Effects of Anabolic Androgenic Steroids on the Reproductive System of Athletes and Recreational

15 Pages·2017·1.31 MB·English

by  Maria A. Christou

SportsMed
DOI10.1007/s40279-017-0709-z
SYSTEMATIC REVIEW
Effects of Anabolic Androgenic Steroids on the Reproductive
System of Athletes and Recreational Users: A Systematic Review
and Meta-Analysis
Maria A. Christou1,2 • Panagiota A. Christou1 • Georgios Markozannes2 •
Agathocles Tsatsoulis1 • George Mastorakos3 • Stelios Tigas1
(cid:2)SpringerInternationalPublishingSwitzerland2017
Abstract (luteinizing hormone, follicle-stimulating hormone) and
Background Anabolic androgenic steroids (AAS) are testosterone levels compared with baseline, during the
testosterone derivatives used by athletes and recreational period of AAS use, as well as following AAS
users to improve athletic performance and/or enhance discontinuation.
appearance. Anabolic androgenic steroids use may have Results Thirty-three studies (three randomized clinical
serious and potentially irreversible adverse effects on dif- trials, 11 cohort, 18 cross-sectional, and one non-random-
ferent organs and systems, including the reproductive ized parallel clinical trial) were included in the systematic
system. review (3879 participants; 1766 AAS users and 2113 non-
Objective Thissystematicreviewandmeta-analysisaimed AAS users). The majority of the participants were men;
to critically assess the impact of AAS use on the repro- onlysix studiesprovided dataforfemaleathletes.Ameta-
ductive system of athletes and recreational users. analysis (11 studies) was conducted of studies evaluating
Methods An electronic literature search was conducted serum gonadotropin and testosterone levels in male sub-
using the databases MEDLINE, CENTRAL, and Google jects:(1)priorto,andduringAASuse(sixstudies,n = 65
Scholar.Studieswereincludedwhenthefollowingcriteria AASusers;sevenstudies,n = 59,evaluatinggonadotropin
were fulfilled: participants were athletes or recreational and testosterone levels respectively); (2) during AAS use
usersofanyage,sex,levelortypeofsport;AASuseofany and following AAS discontinuation (four studies, n = 35;
type, dose, form or duration; AAS effects on the repro- six studies, n = 39, respectively); as well as (3) prior to
ductive system were assessed asstated by medical history, AASuseandfollowingAASdiscontinuation(threestudies,
clinical examination, hormone and/or semen analysis. n = 17; five studies, n = 27, respectively). During AAS
Random-effectsmeta-analysiswasperformedtoassessthe intake, significant reductions in luteinizing hormone
weighted mean difference (WMD) of serum gonadotropin [weighted mean difference (WMD) -3.37 IU/L, 95%
confidence interval (CI) -5.05 to -1.70, p\0.001], fol-
licle-stimulating hormone (WMD -1.73 IU/L, 95% CI
Electronicsupplementarymaterial Theonlineversionofthis -2.67 to -0.79, p\0.001), and endogenous testosterone
article(doi:10.1007/s40279-017-0709-z)containssupplementary
levels (WMD -10.75 nmol/L, 95% CI -15.01 to -6.49,
material,whichisavailabletoauthorizedusers.
p\0.001)werereported.FollowingAASdiscontinuation,
& SteliosTigas serum gonadotropin levels gradually returned to baseline
[email protected] values within 13–24 weeks, whereas serum testosterone
levels remained lower as compared with baseline (WMD
1 DepartmentofEndocrinology,MedicalSchool,Universityof
-9.40 nmol/L, 95% CI -14.38 to -4.42, p\0.001).
Ioannina,Ioannina,Greece
Serum testosterone levels remained reduced at 16 weeks
2 DepartmentofHygieneandEpidemiology,MedicalSchool,
followingdiscontinuationofAAS.Inaddition,AASabuse
UniversityofIoannina,Ioannina,Greece
resulted in structural and functional sperm changes, a
3 EndocrineUnit,‘Aretaieion’Hospital,MedicalSchool,
reduction in testicular volume, gynecomastia, as well as
NationalandKapodistrianUniversityofAthens,Athens,
Greece clitoromegaly, menstrual irregularities, and subfertility.
123
M.A.Christouetal.
