Prevalence of Endocrine Disorders in Obese Patients: Systematic Review and Meta-Analysis

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L T van Hulsteijn and others Prevalence of endocrine 182:1 11–21 Clinical Study disorders in obesity

Prevalence of endocrine disorders in obese patients: systematic review and meta-analysis

L T van Hulsteijn1, R Pasquali2, F Casanueva3, M Haluzik4, S Ledoux5, M P Monteiro6,7, J Salvador8,9, F Santini10, H Toplak11 and O M Dekkers12,13,14

1Department of Clinical Endocrinology and Metabolism, University Medical Centre Groningen, Groningen, The Netherlands, 2University Alma Mater Studiorum, Bologna, Italy, 3Department of Medicine, Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago (CHUS), CIBER de Fisiopatologia Obesidad y Nutricion (CIBERobn), Instituto Salud Carlos III, Santiago de Compostela, Spain, 4Diabetes Centre and Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine and Institute of Endocrinology, Prague, Czech Republic, 5Department of Physiology, Obesity Center, Louis Mourier Hospital (APHP), Colombes and Paris Diderot University, Paris, France, 6Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Oporto, Porto, Portugal, 7Honorary Clinical Senior Lecturer and Obesity Consultant, University College of London, London, UK, 8Department of Endocrinology and Nutrition, University Clinic of Navarra, Pamplona, Spain, 9CIBEROBN, Instituto Carlos III, Madrid, Spain, 10Obesity and Lipodystrophy Center, University Hospital of Pisa, Pisa, Italy, 11Division of Endocrinology Correspondence and Diabetology, Department of Medicine, Medical University of Graz, Graz, Austria, 12Department of Clinical should be addressed Epidemiology, 13Department of Clinical Endocrinology and Metabolism, Leiden University Medical Centre, Leiden, to L T van Hulsteijn The Netherlands, and 14Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Email [email protected]

Abstract

Objective: The increasing prevalence of obesity is expected to promote the demand for endocrine testing. To facilitate evidence guided testing, we aimed to assess the prevalence of endocrine disorders in patients with obesity. The review was carried out as part of the Endocrine Work-up for the Obesity Guideline of the European Society of Endocrinology. Design: Systematic review and meta-analysis of the literature.

European Journal of Endocrinology Methods: A search was performed in MEDLINE, EMBASE, Web of Science and COCHRANE Library for original articles assessing the prevalence of hypothyroidism, hypercortisolism, hypogonadism (males) or hyperandrogenism (females) in patients with obesity. Data were pooled in a random-effects logistic regression model and reported with 95% confidence intervals (95% CI). Results: Sixty-eight studies were included, concerning a total of 19.996 patients with obesity. The pooled prevalence of overt (newly diagnosed or already treated) and subclinical hypothyroidism was 14.0% (95% CI: 9.7–18.9) and 14.6% (95% CI: 9.2–20.9), respectively. Pooled prevalence of hypercortisolism was 0.9% (95% CI: 0.3–1.6). Pooled prevalence of hypogonadism when measuring total testosterone or free testosterone was 42.8% (95% CI: 37.6–48.0) and 32.7% (95% CI: 23.1–43.0), respectively. Heterogeneity was high for all analyses. Conclusions: The prevalence of endocrine disorders in patients with obesity is considerable, although the underlying mechanisms are complex. Given the cross-sectional design of the studies included, no formal distinction between endocrine causes and consequences of obesity could be made.

