Should
o
nJ spermatogenesisnotrecoverafterAASsabuse,apre-existingfertilitydisordermayhaveresurfaced.AASsfrequentlycause
a
e gynecomastiaandacne.Inwomen,AASsmaydisruptovarianfunction.Chronicstrenuousphysicalactivityleadstomenstrual
p
o
r irregularitiesand,inseverecases,tothefemaleathletetriad(lowenergyintake,menstrualdisordersandlowbonemass),
u
E
makingitdifficulttodisentangletheeffectsofsportsandAASs.Acne,hirsutismand(irreversible)deepeningofthevoiceare
furtherconsequencesofAASsmisuse.ThereisnoevidencethatAASscausebreastcarcinoma.DetectingAASsmisusethrough
thecontrolnetworkoftheWorldAnti-DopingAgency(WADA)notonlyaimstoguaranteefairconditionsforathletes,
butalsotoprotectthemfrommedicalsequelaeofAASsabuse.
EuropeanJournalof
Endocrinology
(2015)173,R47–R58
Introduction
Medal-winning athletes are the undisputed icons of them with admiration and dedication, in no way
society. As role models, they are also expected to show objecting to exorbitant financial gains by their idols;
impeccable character and behaviour. Society rewards governments and companies consider athletes’ triumphs
InvitedAuthor’sprofile
EberhardNieschlagisemeritusProfessorattheCenterofReproductiveMedicineandAndrology, Universityof
Mu¨nster,Germany.His clinical and researchactivitiesconcentrateon reproductive endocrinology and andrology,
especiallymaleinfertility,testosteronesubstitution,theagingmale,hormonalmalecontraceptionandsteroiddoping.
www.eje-online.org (cid:2)2015EuropeanSocietyofEndocrinology PublishedbyBioscientificaLtd.
DOI:10.1530/EJE-15-0080 PrintedinGreatBritain
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Review ENieschlagandEVorona Testosterone,AASand 173:2 R48
reproductivefunction
as advertisements for their politics and products respect- Table 1 Anabolic androgenic steroids (AASs) constitute 87%
ively. In addition to exhaustive training, this places ofillegalappearanceandperforming-enhancingdrugs(APEDs)
athletes under tremendous pressure, not only to excel confiscated by customs or on the black market in Germany
intheirdiscipline,butalsotoresistthetemptationtouse 2010–2013; more than half are testosterone preparations
any illicit means, e.g. drugs, to enhance performance. (datafrom(6)).
‘Playtrue’isthemottooftheWorldAnti-DopingAgency
(WADA), appealing to all athletes to refrain from using AAS Kg
illicitdrugs,butwithouttheelaborateworldwidenetwork Testosteronepreparations
Testosteroneenanthate 81.9
of doping controls and sanctions against doping (www.
Testosteronepropionate 32.1
wada-ama.org, (1, 2)), WADA’s call for fairness would Testosteroneisocaproate 18.0
remainwithoutecho.However,dopingisnotreservedfor Testosteronedecanoate 5.5
Testosteronecypionate 5.2
the small squad of elite athletes, it has spread from the
Testosteronephenylpropionate 1.5
idolsat thetoptoall rankand fileparticipants insports, Testosterone(unesterified) 1.3
fromadolescentstoseniors.Thegloballifetimeprevalence Total 145.5
Metandienone 34.3
rate of using anabolic androgenic steroids (AASs) is 6.4%
Nandrolone 26.6
formalesand1.6%forfemales(3).Notonlyclassicalsport Trenbolone 15.9
disciplines are involved; the phenomenon is similarly Stanozolol 10.3
Oralturinabol 10.0
widespread among bodybuilders, so that the drugs used
Boldenone 8.9
have been collectively classified as ‘appearance and Drostanolone 4.7
y performance-enhancing drugs’ (APEDs) and summarised Oxandrolone 1.2
g
o Oxymetholone 1.2
nol intheWADAProhibitedList2015(www.wada-ama.org). Methenolone 0.3
ri Although doping has been practiced since antiquity, Methyldrostanolone 0.3
c
do often with placebo or toxic effects, really effective APEDs Total 259.3
n
E only became available with the rise of modern pharma-
f
o
al cology, and in particular, following the isolation and
n searchterm‘steroidsforsale’(9)!Furthermore,AASsmay
r synthesis of testosterone and AASs. Testosterone came
u
o beadded tofoodsupplements – often undeclaredon the
J intoclinicaluseshortlyafteritssynthesisin1935(4)and
n
ea itsfirstdocumentedusefordopingwasbyGermanrowers label(10,11,12)orfoundinphytopharmakaandanimal
op in1952(tomaintaintheirmaritaldutiesduringexhaust- organ extracts. For example, musk pods used in Chinese
r
u
E ing training) and by Russian weight lifters in 1954 to traditional medicine contain 16 different, undeclared
enhance their power. Since then AASs lead the lists of AASs,asdiscoveredindopingcontrols(13).Finally,secret
APEDsworldwideandamongthesetestosteroneisusedin but official programmes of sport organisations or states
almost 50%, be it in the 4500 doping-positive samples may provide AASs and other APEDs to their athletes, as
collectedbyWADAworldwidein2012(5)orbeitamong demonstratedbythesystematicdopingprogrammeofthe
black market substances confiscated by customs and former German Democratic Republic (GDR) in the1970s
police(6)(Table1). and1980s,whichbecameevidentafterthecollapseofthat
As all licensed testosterone and AAS preparations are re`gimein1989(14).
