Side Effects of Anabolic Androgenic Steroids - Doping.nl

26 Pages·2009·0.6 MB·English

Side Effects of Anabolic Androgenic Steroids:
Pathological Findings and Structure–Activity
Relationships
AndreasBu¨ttnerandDetlefThieme
Contents
1 MethodologicalLimitations............................................................... 460
2 MechanismsofActionandSubstanceSpecificity ........................................ 460
3 AnabolicEffects .......................................................................... 463
3.1 CorrelationofSteroidStructureandAnabolicEffects.............................. 463
3.2 PathologicalFindings ............................................................... 464
4 BioconversionofSteroidstoCharacteristicAndrogensandEstrogens ................... 468
4.1 ConversiontoAndrogens ........................................................... 468
4.2 ConversiontoEstrogens ............................................................ 469
4.3 SuppressionofEndogenousSteroidBiosynthesisandPathologicalEffectsonthe
EndocrineandReproductiveSystem ............................................... 470
4.4 MetabolicSuppressionandHepatotoxicEffects .................................... 471
5 NeurosteroidsandPsychiatricEffects .................................................... 474
5.1 BiosynthesisofNeurosteroids ...................................................... 474
5.2 Behavioral–PsychiatricSideEffects ................................................ 476
Reference ..................................................................................... 479
Abstract Sideeffectsofanabolicsteroidswithrelevanceinforensicmedicineare
mainlyduetolife-threateninghealthriskswithpotentialfataloutcomeandcasesof
uncertain limitations of criminal liability after steroid administration. Both pro-
blems are typically associated with long-term abuse and excessive overdose of
anabolic steroids. Side effects may be due to direct genomic or nongenomic
activities (myotrophic, hepatotoxic), can result from down-regulation of endoge-
nousbiosynthesis(antiandrogenic)orbeindirectconsequence ofsteroidbiotrans-
formation(estrogenic).
Logically, there are no systematic clinical studies available and the number of
causally determined fatalities is fairly limited. The following compilation reviews
typicalabundantobservationsincaseswherenonnaturaldeaths(mostlyliverfailure
A.Bu¨ttner(*)
InstituteofLegalMedicine,St.-Georg-Str.108,18055,Rostock,Germany
D.ThiemeandP.Hemmersbach(eds.),DopinginSports, 459
HandbookofExperimentalPharmacology195,
DOI10.1007/978-3-540-79088-4_19,#Springer‐VerlagBerlinHeidelberg2010
460 A.Bu¨ttnerandD.Thieme
and sudden cardiac death) were concurrent with steroid abuse. Moreover, frequent
associationsbetweenstructuralcharacteristicsandtypicalsideeffectsaresummarized.
Keywords Sideeffects • Heart • Liver • Arteriosclerosis • Psychiatry
1 Methodological Limitations
Theevaluationofsideeffectsofanabolicandrogenicsteroid(AAS)abusecontains
several methodological problems. Firstly, the exorbitant dosages, which are up to
40 times higher than typical medical applications, prohibit any ethically justified
clinical studies. Observations of side effects of therapeutic applications are only
partially valid due to their comparatively low dosages. Moreover, the therapeutic
relevanceofsteroidsisreducedtoafewtestosteroneanalogsfortreatmentof,e.g.,
malehypogonadism,renalfailureassociatedwithanemia,cancerassociatedprotein
wastingdiseases,burns,AIDSandhereditaryangioedema.
Reliableempiricaldatafrombodybuildingarevirtuallyunavailable,becauseself-
reportsofadministereddosagesandcorrespondingsideeffectsarecertainlybiased.
Finally,observationsofpathologicalfindingsinautopsycasesarelessfrequentand
thereforenotstatisticallysignificant.Moreover,thecausalitybetweensteroidabuses,
the cluster of pathological findings and a presumptive cause of death needs to be
challenged,becausesteroideffects(includingsideeffects,healthrisksandhazards)
do not coincide with their analytical identification at the time of death. Therefore,
these observations do reflect a general steroid-associated elevation of health risks
inthebodybuildercohortbuttypicallycannotclarifytheindividualsituation.
2 Mechanisms of Action and Substance Specificity
Genomic steroid action consists of direct regulation of gene transcription by
ligand–receptor interaction or indirect modulation of coactivators. Biochemical
effects (including side effects) of steroids may be categorized according to the
various receptortypes, i.e., androgen(hAR), estrogen, glucocorticoid(hGR), pro-
gesterone(hPR)andmineralcorticoidreceptors.Inaddition,nongenomiceffectsof
steroidsare well described, e.g.the direct activation ofionotropicGABA recep-
A
torsbyneurosteroids.
