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European Journal of Endocrinology -19-0154 induced hormonalandmetabolicabnormalities,butalso toaddressthetherapeuticissuesfortimelyintervention. a varietyofclinicalscenarios.Therefore,itisextremelyimportant forcliniciansnotonlytopromptlyrecognizedrug- disease, cliniciansshouldbeawarethatdrugscancause endocrineabnormalitiesviadifferentmechanismsandmimic targeting novelmolecularpathwaysintheprocessofmalignancies.Inthisnewcontextdrug-inducedendocrine endocrinology isconstantlyexpandingparticularlyduringthelastdecade,withnewoncologicaltherapeuticagents, endocrinopathies, whichwaspresentedinthemonothematicannualComboEndoCourse2018.Thischallenging partof clinicians fromtherightdiagnosis.Thepurposeofthisreviewistocoveracontemporarytopic,-induced Furthermore, drugscaninterferewiththehormonalassays,leadingtoerroneouslaboratoryresultsthatdisorientate axis, onhormonaltransport,bindingandsignaling,aswellsimilarchangestocounter-regulatoryhormonesystems. via differentmechanisms,includingdirectalterationofhormoneproduction,changesintheregulationfeedback easily bedisturbedbyinterferingpharmaceuticalagentslikemedications.Drugscancauseendocrineabnormalities In thecurrentlyoverwhelmingeraofpolypharmacy,balancedynamicanddelicateendocrinesystemcan Abstract University ofThessaly,Larissa,Greece,and Greece, 16 University ofGda , UniversityofBelgrade,Serbia, School, Houston,Texas,USA, Imperial CollegeLondon,UK, Department andDiabetesCentre,NIMTSHospital,Athens,Greece, Obstetrics andGynecology,NationalKapodistrianUniversityofAthens,‘Aretaieion’Hospital, Internal Medicine,LaikonHospitalMedicalSchool,NKUA, Medical andDentalSciences,UniversityofBirmingham,UK, Endocrinology, DiabetesandMetabolism,BirminghamHealthPartners, 3 1 C Tsigos G Mastorakos E Diamanti-Kandarakis a combo-endocrinologyoverview Drug-induced endocrinopathiesanddiabetes: DIAGNOSIS OFENDOCRINEDISEASE Department ofEndocrinology,AthensNaval&VAHospital,Athens,UnitReproductiveGreece, Department ofEndocrinology,DiabetesandMetabolism,HygeiaHospital, Harokopio UniversityofAthensandHYGEIAHospital,Athens,Greece, https://doi.org/ https://eje.bioscientifica.com Review of metabolicandhormonalabnormalities inobesitydiabetesandpolycysticovarian syndrome. research interestshavefocusedforthelast25 years onclinical,molecular andenvironmentalaspects Chairman oftheDepartment ofEndocrinologyandDiabetesHYGEIAHospitalinAthens, Greece.Her Evanthia Diamanti-Kandarakis Invited Author’s profile 18 St. Luke’sHospital,Panorama,Thessaloniki,Greece, 16 , T Tsilchorozidou 10.1530/EJE ń sk, Gda 8 , I Migdalis -19-0154 ń sk, Poland, 12 Department ofEndocrinology,MLHUniversityHospital,Beirut,, 1 , L Duntas 2 9 , A D Miras 17 © 15 11 2019EuropeanSociety ofEndocrinology Department of Endocrinology, Ioannina University Hospital, Ioannina, Greece, Department ofEndocrinology,IoanninaUniversityHospital,Ioannina,Greece, , T Tzotzas Department of Internal Medicine-Endocrine Division, McGovern Medical Department ofInternalMedicine-EndocrineDivision,McGovernMedical others E Diamanti-Kandarakisand 20 Faculty ofMedicine,UniversityLjubljana,Slovenia 2 , G A Kanakis is a Professor of Internal Medicine and Endocrinology and isaProfessorofInternalMedicineandEndocrinology and 14 10 Department of Clinical and Experimental Endocrinology, Medical Department ofClinicalandExperimentalEndocrinology,Medical , S Nader 18 Printed inGreatBritain , A Bargiota 7 Endocrine Unit,MetropolitanHospital, 19 Department of Internal Medicine – Endocrinology, Department ofInternalMedicine–Endocrinology, 11 3 , E Kandaraki 10 , O Papalou Division of Endocrinology Diabetes and Metabolic Medicine, Division ofEndocrinologyDiabetesandMetabolicMedicine, 17 5 19 Institute of and Systems Research, College of Institute ofMetabolismandSystemsResearch,College Private Practice, Endocrinologist, Serres, Private Practice,Endocrinologist,Serres, 6 and Department of Biological Chemistry, First Department of Department ofBiologicalChemistry,First 2 Endocrine Clinic Evgenidion Hospital, University of Athens, Endocrine ClinicEvgenidionHospital,UniversityofAthens, and diabetes Drug-induced endocrinopathies M Pfeifer Published byBioscientifica Ltd. 1 , R Poladian 1 , N Karavitaki 20 onbehalfofCOMBOENDOTEAM:2018 8 Endocrine Unit, 2nd Department of Endocrine Unit,2ndDepartmentof 12 , V Popovic 13 4 School of School of , 5 9 , E Kassi Second Medical Second Medical Downloaded fromBioscientifica.com at09/27/202110:34:28PM 13 6 , D Racho , S Livadas 4 Centre for Centre for (2019) Endocrinology European Journalof should be addressed Correspondence gmail.com e.diamanti.kandarakis@ Email to EDiamanti-Kandarakis 181 181 :2 ń , R73–R105 14 7 , , S Tigas

R73 –R105 15 , via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com checkpoint (ICP)inhibitors have ledtoagreatreliefand The immunetherapiesinadvanced cancerswithimmune Drug-induced Drug-induced pituitary dysfunction along withtheirbroadspectrumofendocrinesideeffects. drug categoriesthatwillbeanalyzedinthefollowingtext, appropriate decisionforthetherapeuticintervention. inorder tomakethe role ofmeticulousmedicalhistory differential diagnosis,emphasizingtheindisputable diabetes, inordertomakeitanintegralpartofclinicians’ promptly recognizingdrug-inducedendocrinopathiesand Conclusively, we aim to raise the clinicians’ vigilance in abnormalities leadingtoendocrinopathiesanddiabetes. recognize thedrug-inducedhormonalandmetabolic the underlyingpathophysiologicalmechanismsto to gobeyondalistofadverseeffectsandviaunderstanding and metabolic disorders. In thisapproach, an effort is made encountered inclinicalpractice,whichinduceendocrine spectrumofdrugs, ofacontemporary overview that disorientatecliniciansfromtherightdiagnosis( resultshormonal assays,leadingtoerroneouslaboratory systems ( hormonewell assimilarchangestocounter-regulatory axis andonhormonaltransport,binding,signaling,as production, changesintheregulationoffeedback mechanisms, includingdirectalterationofhormone broadening challengetoourclinicalpractice. a double-edgedswordforourpatients’wellbeingand estimated atUS$30 1000 peopleeachyear( reactions are responsible forfour hospitalizations per healthcare systems. In the , adverse drug morbidity hasbeenhighlightedasamajorburdenof more drugssystematically( of olderadultsintheUnitedStatesaretakingfiveor abnormalities. whichcanleadtoendocrineandmetabolic system canbedisturbedbymultiplefactorslikedrugsand polypharmacy ( eraof system andorgan.Inthecurrentlyoverwhelming multiple mechanismsmaintainshomeostasisinevery The endocrinesystemwithitspreciseinteractionsthrough Introduction Review The purposeofthisreviewistodelineatea‘combo’ cancauseendocrineabnormalitiesviadifferent It isestimatedthat10%ofthepopulationand30% Table 1 6 ). Furthermore,drugscaninterferewiththe summarizessomethemostcommonlyused 1 ), thebalanceofdynamicendocrine billion ( 4 ), withassociatedannualcosts 2 , 5 ). Therefore,drugscanbe 3 ). Asaresult,drug-related others E Diamanti-Kandarakisand 7 ).

Table 1 Commonly used drug categories with broad endocrine side effects. and diabetes Drug-induced endocrinopathies

Immune Anabolic checkpoint Antiepileptic androgenic Oral deprivation Cytotoxic inhibitors Psychotropics drugs contraceptives inhibitors therapy Antihypertensives agents Drug-induced pituitary + + + dysfunction Drug-induced SIADH + + + + + Drug-induced + + + + (, ) hyperprolactinemia Drug-induced + + + + (beta-blockers) +

Downloaded fromBioscientifica.com at09/27/202110:34:28PM abnormalities Drug-induced and + + + + + (thiazides) + vitamin D deregulation Drug-induced + + + + + + + (loop diuretics) + Drug-induced + + + + + Drug-induced diabetes + + + + + + + (calcium channel blockers, + diazoxide, ) Drug-induced dyslipidemia + + + + + + + 181 Drug-induced adrenal + + + + :2 dysfunction Drug-induced pheo crisis + + + + (beta-blockers) Drug-induced + + + + + + + + () + Drug-induced + + + hyperandrogenemia Drug-induced PCOS + + + R74 Drug-induced male + + + + + + + + (beta-blockers, +

via freeaccess and sperm abnormalities spironolactone) European Journal of Endocrinology major histocompatibilitycomplex(MHC)presentingan activation involvesthebindingofaT-cell receptortothe disorders ( tolerance andpreventingthedevelopmentofautoimmune inmaintainingtheimmuneself- receptors thatserve ). ImmunecheckpointproteinsareT-cell surface (programmed celldeath1/programmed1 pathway andPD-1/PD-L1checkpoint pathways seemtobeimportant:CTLA4checkpoint regulating T-cell activationandimmunetolerance.Two Immune checkpointsignalingpathwaysarecriticalin (ICP) inhibitors Autoimmune hypophysitisrelatedtoimmunecheckpoint reported ( (adrenalitis) have been and primary -dependent diabetesmellitus,hypoparathyroidism hypophysitis and thyroid dysfunction; rare cases of commonly involved.Themostcommonoftheminclude system. Interestingly, endocrinesystemIRAEsarealso system, the lung, musculoskeletal, renal and nervous systems. Typically, IRAEs affect the ,gastrointestinal related adverseevents(IRAEs)affectingalmostallorgan immune responsecanresultinanumberofimmune- who respondtothesetherapies,themodulationof certain typesofcancer( of has resultedinthealterationofnaturalhistory and expandingclassofanticanceragents,theiruse past 15 years, ICPinhibitorshaveemergedasapromising much greater hope in patients and physicians ( endocrine targets,translatedinto themainendocrineadverseassociatedwithimmunotherapy. Potential mechanismsofCTLA-4 andPD-1/PDL-1antibodiesinvolvedinantitumorimmune responses, aswellinmajor Figure 1 Review Along withthepromisingresultsinpatients 11 9 , , 12 10 , ). Thefirstsignalofthenormal T-cell 13 , 14 , 9 15 , 10 ). ). others E Diamanti-Kandarakisand 8 ). In the first reportoncentraldiabetesinsipidusassociated ).Recently,(atezolizumab, durvalumab, the targeting PD-1(nivolumab,pembrolizumab)andPDL1 tremelimumab) isabout11–12%andrarerwithdrugs after treatmentwithCTLA-4antibodies(ipilimumab, type 1in1%( hypophysitis in9–11%,adrenalitis1%anddiabetes endocrine glandscausingthyroiddysfunctionin15%, the activationofTlymphocyteswhosetsighton to recognizeandattackthetumorcells( APCs, thereby taking off the brake and allowing the T-cell block theproteinsfrombindingtotumorcellsand responses. ICP inhibitorsaremonoclonal antibodies that the B7ligands, thus inhibiting T-cell-mediated immune of TcellsareabletocompetewithCD28forbinding the B7ligandonAPC.CTLA4receptorssurface signal involvesthebindingofaT-cell CD28receptorto antigen onanantigen-presentingcell(APC).Thesecond requiring prompttherapeuticmanagement. with ,vomitingandvisualfielddefects, ( cancer, maskingthesymptomsofendocrinopathies. screening, asmostsymptomsaretypicallyrelatedto of endocrinopathiesareidentifiedwithhormonal oncologists becauseoflowT4andTSH.Themajority are seeingthesepatientsasaresultofreferralsfrom aretheleadingsymptoms.Mostendocrinologists enlargement.Headacheand mild-to-moderate pituitary presents insidiouslywithsubtlesymptomsand hypophysitis ICP inhibitor-inducedanteriorpituitary with anti-PDL1 treatment has been published ( and diabetes Drug-induced endocrinopathies i. 1 Fig. The useofCTLA4andPD1/PDL1antibodiesallows ). Rarely, itsclinicalpresentationmaybeacute, 11 , 16 , 17 , 18 Downloaded fromBioscientifica.com at09/27/202110:34:28PM ). Theincidenceofhypophysitis https://eje.bioscientifica.com 181 :2 Fig. 1 ). R75 19 via freeaccess ). ). European Journal of Endocrinology https://eje.bioscientifica.com Adapted withpermissionfromHaugen ( Rexinoids analogs Glucocorticoids Drug-induced suppressionofTSHandunderlyingpathogenetic mechanisms Table 2 and appropriatemanagementisessential.RecentUK deficiency maybelife-threateningandearlyrecognition receiving ICPinhibitorswhoisunwell.Acutecortisol ( subsequent appearanceofseverecorticotrophdeficiency by spontaneousregressionofhypercortisolism and ipilimumab andnivolumabtherapy, wascharacterized Cushing syndrome,whichappearedaftercombined tiredness ( of hypocortisolism may be vague, such as nonspecific 13–53% agonadotropindeficiency( 13–36% ofpatientscontinuetohaveTSHdeficiencyand ACTH deficiencypersistsin86–100%ofcases,while the placeboandmetformingroup( trial, nosignificantreductionofTSHwasfoundbetween a randomized,double-blind,placebo-controlledclinical studied inpatientswithsubclinicalhypothyroidism ( diabetic patientswithconcomitanthypothyroidism with levothyroxine( central ,whichrequiresreplacement rexinoids (bexarotene)induceclinicallysignificant not causeclinicallysignificanthypothyroidism,while analogs anddopamineagonistssuppressTSHbutdo central hypothyroidism.Glucocorticoids,somatostatin ( or drugs thatsuppressesTSHeitheratthelevelofpituitary from immunotherapy, thereisarespectablesubsetof aswell.Apart synthesis andsecretioncanbeobserved, patients. Analogously, isolatedinterruptionofTSH inthese (ACTH)deficiencymaybeobserved hypopituitarism. Notsorarely, isolatedadrenocorticotropic 21 25 Review ). Morning should be measured in a patient ). However, whenmetformineffectonTSHwas Recovery from pituitary deficienciesisvariable. frompituitary Recovery hypophysitisisaccompaniedwith Drug-induced suppressionofTSHandunderlyingpathogenetic mechanisms. 24 ). AcaseoftransientACTH-dependent Table 2 ). Notallcauseclinicallysignificant 20 ). MetforminlowersTSHin 20 others E Diamanti-Kandarakisand ). Mechanism ofaction Increased peripheralmetabolism ofthyroid of TSH Activation ofretinoidXreceptor (RXR).Inhibition Probable alteredthyroidhormonemetabolism Inhibition ofTSHsecretion. thyrotropes. Activation ofsomatostatinreceptorsin Reduced TSHpulseamplitude. thyrotropes. Activation ofdopaminereceptors(D2)on Inhibition ofTRHsynthesis/secretion. Activation ofglucocorticoidreceptor. 22 18 hormone ). , 23 β transcriptioninthepituitary. ). Features immune-mediated endocrinopathies,andspecifically Early recognitionandappropriatemanagementof inhibitor-induced hypophysitis,ithasbeenpostulated hypophysitis asshownin induced hypophysitisisbetterversuspatientswithout therapy. of patients with ipilimumab- Overall survival clinically stableonappropriateendocrinereplacement Immunotherapy canbecontinuedoncethepatientis deficiencies mayimproveexceptforcorticotrophfunction. the antitumorefficacyofICPinhibitors( higher doses of glucocorticoids may negatively affect of intractableheadache.Newerstudiessuggestthat palsiesandinsomecases hyponatremia, cranialnerve beneficial forpatientswithvisualfielddefects,severe Short-term higherdosesofglucocorticoidsmightbe (10+5+5 is suggestedwiththeusualreplacementdoseof inhibitor therapies( of acutelife-threateningendocrinecomplicationsICP guidelines presentendocrineassessmentandmanagement treatments overshadowthepotentialproblems( immunotherapies we must not let excitement of such robustly tocombinationICPinhibitortherapy( treatments includingtemozolomidebutresponding carcinomapatient withpituitary resistanttoallavailable inhibitors hasbeenrecentlynicelydemonstratedina ( T lymphocytes (type IV reaction) (type IIhypersensitivityreaction)andautoreactive to complementactivationandinfiltrationofmacrophages endocrinecells.Thisleads antigen expressionbypituitary immunogenicityismediatedbyCTLA-4 that pituitary and diabetes Drug-induced endocrinopathies 28 , Conclusively, althoughthereisgreatpromisein As for the underlying pathophysiology of ICP 29 , 30 , 31 ). The susceptibility of pituitary cellstoICP ). Thesusceptibilityofpituitary 26 Yes No May causehypothyroidisminpatients Probably not. No Clinically significanthypothyroidism Downloaded fromBioscientifica.com at09/27/202110:34:28PM with euthyroidsicksyndrome. ). Glucocorticoidreplacement mg) or7.5 Fig. 2 . 181 mg . :2 27 ). Hormone 32 ). R76 33 via freeaccess ).