available only by prescription, the drug sources remain AASs – as all other APEDs – may have not only the
obscure. In part, these substances are no longer or have desiredeffect,butalsoadversesideeffects,resultingfrom
neverbeenontheopenmarket.Therehavebeeninstances thecombinationofdifferentAASsinextremelyhighdoses
ogdoctorsprescribingAASsespeciallyunderpressurefrom withotherdrugsandfromdurationofadministrationover
bodybuilders, who undertake any risk to become cham- periods ranging from months to many years. Due to the
pions.Surveysamongfitnesscentreclientelerevealedthat secret nature of this drug abuse type, doses and duration
up to half of APED users obtained the drugs with or aremostlyunknownandproperlycontrolledclinicaltrials
withoutprescriptionfromphysiciansorpharmacies(7,8). do not exist. Hence the scientific assessment of the
LabsinEasternEurope,AsiaandSouthAmericaproducing sequelaeofAASsabusereliesoncasereportsandonafew
multitudes of AASs offer them for sale on the internet retrospectiveinvestigations,makingareviewofthefieldin
which, next to gyms and fitness studios, has become the theageofevidence-basedmedicineextremelydifficultand
majorsourceofAASs.WhencountedinNovember2011, frustrating.Nevertheless,thisreviewisintendedtoinform
there were 328000 internet pages accessible under the theendocrinologistaboutsymptomsanddiseasescaused
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Review ENieschlagandEVorona Testosterone,AASand 173:2 R49
reproductivefunction
Table2 Sideeffectsofhigh-dosesteroidsonreproductiveand (includingdesignersteroids)arecollectivelyreferredtoas
sexualfunctions/organs. AASs, although both chemical structure and biological
profiles of individual AASs differ. In general, the effects
Inmen Inwomen
andsideeffectsofspecificAASsdependontheirchemical
Suppressionofgonadotropins Suppressionsofgonadotropins structure. The full spectrum of biological action requires
Suppressionsofspermatogenesis Anovulationandamenorrhoea
thattheandrogencanbearomatisedtooestradiolaswell
Decreaseintestisvolume Dysmenorrhoea
Infertility Infertility as reduced to 5a-dihydrotestosterone. As indicated in
Baldness Hirsutismandalopecia Fig. 1, the most frequently used AASs, such as, testoster-
Gynaecomastia Atrophyofthebreasts
one,boldenone,metandioneandnortestosterone,canbe
Lossoflibido Striaedistensae
Erectiledysfunction Acne aromatised as well as 5a-reduced, while fluoxymesterone
Profusesweating Clitorishypertrophy and formebolone can be 5a-reduced but not aromatised,
Striaedistensae Dysphonia
andsomeAASscanbeneitheraromatisednor5a-reduced,
Acne (Irreversible)deepeningofthevoice
Globaleffect:anabolic especially those that are dihydrotestosterone derivatives
steroid-induced
(Fig. 1). In addition, the genetic disposition of the
hypogonadism(ASIH)
individualathletemaymodifythereactionofandrogenic
substances, as exemplified by the androgen receptor
by AASs which, without specific knowledge, may be polymorphism modulating testosterone activity (20).
misinterpreted while searching for their origin. Proper However,keepingtheseapartisdifficultduetothevarying
diagnosis is further hindered by the reluctance of the combinationsanddosesinadditiontotheoftenpracticed
y
og dopedpatienttoadmittheconsumptionofAASsandbeing doping polypharmacy (21, 22), includingerythropoietin,
ol
n ignorantabouttheirpossibleserioussideeffects. insulin, IGF1, thyroxine, clenbuterol, amphetamines,
ri
oc This review highlights the effects of testosterone and diuretics, etc. However, the unique common feature of
d
En AASs on male and female reproductive functions and alkylation in the 17a-position of the androgen molecule
of includes effects on the skin and its appendices as shouldbepointedoutbecausetheseAASsarepotentially
al
n secondary sexual characteristics (overview in Table 2). severelylivertoxic(Fig.1).AASsabuseisalsocharacterised
r
u
o For adverse effects on other organ systems, the reader by‘stackingandcycles’,i.e.increasingdosesovertimeand
J
an is referred to previous reviews (e.g. (15, 16, 17, 18, 19)). changingpreparationsandtheircombinationsalternating
e
op For the sake of manageability, testosterone and AASs withAASs-freeperiodsinordertomaximisedesiredeffects
r
u
E
OH OH OH OH OH OH
CH3 HO CH3
H3C
F
O O O O O O
Cl H Cl H
Boldenone 1,2 Clostebol Dihydrotestosterone 2 Dehydrochloromethyl- Drostanolone Fluoxymesterone 2,3
testosterone 2,3
OH OH OH OH OH OH
O HO CH3 CH3 CH3 CH3 CH3
HC
O O H O O H O O
Formebolone 2,3 Mesterolone 2 Metandienone 1,2,3 Methenolone 2 Methyltestosterone 2,3 Nortestosterone 1,2
OH OH OH OH OH
CH3 O CH3 CH3
HC
O
H N
O O H N H O O
Oxandrolone 2,3 Oxymetholone 2,3 Stanozolol 2,3 Testosterone 1,2 Trenbolone
Figure1
Anabolicandrogenicsteroids(AASs)detectedmostoftenininternationaldopingcontroltests.1:AASsthatcanbearomatised,
2:AASthatareorcanbe5a-reduced,3:AASswiththeliver-toxic17a-alkylation(adaptedfrom(1)).