Both mechanisms are characterized by a high specificity of receptor–ligand
binding,requiringstructuralcongruenceofsteroidsandcorrespondingreceptors.
Differentsteroidreceptortypesarestructurallyrelated;thesequencehomologyof
theligandbindingdomainsofhARisrelativelyhigh(e.g.55%withhPR,51%with
hGR; Gao et al. 2005) which suggests the potential of cross-reaction in particular
afteradministrationofhighdosesofsteroids.Extratothishighhomologyofrelevant
19 PathologicalFindingsandStructure–ActivityRelationships 461
receptors,thesteroidalligandsarecharacterizedbyaconsiderablestructuralsimilar-
ityandmayoftenbebiotransformedintoeachother.Therefore,astrictdifferentiation
ofsteroidsintofunctionalsubgroupsisneitherexpectednorobserved.
All relevant endogenous steroid hormones are synthesized and biotransformed
within the biochemical pathway shown in Fig. 1 (compare Kicman 2009). Con-
sequently,biologicalphenomenacanresultfromdirectsubstancesupplementation
(e.g. abuse of anabolic steroids) or indirect effects associated with inhibition
(suppression of gonadotropic hormones) or induction (formation of estrogens
from testosterone) of endogenous biosynthesis. The availability of steroidogenic
enzymesintargettissues(e.g.5a-steroid-reductaseinprostateorskin)ishenceof
primaryimportancefortheregio-specificityofsteroidaleffects.
Regulationofsteroidbiochemistryisacomplexprocessandsubjecttopositive
enzymaticamplificationandnegativefeedbackmechanisms.Anyadministrationof
asteroid–especiallyinamountsfarbeyondendogenouslevels–willcompromise
thebalanceofitsendogenoussynthesis.Theadministrationoftestosteroneleadsto
a rapid down-regulation of gonadotropic hormones (e.g. luteinising hormone),
followed by termination of endogenous production of steroids and atrophy of
steroidogenicorgans(testis).Thismayresultinasuppressionofotherendogenous
steroids(e.g.glucocorticoidsorneurosteroids)producedwithinthesamebiochem-
icalpathway.
Specific correlations between steroid structure and corresponding side effects
are based on exemplary animal or clinical studies in therapeutic dose ranges and
remainvague.
With respect to endogenous steroids, androgenic side effects may clearly
beattributedtoreductionofa4-doublebondto5a-dihydrotestosterone (DHT)by
5a-steroid-reductase and estrogenic effects are due to aromatisation of the steroid
A-ring by steroid-aromatase (CYP19). However, a simplified extension of these
principlestosyntheticsteroidsisnotgenerallyvalid.
Steroid side effects may either result fromdirect receptoragonism (whether or
not in combination with metabolic activation) or may be due to a suppression of
steroidbiosynthesis.Factorsdeterminingtheefficiencyofsteroidactionarethere-
forethestructuralspecificityaswellastheavailabilityofactivatingenzymesinthe
respectivetargetcells(e.g.skin,brainregion).
As a simplified review, main side effects may be associated with compounds
frequentlyabusedinsportsandbodybuildingandtypicalstructuralcharacteristics,
i.e.:
l Anabolicsideeffectsoftestosteroneandanalogs
l Enhancedandrogeniceffects,oftenassociatedwith5a-dihydrogenationofster-
oids
l Estrogenicsideeffects,dependingonsusceptibilitytoA-ringaromatisation
l Antiandrogenic effects based on a suppression of the hypothalamus–pituitary–
adrenal/gonadal(HPA/HPG)axes,withoutclearstructuraldetermination
l Hepatotoxicity,clearlycorrelatedwith17a-alkylationandtherelatedinhibition
ofmetabolicdeactivationofsteroidsbyoxidationofthe17b-hydroxygroup.
462 A.Bu¨ttnerandD.Thieme
HO
Cholesterol
Hypothalamus GnRH Pituitary LH P450scc
O O
O HO
Progesterone Pregnenolone
Aldosterone, O O
Cortisol
3β-HSD
HO
O
Androstene- DHEA
dione
17β-HSD 17β-HSD
OH
OH
3β-HSD
HO
O
Androstenediol
Testosterone
Estradiol 5α-DHT
Fig.1 Biochemicalsynthesisandmetabolismofsteroids
l Psychiatriceffectsofneurosteroids(characterizedby3a-hydroxylationand5a-
conformation of the A-ring) synthesized locally in the brain. The availability,
inductionorblockingofsteroidogenicenzymesinrelevantbrainregionsseems
tobemorerelevantthanperipheralsteroidlevels.