European Journal of Endocrinology with permissionfromJohnWileyandSons. hypophysitis ReproducedfromFaje patients whohadhypophysitis(1Hyp)versuswithout Overall survivalisillustratedafteripilimumabmonotherapyin Figure 2 chronic hyponatremiaandsubtle neurologicalsymptoms management areearlierrecognition ofpatientswith as theserumlevelsof drug.Strategiestoimprove predisposing risk factors are the patient’s age, as well aquaporin-2 inrenalcollecting duct( osmolality orincreasedexpressionofthewaterchannel inappropriate levels of in the state of hypo- comparable betweendifferentmedicationclasses. The clinicalcharacteristicsofdrug-inducedSIADHare cytotoxic agents,painmedicationsandecstasy( , ,antipsychoticdrugs, to beimplicatedin82.3%ofthosepatients,including diagnosed withSIADH,fivedrugclasseswerefound single-center study, which included 198 patients implicated drugsassociatedwithSIADH.Inaretrospective inhibitors andcarbamazepinearethemostcommonly common causeofSIADH.Selectiveserotoninreuptake thyroid andadrenal,nodiuretics)( depletion or of other causes of hyponatremia (normal corresponding hypo-osmolality, absenceofvolume SIADH isacommoncauseofhyponatremiawith antidiuretic hormonesecretion(SIADH) Drug-induced syndromeofinappropriate immunotherapy canbesafelycontinued. stable onappropriateendocrinereplacementtherapy, hypophysitis, isessential.Oncethepatientclinically Review The mechanisms of drug-induced SIADH include others E Diamanti-Kandarakisand et al . ( 27 34 ), Copyright(2018) 34 ). Drugsarea ). Themajor 35 ). the vasopressinwaterreabsorptionpathway( hyponatremia exist,butlikelycandidategenesarepartof variants forcarbamazepineoroxcarbazepine-induced antagonists (vaptans)( with fluidrestrictionortheuseofvasopressin- factors, monitoringandtreatmentofhyponatremia irritability, dowsiness), better analysis of predisposing problems,mental (inability toconcentrate,memory in somecasescanalsoreach valuesover200 serum PRLconcentrations are significantly elevatedand dopamine action(dopamine receptorantagonists), hyperprolactinemia areduetotheinhibition of after (inthepost-partumperiod)( asinthe case inwomen PRL levelsmightalsobeobserved that afterthewithdrawalofOCsmildelevationserum cessation oftheOCsuse.Nevertheless,itmustbestressed not requiretreatmentbutshouldbere-evaluatedafterthe hyperprolactinemia ( oftenthecauseof amoderate ethynylestradiol arevery 40 Therefore, measurementofserumPRLlevelsshould pathology.related to the hypothalamicorpituitary check-up’ ofafemalepatientandinmostcasesisnot (1 µg/L=21.2µUI/mL) often encountered during the ‘hormonal is very 25 µg/L above concentrations (PRL) use ofcertainmedications.Elevationserumprolactin oftenitisduetothe findingandvery common laboratory For the practicing endocrinologist, hyperprolactinemia is a Drug-induced hyperprolactinemia orbutyrophenones) andrisperidoneor The most common are the typical (i.g. use ofestrogen-containingoralcontraceptives(OCs)( cause ofadrug-inducedhyperprolactinemiaisduetothe hyperprolactinemia ( D2 receptorantagonistic effects willcausesignificant it isobviousthatallthedrugspossessingdopamine at the mechanisms, which govern the secretion of PRL, which leadtotheexcessivePRLproduction.Bylooking always excludethepotentialeffectsofmedications, onemust resonance imaging(MRI)ofthepituitary hyperprolactinemia andbeforeperformingthemagnetic or erectiledysfunction)inmen. women orsignsofandrogendeficiency(i.e.losslibido fertility problems,galactorrheaorbenignbreastdiseasein of hyperprolactinaemiasuchasmenstrualirregularities, only beperformedinpatientswhohaveclinicalsigns and diabetes Drug-induced endocrinopathies ). Thesedrugs,whichusuallycontainthepotentestrogen When themechanismofdrug-induced When assessingapatientwithsymptomatic 38 < 100 ). Nevertheless, the most frequent Downloaded fromBioscientifica.com at09/27/202110:34:28PM 36 µg/L). Thesecasesusuallydo ). Noknowngeneticrisk https://eje.bioscientifica.com 181 :2 41 37 µg/L ( ). ). R77 42 39 via freeaccess ). ,

European Journal of Endocrinology OCs, oralcontraceptives. Anti-emetics First generationanti- drugs Drugs causingsignificanthyperprolactinemia(PRL Antihypertensives Selective serotoninreuptakeinhibitors Tricyclic antidepressants replacementtherapy Drugs causingmoderatehyperprolactinemia(PRL Table 3 https://eje.bioscientifica.com prolactinaemia are evident (i.e. amenorrhea in women or signs ofhypogonadismrelatedtothedrug-inducedhyper exacerbation ofthepsychoticsymptoms( of suchpatientsbutontheotherhandposearisk have beenshowntonormalizeserumPRLconcentrations tation withthepatient’s psychiatrist.Dopamineagonists or ), however, always in consul the cautiousadministrationofadopamineagonist(i.e. activity) ( chotic drugwithbothdopamineagonistandantagonist cause (i.e.–anantipsy substitute foradrugwithsimilaraction,whichdoesnot deficiency symptomsinmen),itisrecommendedto (i.e. , amenorrhea, bone lossorandrogen naemia usuallydoesnotrequiretreatment.Ifsymptomatic orapara-sellarmass( out thepresenceofapituitary shouldbeperformedinordertorule a MRIofthepituitary hyperprolactinemia doesnotcorrespondwithitsinitiation, discontinuation ofthedrugisnotpossibleoronset and thenre-evaluateserumPRLconcentrations.Ifthe daysorsubstituteitwithanalternativedrug at least3 it isrecommendedtodiscontinuethemedicationfor The drugsarelistedin elevations ofserumPRLconcentrations( , )canalsocausemoderate (i.e. verapamil, methyldopa) and opiates (i.e. , , ,),antihypertensives reuptakeinhibitors(i.e.,, antidepressants (i.e.doxepinandamitriptyline),selective its analogs( Review When asymptomatic, drug-induced hyperprolacti In order to rule out drug-induced hyperprolactinemia, Drugs inducingmoderateorsignificanthyperprolactinemia. 49 43 ). Ifthisisnotpossibleonemightconsider , 44 ). Nevertheless,drugssuchastricyclic Drug class Table 3 . others E Diamanti-Kandarakisand 45 50 , ). Whenthe 46 < > 100 µg/L) 200 µg/L) , 47 41 , ). 48 (butyrophenone derivative) (phenothiazinederivative) , Butyrophenones (,) Phenothiazines (,,, Tramadol, Buprenorphine,Methadone Verapamil, Methyldopa Fluoxetine, Paroxetine,Sertraline,Citalopram,Fluvoxamine , OCs ). - - - - thiorydazine) significant ones (hypothalamo–pituitary–gonadal and significant ones (hypothalamo–pituitary–gonadal endocrine system,andwewillfocusonthemostclinically ( and 2014,itincreasedby216%inUSA210%globally risen substantiallyinthelasttwodecades,between2000 to itseuphoriceffects(illicituse).Theuseofopioidshas analgesic agents.Heroinisusedasarecreationaldrugdue receptors andinclinicalpractice,theyaremainlyusedas effects aregeneratedafterbindingtoG-protein-coupled or synthetic chemicals that bind to opioidreceptors. Their Opioids includethenaturallyoccurringalkaloidsofopium -induced endocrinopathies require treatment. atic, drug-inducedhyperprolactinaemiausuallydoesnot gen ortestosteronereplacementtherapy( increased riskofboneloss,itisrecommendedtoaddestro androgen deficiencysymptomsinmen)orthereisan hypothalamo–pituitary–gonadal (HPG)axis( hypothalamo–pituitary–gonadal dependence have shown their suppressive action on the assisted addictiontreatmentorasadrugofabuseand using opioidsfortherapeuticpurposesorasmedication- Studies onhealthyhumanvolunteersandpatients Hypothalamo-pituitary-gonadal axis axes). hypothalamo–pituitary–adrenal from thehypothalamus,aswelldecreaseof of -releasinghormone(GnRH)secretion of thereleaseordisruptionnormalpulsatility The pathophysiologicalmechanisminvolvesreduction and diabetes Drug-induced endocrinopathies 52 ). Exogenousopioidscanhavevariouseffectsonthe Drugs Downloaded fromBioscientifica.com at09/27/202110:34:28PM 181 :2 51 ). Asymptom 53 , R78 54 via freeaccess ). - - European Journal of Endocrinology administration havebeen published ( adrenal insufficiency after oral or stress ( diminished cortisolresponse topsychosocialorsurgical response to CRHand leads tobluntedpituitary–adrenal subjects suppressesACTHandglucocorticoidsecretion, even single administration of various opioids in normal ACTH andcortisolrelease( and vasopressinsecretionbyreducingtheireffecton by inhibitingcorticotrophin-releasinghormone(CRH) (HPA) level axismainlyatthehypothalamic–pituitary Opioids suppress the hypothalamo–pituitary–adrenal Hypothalamo–pituitary–adrenal axis systematically assessed. ( or cessationofopioidleadstoreversalhypogonadism use ofshort-actingones( greater oddsofandrogendeficiencycomparedtochronic that chronicuseoflong-actingopioidsisassociatedwith with anovulationinpremenopausalfemales.Itisofnote males andreducedlibido,ameno-oroligomenorrhea fatigue, ,hotflushesandnightsweatsin include erectiledysfunction,decreasedlibido,infertility, are dose related ( changes startassoontheopioidistakenandthey cancerous ornon-cancerouspain( sexes onopioids(oral,transdermalorintrathecal)for hasalsobeenfoundinpatientsofboth systematically assessingthisgrouparenotavailable. have beendescribedinonecaseseries( Amenorrhea andgalactorrheainfemaleheroinaddicts LH and/orfollicle-stimulatinghormone(FSH)( in testosteronelevelsmales,aswellreduction methadone formaintenanceandhadshowndecrease this fieldinvolvedheroinaddictsandpatientson between 21and86%( testicular ( production ofsperm,testicularinterstitialfluidandintra- the gonadshavealsobeenreportedwithreductionin suppressive effectsontheHPGaxis( occasionally foundinopioidusers,alsocontributetothe also beimplicated( in the (LH) pulse amplitude may Negative effectsofopioidsonthekisspeptin-induced rise of testosteroneorestradiolfromthegonads( gland and release of gonadotrophins from the pituitary 65 Review , Although several case reports documenting secondary Although severalcasereports documentingsecondary The reportedprevalenceofhypogonadismranges 66 68 , 67 , 69 ), butthetimecourseofthishasnotbeen , 70 ). 60 56 , 61 ). Hyperprolactinemiathathasbeen 57 , 62 ). 63 55 , 55 , 63 ). Theinitialstudieson 64 ). Ithasbeenshownthat ). Clinical manifestations ). Reductioninthedose others E Diamanti-Kandarakisand 53 55 ). Directactionson ). Thehormonal 66 59 , 67 ), butseries , 71 53 , , 58 55 72 ). ). ). ), based guidanceisnotavailable,patientsonopioidsshould not been systematically reviewed. Although an evidence- dose oftheopioid( returns tonormalafterdiscontinuationorreductioninthe altered HPA axis function of opioid users improves or patients arepossiblyonriskofcortisoldeficiency. The given, thewidespreaduseofopioids,alargenumber response havenotbeenasyetestablished.Nonetheless, insulin tolerancetest(ITT)in15%( or hydromorphinereportedpeakcortisol 72 patientsonintrathecaladministrationofmorphine ACTH stimulationin6%( glucocorticoids, foundfailuretorespondsynthetic andnorecentexposuretoexogenous at least6 months clinics andtreatedwithlong-termopioidanalgesiafor pain in aseriesof48patientsattendingchronictertiary these patientshasnotbeenclearlydefined.Gibb the accurateprevalenceofadrenalinsufficiencyin painless thyroiditispresenting withaninitialphaseof NK cells( thought tobemediatedby circulating CD56,CD16 and another report,pembrolizumab-induced thyroiditiswas patients withpembrolizumab-inducedthyroiditis( an increaseinthyroidantibodieshasbeenreported in antibodies hasapathogeneticroleisalsounclear, although ( of autoimmune thyroid disorders and hypophysitis CTLA-4 It hasbeenhypothesizedthatpolymorphismsinthe IRAEs; however, theexactmechanismsremainunclear. PD1/PDL1 isresponsibleforthedevelopmentofthyroid is possiblethatdisruptionofimmunetolerancevia clinician todistinguishbetweenthetwoentities.It hypophysitis), anditisthereforeimportantforthe (relatedto orsecondary dysfunction canbeprimary In patients treated withICPinhibitors, immunotherapy Thyroid dysfunctionsecondaryto Drug-induced thyroidabnormalities results ofthebasalcortisol. dynamic assessmentoftheHPA axiswilldependonthe clinical manifestations are present) is advised. Further early morningplasmacortisol(particularlyifrelevant be consideredatriskofhypoadrenalismandcheckingan and diabetes Drug-induced endocrinopathies 15 , Factors predictingcompromisedcortisolstress Primary thyroid dysfunction is usually related to Primary 74 , , PD1 75 15 , ). or 76 ). Whetherthepresenceofthyroidauto- PDL1 53 genesmayleadtoahigherincidence , 72 Downloaded fromBioscientifica.com at09/27/202110:34:28PM , 73 73 ), but the interval ofthishas ), buttheinterval ). Abs https://eje.bioscientifica.com 62 181 t al et ). :2 . inaseriesof < 18 μ g/dL on 77 R79 t al et ). In via freeaccess .,