Conclusion The majority of AAS users demonstrated use have also been reported in many other regions of the
hypogonadism with persistently low gonadotropin and world,suchasScandinavia,Brazil,BritishCommonwealth
testosterone levels, lasting for several weeks to months countries, and in continental Europe [5]. A meta-analysis
after AAS withdrawal. Anabolic androgenic steroid use indicated that the global lifetime prevalence rate of AAS
results in profound and prolonged effects on the repro- useis3.3%,withahigherrateof6.4%inmaleindividuals
ductive system of athletes and recreational users and comparedwith1.6%infemaleindividuals[4].Inaddition,
potentially on fertility. AAS use appears more prevalent among teenagers com-
pared with individuals aged older than 19 years; notably,
4–6% of high school boys have used AAS [4].
Key Points In the short term, AAS use results in few serious med-
ical consequences, but their long-term use has been asso-
Thisisthefirstsystematicreviewandmeta-analysisof ciated with several debilitating physical and psychological
theeffectsofanabolicandrogenicsteroiduseonthe adverse effects and even increased mortality. Specifically,
reproductivesystemofathletesandrecreationalusers. adverseeffectsmayrangefromthedevelopmentofacneor
Anabolic androgenic steroid use results in a state of gynecomastia, to serious and life threatening effects such
prolonged hypogonadotropic hypogonadism in male as an increased risk of cardiovascular disease and hepatic
individuals; gonadotropin levels recover after carcinoma [6, 7].
13–24 weeks, whereas serum testosterone does not Normal gonadal function depends on the presence of
appear to recover, remaining reduced at 16 weeks intact hypothalamic pituitary gonadal axis activity through
following discontinuation of anabolic androgenic secretionofthegonadotropin-releasinghormone(GnRH)by
steroids. the arcuate nucleus of the hypothalamus, as well as gona-
dotropins by the pituitary gland [follicle-stimulating hor-
Anabolic androgenic steroid use is associated with
mone (FSH) and luteinizing hormone (LH)]. Anabolic
changes in sperm characteristics, a reduction in
androgenicsteroiduseproducesdose-dependentdepression
testicular volume and gynecomastia in men, as well
of gonadotropin release either by direct actionon the pitu-
as clitoromegaly and menstrual irregularities in
itary gland or by suppression of the hypothalamic GnRH
women and subfertility in both sexes.
release.Inmaleindividuals,reducedgonadotropinsecretion
results in decreased intra-testicular and peripheral testos-
terone levels, leading to AAS-induced hypogonadotropic
1 Introduction hypogonadism manifesting with testicular atrophy,
oligospermia, azoospermia, and other sperm abnormalities
First identified in 1935, testosterone is the principal hor- [8]. Some male AAS abusers experience a lack of libido,
mone controlling the development of androgenic-mas- erectile dysfunction, or even gynecomastia. Effects on the
culinizingeffectsinthemalebody,alongwithitsanabolic prostateglandincludehyperplasia,hypertrophy,andpossi-
propertiesthatincreaseleanmusclemass[1].Theanabolic blycancer[9].Infemaleindividuals,thechangesmostoften
androgenic steroids (AAS) are testosterone derivatives attributedtoAASabusearemenstrualirregularities(delayed
used since the 1950s in an attempt to maximize the ana- menarche, oligomenorrhea, secondary amenorrhea), dys-
bolic effects of testosterone, reduce the rate of its hepatic menorrhea, anovulation, clitoral hypertrophy, libido chan-
inactivation,anddecreaseitsaromatizationtoestradiol[2]. ges,anduterineatrophy,withmanyofthembeingpermanent
Anabolic androgenic steroid formulations may be self-ad- [10].Althoughsomenarrativereviewshavebeenpublished
ministered orally, parenterally by intramuscular injection, in this area [9, 11–13], to our knowledge, this is the first
or transdermally in the form of a patch or topical gel. systematic review and meta-analysis using explicit
EmpiricalevidenceinthepastsuggestedthatAASwere methodology to critically examine AAS effects on the
mostly used by top-level competitive athletes and espe- reproductivesystemofbothmaleandfemaleathletes.
cially weightlifters, bodybuilders, and track athletes [3].