19 PathologicalFindingsandStructure–ActivityRelationships 463
3 Anabolic Effects
3.1 Correlation of Steroid Structure and Anabolic Effects
Theinactiveintracellularreceptorproteinsarelocatedinthecytosol.Afterforma-
tion of a receptor–ligand complex with suitable steroids and dimerisation, the
receptor–ligand complex migrates into the cell nucleus and binds to a specific
sequence of the DNA, leading to transcriptional activation of protein synthesis.
Moreover, anticatabolic effects based on glucocorticoid receptor inhibition may
contributetoanaboliceffects.
TheprocessiscontrolledbythespecificityofligandbindingandDNAbinding
domainofthesteroidreceptors.Owingtothehighsimilarityoftheligandbinding
domainsofallreceptors,steroidligandscross-reactwithdifferentreceptors.
17b-Hydroxylation and an A-ring carrying a 3-keto or equivalent substitutions
are thought to be the essential structural characteristics of anabolic effects and
therefore affected by its biotransformation (Fig. 2). The time-limiting metabolic
reactionoftestosteronedegradationisanA-ringreductionby5a/b-hydrogenation.
Furthermetabolicdegradationleadingto(partial)deactivationofanabolicsteroids
areoxidationof3-and17a/b-hydroxysteroidsbyvarioushydroxysteroiddehydro-
genase (HSD) isoforms. Moreover, anabolic steroids are partially deactivated by
aromatisationoftheA-ringtoyieldestrogens.
Therefore, a protection of the respective groups contributes to the efficacy of
anaboliceffectsandmodifiesthespectrumofpotentialsideeffects.Themostpotent
measuretoprolongitsactivityconsistsofalkylationinposition17aprotectingthe
17b-hydroxygroupandenhancesbioavailabilityandanaboliceffectsinparticular
afteroraladministration.
Typical modifications to prevent aromatisation and/or saturation of the A-ring
arealkylationinpositions1or2,chlorinationinposition4,insertionofthe2-oxa
group (oxandrolone), introduction of a 1–2 double bond, reduction of the 4–5
doublebondtoyield5a-dihydrosteroidsandremovaloftheC19-methylgroup.
OH
OH
17
CH
19 3
1
2
O
4
Fig.2 Modificationsofbiologicaleffectsofsteroidsandtheirbioavailabilitymaybeachievedby
structuralmodifications,particularlyatpositions1,2,4and17orremovaloftheangularC19.The
b-conformationofthe17-hydroxy-groupisessentialforanaboliceffectsofsteroidswhile3-keto
groupsareconsideredtobesupportivebutnotessentialandmaybereplacedbya2–3doublebond
(e.g.,desoxymethyltestosterone)
464 A.Bu¨ttnerandD.Thieme
Generally,androgenicanabolicefficacyofsteroidsisgovernedbytheirreceptor
binding and susceptibility to biotransformation. DHT, metandienone and oxy-
metholone are supposed to be strong anabolic agents. Remarkably, the anabolic
effectsofdesoxymethyltestosterone(1.6timessuperiortotestosterone),stanozolol
orfurazabolaresignificantinspiteoflacking3-ketogroups.
3.2 Pathological Findings
TheuseofAAS inathletesiswidespread,bothforperformanceimprovementand
for augmenting muscular development and strength. However, AAS use is not
limited to elite athletes and seems to be more extensive among recreational and
amateur athletes (Catlin and Hatton 1991; Hartgens and Kuipers 2004). Strength
athletes mainly use AAS to increase muscle mass and strength. Weightlifters and
power-lifters strive primarily for strength, whereas bodybuilders train for muscle
massandbodydimensions(Fig.3).
Thelong-termsideeffects arerelatedtostructure ofsteroids, dosage, frequency
of use, age at initiation and concurrent illicit drug use and have not been fully
elucidated (Yesalis and Bahrke 1995). Nevertheless, there is a broad spectrum of
possibleadverseeffectscausedbysupraphysiologicalAASlevelswhicharesummar-
izedinTable1(CatlinandHatton1991;Eklo¨fetal.2003;Evans2004;Grahamand
Kennedy1990;HartgensandKuipers2004;HauptandRovere1984;Hicksonetal.