European Journal of Endocrinology https://eje.bioscientifica.com During the thyrotoxic phase, before progression to for patientswhodevelop thyroiditis orhypophysitis. 4–6 weeksevery ( IRAEs; regularthyroidfunction testingisrecommended on appropriatescreeningandmanagementofendocrine patients ( of closemonitoringthyroidfunctioninthese hypothyroidism wasshort,emphasizingtheimportance treatment initiation and evolution of thyrotoxicosis to inhibitors use.Thetimetoonsetofthyrotoxicosisafter is the most common thyroid disorder induced by ICP study byLee had todiscontinueICItreatment( asymptomatic duringthethyrotoxicphaseandnopatient (3.4–48.7). Themajorityofpatientsinthisstudywere and themediantimetohypothyroidismwas10.4 weeks weeks(0.6–19.6) median timetothyrotoxicosiswas5.3 eventually recoveredfromtransienthypothyroidism.The of patientsdevelopedhypothyroidismandonly9% due toICPinhibitorsusewereincluded.Overall,84% baseline thyroidfunctionwhodevelopedthyrotoxicosis Anderson CancerCenter( studied inarecentlargeretrospectivestudyfromMD ( 14–20% withcombinationICPinhibitorstreatment thyroiddysfunction as high as report rates of primary in earlierstudies( for hypothyroidismand8.0%, even morecommon,withameanincidenceof13.9% combination, thyroiddysfunction(ofanycause)is of cases( hyperthyroidismin3.3% in 5.9/4.3%andprimary hypothyroidismisobserved inhibitor use,primary is morecommon(7.6%)( hypothyroidismduetohypophysitis whereas secondary 5.2 to5.9%,with‘thyroiditis’beenreportedin3.2%, CTLA4 antibodytreatment(ipilimumab)rangesfrom associated hyperthyroidismmayrarelyoccur( or low-normal.Graves’orbitopathywithwithout suspected whenthefreeT4levelislowandTSH (central)hypothyroidismisonotherhand of secondary elevated TSHandlowornormalfreeT4).Thediagnosis hypothyroidism (i.e. withan present withprimary asymptomatic, itmaybemissedandthepatient hypothyroid phase.Asthethyrotoxicphaseiscommonly a result of thyroid gland inflammation, followed by a thyrotoxicosis duetothereleaseofthyroidhormoneas 74 Review ). The natural history ofICP-relatedthyroiditiswas ). Thenaturalhistory Recent oncologyguidelinesprovidedetailedguidance The incidence of primary hypothyroidismwith The incidenceofprimary 86 10 ). ). WhenbothclassesofICIsareusedin t al et 87 , 81 ., itwasconfirmedthatthyroiditis 88 , ). Endocrine consultation is advised 82 10 , 85 83 , ); 657patientswithnormal 11 , , 84 others E Diamanti-Kandarakisand 14 ). Morerecentstudies , 85 17 ). Inananalogous ). With PD1/PDL1 78 , 79 , 80 ).

when thereisclinicalsuspicion,measurementofthyroid- has improvedto therapy canbewithheldandrestartedwhenthegrade Criteria for Adverse Events) grade severe andtheeventisCTACAE (CommonTerminology need tobediscontinued,unlessthepatient’s symptomsare Importantly, cancerimmunotherapydoesnotusually thyroid therapyisinitiatedtopreventAddisoniancrisis. Adrenal dysfunction should always bereplaced before 50 hypothyroidism) ( primary compared totheusualdoseof1.6 of levothyroxineinonerecentstudy, was1.2 patients whodevelophypothyroidism.Themediandose Thyroid replacementwithlevothyroxineisindicatedfor used. Glucocorticoidsarenotroutinelyrecommended. , symptomatictreatmentwith In patientswithsymptomssuchastachycardia or hypothyroidism, nospecifictreatmentisusuallyrequired. effect have been proposed including their induction who remainedeuthyroid( hypothyroidism onTKItherapy, ascomparedtopatients been shown to be much better in patients who developed has and overall survival median progression-free survival accompanied by an important prognostic value, as most commonsideeffectofTKISisthyroiddysfunction, and angiogenesisinmultiplecancerentities.Oneofthe andgrowth, invasiveness to attenuatecancercellsurvival therapy. Via targetingdifferentreceptors,theymanage as acrucialtherapeuticsteppingstoneinanticancer kinaseinhibitors(TKIs)havebeenestablished thyroid disorders Tyrosine kinaseinhibitors-induced disease ( with itsmanagementbeingsimilarto‘wild-type’Graves’ with afrequencyof20–30%inthesepatients, Specifically, TRAb-positivehyperthyroidismisreported has alsobeenassociatedwiththyroiddysfunction. a monoclonalantibodyusedinmultiplesclerosis(MS) adrenal insufficiencyisusuallypermanent. ispossible(in6–64%ofcases),whereassecondary recovery hypothyroidism developsasaresultofhypophysitis, arranged toruleoutGraves’disease.Whensecondary antibodies (TRAbs)andthyroidscintigraphymaybe stimulating immunoglobulin(TSI)orTSHreceptor and diabetes Drug-induced endocrinopathies μ g daily)shouldbeusedinelderlyorfragilepatients. Many mechanisms with respect to this adverse Apart fromcancerimmunotherapy, alemtuzumab, 89 ). < 1. Forpersistenthyperthyroidismor Downloaded fromBioscientifica.com at09/27/202110:34:28PM 90 85 ). ). Lowerstarting doses (25– µg/kg inotherformsof ≥ 3, in which case ICI 181 β -blockers maybe :2 µg/kg (as R80 via freeaccess

European Journal of Endocrinology selective serotoninreuptake inhibitors(SSRIs),aswell serotonin- reuptake inhibitors (SNRIs), that inhibitthereleaseor thereuptakeofserotonin, documented ( or ofneurolepticmalignantsyndrome(NMS)maybe of amilddegree,higherriskserotoninsyndrome be monitoredforthyroiddysfunction. recommended thatpatientsunderantiepilepticsshould function. Basedonthesefindingsandotherstudies,it is drugs wassignificantlyassociatedwithdecreasedthyroid levetiracetam (24.3%)oracombinationofmorethanthree The drugscarbamazepine(30.1%),(28.6%)and ( duration ofepilepsy( with olderage( 298 patientswithepilepsy, 52(17.4%)showedlowfT4 proliferation ( beta-catenin signalinginlithium-dependentthyrocyte and inhibitsGSK-3beta,suggestingacrucialroleofWnt/ cell linesthatlithiumactivatescanonicalWntsignaling duration oftreatment( particularly in females and also dependent on dose and inhibiting thyroidhormonesecretionandincreasingTSH, weeks,inducegoiterby drug mayrapidly, within3–4 monotherapy orascombinedtreatment.However, the or )( or antipsychotics(aripiprazole,,risperidone (lamotrigine, ,oxcarbazepineorcarbamazepine) hypothyroidism whencomparedwithothertreatments ( presenting the lowestriskwithoxcarbazepine (6.3%) for (8.8%) was 1.39-fold that of thetherapy of treatment, the cumulative risk ofhypothyroidism years looking into the risk of hypothyroidism over 4 antiepileptics mayinducethyroiddysfunction. In astudy psychotropic drugs,particularlyantidepressantsand Despite theirpotenteffectinvariouspsychiatricdisorders, Psychotropics-induced thyroidabnormalities of treatment( well asmonitorthyroidfunctionduringandaftertheend thyroid hormonalevaluationbeforetheirinitiation,as ( ability todecreaseiodineuptakebythethyroidgland antithyroid peroxidaseantibodyproductionandtheir regressioninthethyroidgland, of thyroiditis,capillary 93 91 P Review

= ). Lithiumconferredahigherdegreeofriskfor ). Thus, TKI therapy should be accompanied by a 0.009), whichisstronglyassociatedwithlowfT4( In theeventofundiagnosedhypothyroidism,even Furthermore, arecentcross-sectionalstudyincluding 92 98 96 93 ). ). Serotoninsyndromeiscaused bydrugs ). P

= ). Lithium is usuallyeffective either as 0.004), femalesex( P 94

= 0.001) and intractable epilepsy , 95 ). Itwasshownindifferent others E Diamanti-Kandarakisand P .1) longer =0.014), 97 ). of patients and making this topic of increasing interest. vitamin Dandcalciummetabolism affectingbonehealth More andmoredrugshave beenfoundtointeractwith D metabolism Drug-induced deregulationofcalciumandvitamin metabolism deregulation Drug-induced boneandcalcium number of side effects, including thyroid dysfunction. isapotentantiarrhythmicdrugwith therapeutic particularities Amiodarone-induced thyroiddisorders: unclear shouldhavetheirthyroidfunctionassessed. psychotropic drugtreatmentandwhoseclinicalpictureis picture. Itisthusrecommendedthatpatientsunder administration could completely reverse the clinical to neuroleptics blockade ( altering dopamine activity in centraltractssusceptible hypothyroidism isthoughttopredisposeNMSby degradation of5-HT( is conjecturedthatseverehypothyroidismmayimpairthe brainstem havebeenreportedinhypothyroidpatients,it 5-HT responsivenessandincreasedturnoverinthe monoamineoxidase( the catabolismof5-HTbyinhibitingcatalytic as monoamineoxidaseinhibitors(MOI),whichretards thyroid hormonemetabolism( but alsototheintrinsiceffectsofamiodarone exposure ofincreasediodinelevelsfromamiodarone, totheis notonlyrelatedtoiodineoverload,secondary mechanisms. Thyroiddysfunctionlinkedtoamiodarone quite complex and occur via a number of differing thyroid glandandits metabolism areboth unique and Pathophysiologically, amiodaroneeffectsinthe glands orinwithpreexistingabnormalities. pathologies candevelopinapparentlynormalthyroid induced hypothyroidism(AIH)( induced thyrotoxicosis(AIT)oramiodarone- thyroid dysfunction,whichmaybeeitheramiodarone- range from abnormal thyroid function tests to overt incidence ofthyroiddysfunctionis3.7%.Theeffects with thelowerdosesofamiodarone(150–330 therapy. However, ameta-analysissuggestedthat 14–18% ofpatientsreceivinglong-termamiodarone Thyroid abnormalities have been noted in up to and diabetes Drug-induced endocrinopathies 99 Downloaded fromBioscientifica.com at09/27/202110:34:28PM ). Simultaneously, whileprimary 98 https://eje.bioscientifica.com 102 97 ), thyroid hormone ). Giventhatreduced 100 ) ( 181 Tables 4 , :2 101 , and 102 mg) the ). Both 5 R81 ). via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com 1. Emergenceofsensibilized lymphocytesubsets C. Immunomodulatoryproperties 3. Antigenrelease 2. Oxidativestress 1. Lysis B. Cytotoxiceffectsby 2. Beta-blocking(bradycardia) 1. Alpha-blocking() A. Antiadrenergicproperties Amiodarone properties • • • • • • • • • Amiodarone characteristics Table 4 and antibiotics (cotrimoxazole, ) ( (taxol, ),antihypertensive() among them,antiepileptic,antiretroviral, antineoplastic affect vitamin D metabolism acting mainly as PXRligands in themetabolismofvitaminD.Alonglistdrugscan D, suchasthoseencodingenzymeswhichareimplicated promoter ofgenesthatarenormallyregulatedbyvitamin can bindtovitaminD-responsiveelements(VDREs)atthe vitamin D receptor in the DNA-binding domain. Thus, it kidneys and and shows 63% homology with the various tissuesamongthemthegastrointestinaltract, (PXR) tomediatetheireffectsonvitaminDmetabolism. Most ofthesedrugsactthroughthepregnaneXreceptor Review act asacompetitiveantagonistofT3oncardiomyocytes. Amiodarone anditsmetabolite,desethylamiodarone,can a destructivethyroiditis. cytotoxic effectonthethyroidfollicularcells,whichcauses Amiodarone anditsmetabolitesmayhaveadirect The responseofTSHtoTRHmaybereduced. sufficiently toovercomethepartialblockinT3production. return tonormalin2–3 monthsasT4concentrationsrise for T4replacementinthesepatients.SerumTSHlevels stimulating hormone(TSH)levels.Thisisnotanindication first 1–3 monthsandleadstoanincreaseinthyroid- pituitary duetofeedbackmechanismisobservedinthe Inhibition oftype25 1–4 months oftreatmentwithamiodarone. by anaverageof40%abovepretreatmentlevelsafter thyroid hormonereceptors.SerumT4levelsincrease plasma membrane,andviadirectlybindingtothe via inhibitingthyroidhormonetransportacrossthe Inhibits entryofT4andT3intotheperipheraltissue, by 20–25%. T4 andrT3increasetheserumlevelsofT3decrease T4 andreverseT3(rT3).Consequently,theserumlevelsof (T3)andreducingtheclearanceofboth decreasing theperipheralconversionofT4to Inhibits type15 liver, lungs,cornea&thyroidglandmainly. Highly lipophilic,concentratesinadiposetissue,muscles, which isreleasedasfreeIodide. with alongplasmahalflife,rangingfrom30to100 days. Amiodarone isderivedfromAmphiphilicBenzofurane, PXR isanuclearreceptor, whichisexpressedin