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Review ENieschlagandEVorona Testosterone,AASand 173:2 R50
reproductivefunction
andminimisesideeffects.Whethertheseregimensindeed
fulfilltheirpurposecannotbeassessedastheyarebasedon
300
trialanderrorandappropriatestudiesdonotexist. AAS > 14 weeks ago
200 ml)
s/
AAS 3–14 weeks ago n
Effects of AASs on male reproductive o
functions Current AAS users milli
100 n (
o
Suppressionofspermatogenesis 50 ati
ntr
As endogenous testosterone is the major regulator of the 0 nce
o
hypothalamo–pituitary–testicularaxis,itisnotsurprising 50 m c
thatexogenoustestosteroneandAASsexertasuppressive 100 Sper
effectonthehypothalamo–pituitarysystem.Theresulting Normal volunteers
suppression of luteinizing hormone (LH) and follicle-
stimulatinghormone(FSH)leadstoadecreaseinintrates- 200
ticulartestosteroneandsecretedtestosterone,aswellasto
adecreaseinspermatogenesisandspermproduction.This
effect forms the basis for clinical trials inhormonal male
Figure2
contraception. As there are no systematic investigations
Spermconcentrationsin41bodybuilderscurrentlyusing
y oftheeffectsofdopingwithhigh-doseAASsontesticular
g
o anabolicsteroids,3–14weeksagoorO14weeksago(upper
ol function, contraceptive trials may serve as a model for
n part)andin41drug-freevolunteers(lowerpart).Thebars
ri whathappensunderAASssuppression.
c
o representspermconcentrationsfromindividualbody-builders
d Male hormonal contraceptive trials use testosterone
En alone in therapeutic doses or in combination with (upperpanel)andfromnormalvolunteers(lowerpanel).
f
o Thehorizontallinesindicateaconcentrationof20million/mlas
al gestagenstoinduceazoospermiaorsevereoligozoospermia
n lowerlimitofnormal(modifiedfrom(28)).
r compatiblewithcontraceptiveprotection(forreview(23)).
u
o
J Testosterone derivatives used for doping, such as 19-nor-
n FSHcorrelategrosslywithspermcounts,i.e.thelowerthe
ea testosteroneandMENT,havealsobeenappliedincontra-
p gonadotropins, the lower the sperm counts tend to be.
o ceptivetrials(24,25).Thekineticsofspermsuppressionand
r
u Parallel to the decline in spermatogenesis, testicular
E recovery are quite well known from these carefully
volumesdecreasesignificantlybecausethetubulesoccupy
conductedtrialsusingtherapeuticdoses(26,27).Of1549
about 95%of thetestesvolumeand theiratrophycauses
healthyeugonadalmenparticipatingin30differentclinical
shrinkage of the testis. Varying doses, preparations, and
trials,aftercessationofmedication,67%showedareturn
combinationsofAASsandotherAPEDmakeitdifficultto
to sperm concentrations above 20million/ml within
draw general conclusions from individual observations,
6months,90%within12months,96%within16months
butitisclearthattherecoveryofspermcountscorrelates
and 100% within 24 months (26). While the different
positivelywithdurationoftimesincelastintakeofAASs,
regimensusedinthe30trialswerenotidentical,theyused
as do sperm morphology and motility (Fig. 2). As AASs
similar steroid doses; the differences in recovery time
maybeabusedformanyyearsathighdosesandinvarying
appeartobedeterminedmorebythecharacteristicsofthe
individualthanbythetherapeuticregimen.Nevertheless, combinations, it is impossible to predict accurately their
allmenreturnedtofertilelevelsofspermcounts.Thusa6to impactonspermatogenesiswithoutproperinvestigations.