However, currently, AAS are widely used, not only by
athletes involved in recreational and minor-league sports 2 Methods
but also by non-athletes. Interestingly, at least four out of
fiveAASusersarenotcompetitive athletesbutrathermen 2.1 Protocol and Registration
who desire what they perceive to be an ‘‘enhanced’’
appearance [4]. TheprotocolofthestudyhasbeensubmittedtothePROS-
It is estimated that 2.9–4.0% of Americans have used PERO international prospective register of systematic
AAS at some time in their lives, while high rates of AAS reviews(RegistrationNumber:CRD42015017099)andthe
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AnabolicAndrogenicSteroidsUseandReproduction
guidelines of the Preferred Reporting Items for Systematic participants and personnel (performance bias), blinding of
ReviewsandMeta-Analysesstatementwerefollowed[14]. outcome assessment (detection bias), incomplete outcome
data(attritionbias),selectivereporting(reportingbias),and
2.2 Inclusion and Exclusion Criteria otherbias.Thistoolassignsajudgmentofhigh,unclear,or
lowriskofbiasforeachitem.Todrawconclusionsaboutthe
Studies were included in the systematic review when the overall risk of bias for each study, it is necessary to sum-
followingcriteriawerefulfilled:participantswereathletesor marize assessments across the different domains. The RTI
recreationalusersofanyage,sex,level,ortypeofsport;AAS ItemBanktool,whichconsistsof13questions,wasusedfor
useofanytype,dose,form,orduration;AASeffectsonthe the assessment of risk of bias in observational studies
reproductive system of athletes were assessed as stated by [16,17].Eachstudywasgivenascoreandgradedashigh,
medicalhistory,clinicalexamination,hormoneanalysisand/ unclear,orlowriskofbiasbasedonthenumberofcritical
orsemenanalysis.Medicalhistory and/orclinicalexamina- appraisalitemsmet.Thecut-offscorewasdetermined,based
tionreferredtotheassessmentofspecificsignsandsymptoms, onprevioussystematicreviewsandmeta-analyses[18,19]
suchastesticularorclitorissize,regularityofmenstruation, asfollows;0.00–0.30,highriskofbias;0.31–0.70,unclear
and changes in libido. At least one of the following three riskofbias;and0.71–1.00,lowriskofbias.
hormonevalueshadtobereported:LH,FSH,and/ortestos-
terone.Semenanalysisincludedthemeasurementofdifferent 2.5 Statistical Analysis
spermcharacteristics,suchasspermconcentration,motility,
andmorphology.Nolanguage,publicationdate,orpublica- Quantitativeanalysiswasperformedtoassessthechangefrom
tionstatusrestrictionswereimposed.Allstudydesignswere baselineinmeanhormonevaluesduringtheperiodofAAS
eligibleexceptforcasereports,caseseries,reviews,andmeta- use(i.e.,priorto,andattheendofaperiodofactiveAASuse),
analyses. For studies on overlapping populations, the one as well as following AAS discontinuation (i.e., hormone
providingthemostcompletedatawasincludedintheanalysis. levelsattheendofaperiodofAASdiscontinuationcompared
In the meta-analysis, studies were included when the mean withthosepriortoAASuseandcomparedwiththoseatthe
hormonevaluesandthestandarddeviation,orthenecessary endofaperiodofAASuse).P-valueslowerthan0.05were
data to compute them, were provided for at least two time- consideredstatisticallysignificant.Theywereprovidedwith
points,i.e.,atbaseline,attheendofAASuseand/orattheend precisionatthethirddecimalpoint.Allp-valueslowerthan
oftheperiodofAASdiscontinuation. 0.001werereportedas\0.001.Random-effectsmeta-analy-
siswasconductedowingtothepresenceofstatisticallysig-
2.3 Study Selection and Data Extraction nificant heterogeneity in the included studies. The meta-
analysis was based on the inverse variance method for
Eligible studies were identified by searching electronic data- weighting.TheDerSimonianandLairdestimatorwasusedto
bases, scanning reference lists of included articles, and also poolmeandifferencesofeachstudyandestimatetheoverall
afterscreeningreferencesofpertinentreviews.Thesearchwas weightedmeandifference(WMD),aswellas95%confidence
appliedtoMEDLINE(PubMed),CochraneCentralRegistryof interval (CI) [20]. Heterogeneity was assessed with the
Controlled Clinical Trials (CENTRAL), and Google Scholar Cochran’sQteststatistic[21],withap-value\0.1denoting
(frominceptiontoAugust2016).Thealgorithm‘‘(anabolicOR statistical significance. The degree of heterogeneity was
androgenic OR AAS) AND (reproduction OR fertility OR assessed using the formula: I2 ¼100%(cid:2)Q(cid:3)ðk(cid:3)1Þ; where
Q
hormoneORsemenORspermORhypogonad*)’’wasusedto k represents the number of included studies [22]. The I2
searchforallrelevantstudiesintheaforementioneddatabases.