comprises 37%ofitsmolecularweight,8–17% Amiodarone basiccharacteristicsandproperties. ′ -deiodinase enzymeactivity,thereby ′ -deiodinase enzymeactivityinthe others E Diamanti-Kandarakisand 103 ). It is of Characteristics B. Amiodarone-inducedthyrotoxicosis(AIT) LT-4 therapy,withgradualintroduction.Itimproves Management • • • Characteristics A. Amiodarone-inducedhypothyroidism(AIH) classification, pathophysiologyandmanagement. Table 5 Depends onthetypeofAIT.Type1AITistreatedwith Management Mixed formsofAITmayoccurinanabnormalthyroid Type 2:occursinpatientswithapreviouslynormal Type 1:usuallyaffectspatientswithlatentorpreexisting (1,25(OH) converts both25(OH)Dand itsactiveformcalcitriol include CYP24A1 which acts mainly at the liver and thus theactivityofseveralenzymes inthis family. These mode ofaction.TheyinducecytochromeP450altering ligands, althoughthereareslightdifferencesintheir the alterationsinvitaminDmetabolism,actingasPXR Antiretroviral therapy(ART)ismainlyresponsiblefor Antiretroviral therapy also activatePXR( interest that herbal medicine such as St John’s wort can and diabetes Drug-induced endocrinopathies and subsequenthypothyroidism. peripheral downregulationofthyroidhormonereceptors that leadtodecreasedthyroidhormonesynthesis, postulated tohavesubtledefectsiniodineorganification Patients withoutunderlyingthyroidabnormalitiesare toward hypothyroidism. may acceleratethenaturaltrendofHashimotothyroiditis addition, iodine-induceddamagetothethyroidfollicles load inpatientswithpreexistingHashimotothyroiditis.In to escapefromtheWolff–Chaikoffeffectafteraniodine hormone synthesisandtheinabilityofthyroidgland susceptibility totheinhibitoryeffectofiodineonthyroid The mostlikelymechanismsofAIHareanenhanced Affects 4–22%ofthetreatedpopulation. monitoring isstronglyadvised. quality oflifeandregulateslipidlevels.Thyroidpanel strongly advised. is usedasinitialtherapy.Thyroidpanelmonitoring combination ofglucocorticoidsandthionamides mechanism ofhyperthyroidismisuncertain,a relatively longcourseofglucocorticoids.Whenthe hormone synthesis,whiletype2AITistreatedwitha high dosesofantithyroiddrugstoblockthyroid excess. gland, withfeaturesofdestructiveprocessesandiodine fromthedamagedthyroidfollicularcells. that leadstothereleaseofpreformedthyroid thyroid glandandiscausedbyadestructivethyroiditis phenomenon). thyroid hormonesynthesisandrelease(JodBasedow iodine intake.Itiscausedbyiodine-inducedexcess thyroid disordersandismorecommoninareasoflow Amiodarone-induced thyroiddysfunction: 2 D), totheirinactivemetabolites. Theycanalso 103 ). Downloaded fromBioscientifica.com at09/27/202110:34:28PM 181 :2

R82 via freeaccess European Journal of Endocrinology on vitaminDlevels,inorder tosuggesttheappropriate evaluate theeffectsofconventional andnewerAEDs 25(OH)D levelsdependingontreatmentduration( levels of25(OH)Dthanpatientstakingsingletherapy, with et al antiepileptic drug groups ( enzyme-inducing and37%ofnon-enzyme-inducing < 600 patientsreceivingAEDs,45%had25(OH)Dlevel hyperparathyroidism( and secondary D metabolism and eventually leading to hypocalcemia primidone thatcanactivatethePXR,increasingvitamin such ascarbamazepine,,phenytoinand focused oninducersofcytochromeP450(CYP)enzyme Among theconventionalAEDs,earlyreportshave Antiepileptic drugs 6 months ( enough toreachthegoalof25(OH)D dosage supplementof50,000–60,000 participants receivingEFVorTDF-cARTshowedthata D levelsisrecommended( in patientsreceivingARTs associatedwithlowvitamin AIDS ClinicalSocietyGuidelines,vitaminDscreening in vitaminDlevels( with boosted PI (darunavir) achieved the greatest increase who changedfromefavirenzorzidovudinetoregiment MONET trialshowed( (NRTI), was associated with vitamin D deficiency, as zidovudine, anucleotidereversetranscriptaseinhibitor ART ( weeksinpatientsinitiatingEFV-based 27 to43%at48 of vitaminDdeficiency( ( that efavirenzisassociatedwithlow25(OH)Dlevels most involvedinloweringvitaminDlevels. transcriptase inhibitor(NNRTI),istheantiretroviraldrug ( manner, resulting thus in a decrease of 1,25(OH) and 1-a-hydroxylaserespectively)inadose-dependent CYP2R1 andCYP27B(encodingfor25-hydroxylase protease inhibitors(PIs),havebeenshowntosuppress biotransformation ofactivesubstances(e.g.CYP3A4). induce othercytochromeP450enzymesinvolvedinthe 106 104 20 Review According to the latest version of the European Cross-sectional and longitudinal studies have showed Additionally to the aforementioned mechanisms, To date,there islackofrobustclinicalstudiesto . found that patients taking multiple AEDs had lower ng/mL whiledeficiencywaspresentin54%of , , 108 107 105 ). Apartfromefavirenz,anotherARTregimen, , ). (EFV),anon-nucleosidereverse 108 111 ). Nylen , 112 ). 109 109 et al ). ). Inthesamestudy, participants . showedthattheprevalence 114 < 10 110 ). Interestingly, Tombini ng/mL) increasedfrom others E Diamanti-Kandarakisand ). Recentstudiesin IU permonthwas 113 ≥ gm after 30 ng/mL ). Inatotalof 2 D levels 115 ).

deficiency and bonemetastasis usually treated with higher renal insufficiency, hypomagnesemia,vitaminD resorption; theseincludemalnutrition,malabsorption, of hypocalcemiainthosereceivinginhibitorsbone number ofriskfactorsassociatedwiththedevelopment Case reportsandretrospectiveanalyseshaveidentifieda osteoporosis receivingantiresorptivedrugsissmall. The risk of symptomatic hypocalcemia in patients with Antiresorptive drugsforosteoporosisandhypocalcemia ( 3000–6000 IU/day above 30 treat vitaminDdeficiencytomaintaina25(OH)Dlevel higher; atleast6000–10,000 suggested toreceive a higher dose (twotothreetimes on medicationsaffectingvitaminDmetabolismare Endocrine SocietyClinicalPracticeGuideline,patients use ofvitaminDsupplementation.Accordingtothe respectively) ( compared to those randomized to placebo (58.3 vs 14.9%, administered dose in patients randomized to cinacalcet weeksafterthefirst hypocalcemia developedwithin16 an increased incidence of at least one episode of Lower CardioVascular Events(EVOLVE) trialshowed EValuation OfCinacalcetHydrochlorideTherapyto of therandomized,double-blind,placebo-controlled of hypocalcemia ( dialysis patients)confirmedthesignificanthigher risk (PTH) secretionbytheparathyroidglands. sensing receptorwhichcandecreaseparathyroidhormone Cinacalcet isaknownallostericactivatorofthecalcium- Calcimimetics exposure ( but ‘stabilizes’thereafter, irrespectiveoftheduration zoledronic acidandduringtheinitialstagesoftherapy, in patientsreceivingdenosumabthanthose s.c. ( identically designedphase3trialsofdenosumab120 among denosumab-treatedpatientsparticipatinginthree associated with the risk of developing hypocalcemia phosphatase levels, emerge as factors that are significantly creatinine clearance cell lungcancerandprostatebeingthemostcommon), dosage ofbisphosphonatesanddenosumab( and diabetes Drug-induced endocrinopathies A recentmeta-analysisof24RCTs (including10,031 Body 118 ). Moreover, hypocalcemiaoccursmorefrequently et al ng/mL, followed bymaintenance therapy of 119 . reportedthatthetypeofcancer(withsmall- 121 ). ). 120 116 ). Moreover, a post hoc analysis ). Downloaded fromBioscientifica.com at09/27/202110:34:28PM < 60 mL/min, higheralkaline IU/day) ofvitaminDto https://eje.bioscientifica.com 181 :2 117 ). R83 mg via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com low as2.5 even inpatientswithmedian prednisolonedosesas However, asignificantlyincreasedfracture riskwasseen doses ofotherGCs)areassociated withthegreatestrisk. prednisolone dosesof7.5 GCs ontrabecularbonethancortical( particularly vertebralfracture,duetothegreatereffects of high cumulative GC doses increase the risk of fracture, deprivation treatmentbyGnRHagonists( glucocorticoids, aromataseinhibitorsandandrogen Most harm concerning bone health is done by to screenandtreat -induced osteoporosis:When cytarabin, vinblastin)( ( include novel drugs such as immune check point inhibitors reversible/functional or irreversible hypoparathyroidism Rare casesofhypocalcemiaduetodrug-inducedeither Antineoplastic drugs sufficiency ( (two tothreetimeshigher)maintainvitaminD glucocorticoids aresuggestedtoreceiveahigherdose affecting vitamin Dmetabolism, thereby patients taking glucocorticoids areincludedinthemedications to theEndocrineSocietyClinicalPracticeGuideline, calcium ATPase 1b (PMCA1b) expression( 6 (TRPV6),Calbindin-9k(CB9k)andplasmamembrane transient receptorpotentialvanilloidsubfamilymember pathway of intestinal absorption via reducing duodenal 1,25(OH) intestinal calcium absorption. Moreover, independently of in vitamin D depletion and consequently in reduced dominant enzymesforvitaminDdegeneration,resulting while enhancetheexpressionsofCYP3A1,CYP24A1 In particular, glucocorticoidsdecreasetheCYP27B1, levels viadisturbingitsbiosynthetic and catabolicenzymes. It iswellknownthatglucocorticoidsreduce1,25-(OH) Glucocorticoids osteoporotic fracture( of patientsonlong-termGCtreatmentwillsufferan monthsofstartingGCs,andup to30–50% within 3–6 (GC)therapy. Skeletalfractures mayoccur Significant bone loss starts immediately after introducing Glucocorticoid-induced osteoporosis(GIO) 123 Review ) antineoplasticdrugs(adriamycin,doxorubicin, 2 D mg daily. Decreased bonemassandincreased 3 116 , glucocorticoids can decrease the transcellular , glucocorticoidscandecreasethetranscellular ). 124 126 ). , mg orhigher(orequivalent 127 ). Bothhighdailyand others E Diamanti-Kandarakisand 122 125 ). According ) (

128 Table 6 ). Daily 2 ). D 3

introducing GCs,duringthefirst6 monthslatest( benefit fromappropriatepreventativetreatment,soonafter to identifypatientsatmoderateandhighriskwhowould bone remodelingensueslongterm( recruitment ofnewosteoblastsandastatedecreased by apoptosisofexistingosteoblastsanddecreased exposure toGCscontinues,boneformationissuppressed by coordinatingboneremodeling.Finally, asskeletal mechanosensors thatnormallymaintainbonestrength GCsalsopromoteapoptosisofosteocytes,the survival. stimulates osteoclastogenesisandanincreaseinosteoclast resorption, increasedformationofRANKligandthat osteoprotegerin, anendogenousinhibitorofbone mechanisms, includingdecreased production of Bone resorptionisinitiallyincreasedthroughvarious alternate daytreatmentregimenswithGCs( fracture risk has also been demonstrated with inhaled and inhibitors. proliferator-activated receptorgamma; SSRI,selectiveserotoninreuptake GnRH, gonadotropin-releasinghormone; PPAR-gamma,peroxisome Proton pumpinhibitors Drugs withactionsonthegastrointestinal tract Loop diuretics Diuretics Heparin Anticoagulants Antiretroviral therapy Immunosuppressants (calcineurininhibitors) Drugs withactionsontheimmunesystem Anticonvulsants Antidepressants (SSRI) Drugs withactionsontheCNS PPAR-gamma inhibitors(thiazolidinediones) GnRH agonists acetate Aromatase inhibitors Sex hormonesloweringagents Glucocorticoids Hormones anddrugswithactionsontheendocrinesystem and Canalis( Table 6 treatment isinappropriate,anintravenousbisphosphonate fracture riskshouldreceiveanoralbisphosphonate.Ifthis andsmoking.Patientswithmoderatehigh regular weight-bearingphysicalactivityandavoidanceof lifestyle modifications,suchasawell-balanceddiet, of calciumandvitaminD,togetherwithappropriate GCs for and diabetes Drug-induced endocrinopathies As GCs rapidly increase fracture risk, it is important AsGCsrapidlyincreasefracturerisk,itisimportant All guidelines recommend that patients treated with GCs adverselyaffectallphasesofboneremodeling. List ofdrugsinducingboneloss.AdaptedfromMirza ≥ monthsshouldhaveanoptimizedintake 3 125 ) Downloaded fromBioscientifica.com at09/27/202110:34:28PM 126 181 ). :2 128 ). 128 R84 ). via freeaccess