European Journal of Endocrinology (2020) 182, 11–21

Introduction 10–30% of adults in European Union countries (http:// www.euro.who.int/en/health-topics/noncommunicable- The prevalence of obesity is rapidly increasing. According diseases/obesity/data-and-statistics). Although most to the World Health Organization, obesity now affects

https://eje.bioscientifica.com © 2020 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0666 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 11:11:14PM via free access

-19-0666 European Journal of Endocrinology https://eje.bioscientifica.com hypothyroidism (i.e. raisedTSH,normal free thyroid (TSH) andlowfreethyroidhormone levels)andsubclinical between clinical (i.e. raised thyroid-stimulating hormone With regard tohypothyroidism,adistinctionwasmade hypogonadism (males)andhyperandrogenism(females). were considered:hypothyroidism,hypercortisolism, were considered. The following endocrine conditions with stratifieddataforthegroupsmentionedabove under ‘Risk of bias assessment’) were eligible; also studies by region-andethnic-specificcut-offpointvalues, see kg/m inclusion. Studiesincludingpatientswithobesity(BMI endocrine disordersinobesepatientswereeligiblefor Cross-sectional studies assessing the prevalence of Eligibility criteria Methods Endocrinology. for the Obesity Guideline of theEuropean Society of review wascarriedoutaspartoftheEndocrineWork-up hypo- orhypergonadism)inpatientswithobesity. The disorders (i.e.hypothyroidism,hypercortisolism or review andmeta-analysisontheprevalenceofendocrine The objectiveofthisstudywastoperformasystematic of endocrineconditionsinobesityisaprerequisite. guided testing,detailedknowledgeoftheprevalence disorders inobesepatientsremainunclear. Forevidence- precise meritsofbiochemicaltestingforendocrine share manyclinical characteristics andtherefore the obesity andabovementionedendocrinedisorders promote thedemandforendocrinetesting.However, clinical findingsorsymptomsarepresent( hypothyroidism orhypercortisolism isindicatedifrelated of PatientswithObesitystatethatbiochemicaltestingfor suspicion ( evaluation forCushing’s syndromeincaseofclinical obese patient, and an endocrine function for every examinationsshouldincludethyroid and thatlaboratory takingshouldconsiderendocrineabnormalities history for ObesityManagementinAdultsthereforestatethat or hyperandrogenism(females).TheEuropeanGuidelines such ashypothyroidism,hypercortisolism orhypo-(males) be identified.Thesecausesincludeendocrineconditions causes can caloric intake, ina small proportion, secondary lifestyleandincreased unfavorable genesandasedentary cases of obesity are related to the interaction between Clinical Study The increasing prevalence of obesity is expected to 2 ) oranincreasedwaistcircumference (determined 1 ). TheAACE/ACEGuidelinesforMedicalCare L TvanHulsteijnandothers 2 ). > 30 authors forclarificationwhenreporteddatawerenot by contactingtheauthors.We alsotriedtocontactthe Articles that were irretrievable online were requested authors (English, French, German, Dutch and Spanish). Eligible studieswererestrictedtolanguagesfamiliarthe comprised thehighestnumberofsubjectswasincluded. studies describingthesamecohort,studywhich patients withobesitywereeligible.Incaseofmultiple bias, onlystudiesreportingapopulationoftenormore series, whicharemorepronetoselectionandpublication divided bythetotalnumberoftestedpatients. number ofpositivelytested(orknowntreated)patients prevalence ofanendocrinedisorderwasdefinedasthe based oncut-offvaluesprovidedinincludedarticles.The included articlesandthedefinitionofapositivetestwas We relied on the choice of endocrine tests as presented in data on endocrine disorders based on biochemical tests. hormone levels)ifpossible.Eligiblearticlesshouldpresent 1. outcome (endocrinedisorders) ( population understudy(patients withobesity)andthe that potentiallybiasanassociationbetweentheexposed Risk of bias assessment was based on design elements Risk ofbiasassessment consensus. O D).Disagreementsbetweenreviewerswereresolvedby independently extracted bytworeviewers(LTvHand for detailedassessment.Foreligiblestudies,datawere and abstract. Potentially relevant studies wereretrieved Analytics, Philadelphia, PA) and were screened on title into reference manager software (EndNote X8, Clarivate All studiesobtainedfromthesearch strategywereentered Data extraction assessed foradditionalrelevantarticles. the endofthisarticle).Referenceskeyarticleswere data 1, see section on studies, publishedfrom1980onward(Supplementary COCHRANE were searched toidentify potentially relevant In May 2018, PubMed, EMBASE, Web ofScience and Search strategy sufficient foraccuratedataextraction. disorders inobesity Prevalence ofendocrine patients, notselectedforendocrine testingbecauseof Selection ofpatients.Inclusion ofconsecutive exposed In ordertoavoidtheinclusionofcasereportsor supplementary supplementary Downloaded fromBioscientifica.com at09/29/202111:11:14PM 3 ): 182 materials :1 given at 12 via freeaccess European Journal of Endocrinology Meta-analysis was performed using the (95%CI)wereestimated. exact 95%confidenceintervals prevalence of endocrine dysfunction. For all prevalences of patients(denominator) were usedtoestimatethe endocrine dysfunction(numerator) andthetotalnumber For allstudies,thenumberofpatientstestedpositivefor Statistical analysis heterogeneity. of studyqualityandwereusedtoexplorepotential Elements ofriskbiasassessmentwereusedasamarker 3. 2. Clinical Study adequate outcomedetermination. used in included articles) were therefore considered an (definition ofenlargementbasedondifferentcriteria and/or largeWCasexpressionofabdominalobesity obesity-related disease risk ( in thisBMIrangebutisanexcellentmarkerfor values, sinceabdominalobesitymaynotbecaptured WC withregion-andethnic-specific cut-offpoint advised todetermineabdominalobesity, assessedby In addition,inpersonswithBMI uses aBMI30kg/m Ascertainment oftheexposure(obesity).TheWHO – – – – adequate assessmentsofendocrinedysfunction: The followingbiochemicaltestswereconsideredas Determination ofexposure(endocrinedysfunction). hypercortisolism) wereconsideredadequate. use ofexogenousglucocorticoidsincasetestingfor whom biochemicaltestingcouldbeunreliable(e.g. for androgenexcess)andexclusionofpatientsin (e.g. onlyfemaleswithobesityandhirsutismtested a high pre-test probability for endocrine conditions cycle ( FT, measured atanytimeduringthemenstrual two separatedaysinafastingstate( testosterone (TTorFT, respectively),measuredon 48 h)(LDDST)( dexamethasone suppressiontest(2mg/dayfor suppression test(ODST)orafterlongerlow-dose cortisol after 1-mg overnight dexamethasone cortisol(LNSC),elevatedserum night salivary normal rangefortheassay, elevatedlate- measurements: urinefreecortisol(UFC) hormone (TSH)( For female hyperandrogenism: a high TT or For female hyperandrogenism: a high TT or For malehypogonadism:alowtotalorfree For hypercortisolism: For hypothyroidism:raisedthyroid-stimulating 7 ). 5 4 ). 2 ). asthresholdtodefineobese. 2 L TvanHulsteijnandothers ≥ ). A BMI of 2 ofthefollowing metaprop < 35 kg/m 6 ). ≥ command 30 kg/m 2 itis > the 2