statisticrangesfrom0%to100%andcut-offvaluesof25,50,
Screeningoftheretrievedrecords(titles,abstracts,fulltexts)
and75%indicatelow,moderate,high,andveryhighdegreeof
and data extraction of the included studies were performed
heterogeneity, respectively. Data analyses were conducted
independently in an unblended standardized manner by two
usingthestatisticalprogramStata(Version13.1;StataCorp,
reviewers(M.A.C.,P.A.C.).Disagreementsbetweenreviewers
CollegeStation,TX,USA).
wereresolvedbyconsensus.Ifnoagreementcouldbereached,
thenathirdauthor(S.T.)decided.
2.4 Risk of Bias Assessment 3 Results
Risk of bias of the included studies was assessed by the 3.1 Characteristics of Included Studies
Cochrane Collaboration Tool for Randomized Controlled
Trials[15].Thedomainsusedpertaintorandomizationand Based on electronic databases search, 19,112 potentially
allocation concealment (selection bias), blinding of eligible citations were identified. Thirty-four additional
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M.A.Christouetal.
Fig.1 Preferredreporting
itemsforsystematicreviews
andmeta-analysesflowdiagram
eligiblestudieswerefoundthroughothersources.Ofthese included in the main analysis and the DHEAS experiment
19,146 citations, 18,978 did notmeetthe inclusion criteria data were used for sensitivity analysis. Regarding study
afterreviewingtheabstracts.Thefulltextoftheremaining design, 11 cohort studies (33%), 18 cross-sectional studies
168 citations was examined in more detail. Thirty-five (55%), three randomized controlled trials (9%), and one
studiesmettheeligibilitycriteria.However,infourstudies, non-randomized parallel clinical trial (3%) were consid-
overlapping populations were studied. Specifically, the ered eligible. In the randomized controlled trials, either a
studybyStrommeetal.[3]referredtothesamepopulation parallel [23] or a cross-over design was used [26, 27].
as that of Aakvaag and Stromme [23], and therefore only The publication year of studies included in the analysis
the latter was included in the analysis as it provided more extended from 1972 to 2016, with most studies being
complete data. Studies by Holma and Adlercreutz and published between 1980 and 1990 (n = 10, 30%). The
Holma included the same distinct population, but assessed majority of studies were conducted in Europe (18 studies,
different outcomes; they were therefore analyzed as a 55%; eight of which studies from Finland) and USA (11
single study [24, 25]. Finally, 33 studies were included in studies, 33%). The median (25th–75th percentile) duration
the systematic review. The process of study selection is of the follow-up period was 24.5 (15–42) weeks. The
detailed in the flow diagram provided in Fig. 1. language of all eligible publications was English.
One study [26] involved two partially overlapping
populations for two separate experiments [methandienone 3.1.1 Participants
experiment, n = 12 and dehydroepiandrosterone sulfate
(DHEAS), experiment n = 16]. Owing to the fact that The total number of participants in the studies included in
methandienone is considered a potent AAS, whereas thesystematicreviewwas3879(1766AASusersand2113
DHEAS is actually a natural weak androgen and hormone controls), with a mean (standard deviation) age of 28.7
precursor, results of the methandienone experiment were (4.9) years. Most studies involved only men (27 out of 33
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AnabolicAndrogenicSteroidsUseandReproduction
studies), four studies [28–31] referred only to women, and outcomeassessmentisshowninElectronicSupplementary
two more studies included both male and female athletes Material Tables S2 and S3.
[32, 33]. The most common type of exercise was strength
training and particularly bodybuilding, weightlifting, and
3.2.1 Hormone Changes During AAS Use (Comparison
powerlifting. When the comparator group was available, it
of Hormone Levels Prior to, and During Active AAS
usually referred to athletes not using AAS.