European Journal of Endocrinology of all available randomized trial data support additional of allavailablerandomized trialdatasupportadditional studies aswellanindividual patientdatameta-analysis 60 evidence forfractureprevention isstrongestfordenosumab AIBL includingoralandi.v. .Overall,the ofsmoking( or history 50 years, oralcorticosteroiduseof offragility fracture afterage fracture, personalhistory > should receive antiresorptive therapy: T-score AI therapywithanytwoofthefollowingriskfactors risk factors)( risk of osteoporotic fractures (DXA measurement; clinical therapy withAIsshouldbecarefullyassessedforbaseline women onAIs( incidence ishigherandoccursearlierinpostmenopausal in thisagegroupwithoutbreastcancer. Evenhipfracture younger agesandhigherBMDthanexpectedforpatients postmenopausal BMDloss( to 4-foldincreasedbonelosscomparedphysiologic leads toamarkedincreaseofboneresorption,with2- determines bonestrength.AI-associatedloss(AIBL) bone thatcomposes80%oftissueandmostly In contrasttoGCs,AIspredominantlyaffectcortical oestrogens adversely affects bone quantityand quality. a crucialroleinbonetissuehomeostasis( reduce estrogenlevelsby98%( Aromatase inhibitors (AIs) lower aromatase activity and bone loss Aromatase inhibitorsinwomenwithbreastcancerand the patientremainsatincreasedriskoffracture. therapy couldbestoppeduponwithdrawalofGCunless ( is terminated,BMDincreasesandfractureriskdeclines reversible riskfactorforosteoporosis;whenGCtreatment oral bisphosphonates ( shown toproducesuperiorBMDincreasescompared formation shouldbeintroduced.Teriparatide hasbeen prevalent fracturesteriparatidetherapystimulatingbone highfractureriskor bone formation,inpatients with very long-lasting pathogeneticmechanisminGIOisreduced those usedinpostmenopausalosteoporosis.Asthemain are generallywelltolerated.Themedicationdosesequal are themostcommonlyusedtreatmentforGIOand a is not appropriate. Bisphosphonates formulation shouldbeconsidered,andteriparatideif 127 5 years,lowBMI( 65 Review mg s.c. every 6 months ( 6 months mg s.c.every Several antiresorptive agents can prevent and treat Several antiresorptiveagentscanpreventandtreat It isrecommendedthatallwomenstartingadjuvant , 128 , 135 130 134 , ). Pharmacologicalanti-osteoporotic 136 ). ). Allpatientsinitiatingorreceiving < 129 135 20 kg/m ). GC treatment is a potentially ). 135 , 133 2 137 131 ), family history ofhip ), familyhistory others E Diamanti-Kandarakisand > ). Fracturesoccurat 6 months andcurrent ). Additionally, recent ). Asoestrogensplay 132 < ) reducing − 1.5, age cardiovascular diseasecancontribute toweightgainboth conditions like diabetes,mental health disordersand Modern pharmacological treatments for various medical therapeutic options consequences: focusonmechanismsandpossible Drug-induced obesityanditsmetabolic metabolic complications Drug-induced diabetes,obesityandits increases to 53% in patients with cancer receiving increases to53%inpatientswithprostatecancerreceiving have ahighprevalenceofosteoporosis(4–38%)( year ( cancer inmenreceivingGnRHanalogsis4%BMDlossper fracture ( in earlymenopauseandresultsanincreasedriskof high boneturnoverwithrapid loss similar to that testosterone andoestrogenconcentrations,inducesa Androgen deprivation therapy (ADT) dramatically reduces cancer andboneloss Androgen deprivationtherapyinpatientswithprostate into accountwhenadvisingonmanagementofAIBL( decrease in cancer mortality that needs to be taken risk reductioninbonemetastasisand17%relative treatment inpostmenopausalwomenwitha34%relative anticancer benefitsfromadjuvantbisphosphonate with denosumabversus3.9%placebo)( a 62%relativereductioninnewvertebralfractures(1.5% ofdenosumabtreatmentwasassociatedwith 36 months men receivingADTfornonmetastaticprostatecancer, In aplacebo-controlledtrialofdenosumabin1468 considered the most convenient and reliable treatments. monthly zoledronic acid and 6-monthly denosumab are ( all beenshowntopreventlossofBMDinpatientswith bone healthshouldbefollowed.Bisphosphonateshave subsequent nonmetastaticfracture.Generalmeasuresfor or causes ofosteoporosis.AninitiallowBMD(T-score BMD, fracture risk by FRAX® tool and other secondary with thenumberofGnRHagonistdosesgiven( receive ADT( compared withmenprostatecancerwhodidnot had ADTanincreasedriskofoverallfracture23% ADT ( and diabetes Drug-induced endocrinopathies < The extent of bone loss observed under ADT for prostate underADTforprostate The extentofbonelossobserved Before introducingADT, menshouldbeassessedfor − 140 142 1, with other risk factors) indicates a high risk of 139 ). Patients with untreated prostate cancer already ). Patientswithuntreatedprostatecanceralready ). In a large meta-analysis of 14 trials, men who ). Inalargemeta-analysisof14trials,menwho ). 143 145 ). The fracture risk is directly correlated ). Thefractureriskisdirectlycorrelated ). Ofantiresorptivemedications,6–12 Downloaded fromBioscientifica.com at09/27/202110:34:28PM https://eje.bioscientifica.com 181 :2 146 144 141 ). ). ). This ). This < R85 138 − 2.5 via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com due totheirinterferencewith centralneurotransmitters Drugs forepilepsyarealso associatedwithweightgain Epilepsy medications their idealbodyweightby20%( psychotropic medicationswithpatientsoftenexceeding the mostpotentweightinducersamongclass of e.g. fluoxetine andcitalopram( than selective serotonin reuptake inhibitors class e.g.amitriptyline,mirtazapinetendtoinducemore weight gain.Antidepressantsofthetricyclic/tetracyclic to becertainabouttheprecisemechanismunderlying in selectiveandnon-selectivewaysmakingitchallenging of dopamine,serotonin,histamineandendocannabinoids The medications interfere with central neurotransmission but alsohaveapreferenceforenergy-densefoods( sign. Patients on psychotropic medication tend to overeat ofinitiationisapoorprognostic within thefirst4 weeks gain happens rapidly, and a 5% increase of body weight have deleteriouseffectsonmetaboliccontrol.Theweight treatment oftheunderlyingpsychopathologybutcan Psychotropic medicationmaybeeffectiveforthe Psychotropic medication dose dependent,rangingfrom2to4 fluid retentionandincreaseofsubcutaneousfat,being in thethiazolidinedionesgroup,weightgainisvia meglitinides appeartobeworkinginsimilarways,while to preventortreathypoglycemia.Sulphonylureasand anabolic effectsofinsulinaswellsnackinginorder the stimulationofhunger, the‘retention’ofcalories, The mechanism appears to be multifactorial and includes be betterthanothersinthisrespect(e.g.detemir)( evidence thatspecifictypesoflong-actinginsulinsmay friendly thanbasalbolusregimensandthereissome Long-acting insulinusealonetendstobemoreweight tends toplateauunlessfurtherincreasesindosearemade. takes placeduringthefirstyearoftreatmentandthen 4 is alsowellrecognizedininducingameanofapproximately effectiveincontrollingglycaemiarapidlybut Insulin isvery Glucose-lowering medications . healthcare professionalswarnthepatientofthispotential that thisisrecognizedbythemedicalcommunityso in patientswithandwithoutthispredisposition.Itisvital kg weightgaininadose-dependentmanner( Review 152 151 others E Diamanti-Kandarakisand ). ). Antipsychotics are kg ( 149 ). 147 ). This ). This 150 148 ). ). ). energy X-ray absorptiometry andMRI)insulin energy X-rayabsorptiometry ( changes inglucoselevels ( agents wasassociatedwith differential weightgainand that chronictreatmentwith differentantipsychotic 161 with weightgain,obesity, hypertriglyceridemia ( worsening hyperglycemia( antipsychotic drugs(SGAs)hasbeenassociatedwith In patientswithpreexistingdiabetes,theinitiation of Antipsychotic drugsinduceddiabetes(SGAs) available. is stableandthereappropriatepsychologicalsupport and eventhosewithseverementalillnessaslongthis ( treatment both for and metabolic control isbyfarthemosteffective health disease.Obesitysurgery frequent monitoringespeciallyinpatientswithmental shouldbeconsidered, butwithcautionand e.g. /naltrexone, topiramate/ and The useofcentrallyactingnon-hormonaltreatments principles of weight loss apply. Indeed, these could be disease stability. Ifthisisnotfeasible,thenthestandard in patientswhohavebenefitedfromthedrugandtheir of thetherapy, butthiscanbechallengingspecifically By farthemosteffectivetreatmentisdiscontinuation Principles oftreatment in themetabolicsyndromeanddiabetes( hepatic andperipheralinsulinresistance,oftenresulting possibly metabolic complications ( GCs, almost invariably associated with weight gain and Glucocorticoids topiramate areassociatedwithweightloss( lamotrigine andlevetiracetam,whileagentslike and gabapentintendtocausemoreweightgainthan and .Valproate, , pregabalin disorders aspartofarandomizedcontrolledtrial( been appliedsuccessfullyinpatientswithmentalhealth the safestoptionformajorityofpatientsandhas considered in allcases. The use of GLP-1 analogs is probably of theweightgain.Obesitypharmacotherapyshouldbe way, andoneshouldconsiderthestrongbiologicaltriggers Lifestyle modificationshouldbeperformedinasupportive introduced upon initiation of therelevantmedication. and diabetes Drug-induced endocrinopathies 163 157 ). Aprospectiverandomizedstudy, CATIE, showed ) usedgold-standardmeasures ofadiposity(dual- ). Itshouldcertainlybeconsideredinallpatients Downloaded fromBioscientifica.com at09/27/202110:34:28PM 158 162 ), andinnon-diabetics ) ( al 7 Table 181 154 :2 155 ), also induce ). Nicol 153 ). ). 159 R86 , t al et 156 160 via freeaccess ). . , European Journal of Endocrinology ( treated withGCswas32.3 and18.6%,respectively rate ofhyperglycemiaand diabetesamongpatients meta-analysis of 13 studies has shown the overall event greatly.individual susceptibilitymay vary Alargerecent formulations, treatment duration, dosing regiments and (SIH) anddiabetes(SIDM)arequitedifficult,assteroid estimations oftheriskforsteroid-inducedhyperglycemia effects ofglucocorticoid administration ( Hyperglycemia isoneofthemostimportantadverse New insightsinsteroiddiabetes during treatmentwithallantidepressants( and monitorbloodglucoselevelsatreasonableintervals elucidated, itisprudenttoscreenfordiabetesatbaseline of treatment( significantly relatedtopoorappetiteatthebeginning medication prescribedandthelengthoftreatment. The effectofSSRIsuponweightdependsthespecific with weightlossandimprovedinsulinsensitivity( are largelyweightneutral;somehavebeenassociated patients ( with weightgainandworseningglycemiaindiabetic antipsychotic-induced hyperglycemia( release hasalsobeensuggestedasapossiblemechanismof SGAs ( contribute tohyperglycemiaandpancreatitisreportedwith Blockade ofpancreaticbeta-cell5HT-1A receptorsmight mechanisms underlyingtreatment-relatedketoacidosis. used risperidoneandaripiprazole. in thosewhousedolanzapinecomparedwiththat changes inadiposityandinsulin,withlargerincreases were antipsychotic-naïve,producedrapid-onsetadverse olanzapine, risperidoneoraripiprazoleinyouthswho weeksoftreatmentwithlow-dose and foundthat12 sensitivity (ahyperinsulineric-englycemicclamp) Perphenazine Risperidone Quetiapine Olanzapine Antipsychotics antipsychotic agents(Lieberman Table 7 173 Review In addition,weightgainduringSSRItreatmentis Tricyclic antidepressants (TCAs) have been associated Other proposedmechanismsmaybemorerelevantto ). Moreover, GCsapproximatelydouble theriskof 164 Weight andHbAICchanges,duringtreatmentwith 167 , 165 ). However, SSRIsandotherantidepressants ). Alpha 2 inhibition of insulin ). Alpha2adrenergicinhibitionofinsulin 169 ). Untiltheexactmechanismsare Change inHbAIC 0.09 0.11 0.07 0.04 0.40 ± ± ± ± ± 0.09 0.09 0.08 0.08 0.07 et al others E Diamanti-Kandarakisand . ( (%) 162 166 )). Change inweight 171 ). 170 − − 2.01 , 1.6 0.8 1.1 9.4 ). 172 (lb) ± ± ± ± ± 1.1 1.1 0.9 0.9 0.9 ). Real 168 ). controlled diabetes,dietandlifestylemaybesufficientto ofdiabetesorwithadequately patients withoutahistory activity. steroidtherapy in Especially for temporary of carbohydratesandadviceforincreasedphysical counseling for restriction control should provide dietary postprandial hyperglycemiaandimproveglycemic contribute totheirdiabetogeniceffects. of weightgainandvisceralfatexpansionmayfurther transporter type 4. During chronic therapy, promotion ,primarilybyinhibitingglucose they alsoinhibitglucoseuptakeinmuscleand hepatic gluconeogenesisandglucoseoutput,while particularly athigherdoses( function andinsulinsecretionarealsoimpaired predominantly involvesinsulinresistance,but hyperglycemia ( of developing diabetesinpatientswithoutapriorhistory with theremaining70%divided betweenmeals( should be reduced to 30% of daily insulin requirements or longer-actingGCs(), basalinsulin intermediate-acting GCs.In caseofmultiplesteroiddoses morning inordertoblunt thelateafternoonpeakof morning dose, is to opt for basal insulin in the Another possibility, especially for those receiving a single with astartingdoseof0.1 glucocorticoids, mainlyinpatientswithexistingdiabetes, risk ofhypoglycemia. into account their profile of action, tolerance, cost, and choice drugs orinsulin therapy can be considered, taking fractures, which they share withGCs ( however, is limitedbecauseoftheriskedemaandbone their adverse effects on of steroid-induced insulin resistance and byneutralizing may alsoimproveglycemiabyantagonizingthepathways and reducinggluconeogenesis.Thiazolidinediones(TZDs) glucocorticoid effectsbyenhancinginsulinsensitivity liver andrenalfunction,becauseitdirectlycounteracts can representanattractiveoptiongivenacceptable are indicatedasthefirstchoice( hypoglycemic drugswithinsulinsensitizingactions ( comorbidities. as well as preexisting glycemic status and the presence of and pharmacodynamicsoftheusedsteroidcompounds, of therapyshouldtakeintoaccountpharmacokinetics achieve therapeuticgoals.Inthemoreseverecases,choice and diabetes Drug-induced endocrinopathies < 200 The initialstepstopreventdevelopmentof The mechanism by which GCs cause diabetes Basal insulin should be used with high doses of Basal insulinshouldbeusedwithhighdosesof In thecaseswhereglycemiaisrelativelymild mg/dL), togetherwithorafterlifestylemeasures, 174 ). Downloaded fromBioscientifica.com at09/27/202110:34:28PM β -cell function. Their usefulness, U/kg beforebedtime( 175 https://eje.bioscientifica.com ). Thus,GCsincrease 172 181 , 175 :2 175 , ). 176 177 ). Second , R87 β 178 177 -cell via freeaccess ). ).