24-monthspanprovidesatimeframeforrecoveryinAASs In some AASs abusers, recovery may take irritatingly
abusers,althoughithastobekeptinmindthatdosesused long. This, in addition to individual predisposition, is
for doping far exceed those used for male contraception, most likely due to the depot effects of the huge steroid
andthereforeevenlongerperiodsmaybeanticipated. concentrations consumed (30, 31). For example, after
These results may help to interpret case reports and termination of nandrolone abuse metabolites could still
small retrospective studies in AASs abusers. These show bedetected inurineafter more thana year insome men
a wide spectrum of sperm counts in AASs users under (32).Inothercandidates,spermcountsmaynotreachthe
treatment,aswellasaftercessationofabuse,rangingfrom normal range after cessation of doping, possibly due to
normal levels to azoospermia (Fig. 2) (28, 29). LH and preexisting fertility problems. When infertile men with
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Review ENieschlagandEVorona Testosterone,AASand 173:2 R51
reproductivefunction
subnormalspermcountswereincludedinacontraceptive resultinginhighoestrogenlevels.Althoughphysiological
trialusingtestosteroneundecanoatealone,allreturnedto levels of oestrogens are necessary for normal sexual
their (subnormal) baseline levels after cessation of function(38),theextremelyhighdosesandtheimbalance
testosterone undecanoate administration, but did not betweentestosteroneandestradiolappeartobethecause
become better or worse than before the trial (33). In of sexual dysfunction in thesecases. Thismay also occur
analogy,thoseAASsuserswhoapparentlydonotreturnto duringtherecoveryphaseafterterminationofexogenous
normalspermcountsmayneverhavehadnormalvalues AASs supply, when endogenous production has not yet
beforeinitiationofAASsabuse. resumedfullactivity.Thistypeofhypogonadism(31)has
Inconclusion,todatethereisnoindicationthatAASs been referred to as ‘anabolic steroid-induced hypogona-
abuse causes permanent damage to spermatogenesis, dotrophichypogonadism’(39)andmorerecently,simply
although suppression may cause transient azoospermia as ‘anabolic steroid-induced hypogonadism’ (ASIH) (40,
andrecoverymaytakeupto2years.However,nosystematic 41).InalargeUSurologydepartment,96of6033(Z1.6%)
investigationsexisttoprovideadefinitiveanswer. patientsconsultingforhypogonadismsufferedfromASIH.
Considering the great number of teenage boys using One-quarter of these patients presented with infertility
AASs,thequestionariseswhethertheirusebyboysaround and three quarters with sequelae of hypogonadism (41).
puberty may be harmful to spermatogenesis. Although ManyoftheseAASsabuserswerefirstoverlookedandonly
systematic investigations in pubertal AASs users are diagnosed after renewed interviewing following incon-
lacking, treatment of over-tall boys with high doses of clusive investigations. This reflects the fact that patients
testosterone–closetodopingdoses–forreductionoffinal seekingmedicalcareonlyreluctantlyadmittoAASsabuse,
y heightprovidesananalogy.Initiallyitwassuspectedthat and targeting AASs abuse directly should be part of the
g
o
ol this treatment would be harmful to the testes and leave routinework-upofhypogonadalmen(17).
n
ri permanent damage. However, when the proper control CessationofAASsabuseistheprimemeasuretotreat
c
o
d groups were co-investigated, the incidence of subnormal ASIH.Inaddition,varioustherapeuticattemptshavebeen
n
E semen parameters was the same in both groups (34, 35), undertaken to overcome ASIH and to hasten recovery.
f
o
al indicating that at this age the testes do not differ from Humanchorionicgonadotropin(hCG)hasbeengivenin
n
r adultmenintheircapacitytorecoverfromsuppression. individual cases (42), and has also been combined with
u
o
J tamoxifen or clomiphene to counteract the increased
n
ea oestrogen levels under hCG, inducing or worsening
p Testiculartumours
o gynecomastia (43, 44). However, hCG administration
r
u
E In connection with AASs abuse, testicular germ cell simultaneouslywithAASsinordertomaintainfertilityin
tumourshavenotbeenreportedintheliterature.Asingle power athletes showed an increase in morphologically
caseofaleiomyosarcomainaformerGDRweightlifterhas abnormal sperm in comparison with a control group
beenreported.Heusedoralturinabolathighdoses(upto receiving only AASs. This may be due to the lack of FSH
20tablets/day) from 18 to 23 years of age. He developed understimulationbyhCGalone(45).Therefore,although
gynaecomastiaunderthetreatmentandwas,attheageof sperm counts were maintained under this treatment,
32, operated for a unilateral intratesticular leiomyo- fertility may still be compromised due to deteriorated
sarcoma (36). As these tumours are extremely rare and sperm morphology. In cases with erectile dysfunction,
have been described in hamsters after treatment with PDE5 inhibitors have been prescribed, but again no
testosterone propionate and diethylstilbestrol (37), the systematicstudiesexist.