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European Journal of Endocrinology https://eje.bioscientifica.com hypothyroidism froma random-effects modelwas from 0to58.3%.Thepooled prevalenceofsubclinical 32.9 and43.7%( and 37kg/m in fact,twostudieswitharelativelylowmeanBMI(34 prevalence ofoverthypothyroidisminameta-regression; I a prevalence of 12.7%, 95% CI 10.1–15.1 (six studies, showed restricted topatientsundergoingbariatricsurgery 95% CI9.7–18.9%(19studies, hypothyroidism fromarandom-effectsmodelwas14.0%, and 7.7–25%,respectively. Thepooledprevalence ofovert 35.0–39.9 or surgery, thatis,patientswithobesitygradeIIorIII(BMI studies including patients who were evaluated for bariatric treated) hypothyroidism ranged from 1.7 to 43.7%. In Reported prevalenceofovert(newlydiagnosedoralready Prevalence ofhypothyroidism releasing hormone(TRH)intravenously( measured TSHlevelsafteradministrationofthyrotropin- hypothyroidism basedonraisedTSHlevels;twostudies hypothyroid. All other studies diagnosed (subclinical) 22 hypothyroidism ( Two studies did not specify a definition of (subclinical) determined obesitybyWC,theotherstudiesBMI. with type2diabetesmellitus(T2DM)( for sleep-disordered breathing ( 14 forinclusion( evaluated forbariatricsurgery Nine studiesselectedpatientswithobesitywhowere Risk ofbias data2. characteristics aredisplayedinSupplementary mean WC from 95.7 to 137.5 cm. Individual study from 35.8 to 52.7 years, mean BMI from 27.2 to 53.0 kg/m (3 studiesdidnotdifferentiategender).Meanageranged included, of whom at least 1288 males and 5256 females and 2018.Atotalof7446patientswithobesitywere hypothyroidism were included, published between 1987 Twenty-seven studiesconcerning(subclinical) Study characteristics Hypothyroidism 2