European Journal of Endocrinology https://eje.bioscientifica.com drugs andantidiabeticmedications. affecting lipoproteinprofile aresteroidhormone-based principal lipoproteins.The onesmostcommonlyused Several drugs can affect either positively or negatively with endocrinopathies Drug-induced dyslipidemiasassociated particularly ifhyperglycemiacanbetreatable( the drugoftenoutweighsriskofdiscontinuation, responsible agent.However, thebenefitofcontinuing mild andusuallyreversibleupondiscontinuationofthe treatment. Inthemajorityofpatients,hyperglycemia is and/or antidiabeticmedicationsarerecommendedfor is recommendedandoncenoted,lifestylemodification hyperglycemia (bloodsugars been associated with 5.3% incidence of high grade (mTOR) inhibitors, temsirolimus and everolimus, have anticancer agents, mechanistic target of rapamycin compared to or lanreotide ( with hyperglycemiaanddiabetesinupto30%ofpatients, almost triplednewonsetdiabetesandhasbeenassociated Particularly, pasireotide, the newer and more potent SA, diabetes, viainhibiting insulin and secretion. are characterized by anincreasedriskfordeveloping acromegaly andCushing’s diseasebyendocrinologists, diabetes riskfactors( associated withdoseanddurationoftheiruseother insulin secretionandaction,withdiabetesriskbeing pathwaysresultingindecreased many glucoregulatory diabetogenic potential,isstatins.Statinsinterferewith patients withcardiovasculardiseasethatmayalsohave cohorts ( diabetes with a relative risk of 1.20–1.32 in prospective of beta-blockersorthiazidediureticsincreasednewonset drug-induced hyperglycemia. Specifically, long-termuse and beta-blockershavebeenhistoricallyimplicatedwith potentially haveaneffectonglucosemetabolism.Diuretics broad spectrumofcommonlyprescribeddrugsthatcan Apart fromcorticosteroidsandantipsychotics,thereisa treatment withcommonlyuseddrugs Hyperglycemia anddiabetessecondaryto therapeutic strategies. treatment oftheseconditionsovertakingempirical and universallysharedinordertoharmonizethe management of SIDM and SIH ( Review In all the above drug classes, surveillance fordiabetes In alltheabovedrugclasses,surveillance Somatostatin analogs(SA),primarilyusedfor Conclusively, isclearthatguidelinesforthe 180 ). Another drug class, commonly used in 181 ). > gd) ( 250 mg/dL) 179 others E Diamanti-Kandarakisand ) should be developed 182 183 ). Finally, the 184 ). ). teins (VLDL)byoralestrogensaswellthereduced low-densitylipopro the hepaticoverproductionofvery of acutepancreatitis.TheincreaseinTGlevelsarisesfrom and thiscanleadtogrosshyperchylomicronemia andrisk patients with genetic background of hypertriglyceridemia increase triglyceride(TG)levelsby30–40%mainlyin ( been observed pendent cardiovascularriskfactor, by20–25%hasalso lipoprotein (a)[Lp(a)]concentration,whichisaninde apolipoprotein B(apoB)levels.Additionally, adecreasein in apolipoprotein(apoA due inparttotheinductionLDLreceptors,increase by 5–20%respectively( low-density lipoprotein (LDLc) by 2–10%and in adose-dependentmanner, totalcholesterol(TC)and larly theHDL lipoprotein cholesterol(HDLc)levelsby5–20%(particu Estrogens Steroid hormonesbaseddrugs therapy containingestrogens ( and taken into account before considering any hormonal affected ( elevation isbluntedbutthe reductioninLDLcisnot combining bothsteroids, the estrogen-inducedHDLc menopausal hormonetherapy(HRT).Ingeneral,when in combinedpreparationsfororalcontraception or levels butmaycausehypertriglyceridemia( have neutralorevenfavorableeffectsonLDLcandHDLc pounds (,)arelessandrogenicand induce milder lipid changes. The third-generation com likedesogestrelandnaturalprogesterone reduce HDLc levels as low as 10 such asnorethisterone,norgestrelandlevonorgestrelcan each molecule.Progestogenswithstrong‘androgenicity’ ity. Theseeffectsdependontheandrogenicpotencyof ticle inducedprincipallybyanincreaseinHLlipaseactiv decline inHDLcisduetoincreasedcatabolismofthispar sometimes intensely, HDLclevelsby15–30%( induced lipidchanges,raisingLDLcanddecreasing, olism iscomplex.Ingeneraltheyantagonizetheestrogen- Progestogens abnormalities ( dosing regimen,geneticbackgroundandbaselinelipid file suchasrouteofadministration,typepreparations, eral factorscanmodulateestrogeniceffectsonlipidpro resulting inareductionofTGclearance( lipoprotein lipase(LPL)andhepatic(HL)activities and diabetes Drug-induced endocrinopathies Estrogens and progestogens are used frequently 185

Estrogen administrationraiseshigh-density ). Triglycerides, however, shouldbemeasured 2

cardioprotectivesubfraction)andlowers, 185 The effectofprogestogensonlipidmetab 185 ). , 186 185 1 Downloaded fromBioscientifica.com at09/27/202110:34:28PM ) productionandthedecreasein ). However, estrogens can also ). Theseestrogeniceffectsare 187 mg/dL. Less androgenic mg/dL. Less androgenic ). 181 :2 185 185 , , 187 188 187 ). Sev ). The ). The ). R88 via freeaccess ------European Journal of Endocrinology the impactonlipidprofilewereperformedwitheither GLP-1 receptor agonists effect onfastingTGwaslessnotable( dial chylomicronTGandapoB48itwasshown,whilethe gliptin, vildagliptinandalogliptinadecreaseinpostpran hypolipidemic properties. Inshort-term studies withsita DPP-4 inhibitors Antidiabetic drugs important modulatingvariables. tration, preexisting obesityormetabolic syndrome are dose ofGCs,sex,durationtreatment,routeadminis more constantlyincreaseHDLlevelsupto20–40%.The increase TC(+10–15%),moreoftenTG(until+40%),but or TGprofile( with higherHDLcandApoA oralandinhaledGCs wereassociated over age60 years, (NHANES)with15.000subjects tion ExaminationSurvey an increasedriskandothersno( have shown conflicting resultswith some studiesreporting terone treatmentimpactonCVdiseaseandatherosclerosis the liverandincreaseinHLactivity. Studiesofthetestos increases ofthescavengerreceptorclassBtypeI(SRBI)in nisms forthedecreaseinHDLconcentrationsinclude intramuscular administrationororalpreparations.Mecha terone regimenhaslessinfluenceonHDLclevelsthan no changeinHDLc( find nochangesorsmallreductioninTCandTGlevels concentrations ( TC andLDLclevelsmoreprofounddecreaseinHDLc terone inearlyclinicalstudiesshowedsmalldecreases Estrogen SGLT-2 inhibitor GLP-1R DPP-4 inhibitor Antidiabetic drug Corticosteroids Androgen Drug Table 8 glucagon likepeptide-1receptor,SGLT-2, sodiumglucoseco-transporter-2. cholesterol, HDLc,high-densitylipoprotein cholesterol,TG,triglycerides,LP(a),lipoprotein(a),CV,cardiovascular, DPP-4,dipeptidylpeptidase-4,GLP-1R, ↑ increase, Review ↓ Effect ofendocrine-baseddrugsonserumlipidlevelsandCV risk. decrease,

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levels toinduceketoneandhepaticTCproduction. lipid utilization,therebyincreasinghepaticfattyacids be thatthesedrugscauseaswitchfromcarbohydrateto increase inLDLcremainsunclear. Oneexplanationcould weight reduction,themechanismbehindsmall and TG concentrations couldbe explained by body ( no effectonTGandincreaseLDLclevelsfrom3to8% agents mediatesmallincreaseinHDLc,decreaseorhave SGLT-2 inhibitors tion ofAPOB48pool( involved inthebiosynthesisofchylomicronandareduc there isdirecteffectofthedrugonexpressiongenes HDLc levels( in TCandLDLcsmallornosignificantchange and postprandial chylomicron TGlevels, modest decreases with T2DMandshowedsignificantreductionoffasting liraglutide orexenatideinhealthysubjectsandpatients prevent theconsequences of androgen excess, while aims toreplacethelackofendogenouscortisoland and androgenssecretion.InCAH,theiradministration lead tosuppressionofadrenocorticalglucocorticoids hyperplasia (CAH),caninhibitHPA axisactivityand adrenal function,asinthecaseofcongenital GCs whenadministeredexogenouslytosuppress Cushing syndrome:Adelicatebalance Glucocorticoid-induced adrenalsuppressionand Drug-induced adrenaldysfunction risk aresummarizedin expression andLDLccatabolism( Empagliflozin was also associated to a lower LDL receptor and diabetes Drug-induced endocrinopathies 187 ↑ ↔ ↔ Drug-induced effectsonserumlipidlevelsandCV ↓ , or (pp) TG or or 197 ↓ ↓ ↑ ↑ ↓ ↓ ↑ ). While the favorable effects observed inHDLc ). Whilethefavorableeffectsobserved 195 ). Inthecaseofliraglutide,itseemsthat ↔ HDLc