authors suspected a causal relationship between AASs The continuing lack of conclusive studies prevents
abuseandthesarcoma.Asthisremainstheonlyreported clear recommendations on how to treat ASIH except to
case, possible involvement of AASs in the pathogenesis stopAASsandotherdrugintakeimmediatelyandtoawait
ofthetumourremainsunclear. recoveryinpatience.Italsoremainsethicallyquestionable
whether the consequences of hormone abuse should
be counteracted by additional hormone treatment,
Hypogonadisminducedbyanabolicsteroids
when normal conditions can be reconstituted by strict
Inadditiontodecreasedspermcountsandtestesvolumes, termination of abuse and waiting for spontaneous
some AASs abusers experience lack of libido and erectile recovery. Gonadotropin treatment may be justified
function as well as other signs of hypogonadism. This only if no improvement has been observed within
occursespeciallyinthosemenabusingaromatisableAASs, 24months(30,46).
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reproductivefunction
Prostate attributed to AASs abuse. However, physical and athletic
activityoftenresultinreproductivedisregularitiesdueto
Prostate development and growth are dependent on
disruptionoftheGNRHpulsegeneratoratthehypothala-
androgens (47). The prostate grows during puberty and
miclevel.ThisleadstoadecreaseinLHandFSHandthus
thesmallprostatesofhypogonadalpatientsattainnormal
todecreasedoestrogenproduction(53,54).Apopulation-
adult dimensions under testosterone treatment. Further-
based survey among 3887 Norwegian women revealed
more, androgens are often considered promoters or even
thatthosewhowerephysicallyactiveonmostdayswere
initiatorsofprostatecarcinomasothatonewouldexpect
3.2 times more likely to have fertility problems than
a high rate of benign prostatic hypertrophy (BPH) and
inactivewomen.Exercisingtoexhaustioncausedafurther
prostatecarcinomainAASsabusers,oftenexposedtohigh
increaseinfertilityproblems.However,afterterminating
doses of various AASs. Despite these considerations, only
the active sport, the number of nulliparous women was
one case has been reported of a bodybuilder who used
thesameintheinactiveandformerlyactivewomen(55).
combinations of different oral and injectable AASs at
When the influence of physical activity in 2232 women
high doses over a time span of 18 years, occasionally
undergoingIVFtreatmentwasinvestigated,thosewomen
augmented by growth hormone injections, who develo-
whoexercised4ormorehoursperweekfor1–9yearswere
ped an adenocarcinoma of the prostate at age 40 (48).
40% less likely to experience a live birth in the first IVF
Consideringthisdruganamnesis,itistemptingtosuspect
cycle thanthose who didnot exercise at all (56). Among
acausalrelationship,butthelackoffurthercasereportsor
717of849elitefemaleathletesparticipatinginthe2011
systematic investigations do not support this suspicion
IAAF Championship using neither hormonal contracep-
(49).Theobservationthatthetypeanddurationofsport
y tivesnorAASs,168wereoligo-oramenorrhoic.Onlyfive
g activities may influence the occurrence of prostate
o
nol carcinoma (as wellas erectile dysfunction andinfertility) of the 849 women were identified as AASs abusers (57).
ri This indicates that ovulation and menstrual disorders
oc makesinterpretationofAASsabuseevenmoredifficult.In
d leadingtoinfertilityarecommonamongphysicallyactive
n cyclists over 50 years of age, a clear positive correlation
E women and especially among competitive athletes, even
of between the incidence of prostate cancer and hours of
nal weekly cycling time (!3.75 vs O8.5h/week) was found withoutAASsabuse.
r Furthermore, the type of sport and the body compo-
ou (50).Furthermore,theobservationthathypogonadalmen
J sition required influence reproductive functions. Ballet
n treatedwiththerapeuticdosesoftestosteronedonotsuffer
ea dancersandcompetitivegymnastsstartstrenuoustraining
p from a higher incidence of prostate carcinoma than
o atanearlyageandretainaleanphysiquewithextremely
ur patients not treated with testosterone (51) supports the
E lowfatmass.Consequently,theirmenarcheoccurs2years
hypothesis that prostate carcinoma develops indepen-
later than in less active girls. In runners, menstrual
dentlyofpossibleandrogentreatment.
disorders occur in 25% on average, with frequency
Similarly,therearenoclearindications,casereportsor
correlating positively with distances covered per week.
systematic investigations demonstrating that AASs abuse
Swimmers have fewer irregularities than other athletes,
causes BPH. As shown in the preclinical model of the
probablyduetotheirhigheroestrogen-generatingfatmass
cynomolgus monkey, co-administration of testosterone
thanothersportswomen(forreview(53,58)).Thelackof
and norethisterone prevents the testosterone-induced
oestrogensmaybecomesoseverethatthesyndromeofthe
prostate growth and hypertrophy (52). As several AASs
‘female athlete triad’ (disturbed energy balance due to
also have gestagenic activity in addition to androgenic
disturbed eating behaviour, menstrual irregularities and
effects, some AASs may prevent testosterone-dependent
lowbonemineraldensity)hasbeenidentifiedasasevere
prostategrowthwhengivenincombination,andthismay
consequenceofintensivesportactivity(59,60).Thehigh
explainthelowincidenceofBPHinAASsabusers.