= Clinical Study , ) classifiedpatientsonthyroxinesubstitutionas 72%). BMIwasnotpositivelycorrelatedwiththe 15 Prevalence ofsubclinical hypothyroidism ranged , 16 , 17 ≥ 2 , respectively)reportedhighprevalencesof 40 kg/m 18 Figs 2 ), onestudyselectedpatientsevaluated 15 , 21 and 2 ), thesenumberswere10.3–18.1% ) and four studies( 3 ). 19 I 2 L TvanHulsteijnandothers =96%, ) and one study patients 20 P 23

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European Journal of Endocrinology 32 Seven studiesselectedpatients withT2DM( Risk ofbias with morbid/severeobesity, definedbyBMI of includedstudiesreporteddataonsubgroupspatients 61.9 years.MeanBMIrangedfrom24.8to50.3kg/m obese malepatients,withameanagerangingfrom27.9 to data4).Theycomprisedatotal of4546 (Supplementary 2016, reportedonprevalenceofmalehypogonadism Eighteen included studies, published from 1994 to Study characteristics Hypogonadism inmales to thereportedprevalence( 70%). MeanBMIatthestudylevelwasnotclearlyrelated analysis (11 studies,prevalence1.1%, 95% CI 0.3–2.1, with T2DM did show a similar prevalence in a subgroup (22 studies, from arandom-effectsmodelwas0.9%,95%CI0.3–1.6% of 0%( features ofCushing’s syndromebothreportedaprevalence studies includingpatientswithobesityandtwoother hypertension reportedaprevalenceof2.6%( were 0to5.5%;thestudyincludingpatientswithresistant In studiesincludingpatientswithT2DMthesenumbers Prevalence ofhypercortisolism rangedfrom0to9.3%. Prevalence ofhypercortisolism https://doi.org/10.1530/EJE-19-0666 obesity. Afullcolourversionofthisfigureisavailableat Prevalence ofsubclinicalhypothyroidisminpatientswith Figure 3 Clinical Study , Overall (I^2=96.9%,p0.0) Zhang Verma Saluja Rotondi Resta Moulin deMoraes Montoya-Morales Mohammad Michalak Marzull Lima Khan Janssen Jankovic Gupta Ghazali Duntas Chikunguwo Agarwal Author 33 o i , 26 34 , , 27 534 450 52 144 population (n 71 350 78 72 200 168 1987 173 503 433 60 49 43 86 74 Study I 2 35 =79%, ). Thepooledprevalenceofhypercortisolism ) andonepatientswithbenign prostatic ) 0

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colour versionofthisfigureisavailableat Prevalence ofhypercortisolisminpatientswithobesity.Afull Figure 4 org/10.1530/EJE-19-0666 (PCOS) in a total of 2185 premenopausal obese women, syndrome investigated prevalenceof polycystic ovary All threeincludedstudiesconcerning hyperandrogenism Study characteristics PCOS to thereportedprevalence( P was 32.7%,95%CI23.1–43.0%(11studies, pooled prevalenceofhypogonadismwhenFTwasmeasured 95% CI37.6–48.0%(13studies, hypogonadism whenTTwasmeasured42.8%, ranged from 15.2 to 78.8%. The pooled prevalence of of patientswithmorbid/severeobesity, prevalence from 22.6to57.9%.Instudiesdescribingsubgroups studies including patients with T2DM, prevalence ranged low FT was used to define hypogonadism, respectively. In and from0to51.5%dependingonwhetherlowTTor Prevalence ofhypogonadismrangedfrom22.9to78.8% Prevalence ofhypogonadism levels ofFTorboth,respectively. of bias.Six,fiveandsevenstudiesreportedonlevelsTT, testosterone andwerethereforeconsideredathigherrisk ( one measuredWC( hyperplasia ( disorders inobesity Prevalence ofendocrine 33