Use)
3.1.2 Type of Exposure/Intervention
Six studies, involving 65 AAS users, were included in LH
and FSH meta-analysis [24, 26, 34–37]. The random-ef-
Exposure or intervention in all eligible studies was AAS
fects model suggested significant reductions in both LH
use.Themedian(25th–75thpercentile)numberofdifferent
(WMD -3.37 IU/L, 95% CI -5.05 to -1.70, p\0.001)
AAS agents per study was 5.5 (3–11) and the median
and FSH levels (WMD -1.73 IU/L, 95% CI -2.67 to -
(25th–75th percentile) duration of AAS use was 12 (8–25)
0.79, p\0.001) during the period of AAS use (Fig. 2).
weeks. The AAS substances used more often were testos-
There was significant high and moderate heterogeneity
terone esters (94% of studies), methandrostenolone or
acrossthesestudies(I2 = 88.6%,p\0.001andI2 = 55%,
methandienone (79% of studies), and stanozolol (67% of
p = 0.049,respectively).Fivestudiesthatdidnotfulfillthe
studies). The large diversity across different studies
criteria for inclusion in the meta-analysis, showed that
regarding the dose and route of AAS self-administration
serum gonadotropin levels decreased from baseline when
made the conduction of descriptive analysis for these
AAS use was started, or alternatively a lower level com-
parameters impractical. Characteristics of the included
pared with controls or normal values was reported
studies are shown in summary in Table 1 and in more
[27,31,38–41],whereasinthreestudiesnodifferencewas
detail in the Electronic Supplementary Material Table S1.
found [23, 42, 43].
Dataanalysisfromstudiesinwhichtestosteronehadnot
3.1.3 Outcome Definition and Method of Assessment
beenusedintheAASregimen[23,24,26,34],comprising
43AASusers,revealedadecreaseintheendogenousblood
The main outcome was AAS effects on the reproductive
testosterone level of 10.75 nmol/L (95% CI -15.01 to -
system of athletes, as assessed by medical history and/or
6.49, p\0.001) during the period of AAS use (Fig. 2).
clinical examination (in 23/33 studies, 70%), hormone
Highheterogeneitywasfoundamongstudies(I2 = 87.8%,
analysis (in 19/33 studies, 58%), and semen analysis (in
p\0.001). Data analysis from studies in which testos-
9/33 studies, 27%). The most common method of testos-
terone was self-administered as part of the AAS regimen
terone measurement was by radioimmunoassay (in 13/19
[35, 36, 44], involving 16 AAS users, revealed a margin-
studies, 68%). Semen analyses were usually based on
ally non-significant increase in testosterone levels (WMD
World Health Organization guidelines at the time (in 5/9
17.55 nmol/L, 95% CI -0.77 to 35.86, p = 0.060)
studies, 56%). In 14/33 studies (42%), athletes were fol-
(Fig. 2). There was significant high heterogeneity across
lowedforaperiodoftimefollowingAAScessation,lasting
studies (I2 = 75.9%, p = 0.016). The study by Bonetti
12–24 weeks (25th–75th percentile), with a median of
et al. [37] was excluded from the analysis as testosterone
16 weeks.
wasself-administeredinsomebutnotallstudyparticipants
and testosterone levels were provided for the study popu-
3.2 Outcomes of Included Studies
lation as a whole only (a non-significant decrease in
testosterone of 1.15 nmol/L was reported). Another two
Outcomesofthe33eligiblestudiesincludedthefollowing:
studies that did not provide all necessary data to be
(1) changes of serum hormone levels (LH, FSH, testos-
included in the meta-analysis and in which testosterone
terone) during AAS use, and following AAS discontinua-
was not part of the AAS regimen, reported a lower serum
tion; (2) changes of semen characteristics during AAS use
testosterone level during AAS use [27, 40], whereas, as
and following AAS cessation; and/or (3) reproductive
expected, the opposite was reported in studies in which
system changes as assessed by medical history and/or
testosterone was included in the regimen
clinical examination. To examine changes in endogenous
[31,38,39,42,43].Remarkably,inthestudyofMalarkey
testosterone during AAS use, we separately examined
et al. [31], the mean serum testosterone levels were 30
studies in which testosterone was included in the AAS
times those found in the non-AAS female weightlifters or
regimenandstudiesinwhichtheAASuseddidnotcontain
in the normal female population. In the study of Remes
testosterone and/or the AAS compounds were such that
et al. [26], results for all three hormones did not differ,
interference with the levels of serum testosterone was
independent of whether the AAS agent used was DHEAS
unlikely (methandienone, mesterolone, nandrolone). The
123
M.A.Christouetal.