frequency of reproductive anomalies among female
athletes highlights the difficulty in disentangling the
effectsofexhaustingsportactivitiesandofAASsabusein
Effects of AASs in women the absence of controlled studies and based on only few
casereports.Incasesofthefemaleathletetriad,ithasbeen
Reproductivefunctions
speculated that (moderate) AASs intake could prevent
In females, delayed menarche, dysmenorrhoea, oligome- someofthesymptoms.
norrhoea, secondary amenorrhoea, anovulation and, as To approach the possible influence of androgens on
their consequence, infertility are the changes most often thefemaleorganism,investigationsonthetherapeuticuse
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reproductivefunction
of testosterone in women may be consulted. A large mistakenformen.Itisaccompaniedbyhoarsenesswhich
investigationwiththeaimofevaluatingthesideeffectsof mayintensifyuponlongeruseofthevoice.Thisdysphonia
testosterone administration in therapeutic doses in may become a problem for teachers, actors, and singers
womenshowednosignificantdifferencesconcerningthe whoareprofessionallydependentontheirvoices.
frequency of cerebrovascular diseases, coronary heart Suchvoice alterationsare observedwith endogenous
disease, breast carcinoma, deep venous thrombosis/lung elevation of testosterone levels e.g. congenital adrenal
embolism, diabetes mellitus, or acute hepatitis between hyperplasia(67)orinwomensensitivetotheandrogenic
women receiving testosterone therapy and the control action of some oral contraceptives. Effects of androgens
group(61,62). prescribed for other than doping purposes in women
Ifchangesinthereproductivesystemduetosuppres- (endometriosis, climacteric complaints, low libido, cellu-
sionofthehypothalamic–pituitary–gonadalaxis,suchas litisetc.)havebeendescribedinsomedetail(68,69,70).
dysmenorrhoea, secondary amenorrhoea with anovula-
In low-dose transdermal testosterone trials, 12/545
tion or reduction of breast size, are attributed to AASs
postmenopausal women receiving placebo and 15/549
abuse,theyshouldalsobereversibleifcausedbyAASs.It
ontestosteronereportedvoicechanges(64),emphasising
cantakeweeksormonthsuptocompleterecoveryofthe
the importance of controlled studies when evaluating
axis. In some cases, it has been reported that after
subjectiveparameters.
cessation of AASsadministration inwomen ittookup to
Incontrasttoacne,hirsutism,alopeciaandmammary
20 months until testosterone concentrations in serum
atrophy, deepening of the voice due to AASs tends to be
dropped to normal levels (62), correlating with obser-
irreversible. However, although deepening of the female
y vations on spermatogenesis in male AASs abusers (see
g voice is mentioned in all pertinent reviews dealing with
o
ol above). Concerning possibly irreversible side effects AASs abuse, it is surprising that no systematic investi-
n
cri of AASs use in women, such as clitoris hypertrophy, no gations exist, and even case reports are very rare. Most
o
d well-documentedcasereportsorstudiesareavailable.
n informationisanecdotalandsomecomesfromtelephone
E
of interviews or hotlines. For example, 11% of 217 women
nal Hirsutismandalopecia consultingtheanti-dopinghotlineofaSwedishuniversity
r
ou hospitalcomplainedofhoarsenessorloweringofthevoice
J Hirsutismandalopeciaarefrequent,butinmostinstances
n (71); however, as only those with complaints use such
ea reversiblesideeffectsofandrogenandAASsuseinwomen
p hotlines,thefiguresarenotrepresentative.Aschangesin
o (63,64,65).Assessmentofbodyhairandhirsutismhasto
r
u the voice are mostly irreversible, androgen application
E take ethnic dispositions into account. The degree of
mustbesuspendedattheearliestsignofsymptoms,ifthey
increased facial or body hair growth depends on dose
aretobeavoided.
and duration of AASs abuse and can be described
according to the hirsutism score by Ferriman–Gallwey,
establishedin1961.Basedontheintensityofhairgrowth Theriskofbreastcancer
in nine face/body areas, hirsutism can be diagnosed as
Breast cancer is the most frequent carcinoma in women
mild,moderate,orsevere(66).However,properanalysisof
with96newcasesper100000womenandyearinWestern
the grade of hirsutism and alopecia in AASs abusers has
Europe(72).Thishighprevalencehastobekeptinmind
notbeenundertaken.
whenconsideringanyadditionalchangesinAASsabusers.