1989;Karila2003; LaBree1991; Maraveliasetal.2005; Melniketal.2007; Mod-
linskietal.2006;Narduccietal.1990;YesalisandBahrke1995).Ofthese,someare
reversibleandoftenconstitutecosmeticproblemsonly.However,othersareirrevers-
ibleandmayleadtoseriousharm.Ofthese,thebestdocumentedeffectsarethoseon
thecardiovascularsystem,serumlipids,liverandthereproductivesystem.
Although life-threatening side effects seem to be rare, nearly 100% of persons
usingAASexperiencesubjectivesideeffectsasaresultofAASuse(Evans2004;
ParkinsonandEvans2006).However,therearenumerouscasestudiesandreports
which reported serious adverse effects and deaths. Obviously, even many well
designed studies do not reflect the AAS problem in real life. Many studies lack a
control group and do not account for individual, exercise and environmental
Fig.3 Externalaspectofaprofessionalbodybuilder(left)andofarecreationalAASuser
19 PathologicalFindingsandStructure–ActivityRelationships 465
Table1 PossibleadverseeffectsofAASabuse
Cardiovascularsystem Psychic/behavioraldisturbances
Disturbedlipidmetabolism Moodswings
Elevatedbloodpressure,hypertension Aggressiveness
Cardiacarrhythmias Depressivesymptoms
Myocardialhypertrophy Manicsymptoms
Cardiomyopathy Sleepdisturbances
Thrombosis Withdrawal,dependence
Earlymyocardialinfarction Psychosis
Suddencardiacdeath
Endocrine/reproductivesystem Kidney
Decreaseoflibido Pollakisuria
Decreaseoffertility Increaseofserumcreatinine
DecreasedLHandFSH Kidneystones
Alteredglucosemetabolism
Male-specificsideeffects Skin
Testicularatrophy Acne
Erectiledysfunction,impotence Urticaria
Subfertility Striae
Prostatichypertrophy Alopecia
Impairedspermatogenesis
Gynecomastia
Female-specificsideeffects Gastrointestinaltract
Hirsutism,virilization Queasiness
Voicedeepening Emesis
Menstrualirregularities Diarrhoe
Clitoralenlargement Hematemesis
Reducedbreastsize
Liver Musculoskeletal
Cholestasis,jaundice Tendondamage
Peliosishepatis Bonepain
Neoplasia Prematureepiphysealclosure(adolescents)
Gallbladderstones
Injection-related Various
Hematoma Edema
Infection Fever,shivers
Fibrosis Anaphylacticshock
Neuro-vascularinjury
HepatitisBorCandHIVinfection
variables. Furthermore, the covert nature of their misuse may explain the limited
andconflictingdataconcerningtheirsideeffects.Therefore,adverseeffectsmight
bemuchmoreseverethanreportedintheliterature.
In a prospective study, a Finnish cohort of former elite power-lifters with
presumed,butnotverified,earlieruseofAASexhibiteda4.6-foldhighermortality
compared to a control population, with myocardial infarction (Fig. 4) asthe main
causeofdeath(Pa¨rssinenetal.2000).ASwedishstudysuggestedthatAASabuseis
associated with an increased risk of premature death, especially among persons
withadditionalsubstanceabuseand/orpsychiatricdisease(Peterssonetal.2006a).
466 A.Bu¨ttnerandD.Thieme
Fig.4 Oldmyocardialinfarctionina30-yearoldAASabuser
After long-term AAS abuse (sudden) cardiac death is the most common mani-
festation of AAS toxicity (Di Paolo et al. 2007; Dickerman et al. 1995; Fineschi
etal.2007;Hausmannetal.1998;Lukeetal.1990;ownobservation).
Upon autopsy as well as in living persons, a dose-dependent left-ventricular
hypertrophy has been observed (De Piccoli et al. 1991; Dickerman et al. 1997;
Karila2003;Karilaetal.2003;Kriegetal.2007;McKillopetal.1986;Nottinetal.
2006;Sachtlebenetal.1993;Saderetal.2001;Thiblinetal.2000;Urhausenetal.
2004; Yeater et al. 1996; own observation). Similar findings have been described
forthecardiacventricularseptum(Saderetal.2001).Accordingtoanechocardio-
graphic study this concentric left-ventricular myocardial hypertrophy can still be
demonstratedalongtimeaftercessationofAASabuse(Urhausenetal.2004).