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NA/I ↔ or or ↔ ↓ ↓ or R89 ↑ ↑ ↓ via freeaccess - European Journal of Endocrinology https://eje.bioscientifica.com carcinoma. Acting via interfering with one or more of the control ofexcesssteroidproduction inadrenocortical for anyetiologyofendogenous Cushing’s syndrome or the therapeuticmanagement ofseverehypercortisolism etomidate, andmitotane,havebeencommonlyused in Several compounds,includingketoconazole,, unavoidable necessity Adrenolytic agentsinduceadrenalsuppression:an areurgentlyneededtoimprove outcomes. interventions ofthediseaseaswelloptimal therapeutic natural history unmet medicalneeds,andadditionalresearch inthe from beingachieved.Thesepatientspresentwithmany secretion leadingtohypogonadotropichypogonadism( Furthermore, glucocorticoidovertreatmentinhibitsGnRH myopathy, insulinresistanceandadversemetabolicprofile. obesity, , osteoporosis, muscle and cushingoid appearance,psychologicaleffects,shortstature, can leadtoovertreatmentwithdeleteriousoutcomes(i.e. CAH ( pressure should be monitored regularly in adults with by measurementofplasmarenninactivity),andblood concentrations ofreninbelownormalrange(asevaluated replacement therapyshouldavoidsuppressingplasma fertility. Hypertensioniscommon,somineralocorticoid of androgensonwaking.Goodcontrolisimportantfor dexamethasone might have normal or low concentrations patients treatedwithanight-timedoseofprednisoloneor concentrations fallaftertakingthetreatment.Bycontrast, before takingtheirmorninghydrocortisonedose;thenthese will inevitablydemonstratehighconcentrationsof17OHP are low. Patients receiving hydrocortisone during the day below normalrangeandandrostenedioneconcentrations is suspectedwhen17OHPconcentrationsarewithinor be withinnormalrange.Excessglucocorticoidexposure Circulating concentrationsofandrostenedioneshould limit and three times the upper limit of normal range). above normalrange(betweenslightlytheupper serum levelsof17-OHprogesterone(17OHP)arefound optimal treatmentwithglucocorticoidsisachievedwhen have beenused( androgens, avarietyofglucocorticoidtreatmentregimens to thepoorhealthstatusofadultswithCAH. attainable, non-optimizedtreatmentofCAHcontributes of Cushingsyndrome.Becausethisgoalisnoteasily avoiding glucocorticoidovertreatmentanddevelopment Review Optimal management of adults with 21OHD is far To controltheovernightHPA-driven increase in adrenal 200 ). Trying tonormalizeandrogenconcentrations 199 ). Regarding, biochemical monitoring, ). Regarding,biochemicalmonitoring, others E Diamanti-Kandarakisand 201 ). life-threatening condition( commonly usedinclinicalpractice,abletotriggerthis pheochromocytoma crisis,therearealsoothermedications, which arethemostknownprecipitatingfactorsinacute ( by exercise, abdominalpalpation,urinationorbydrugs symptoms. ( surge of , manifested with a complexity of characterized byhemodynamicinstabilityinduceda Phaeochromocytoma crisisisalife-threateningcondition, Drug-induced phaeocrisis ( may bemandatory closely to these patients, as hydrocortisone replacement insufficiency. Thus, adrenal function should be monitored subsequent decreaseincortisolsecretionandadrenal inthesteroidogenicpathway, theycancause administration, theanatomical andfunctionalalterations production andreleaseisnot affectedbyglucocorticoid precursor ( metabolism, andproopiomelanocortin, anACTH hydroxylase, arate-limitingenzymeincatecholamine that convertsnorepinephrinetoepinephrinetyrosine enzymes suchasphenylethanolamineN-methyltransferase inducing effectsincrucialcatecholaminebiosynthetic pheochromocytoma cells( not only in healthy adrenal medulla but also in in catecholaminemetabolism,production,andrelease peptide secretion( of metoclopramideoncatecholamine-andgranin-derived action receptors thatareresponsibleforthestimulatory pheochromocytomas actuallyexpressfunctional5-HT4 type 4.Recently, GuillemotJ. act asapartialagonistattheserotonin(5-HT4)receptor receptors arealsoinvolved.Metoclopramideisableto cells. However, recentlyitwasshownthatserotonin effect ofthedrug on pheochromocytoma stimulatory action of norepinephrine and epinephrine, and a direct of dopamineleadingtopotentiationthehypertensive effect receptor blockade,aninhibitionofthevasodilatory an increaseinnorepinephrinereleaseviapresynapticD2 evoked hypertensivecrisisinthesepatientslikelyinvolves pheochromocytomas. Themechanismofmetoclopramide- is knowntostimulate secretion from oftentotreatnauseaandvomiting, medication usedvery the gastroprokinetic agent and diabetes Drug-induced endocrinopathies 205 Crises canoccurspontaneouslyorbeprecipitated Interestingly, glucocorticoidsareactivelyinvolved ). However, apartfrom anesthesia andbeta-blockers, 207 204 ). Whileinnormalmedulla catecholamine ). 206 202 ). , Downloaded fromBioscientifica.com at09/27/202110:34:28PM 203 205 al 9 Table metoclopramide ). et al ). Infact,theycanexert . havediscoveredthat ) ( 181 205 :2 ). Forexample, , a worldwide R90 via freeaccess European Journal of Endocrinology 1. Medications canaffectthisaxisinoneofthreeways: Hypothalamic–pituitary axis of theHPGaxisandoutflowtract Medications canhaveprofoundeffectsonallcomponents , theHPGaxisisactiveandfunctioning. During women’s reproductivelives, from menarche to and clinicalworkup Drug-induced amenorrhea:Differentialdiagnosis Drug-induced gonadaldysfunction yet, withthisdose( cases of pheochromocytoma crisis have been reported, as overnight dexamethasone suppression protocol, as no the endocrinologistshouldpreferablyproceedwith beforerulingoutpheochromocytoma, sidered necessary ( especially ifthesuspicionforpheochromocytomaishigh corticoids shouldbeavoidedoradministeredcautiously pheochromocytoma crisis. and longdurationofaction,aremorelikelytoinducea betamethasone, whichhavehighglucocorticoidpotency chromaffin cellstoglucocorticoids.Dexamethasoneand in pheochromocytomasmayincreasethesusceptibilityof Neuromuscular blockingagents Peptides Corticosteroids Monoamine oxidaseinhibitors Serotonin reuptakeinhibitors(rarelyreported) Norepinephrine reuptakeinhibitors(includingtricyclic Opioid analgesics Sympathomimetics Beta-adrenergic receptorblockers Dopamine D2receptorantagonists(includingsomeantiemetic crisis ( Table 9 208 Review antidepressants) agents andantipsychotics) outlined inthesectiononopioids. release andmaycauseamenorrhea inyoungwomenas Opioids: Alter theproductionor action ofGnRH: Thus, in patients with adrenal incidentalomas, gluco ). However, if dexamethasone suppression test is con 205 ). Medications thatareimplicatedinadversereactionspatientswithpheochromocytomaandcanprecipitatea OpioidsdecreaseGnRH productionand 209 Type ofmedication ). others E Diamanti-Kandarakisand - - Succinylcholine, tubocurarine,atracurium ACTH, glucagon Dexamethasone, ,hydrocortisone,betamethasone , , Paroxetine, fluoxetine Amitriptyline, , ,tramadol , ,,, , ,,, Metoclopramide, ,,, 2. and diabetes Drug-induced endocrinopathies phentermine, dexamfetamine chlorpromazine, , axis whichpromotesamenorrheaasthefunctional is cross-talkbetweentheHPA axisandtheHPG hyperprolactinemia andcategorizedin Discussed inthesectionondrug-induced surges duringovarianstimulation. as inassistedreproductiontopreventprematureLH endometriosis, hormone dependentcancersaswell useful inthetreatmentofcentralprecociouspuberty, ) inducedbyGnRHagonistshasproved This ‘medicalhypophysectomy’(asregards appears torelateGnRHreceptordownregulation. state ensuesinbothmenandwomen.Thiseffect LH concentrationsplummetandahypogonadotropic thereafter agonists stimulateLHreleasefor5–12 days, developed toprolongitseffect.However, whilethese GnRH long-actingagonists,suchasleuprolide,were effect( suggesting apituitary prednisolone havedecreasedLHresponsetoGnRH, addition, womengivensupraphysiologicaldosesof an effectpreventedbyGnRHadministration.In hormone infusioninwomendecreasesgonadotropins, adaptation tostress( with thetreatingpsychiatrist. These changescanonlybe considered inconjunction agonistic andantagonistic properties, canbeadded. quetiapine, oraripiprazole, which hasbothdopamine changed toonethatdoesnotelevateprolactin,suchas in the case of antipsychotics, the medication can be the medicationcannotbediscontinued,forexample Induce hyperprolactinemia: Hypothalamic–pituitary–adrenal axis(HPA):Hypothalamic–pituitary–adrenal GnRH agonists: AsGnRHeffectisshortlived, Downloaded fromBioscientifica.com at09/27/202110:34:28PM Drugs 210 ). Corticotropinreleasing https://eje.bioscientifica.com 210 ). 181 :2 al 2 Table There R91 . If via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com relate to theaccumulation of the drug within adipose amenorrheic uptoayearafter thelastinjection.Thismay 3 months, may last longer and 25% of women can remain depot medroxyprogesterone acetate,givenevery during their use. However, the effect of intramuscular for manywomenmaybeadesirableeffect,lasting only implants areoftenassociatedwithamenorrhea,which Progestin-releasing intrauterinecontraceptivedevicesand Outflow tract menopause maybeanticipated. in thosewhosemensesreturnafterchemotherapy, earlier 8% hadovarianfailure,versus0.8%ofsiblings( ofage, greaterthan18 years childhood cancersurvivors appear tohavelesstoxicity. Inareportofover2000 (doxorubicin, bleomycin, vinblastine, dacarbazine) in 12–46%,whereasnewerregimensuchasABVD and prednisone)mayleadtopermanentovarianfailure MOPP (mechlorethamine,vincristine,procarbazine is availableforcertaindrugregimen:example, low probabilityofcausingamenorrhea.Information fluorouracil, 6-mercaptopurine andvincristinehavea and .Antimetabolitessuchasmethotrexate, include vinblastine,cytosinearabinoside,cis-platinum heavy metalsandTKIsmayalsocauseamenorrhea.These busulfan. Agentssuchasvincaalkaloids,antimetabolites, chlorambucil, melphalan,procarbazine,dacarbazine and and dividingcells.Theseincludecyclophosphamide, the mostdamaging,affectingbothresting(oocytes) do thesameinyoungerwomen.Alkylatingagentsare in awomanher40sbut10 cyclophosphamide maycausepermanentamenorrhea drugs is also age dependent. For example, 5 of primordialfolliclesdecreasewithage,theeffectthese variable andagentdependent.Inaddition,asthenumber effect ofsuchdrugsontheoocytes/primordialfolliclesis but menstrual function may return months later. The chemotherapy, withhighFSHandLHlowestradiol women ofreproductiveagedevelopamenorrheaduring cells, suchasgranulosaandthecacells.Thusmany be profound.Mostanticancermedicationsaffectdividing can The effectofchemotherapeutic agents on the Ovary 3. Review may occurinyoungwomen. Discussed inthesectiononhypophysitis.Amenorrhea hypophysitis: inflammationcausing Induce pituitary g ormoreareneededto others E Diamanti-Kandarakisand g of cumulative 211 ). Even Previous studiesdescribedthat bothfolliculogenesisand varying degree. varying exhibit bothmasculinizingaswellanaboliceffectstoa exert theiractionbybindingtoandrogenreceptorand compounds, whicharestructurallyrelatedtotestosterone, (androgenic effects)inbothmalesandfemales( effects) and the development of male sexual characteristics which promotethegrowthofskeletalmuscle(anabolic to ‘anabolic steroids’, are synthetic steroidal androgens, Anabolic-androgenic steroids (AASs),oftenshortened of females Anabolic steroidsonthereproductivesystem contraindicated. boneandcardiovascularhealth,ifnot women topreserve progestin replacementmustbegiventohypoestrogenic as intheuseofchemotherapeuticagents,estradioland suitable substitute or the drug has had a permanent effect, tissue. Ifthedrugcannotbediscontinued,thereisno causes irreversibledamage to theovariantissue( to an increase in circulating androgen levels, but also serum levels of LH, FSH, and estrogen due athletes andnon-athletes,not onlyresultsindecreased decanoate, the most commonly used injectable steroid by collectively shown that administration of female athletesandbreastcancer( connection betweentheadministrationofAASsinyoung women areavailable( irreversible clitoris hypertrophy as a result of AASs use in documented casereportsorstudiesconcerningpossible of the voice are further consequences of AASs use. No well- atrophy, clitorishypertrophyandirreversible deepening masculinization. ,hirsutismalopecia,mammary AASs use ( difficult to distinguish the effects of intensive exercise and due to disruption of the GnRH pulse generator, making it strenuous exercise canoften leadtothesamesymptoms and FSHsecretion.Itisknown,however, thatchronic LH gonadal axis,andsubsequentsuppressionofpituitary feedback in the regulation of the hypothalamic–pituitary– with menstrualirregularityandinfertilityduetoanegative ( hematologic, psychiatric,hormonalandmetaboliceffects systems havebeendescribed,includingcardiovascular, A varietyofadverseeffectsAASsuseonseveralorgan use hasbecomeaseriousglobalpublichealthproblem. appearance and performance drugs (APEDs)andtheir and diabetes Drug-induced endocrinopathies 213 Animal studiesinfemaleratsandmicehave Nowadays, AASs are the most widely misused ) ( al 10 Table 214 ). In females, anabolic steroids can also cause ). Infemales,AASsusecanbeassociated 215 Downloaded fromBioscientifica.com at09/27/202110:34:28PM ). Finally, thereseemstobeno 215 181 ). :2 212 ). These R92 216 via freeaccess ). European Journal of Endocrinology Adopted from:PopeJr Focal segmentalglomerulosclerosis Renal failuresecondarytorhabdomyolysis Neoplasms (rare) Inflammatory andclolestaticeffects Hepatic Tendon rupture Premature epiphysealclosure(inadolescent) Musculoskeletal Cognitive defects AAS dependence Aggression Mood disorders:mania/depression Psychiatric Masculinization effects Menstrual irregularities Mammary atrophy HPO suppression Endocrine (females) Prostatic hypertrophy/cancer Hypogonadism HPT suppression Endocrine (males) Hypertension Polycythemia Cardiac conductionabnormalities Cardiomyopathy Atherosclerosis Dyslipidemia Cardiovascular system (AASs) use. Table 10 these substances,onestepahead oftestingefforts.We can detect steroiduse,novelcompounds putathleteswhouse all, depression. , reducedlibido and themostdangerousof can include fatigue, restlessness, loss of appetite, withdrawal onceAASsusestops.Withdrawal symptoms Symptoms ofdependencecanincludetolerance or dysmorphic syndromeanalogoustoanorexia( by extremedissatisfactionwithbody image anda body show thatanabolicsteroiduseinwomenisaccompanied androgenic andhedonicmechanisms( least three separate pathways:theanabolic,via at people whomisuseAASsdevelopdependence syndrome atrophy ( resulting infollicularapoptosis,ovariandegenerationand decanoate inadose-andtime-dependentmanner, luteogenesis havebeenseverelyaffectedbynandrolone Review Accumulating evidenceshowsthatabout32%of Although testingprocedures arenowinplaceto 217 Adverse effectsofanabolic-androgenicsteroids , 218 et al ). . ( 213 ). others E Diamanti-Kandarakisand 219 , 220 ). Data 221 ). ).

mostly prohormonesinlowconcentrationsand/oractive intentionally orunintentionally, withbannedsubstances, aminoacids. Thesesupplementscouldbecontaminated, supplements, suchasvitamins,minerals,herbs,plantsand ‘thermogenic’, ‘non-anabolic’,‘non-androgenic’ nutritional supplements’thatareclaimedtobe their physiciansaboutuse( with onestudyreportingthat56%ofusershadnevertold reluctant to discuss this with their physicians, are very taking exogenousAASsisreallychallengingasindividuals levels and low SHBG levels. The approach to the patient usually develophigh hematocrit, low-toundetectable LH mass and decreased body fat. In tests, these patients deepening ofthevoice,, increasedmuscle , acne,breastatrophy, temporalhairrecession, or in a woman who develops irregular menstrual cycles, in behavior, suchasdepression,irritabilityoraggression suspect AASsabuseinsomeonewhoexhibitsachange hyperthecosis andovarian/adrenocortical carcinoma several causessuchasPCOS, non-classicalCAH,ovarian hyperandrogenemia isa diagnosis ofexclusionand female withhirsutismthe diagnosisofdrug-induced and minoxidil( diazoxide, penicillamine, , streptomycin acid, ,citalopram,topicalcorticosteroids, this phenomenonarecyclosporine,acitretin,azelaic of androgen stimulation. Drugsusuallyassociated with be differentiatedfromhirsutismbecauseitisindependent of drug-induced ( mentioned areasofthebody, strengthensthe possibility non-pigmented) located anywhere else fromtheabove- other hand,thepresenceofvellushair(short,fine, induced hypertrichosisisnotsubstantiated.Onthe eyelashes, faceandpubisthenthediagnosisofdrug- (long, thick and pigmented) located in scalp, eyebrows, the voice.Specifically, ifapatientexhibitsterminalhair hypetrichosis, acne,clitoromegalyanddeepeningof the presenceofhyperandrogenicsignssuchashirsutism, Hyperandrogenemia is suspectedinafemaleofanyage Drug-induced hyperandrogenemia their use. drugs andthatconsultationisneededbeforeduring should informtheirpatientsthatsupplementsare hormone synthesis. Professionals in many disciplines and childrenduetogenderdifferencesinsex-steroid health riskishigh,especiallyforpregnantwomen,women ingredients couldbemisrepresentedonthelabel.The and diabetes Drug-induced endocrinopathies Special attentionshouldalsobepaidon‘dietary/ 224 ). Nevertheless,inthepresence ofa Downloaded fromBioscientifica.com at09/27/202110:34:28PM https://eje.bioscientifica.com 223 222 ). However, it should ). 181 :2 R93 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com phenobarbital, phenytoin,carbamazepine theinduction classes of drugsusedin the treatment of epilepsy such as and decreasedestradiollevels ( total testosteronelevels,free androgenindex,SHBG, androgen levelscanbesummarizedasfollows:increased levels. The total effects of valproate in circulating and CYP11Agenesbyvalproateleadstohigherandrogens increased leading to effect on follicular steroidogenesis in theovary gonadotropin levels.Additionally, valproate exertsdirect GABA-ergic neurotransmissionleadingtoreducedserum valproate inducescentrallymediatedmodification of is linkedtoseveralaspectsofandrogenproduction.Namely, Second, theuseofvalproate,aneffectiveantiepilepticdrug generator duetoneuronalparoxysmaldischarges( is astateassociatedwithdysregulationofGnRHpulse be attributedtotwodifferentfacts.First, epilepsy hyperandrogenemia isepilepsy. should Thisobservation in postmenopausalwomen( hasdoubledcirculating testosteronelevels for 12 months the oralconsumptionofamoderatedose50 supplementation has not been demonstrated universally, DHEA supplements.Althoughbeneficialeffectsof in women.Of note the gold stone in this market is important andcommoncauseofhyperandrogenemia dose ofjust300 percentage mightbereceiving morethanthesuggested various dosagesanddifferentformulations,anunknown in USA.Sincewomenareprescribedtestosteroneat formulations oftestosteroneforwomenin2006–2007 of twomillionprescriptions for off-label compounded ( increased levelsofbioavailabletestosterone engagement andtheseactionsaredirectlyrelatedto of sexualfunctionsuchasfantasies,desireand shown asignificantimprovementondifferentaspects several experimentsoftestosteroneadministrationhave testosterone infemalesexuality. Basedonthisnotion, of postmenopausalwomen,giventheprincipalrole with thelossofsexualdesireinasignificantproportion testosterone duringmenopausehasbeenassociated be excludedistestosterone.Thegradualdecreaseof in thebloodofafemale,firstdrugthatshould will guidethediagnosis. thorough anddetailedreviewofmedicaldrughistory must be ruled out by appropriate testing. Additionally, a 225 Review A commondisorderassociatedwithdrug-induced The widespreaduseofsupplementsisanother Regarding the presence of increased androgen levels ). Thisapproachhasledtotheenormousnumber Δ 4A levels( μ g dailywithunknowneffects. 228 ). Finally, theinductionofCYP17 226 229 ). others E Diamanti-Kandarakisand ). Regardingtheothers mg DHEA per se 227 Δ 4A ).