Theeffectofexogenousandrogensonthedevelopmentof
Deepeningofthevoice
breast cancer has been discussed controversially in the
Loweringofthevoiceiscausedbygrowthofthelarynxin scientific literature. The lack of controlled studies and
girlsandbythickeningofthevocalchordsinwomenafter epidemiologicinvestigationscontributestotheuncertain-
puberty and can be monitored objectively. As laryngeal tiessothatindirectevidencefromotherclinicalsituations
tissue has androgen receptors, the voice is part of the hastobereferredto.
virilisationthatandrogenicsubstancesandAASscancause Inpremenopausalwomen–thegrouptowhichmost
inwomen.Thevoiceisanimportantphenotypiccharac- AASsabusersbelong–moststudiesdonotdemonstratean
teristic of a person’s identity and changes are easily association between serum testosterone levels and breast
recognised during social contacts. The voice change can cancer risk (62). In postmenopausal women, however, a
be so pronounced that on the telephone women may be small increase in the risk for breast cancer in correlation
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Review ENieschlagandEVorona Testosterone,AASand 173:2 R54
reproductivefunction
with testosterone and androstenedione serum levels was takenhormonaldrugs,hadahigherriskfordevelopment
found,butonlyinEC/PCcancers(73). of breast cancer. Women who in the past had received
In recent years, low-dose testosterone – mainly hormonaltherapydidnothaveahigherriskformamma
transdermal – has been used for the treatment offemale carcinoma.
sexual dysfunction, in particular of hypoactive sexual Ithasalsobeenshownthatadditionaladministration
desiresyndrome(HSDD).Inthiscontext,theriskofbreast of testosterone during hormonal replacement therapy
cancerhasbecomeaconcern.Recentreviews(62,74)and in postmenopausal women (oestrogen–gestagen prep-
practiceguidelines(75)findnoevidenceforanincreased arations) inhibited the proliferation of breast cells and
risk, but also conclude that no randomised controlled thereby decreased the risk of mammary carcinoma (85).
trials (RCTs) have been of sufficient size or duration to A recent 5-year interim analysis of a 10-year prospective
provide a definitive answer concerning the impact of study has demonstrated that in women treated with
testosteroneonbreastcancerrisk. testosterone implants the incidence of breast cancer
Experience with long-term hormonal therapy in was significantly reduced compared with untreated
transsexuals (female-to-male)aimingatvirilisation(stan- women(86).
dard therapy: testosterone enanthate 250mg i.m. every In animals and also in postmenopausal patients
second week or testosteone undecanoate 1000mg every androgens (e.g. testosterone, dihydrotestosterone (DHT))
10–12 weeks for 2–3 years before surgical therapy, e.g. blocked proliferation of breast cells in vitro, caused by
mastectomy, ovarectomy and hysterectomy, and for oestrogens as well as expression of oestrogen receptor
yearsafterthat)showsnoincreasedriskforbreastcancer genes (87, 88, 89, 90, 91). The antiproliferative and
y (76, 77). Since the 1970s, when hormonal therapy of proapoptoticactionsofandrogensareprobablymediated
g
o
ol transsexuals was first documented, only one clinical case through the androgen receptor, despite the potential of
n
ri hasbeenreported;inthiscaseamammacarcinomaofthe testosteronetometabolisetooestrogens(79).Beforethese
c
o
d residual breast tissue developed 10 years after bilateral interrelationswereknown,advancedstagesof mammary
n
E mastectomyandcontinuoustestosteronetherapy(78). glandcarcinomahadevenbeentreatedwithtestosterone
f
o
al The polycystic ovary syndrome (PCOS) is character- from the 1940s until the 1970s (92). The underlying
n
r ised by a significant increase in the testosterone concen- clinical experience was that testosterone inhibits rather
u
o
J trationinbloodandoftenservesasamodelforlong-term thanproliferatesabreastcarcinoma.Ageneticdisposition
n
ea testosterone exposure in women. Studies showed that concerningmutationsinBRCA1andBRCA2genes(breast
p
o the risk for breast cancer in these women does not cancergene)canexhibitahigherriskforthedevelopment
r
u
E increase(79). ofabreastcarcinoma.
Exogenous androgens are partially metabolised to Inconclusion,therearenoappropriateepidemiologic
oestrogensinbreasttissue(seeTable1).However,notall studies which clearly document or negate a causal
synthetic androgens are subject to aromatisation, e.g. connection between the administration of AASs in
tibolone and its metabolites cannot be aromatised (80). young female athletes and the development of breast
This also applies to the metabolism of oralturinabol carcinoma later in life. Nor is there an accumulation of
(chlordehydromethyltestosterone) predominantly used case reports which would argue for such a connection.
in the former GDR. Unless taken at extremely high Indirectly,itcanbeassumedthattheuseofAASsatyoung
doses,themoleculeisnotaromatised,sothatoestrogenic agescannotbecausalforbreastcancer.However,asinthe
sideeffectsbecomeclinicallyirrelevant(81). case of clinical low-dose testosterone treatment, suffi-
Alargerandomisedstudyshowedthatpostmenopau- ciently powered epidemiologic studies are required to
sal women receiving oestrogens exclusively did not have provide a definitive answer concerning the breast cancer
an increased risk of mammary carcinoma, in contrast to riskinAASsabusers.
