2 181 E Diamanti-Kandarakis and Drug-induced endocrinopathies 181:2 R73–R105 Review others and diabetes DIAGNOSIS OF ENDOCRINE DISEASE Drug-induced endocrinopathies and diabetes: a combo-endocrinology overview E Diamanti-Kandarakis1, L Duntas2, G A Kanakis3, E Kandaraki1, N Karavitaki4,5, E Kassi6, S Livadas7, G Mastorakos8, I Migdalis9, A D Miras10, S Nader11, O Papalou1, R Poladian12, V Popovic13, D Rachoń14, S Tigas15, C Tsigos16, T Tsilchorozidou17, T Tzotzas18, A Bargiota19 and M Pfeifer20 on behalf of COMBO ENDO TEAM: 2018 1Department of Endocrinology, Diabetes and Metabolism, Hygeia Hospital, 2Endocrine Clinic Evgenidion Hospital, University of Athens, 3Department of Endocrinology, Athens Naval & VA Hospital, Athens, Unit of Reproductive Endocrinology, Athens, Greece, 4Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, 5Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK, 6Department of Biological Chemistry, First Department of Internal Medicine, Laikon Hospital Medical School, NKUA, 7Endocrine Unit, Metropolitan Hospital, 8Endocrine Unit, 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, ‘Aretaieion’ University Hospital, 9Second Medical Department and Diabetes Centre, NIMTS Hospital, Athens, Greece, 10Division of Endocrinology Diabetes and Metabolic Medicine, Imperial College London, London, UK, 11Department of Internal Medicine-Endocrine Division, McGovern Medical School, Houston, Texas, USA, 12Department of Endocrinology, MLH University Hospital, Beirut, Lebanon, 13School of Medicine, University of Belgrade, Belgrade, Serbia, 14Department of Clinical and Experimental Endocrinology, Medical Correspondence University of Gdańsk, Gdańsk, Poland, 15Department of Endocrinology, Ioannina University Hospital, Ioannina, Greece, should be addressed 16Harokopio University of Athens and HYGEIA Hospital, Athens, Greece, 17Private Practice, Endocrinologist, Serres, to E Diamanti-Kandarakis Greece, 18St. Luke’s Hospital, Panorama, Thessaloniki, Greece, 19Department of Internal Medicine – Endocrinology, Email University of Thessaly, Larissa, Greece, and 20Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia e.diamanti.kandarakis@ gmail.com Abstract In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback European Journal of Endocrinology axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug- induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention. European Journal of Endocrinology (2019) 181, R73–R105 Invited Author’s profile Evanthia Diamanti-Kandarakis is a Professor of Internal Medicine and Endocrinology and Chairman of the Department of Endocrinology and Diabetes HYGEIA Hospital in Athens, Greece. Her research interests have focused for the last 25 years on clinical, molecular and environmental aspects of metabolic and hormonal abnormalities in obesity diabetes and polycystic ovarian syndrome. https://eje.bioscientifica.com © 2019 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0154 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 06:30:59PM via free access -19-0154 E Diamanti-Kandarakis and Drug-induced endocrinopathies others and diabetes https://eje.bioscientifica.com checkpoint (ICP)inhibitors have ledtoagreatreliefand The immunetherapiesinadvanced cancerswithimmune Drug-induced hypopituitarism Drug-induced pituitary dysfunction along withtheirbroadspectrumofendocrinesideeffects. drug categoriesthatwillbeanalyzedinthefollowingtext, appropriate decisionforthetherapeuticintervention. role ofmeticulousmedicalhistory inordertomakethe differential diagnosis,emphasizingtheindisputable diabetes, inordertomakeitanintegralpartofclinicians’ promptly recognizingdrug-inducedendocrinopathiesand vigilance in clinicians’ raise the aim to we Conclusively, abnormalities leadingtoendocrinopathiesanddiabetes. recognize thedrug-inducedhormonalandmetabolic the underlyingpathophysiologicalmechanismsto to gobeyondalistofadverseeffectsandviaunderstanding made effort is In thisapproach,an metabolic disorders. and encountered inclinicalpractice,whichinduceendocrine overview ofacontemporary