Other cardiac complications of AAS abuse include myocardial fibroses and
myocardial necroses (Halvorsen et al. 2004; Luke et al. 1990; Sullivan et al.
1998; own observation), as well as early coronary sclerosis (Santora et al. 2006;
ownobservation,Fig.5).
As the cause of these alterations, coronary spasm, increased atherogenesis,
impairmentofcoagulationandfibrinolyisaswellasdirectcardiotoxic(arrhythmo-
genic)effectsofAAShavebeenproposed.
The effects of AAS on blood pressure are still discussed controversially (Hart-
gens and Kuipers2004;Sullivan etal. 1998).Insomestudiesthe development of
hypertensioncouldnotbedemonstratedafterthechronicintakeofAAS(Hartgens
et al. 2003; Karila et al. 2003; Kuipers et al. 1991). In contrast, other studies
19 PathologicalFindingsandStructure–ActivityRelationships 467
Fig.5 MicrophotographofmyocardialfibrosisinanAASabuser
Fig.6 Markedcoronaryarterysclerosis
observed the occurrence of hypertension after long-term AAS abuse (Grace et al.
2003;Rockhold1993).
Besides morphological alterations, functional changes of the vascular system
have been described after AAS abuse. These consisted of an increased aortic
stiffness(Kasikciogluetal.2007)andanimpairedvascularreactivity(D’Ascenzo
etal.2007;Ebenbichleretal.2001;Laneetal.2006).Althoughthealterationsof
468 A.Bu¨ttnerandD.Thieme
impaired vascular reactivity seem to be partially reversible after abstinence, con-
sumersareatriskforvasospasmwithsubsequentmyocardialinfarction(Fig.4).In
anownautopsycase(Fig.6),a41-yearoldmandiedduetosuddencardiacdeath.
The heart weighted 482 g and showed a severe coronary artery sclerosis. Toxico-
logicalanalysesrevealedhighlevelsofmetandienone.
4 Bioconversion of Steroids to Characteristic Androgens
and Estrogens
4.1 Conversion to Androgens
Althoughandrogenicandanaboliceffectsaremediatedthroughthesamereceptor
(hAR),thebalancebetweenbotheffectsofsteroidsvariessignificantlyandseems
tobeassociatedwithcertainstructuralcharacteristics.DHTinparticularexhibitsa
hARbindingwhichis2–10timessuperiortotestosterone.Therefore,conversionof
TtoDHTinandrogen-responsivetissues(prostate)amplifiestheandrogeniceffects
considerably.
Since5a-DHTisapotentandrogenicsubstance,5a-reductionofsteroidA-rings
is supposed to be a characteristic structural feature of androgens. Similarly, syn-
thetic steroids with original 5a structure, e.g. mesterolone or methenolone, are
potent androgenic compounds. Steroids with A-ring modifications stabilizing the
A-ring conformation, e.g. stanozolol, oxandrolone or oxabolone, appear to be
comparatively less androgenic. Another promising approach to partial separation
ofandrogenicandanaboliceffectsistheremovalof19-methyltoyield19-norster-
oids. Nandrolone (19-nortestosterone) exhibits reduced androgenic effects but
retainsanabolicactivitycomparabletotestosterone(Gaoetal.2005).
The ratio of anabolic (myotrophic) to androgenic effects of nandrolone is
significantly higher than the corresponding index of testosterone, although both
steroids are biotransformed by analog enzymes and pathways (Fig. 7). This is
assumed to be due to the fact that 5a-dehydro-19-nortestosterone (relative to
nortestosterone) binds with weaker affinity to the hAR, opposite to DHT which
exhibitsahigheraffinitythantestosterone.
Consequently,adrenergiceffectsofsteroidsareinconsistentanddependonthe
particular chemical structure. The administration of metandienone, nandrolone
decanoate or testosterone cypionate stimulated male sexual behavior after gonad-
ectomy, while stanozolol, oxymetholone or methyltestosterone showed no effect
(ClarkandHarrold1997;Clarketal.1997).
InfemalestheadministrationofAASwillinducemasculinization.Acne,reduc-
tion of libido and voice deepening was reported in the first weeks of abuse. After
long-term AAS abuse menstrual irregularities, enlargement of the clitoris and
reduction of breast size usually develops (Evans 2004; Hartgens and Kuipers
2004; Wu 1997). In contrast to males, some changes, e.g. voice deepening, are
notfullyreversible(Maraveliasetal.2005).