Follow-up 12weeks 12months 24months a6months 25weeks 15weeks 42weeks 42weeks 12months Upto37weeks 5months NA NA NA NA NA NA NA NA MA NA NA NA NA
S
A s
A ek
e
Durationofcessation 12weeks 12months NA a6months 13weeks 3weeks 16weeks 16weeks 6months Upto24w 3months NA NA NA NA NA NA NA NA NA NA NA NA NA
y er
Typeofexercise Bodybuilding Workingoutatgymfacilities Bodybuilding Powerathletes Powerathletes Powerathletes Bodybuilding,powerlifting,wrestling Powerathletes Powerathletes Activeinsports,undertakeheavphysicaltraining Well-trainedathletes Bodybuilding,strengthtraining,othersports Weightlifting Bodybuilding NR Strength-trainedexercise Bodybuilding Bodybuilding,weightlifting,othsports Bodybuilding,powerlifting Bodybuilding Bodybuilding,weightlifting Weighttraining Subjectsattendinggymnasia Weightlifting
of s
ationSuse month weeks onths weeks weeks onths weeks onths
DurAA NA NA 24 NA 12 3m 26 26 6m 13 2m NA NA NA NA NA NA NA NA NA NA NA NA NA
T, NL, FB, TB,
AN,DHEAS,M MAN,TU,TES, BU,ME E,TP,MD,OX Y,ST,BO,DS, MD,OY DS,BO,TC,TP, MD,MS,MT,O
TypeofAAS MD,ND,TE TS,ND,ST NAN,NAL,NAND,NALD,AL,MD,OX,ML,NL,ST,TS MD,MS,OY,ST,MT,OX,FM,ML,TR,BU,TS ST,NL,MD,TS TS,MD,ND,ST MD,ST,NL,TS MD,NL,ST,TS MD,NL,ST,ML,TS NTH MD ST,ME,NL NR TS,NL,OY,O ND,ST,MD,TR,OX,OY,DP, OX,NL,BO,ST,MD,TP,TE MD,ML,OY,ND,TP,TB ND,TB,BO,ST,TR,TS,TC,T DMT,FM,MS,ML,MD,OX,ONL,ETT OY,MA,ND,TDP,MS,TE,TP ST,MA,NL,OX,MS,BO,TES, ND,ST,MD,ML,TR,OX,OY,TH,TE,TU OX,ST,MD,TES,ND TS,NL,OY,ST,ML,BO,OX,
e e
Sex Male Male Male Male Male Male Male Male Male Male Male Female Male Male Male Males,femal Male Male Male Male Female Male Male,femal Male
s
eristic N 24 35 20 18 15 6 11 9 14 5 16 8 55 250 80 748 30 207 31 30 75 100 1,669 156
ct
Table1Studieschara Firstauthor(yearofpublication) Cohortstudy Al-Janabi(2011)[45] Garevik(2011)[41] Bonetti(2008)[37] Karila(2004)[39] Alen(1987)[36] Martikainen(1986)[46] Alen(1985)[35] Ruokonen(1985)[44] Alen(1984)[47] Schurmeyer(1984)[34]bHolma(1976)[24] Cross-sectionalstudy ¨Borjesson(2016)[30] Kanayama(2015)[53] Razavi(2014)[56] Coward(2013)[51] Ip(2010)[32] Taher(2008)[40] Perry(2005)[52] Urhausen(2003)[38] Torres-Calleja(2001)[43] Gruber(2000)[29] Evans(1997)[50] Korkia(1997)[33] Pope(1994)[49]
123
AnabolicAndrogenicSteroidsUseandReproduction
Table1continued NFirstauthor(yearofSexTypeofAASDurationofTypeofexerciseDurationofAASFollow-uppublication)AASusecessation Malarkey(1991)[31]16FemaleMD,ST,ND,OX,TES,MI,MA,TRA,TRNAWeightliftingNANA Knuth(1989)[42]82MaleTES,NTE,MD,ML,ST,TR,BO,OX,CL,MS,OYNABodybuildingNANA Yesalis(1988)[55]45MaleMD,OX,OY,ST,ML,MS,FM,NE,MT,TES,NDE,NAPowerliftingNANATR,TA,BU,FB Strauss(1985)[28]10FemaleMS,MD,MA,MT,OX,ST,BU,ME,ND,SA,TC,NAWeighttrainingNANAMTE Strauss(1983)[54]39MaleMD,OX,ST,ET,OY,MT,ND,TC,TE,ME,NP,NABodybuilding,powerliftingNANATRB,TN,HM,THR RCTcRemes(1977)[26]12MaleMD2monthsRunnersNA8months Hervey(1976)[27]11MaleMD12weeksWeighttrainingNA20weeks Aakvaag(1974)[23]21MalesMS8weeksNRNA8weeks Non-randomizedparallelclinicaltrial