Drugs thatcanunravelpreexistingPCOS equally diagnosticallychallenging. difficulties ofthesyndrome,drug-induced PCOSmaybe imitating PCOS. Analogously tothe intrinsic diagnostic or inducehormonal/metabolicsignsandsymptoms can eitherunravelanunderlying,preexistingPCOS PCOS symptoms and signs, originating from drugs that induced PCOS can be defined as the manifestation of including reproductiveandmetabolicaxes( can actonmultiplelevelsofitsmultifactorialetiology, PCOS isaclinicalentitythatInfact a plethoraofdrugs Drug-induced PCOS and estrogenconcentrations. production andreductionoffree,circulating androgen of hepaticmicrosomalenzymes,leadstoincreasedSHBG PCOS misdiagnosis. manifestation of PCOS components and prevent a possible reveal pharmaceuticalcausesthatcantriggertheclinical with highclinicalsuspicion,areparamountinorderto andclinicalexamination,along a meticuloushistory clinically silentandoccultPCOS( potentiate androgenexcess,contributingtounravelinga hyperinsulinemia, which may further and compensatory background to metabolic dysfunction, insulin resistance and antidiabetic agents, can lead a PCOS prone SSRIS, atypicalantipsychotics, lithium, anticonvulsants gain andobesity, includingtricyclicantidepressants, Multiple drugcategoriesthatcanpromoteweight Pathophysiological mechanisms underlyingdrug-inducedPCOS. Figure 3 and diabetes Drug-induced endocrinopathies Downloaded fromBioscientifica.com at09/27/202110:34:28PM 230 181 ). Inthiscontext, :2 Fig. 3 ). Drug- R94 via freeaccess European Journal of Endocrinology criteria ofPCOS( detected according to different definitions or diagnostic patients, althoughsomedifferences intheresultswere (approximately 1.95-fold) with respecttonontreated VPA-treated epilepticwomenwassignificantlyhigher this closeassociation.TherawincidenceofPCOS in epilepsy and329healthycontrols,hasalsoverified antiepileptic drugs(AEDs),120womenwithuntreated treated withVPA, 593womentreatedwithother involving 11studiesand556womenwithepilepsy with PCOSmanifestation.Ameta-analysisbyHu consistently provedthatVPA treatmentisassociated axis), alltheaboveexperimentalandclinicaldatahave PCOS (viaperturbingthehypothalamic–pituitary various reproductiveendocrinedisorders,including syndrome ( PCOS andleadstoaclinicalphenotypemimickingthis similartothatofa pathophysiologicalprocessvery female metabolicandreproductiveaxesrepresents deregulationinmultiplepathwaysofThe observed also toincreasedappetiteand,thereby, weightgain. leading notonlytoLH/FSHalteredsecretionbut VPA canalsodisruptnormalhypothalamicsignaling, cells weresimilar( (enhanced Akt/PKBsignaltransduction)inhumantheca that VPA- andPCOS-inducedchangesingeneexpression a PCOS-likegenomicphenotype,viatheobservation same research groupshowed thatVPA can alsoinduce of epilepsyandbipolardisorder( which representsthetherapeuticlevelsintreatment inthedoserange of 300–3000microm, was observed most pronouncedeffectofVPA onandrogenbiosynthesis of steroidogenic genes. Interestingly, the modifications (histoneacetylation)thataugment steroidogenesis was attributed to changes in chromatin incrementofstimulated ovulating women.Theobserved increased steroidogenesis,incomparisonwithnormal of womentreatedwithVPA for72 long-term culturesofthecacellsisolatedfromfollicles al et morphology ( testosterone bloodlevelsandpolycysticovarian had cardinalfeaturesofPCOS,includingincreased treated withvalproate(VPA) for epilepsy, most of them scientific data that in reproductive-agedwomen andcoworkerspublishedthefirst In 1993,Isojärvi Drugs inducingthecompletespectrumofPCOSsyndrome Review Although epilepsy Apart fromtheeffectsinandrogenbiosynthesis, . providedanalogousbiochemicaldata,inwhich Fig. 4 231 ) ( 235 233 ). Adecadelater, Nelson-DeGrave 234 ). ). ). per se hasbeenassociatedwith others E Diamanti-Kandarakisand 232 ). Furthermore,the hours displayed et al ., ., pathophysiological processverysimilartothatofPCOS. female metabolicandreproductiveaxes,creatinga Valproate inducesderegulationsinmultiplepathwaysof Figure 4 Drug-induced maleinfertilityand receptors respectively, resultingin‘chemical’castration. antagonists desensitizeor block theGnRHpituitary function andlibido( symptoms ofandrogendeprivation suchaslossoferectile decrease inspermparametersandisaccompaniedby for prostatecancer, whichisassociatedwithareversible anti-androgenic propertiesusedinthepalliativetreatment anti-androgens). Cyproteroneacetateisaprogestinwith by drugsthatdiminishorhampertheactionofT(e.g. ( dose, routeofadministrationanddurationtreatment timedependson age, testosterone T andtherecovery months after stopping generally reversiblewithin3–12 testicular Tlevels.Theseeffectsonspermparametersare mL) bysuppressingtheHPGaxisanddiminishingintra- leads upto95%ofmensevereoligospermia( exogenous testosterone(T)withorwithoutprogestins Landmark studiessupportedbyWHOhaveshownthat administration onmalefertilityarewellestablished. above ( semen transition and maturation or combinations of the targeting the HPG axis, the seminiferous epithelium, disrupting ;thelatterasaresultofinsults (including erectileor/andejaculationdysfunction)orby in manyways:eitherbycausingsexualdysfunction challenging, sinceacompoundmayaffectmalefertility Studying the reproductive effects of a drug may be sperm abnormalities and diabetes Drug-induced endocrinopathies Fig. 5 On theotherhand,spermatogenesismaybeaffected The detrimentaleffectsofexogenousandrogen ) ( 236 237 ). ). 238 Downloaded fromBioscientifica.com at09/27/202110:34:28PM ). SimilarlyGnRHagonists or https://eje.bioscientifica.com 181 :2 < 10 6 sperm/ R95 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com respect tomalefertilityare SSRIswhichmayincrease among untreatedmenwithdepression aswell( dysfunction is also prevalent consider that ejaculatory possibly adirectactiononsmooth musclecells.Oneshould on thehypothalamus,moderateelevationofPRLand may beattributedtoacentralactionofelevatedserotonin and recreational drugs, such as opioids and . This on malefertilityandincludeantidepressants,antipsychotics for male-patternbaldness( common amongmentreatedwithlowerdosesof5-ARIs prior totreatment.Theabovesideeffectsaregenerallyless insufficient toreduce fertility inmenwith normalsemen decrease sperm count and mobility; however, this effect is Syndrome’) ( may persistseveralmonthsafterdiscontinuation(‘Post negative effectsonlibidoanderectilefunction,which . Thesedrugshavewell-documented block theconversionofTtoitsdrasticmetabolite (5-ARI), suchasfinasterideanddutasteride,which benign prostate hyperplasia are 5 A relevantclassofdrugs,frequentlyprescribedfor individuals were expected to recover by 24 months after individuals wereexpectedtorecoverby24 monthsafter in 12 weeksafterTadministration,whereasalmostall concentration fellinthemajorityofsamplesbelow1 million/mL SE (errorbar)ofsemensamplesgroupedwithinweeks.Sperm studies. Datapointsrepresentspermconcentrationmeanand discontinuation, usingpooleddatafromtheWHOcontraceptive administration forcontraceptionandrecoveryafterT Suppression ofspermoutputaftertestosterone(T) Figure 5 with permissionbyLy discontinuation. Notecube-rootscaleonthey-axis.Reprinted Review Psychotropic drugs also have profound negative effects Psychotropic drugsalsohaveprofoundnegativeeffects The mostpopularandstudied antidepressantswith et al . ( 239 237 240 ). 5-ARIs can also significantly ). ). others E Diamanti-Kandarakisand α -reductase inhibitors 240 ). platin-based regiments show long-term spermatogenesis platin-based regimentsshowlong-termspermatogenesis with almost100%permanentazoospermia,while Alkylating agentsandespeciallymustineareassociated damage ofthegerm-cellsandseminiferousepithelium. drugs crossthe blood-testis barrier and cause irreversible assessed sofar( while theireffectsonsemenqualityhavenotbeen alternatives to SSRIs in men with sexual dysfunction, have minimal sexual side effects and could be used as and serotonin antagonists and reuptake inhibitors (SARIs) as norepinephrine/dopaminereuptakeinhibitors(NDRIs) of spermatogenesis( abnormal epididymalspermtransitratherthanadefect after the initiation of therapy, which is possibly a result of weeks DNA fragmentation,aneffectseenassoon4 may negativelyaffectspermquality-especially they causeretrogradeejaculation.Treatment withSSRIs latencyupto50–65%,whilein5.6%ofpatients ejaculatory effect seen less often with ‘cardioselective’ beta-blockers areassociatedwith erectiledysfunction(ED),an Peripheral while specificactionsare mediated byreceptorbinding. the nethydrauliceffectsthat itmayhaveonerection, impact isgenerallyrelatedtothedecreaseofpressureand link theirusewithtesticulardysfunction.Theirnegative dysfunction, whereas thereisinsufficient evidenceto dysfunction, including both erectile and ejaculatory options inmenwhoseekfertility( anomalies intheoffspring,representingalternative changes insemenqualityduringtreatmentorcongenital azathioprine/mercaptopurine hasshownnosignificant evidence inmenislimited( gonadotoxic andprobablyteratogenicaction,whereas methotrexate, thereisevidencefromanimalmodelsof disruptors (azathioprine, methotrexate). Regarding that impactnegativelyfertilityarepurinemetabolism be recommended.Otherimmunosuppressantdrugs priortotherapyshould 90% andcryopreservation sustained azoospermiaoroligozoospermiareaches diseases(e.g.SLE).Similarlytheriskof inflammatory immunosuppressants for the treatment of severe, chronic cyclophosphamide havebeenusedinlowerdosesas represents the most rational option ( cryopreservation agonists/ testosterone;however, pretreatmentsperm prophylactic downregulationoftheHPGaxiswithGnRH been appliedtominimizethesesideeffects,suchas recovery. Various cytoprotectivestrategieshave and diabetes Drug-induced endocrinopathies Regarding chemotherapy, manychemotherapeutic Antihypertensives arealsowellknowntocausesexual Some ofthesecytotoxicagentssuchas β 1-adrenergic antagonists and especially 242 ). 241 Downloaded fromBioscientifica.com at09/27/202110:34:28PM ). Non-SSRIantidepressantssuch 244 ). On the contrary dataon ). Onthecontrary 245 181 ). :2 R96 243 via freeaccess ). European Journal of Endocrinology The authors declare that there is no conflict of interest that could be could that interest of conflict perceived asprejudicingtheimpartiality ofthisreview. no is there that declare authors The Declaration ofinterest importantly proceedontime therapeutically. hormonal andmetabolicabnormalities,butmore should not only promptly recognize drug-induced clinical expressedendocrinopathy. Therefore,clinicians imperceptible drug-inducedderegulationscanleadtoa of thedelicatebalanceendocrinesystem,even mimic avarietyofclinicalscenarios.Inthecontext endocrine abnormalitiesviadifferentmechanismsand disease, cliniciansshouldbeawarethatdrugscancause malignancies. Inthisneweraofdrug-inducedendocrine targeting novelmolecularpathwaysintheprocess of decade, withthenewoncologicaltherapeuticagents, is constantlyexpanding particularly during thelast Endo Course2018.Thischallengingpartofendocrinology which waspresentedatthemonothematicannualCombo topic,thedrug-inducedendocrinopathies, contemporary In the era of polypharmacy, this review aimed to cover a Conclusions exists onlyforSimvastatinandPravastatin( rich incholesterol.Nevertheless,lowlevelofevidence as disruptionofspermmembraneswhichareparticularly to depletionofthesubstratessteroidogenesisaswell are thoughttocauseapossibledecreaseinTlevelsdue fertilization capacity of spermatozoa ( to decrease , which are relevant to the mechanism for this effect is the ability of that arereversibleanddoserelated( fragmentation, andtoincreasetimepregnancy, effects been showntocausespermabnormalities,includingDNA possibly themostfrequentlyconsumedpainkiller, has on semenparameters( are nodataondetrimentaleffectstheHPGaxisor and iswellknowntoincreasePRLlevels;however, there 2, used for and vomiting function. Metoclopramideisanantagonistofthe been implicated in derangementofmale reproductive blocker eplerenone. that canbeamelioratedbytheuseofmoreselective to cross-reactivitywiththeandrogenreceptor, effects action byexertingaperipheralanti-androgeneffectdue antagonists, suchasspironolactonedisruptandrogen such asnebivolol( Review Miscellaneous drugs used in everyday practice have Miscellaneous drugs used in everyday 246 247 ). Mineralcorticoidreceptor ). Interestinglyparacetamol, others E Diamanti-Kandarakisand 249 248 ). Statins finally 250 ). Apossible ). References commercial ornot-for-profitsector. public, the in agency funding any from grant specific any receive not did Science of Republic of Serbia (Project 175033). The rest of the authors V Popovic:ThisstudywassupportedbyagrantfromtheMinistryof Funding

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