< Overall (I^2=79.18%,p0.00) Tiryakioglu Terzolo Sahin Newsom Ness-Abramo Mullan Mert Liu Leibowit Lammert Karaman Jankovi Gagliard Fierabracci Catargi Cardos Cansu Caetano Baid Alhambra Exposit Abraham Aberle Author

0.01). Mean BMI at the study level was not clearly related 0.01). MeanBMIatthestudylevelwasnotclearlyrelated ) includedstudiesperformedonlyonemeasurementof o c z i e f o 813 171 86 201 148 46 90 276 200 433 106 783 200 400 399 369 population (n 150 354 39 103 369 83 Study 36 ). Allstudiesadequately assessed exposure; ) 0 33 ), allotherstudiesBMI.Allbutone . Downloaded fromBioscientifica.com at09/29/202111:11:14PM 10 P .6 ( =0.16) https://eje.bioscientifica.com I 2 Figs 5 =89%, 182 20 https://doi. :1 and 25 0.87 (0.33,1.61) 0.87 (0.33,1.61) 9.33 (5.64,15.06) 9.33 (5.64,15.06) 0.74 (0.34,1.60) 0.74 (0.34,1.60) 0.56 (0.16,2.04) 0.56 (0.16,2.04) 0.00 (0.00,2.20) 0.00 (0.00,2.20) 5.81 (2.51,12.90) 5.81 (2.51,12.90) 0.00 (0.00,1.88) 0.00 (0.00,1.88) 2.70 (1.06,6.74) 2.70 (1.06,6.74) 0.00 (0.00,7.71) 0.00 (0.00,7.71) 3.33 (1.14,9.35) 3.33 (1.14,9.35) 0.72 (0.20,2.60) 0.72 (0.20,2.60) 1.50 (0.51,4.32) 1.50 (0.51,4.32) 0.00 (0.00,0.88) 0.00 (0.00,0.88) 0.00 (0.00,3.50) 0.00 (0.00,3.50) 0.77 (0.35,1.66) 0.77 (0.35,1.66) 5.50 (3.10,9.58) 5.50 (3.10,9.58) 2.56 (0.45,13.18) 2.56 (0.45,13.18) 1.25 (0.54,2.89) 1.25 (0.54,2.89) 2.91 (1.00,8.22) 2.91 (1.00,8.22) 0.00 (0.00,1.03) 0.00 (0.00,1.03) 0.25 (0.04,1.41) 0.25 (0.04,1.41) 0.00 (0.00,1.03) 0.00 (0.00,1.03) 0.00 (0.00,4.42) 0.00 (0.00,4.42) ES (95%CI) ES (95%CI) P