Johnson(1972)[48]31MaleMD21daysWeighttrainingNA7weeks AASALANBOBUCLDHEASDMTanabolicandrogenicsteroids,androstenediol,androstenedione,boldenone,boldenoneundecylenate,clostebol,dehydroepiandrosteronesulfate,DPDSETETTFBFM4-dehydrochlormethyltestosterone,drostanolonepropionate,drostanolone,ethylestrenol,differentestersoftestosteroneandtrenbolone,formebolone,fluoxymesterone,HMMAMANMDMEMIMLMShexoxymestrolum,methenoloneacetate,methylandrostenedione,methandienone/methandrostenolone,methenoloneenanthate,mibolerone,methenolone,MTMTENNANALNALDNANmesterolone,methyltestosterone,mixtureoftestosteroneesters,totalnumberofparticipants,notapplicable,norandrostenediol,19-nor-4-androstenediol,NANDNDNDENENLNPNRnorandrostenedione,19-nor-4-androstenedione,nandrolonedecanoate,nandroloneesters,norethandrolone,nandrolone,nandrolonephenpropionate,notNTENTHOOXOYRCTSAreported,19-nortestosteroneesters,19-nortestosterone-hexoxyphenylpropionate,other,oxandrolone,oxymetholone,randomizedcontrolledtrial,stenboloneSTTATBTCTDPTETESacetate,stanozolol,testosteroneaqueous,testosteroneblend,testosteronecypionate,testosteronedecanoateandpropionate,testosteroneenanthate,testosteroneTHTHRTNTPTRTRATRBTSTUesters,testosteroneheptylate,therobolin,testosteronenicotinate,testosteronepropionate,trenbolone,trenboloneacetate,trophobolene,testosterone,testosteroneundecanoateaDurationofAAScessationandfollow-upare6monthsforhormoneandsemenanalysis,and6yearsforfertilityassessment(numberofchildrenconceivedandsuccessfulpregnancies)bDataofthestudiesHolmaandAdlercreutz[24]andHolma[25]werecombinedbecausetheyreferredtooverlappingpopulationsandtheyassesseddifferentoutcomescDatarefertocharacteristicsofthemethandienoneexperiment
123
M.A.Christouetal.
Fig.2 Hormonechanges
duringanabolicandrogenic
steroid(AAS)use.FSHfollicle-
stimulatinghormone,LH
luteinizinghormone
123
AnabolicAndrogenicSteroidsUseandReproduction
or methandienone (sensitivity analysis, Electronic Supple- lower compared with baseline levels (WMD -9.40 nmol/
mentary Material Fig. S1). L, 95% CI -14.38 to -4.42, p\0.001) (Fig. 4). The
periodofAASdiscontinuationinthesefourstudiesranged
3.2.2 Hormone Changes Following AAS Cessation from 13 to 16 weeks apart from that in the study by
(Comparison of Hormone Levels at the End Martikainen et al. [46], in which a shorter AAS discon-
of a Period of Active AAS Use and After a Period tinuation period of only 3 weeks was used, potentially
of AAS Discontinuation) explainingthelargerserumtestosteroneleveldifferenceat
the end of this study. There was non-significant moderate
Fourstudies,involving35AASusers,wereincludedinthe heterogeneity across studies (I2 = 36.6%, p = 0.192). In
LHandFSHmeta-analysis[34–36,39].LHandFSHlevels the study of Schurmeyer et al. [34], in which testosterone
increased during the period following AAS withdrawal was not included in the AAS regimen, endogenous serum
(WMD 2.68 IU/L, 95% CI 1.59–3.77, p\0.001 and testosterone levels returned to normal after 6 months.