spectrumofdrugs, that disorientatecliniciansfromtherightdiagnosis( hormonal assays,leadingtoerroneouslaboratory results systems ( well assimilarchangestocounter-regulatory hormone axis andonhormonaltransport,binding,signaling,as production, changesintheregulationoffeedback mechanisms, includingdirectalterationofhormone broadening challengetoourclinicalpractice. a double-edgedswordforourpatients’wellbeingand estimated atUS$30 1000 peopleeachyear( per responsible forfourhospitalizations reactions are drug States, adverse the United systems. In healthcare morbidity hasbeenhighlightedasamajorburdenof more drugssystematically( of olderadultsintheUnitedStatesaretakingfiveor abnormalities. medications whichcanleadtoendocrineandmetabolic system canbedisturbedbymultiplefactorslikedrugsand polypharmacy ( system andorgan.Inthecurrentlyoverwhelming eraof multiple mechanismsmaintainshomeostasisinevery The endocrinesystemwithitspreciseinteractionsthrough Introduction Review The purposeofthisreviewistodelineatea‘combo’ Drugs cancauseendocrineabnormalitiesviadifferent It isestimatedthat10%ofthepopulationand30% Table 1 6 ). Furthermore, drugs can interfere with the ). Furthermore,drugscaninterferewiththe summarizessomethemostcommonlyused 1 ), thebalanceofdynamicendocrine billion ( 4 ), withassociatedannualcosts 2 , 5 ). Therefore,drugscanbe 3 ). Asaresult,drug-related European Journal of Endocrinology 7 ). Table 1 Commonly used drug categories with broad endocrine side effects. Immune Anabolic Androgen checkpoint Antiepileptic androgenic Oral Aromatase deprivation Cytotoxic inhibitors Opioids Psychotropics drugs Glucocorticoids steroids contraceptives inhibitors therapy Antihypertensives agents Drug-induced pituitary + + + dysfunction Drug-induced SIADH + + + + + Drug-induced + + + + (verapamil, methyldopa) hyperprolactinemia Drug-induced thyroid + + + + (beta-blockers) + Downloaded fromBioscientifica.com at09/30/202106:30:59PM abnormalities Drug-induced calcium and + + + + + (thiazides) + vitamin D deregulation Drug-induced osteoporosis + + + + + + + (loop diuretics) + Drug-induced obesity + + + + + Drug-induced diabetes + + + + + + + (calcium channel blockers, + diazoxide, clonidine) Drug-induced dyslipidemia + + + + + + + 181 Drug-induced adrenal + + + + :2 dysfunction Drug-induced pheo crisis + + + + (beta-blockers) Drug-induced amenorrhea + + + + + + + + (spironolactone) + Drug-induced + + + hyperandrogenemia Drug-induced PCOS + + + R74 Drug-induced male infertility + + + + + + + + (beta-blockers, + via freeaccess and sperm abnormalities spironolactone) Review E Diamanti-Kandarakis and Drug-induced endocrinopathies 181:2 R75 others and diabetes much greater hope in patients and physicians (8). In the antigen on an antigen-presenting cell (APC). The second past 15 years, ICP inhibitors have emerged as a promising signal involves the binding of a T-cell CD28 receptor to and expanding class of anticancer agents, and their use the B7 ligand on the APC. CTLA4 receptors on the surface has resulted in the alteration of the natural history of of T cells are able to compete with CD28 for binding to certain types of cancer (9, 10). the B7 ligands, thus inhibiting T-cell-mediated immune Along with the promising results in the patients responses. ICP inhibitors are monoclonal antibodies that who respond to these therapies, the modulation of block the proteins from binding to the tumor cells and immune response can result in a number of immune- APCs, thereby taking off the brake and allowing the T-cell related adverse events (IRAEs) affecting almost all organ to recognize and attack the tumor cells (Fig. 1). systems. Typically, IRAEs affect the skin, gastrointestinal The use of CTLA4 and PD1/PDL1 antibodies allows system, the lung, musculoskeletal, renal and nervous the activation of T lymphocytes who set sight on the system. Interestingly, endocrine system IRAEs are also endocrine glands causing thyroid dysfunction in 15%, commonly involved. The most common of them include hypophysitis in 9–11%, adrenalitis in 1% and diabetes hypophysitis and thyroid