womenwhoreceivedanoestrogen/gestagencombination
(82).Theageofthepatientandthedurationofoestrogen
SideeffectsofAASsontheskininbothsexes
therapyareconsideredasriskfactorsforthedevelopment
of breastcancer inwomen. Comparable resultshave also TheuseofAASscanveryrapidlyleadtocutaneouschanges
been shown in other studies (83, 84). However, women inpreviouslyunaffectedathletessothatthedermatologist
who received hormone replacement therapy (oestrogen maybeamongthefirstphysicianstobeconfrontedwith
or oestrogen/gestagen preparations) at the time point of AASs abuse. AASs act through the androgen receptor,
theevaluation,incomparisonwiththosewhohadnever presenting in epidermal and follicular keratinocytes,
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via free access
Review ENieschlagandEVorona Testosterone,AASand 173:2 R55
reproductivefunction
sebocytes, sweat gland cells, dermal papilla cells, dermal doses, long-term duration and the combination of AASs
fibroblasts,endothelialcells,andgenitalmelanocytes.The with other drugs would be unethical; ii) some AASs are
effectsaremediatedthroughaffectingthesebaceousgland not licenced drugs with no or only limited toxicology
growthanddifferentiation,hairgrowth,epidermalbarrier available; iii) high-risk behaviour and lifestyle factors of
homeostasisandwoundhealing(93).TheARpolymorph- thedopingindividualscannotbere-createdinthesetting
ismappearstoplayaroleintheseverityofsymptoms(93). ofaRCT;iv)AASsmaybehiddeninfoodsupplementsand
The most frequent skin manifestations are acne are not easily accessible; and v) studies extending over
vulgaris,oily skin,seborrhoea,striae,hirsutism andmale years and decades are unattractive to researchers (19).
pattern alopecia (64). The incidence of acne in AASs Under current circumstances, the recent US Endocrine
abusersrangesfrom17%inpersonsconsultingaSwedish Society’s Scientific Statement Task Force (SSTF) has
anti-doping hotline (71) to over 50% of athletes taking recommended the following: i) establishing prospective
part in a questionnaire aiming to identify unsupervised observationalcohortstudies(registries)todeterminelong-
AASs regimens and side effects of AASs (94). After
termhealtheffectsofAASsandAPEDuse;ii)establishing
eliminationofthecausalagent,thesechangesaremostly
epidemiologic surveys to determine the prevalence of
reversible. To speed up recovery, anti-androgen therapy
AASsandAPEDuseinthegeneralpopulation;iii)carrying
with cyproterone acetate or spironolactone may be tried
outhumanandanimalstudiestodeterminethemechan-
(93). However, severe forms of AASs-induced acne con-
isms by which APEDs exert their adverse effects; and
globata will leave extensive scarring on the affected skin
iv) conducting randomised trials of various therapeutic
areas(95).
strategies to treat adverse effects of AASs and APED use
y Afteracne,striaedistensaeasaresultofrapidmuscular
g (19). In addition, as athletes, bodybuilders and fitness
o
ol hypertrophy, supported by AASs intake, is the most studiocustomersappeartohaveonlyvagueknowledgeof
n
cri prevalent skin side effect in athletes, especially in body- the side effects of AASs, which they often belittle in the
o
d builders. Over 40% of athletes complained about stretch
n light of the relatively few severe long-term problems in
E marks of the skin (96) with typical localisation in the
of relationship with the vast number of AASs abusers (99),
nal musculus pectoralis or upper arm region. After discon- moreeducationofconsumers,aswellasathleticeducators
r tinuation of drug misuse, striae can persist as white
ou and health care providers, about the possible sequelae of
J streaks(70).
n AASs and APED abuse is mandatory to prevent negative
a
e
p long-termeffects(100).
o
ur Conclusion
E
Thereisadearthofcontrolledclinicaltrialsandlong-term
Declarationofinterest
observationsonthesideeffectsofAASs(andotherAPEDs),
The authors declare that there is no conflict of interest that could be
andourknowledgeonadverseeffectsisbasedonlyoncase
perceivedasprejudicingtheimpartialityofthereview.
reports and a few retrospective investigations. Strangely
enough, medicine had turned a blind eye on APEDs. For
a long time, scientific medicine even negated positive
Funding
effects by AASs on muscle mass and strength, as Thisreviewdidnotreceiveanyspecificgrantfromanyfundingagencyin
documented in a 1991 meta-analysis concluding from a thepublic,commercialornot-for-profitsector.
Medline search for publications (1966–1990) that there
was no convincing evidence that AASs were increasing
Acknowledgements
muscle power (97). This conclusion was partly based on
LanguageeditingofthemanuscriptbySusanNieschlagMAisgratefully
thefactthatAASsdosesusedinacademicstudieswerein
acknowledged.
therangeoftherapeuticreplacementdoses,farbelowthe
doses and combinations used in the real doping world.
Bhasinetal.(98)wereamongthefirsttoapplytestosterone
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