WMD 1.89 IU/L, 95% CI 1.05–2.74, p\0.001, respec-
tively) (Fig. 3). There was moderate heterogeneity across 3.2.4 Semen Changes During and Following AAS Use
studies (I2 = 70.3%, p = 0.009 and I2 = 54.5%,
p = 0.066, respectively). Consistent with these results, the Sevenoutofeightstudiesshowedimpairmentofnumerous
two studies that were excluded from the meta-analysis sperm characteristics, such as total number, concentration,
because of a lack of appropriate data, showed that gona- motility,andnormalmorphology[25,34,37,39,42,43,47].
dotropin levels gradually recovered when AAS were However, in one study, no significant change in spermato-
withdrawn [41, 45]. genesiswasobserved[48].Allstudiesinwhichthisoutcome
Data analysis from studies in which testosterone was wasassessedshowedpersistentquantitativeandqualitative
part of the AAS regimen [34–36, 39, 44], involving 34 sperm changes 8–30 weeks following AAS withdrawal
AAS users, revealed, as expected, a decrease of testos- [25,34,39,42,45,47].
terone levels following AAS cessation (WMD In general, in the above studies, changes were assessed
-28.04 nmol/L, 95% CI -45.11 to -10.98, p = 0.001) and reported in a non-quantitative fashion. In the study by
(Fig. 3). High heterogeneity across studies was found Holma[25],the‘fertilityindex’wasused(ascorebasedon
(I2 = 75.5%,p = 0.003).InthestudyofSchurmeyeretal. sperm numbers, motility, quality of motility, and mor-
[34], in which testosterone was not included in the AAS phology).ThisindexdeterioratedduringAASusefrom1.7
regimen, a statistically significant increase in testosterone (3.0) to 14.7 (14.6), which is interpreted as ‘severely
of 10.64 nmol/L was reported. pathological’ [mean (standard deviation)] [25].
Finally, in a study that did not fulfill the criteria for
inclusioninthemeta-analysisandinwhichacontrolgroup 3.2.5 Outcomes Assessed by Medical History and/
was compared with a group of athletes during AAS use or Clinical Examination
including testosterone, serum testosterone levels were
lower compared with controls and did not increase signif- A number of studies reported testicular atrophy
icantly compared with the timepoint when AAS were [32–34, 37, 47, 49–52] in male athletes. Following AAS
withdrawn [45]. withdrawal,onestudyfoundthatformerAASusersdisplayed
smaller testicular volumes compared with non-users [53].
3.2.3 Hormone Changes Prior to AAS Use and After However, testicular atrophy was more prominent among
a Period of AAS Discontinuation currentthanpastusers,indicatingthattesticularsizetendsto
normalizeafterAASwithdrawal[49],althoughthismaytake
Threestudies[34–36],including17AASusers,wereincluded upto16 weeks[34].Somestudiesreportedgynecomastiain
in LH and FSH meta-analysis. LH and FSH levels were maleindividuals[32,33,37,38,50,52,54,55],whereastwo
similartobaselineattheendofaperiod(range13–24 weeks) other studies stated no effects of AAS use regarding this
ofAASdiscontinuation(WMD0.57 IU/L,95%CI-0.60to outcome[34,42].Remarkably,inthestudyofPopeetal.[49],
1.74,p = 0.340andWMD0.43 IU/L,95%CI-0.63to1.49, gynecomastiawasequallycommonbetweencurrentandpast
p = 0.426,respectively)(Fig. 4).Therewasnon-significant users, indicating that AAS-induced gynecomastia is often
low heterogeneity across studies (I2 = 0%, p = 0.524 and irreversible.Intheonlysixstudiesinvolvingfemaleathletes,
I2 = 0%,p = 0.639,respectively). clitoromegaly and menstrual irregularities were reported as
Data from four studies in which testosterone was self- themainAAS-relatedsideeffectduringtheperiodofAASuse
administered as part of the AAS regimen [35, 36, 44, 46], [28–33].
involving 22 AAS users, revealed that serum testosterone Only three studies determined AAS effects on fertility.
levels at the end of a period of AAS discontinuation were InthestudyofKarilaetal.[39],subjectswereaskedabout
123
M.A.Christouetal.
Fig.3 Hormonechanges
followinganabolicandrogenic
steroid(AAS)cessation.FSH
follicle-stimulatinghormone,
LHluteinizinghormone
123