< 6 0.01). The The 0.01). ). I 2 96%, =96%, 100.00 100.00 4.38 4.38 5.85 5.85 5.32 5.32 4.55 4.55 3.56 3.56 4.75 4.75 4.36 4.36 2.58 2.58 3.63 3.63 5.09 5.09 4.74 4.74 5.49 5.49 3.88 3.88 5.84 5.84 4.74 4.74 2.34 2.34 5.42 5.42 3.84 3.84 5.36 5.36 5.42 5.42 5.36 5.36 3.50 3.50 Weight Weight % % 15 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com dysfunction. hyperandrogenism (measuredbyFT)andovulatory PCOS asthepresenceofclinicaland/orbiochemical obesity wasdefinedbyBMI.Allthreestudies female patients with adequateassessment of exposure; All studiesincludedunselectedobesepremenopausal Risk ofbias from 2006to2015. 5). Mean BMI was not reported. Studies were published data with a reported mean age of 37 years (Supplementary https://doi.org/10.1530/EJE-19-0666 testosterone). Afullcolourversionofthisfigureisavailableat Prevalence ofhypogonadisminpatientswithobesity(total Figure 5 https://doi.org/10.1530/EJE-19-0666 testosterone). Afullcolourversion ofthisfigureisavailableat Prevalence ofhypogonadismin patientswithobesity(free Figure 6 Clinical Study Overall (I^2=95.5%,p0.0) Pelliter Liu Ippersie Hofstra Giagulli Ganesh Dhinds Dhinds Cooper Chande Calderon Author Overall (I^2=89.2%,p0.0) Samavat Rabijewsk Pelliter Nielse Liu Kapoor Kaplan Ippersiel Hofstra Dhindsa Cooper Calderon Alhayek Author n o a a o l l i 33 139 75 149 40 31 716 63 1647 21 100 population (n Study 55 151 33 70 139 221 494 75 149 716 1647 100 477 population (n Study ) ) 0 0

10 10 20 20 30 30 40 40 50 50

60 60 . . 70 L TvanHulsteijnandothers 70 80 80 90 90 100 100 32.7 (23.1,43.0) 32.7 (23.1,43.0) 51.5 (35.2,67.5) 51.5 (35.2,67.5) 23.7 (17.4,31.5) 23.7 (17.4,31.5) 38.7 (28.5,50.0) 38.7 (28.5,50.0) 35.6 (28.3,43.5) 35.6 (28.3,43.5) 25.0 (14.2,40.2) 25.0 (14.2,40.2) 22.6 (11.4,39.8) 22.6 (11.4,39.8) 43.3 (39.7,47.0) 43.3 (39.7,47.0) 38.1 (27.1,50.4) 38.1 (27.1,50.4) 16.2 (14.5,18.1) 16.2 (14.5,18.1) 38.1 (20.8,59.1) 38.1 (20.8,59.1) 34.0 (25.5,43.7) 34.0 (25.5,43.7) ES (95%CI) ES (95%CI) 42.8 (37.6,48.0) 42.8 (37.6,48.0) 47.3 (34.7,60.2) 47.3 (34.7,60.2) 52.3 (44.4,60.1) 52.3 (44.4,60.1) 78.8 (62.2,89.3) 78.8 (62.2,89.3) 22.9 (14.6,34.0) 22.9 (14.6,34.0) 30.9 (23.9,39.0) 30.9 (23.9,39.0) 25.8 (20.5,31.9) 25.8 (20.5,31.9) 39.3 (35.1,43.6) 39.3 (35.1,43.6) 42.7 (32.1,53.9) 42.7 (32.1,53.9) 57.7 (49.7,65.4) 57.7 (49.7,65.4) 41.2 (37.7,44.8) 41.2 (37.7,44.8) 48.4 (46.0,50.8) 48.4 (46.0,50.8) 44.0 (34.7,53.8) 44.0 (34.7,53.8) 40.0 (35.7,44.5) 40.0 (35.7,44.5) ES (95%CI) ES (95%CI) 100.00 100.00 8.17 8.17 9.75 9.75 9.27 9.27 9.79 9.79 8.48 8.48 8.06 8.06 10.25 10.25 9.08 9.08 10.32 10.32 7.30 7.30 9.52 9.52 Weight Weight % % 100.00 100.00 5.98 5.98 7.90 7.90 4.77 4.77 6.51 6.51 7.78 7.78 8.40 8.40 9.08 9.08 6.65 6.65 7.88 7.88 9.26 9.26 9.51 9.51 7.22 7.22 9.05 9.05 Weight Weight % % are generallyconsideredto be modest( However, theeffectsofhypothyroidism onweightgain clear sources ofheterogeneity. subgroup analysesandmeta-regressiondidnotreveal made. Although heterogeneity was high for all analyses, endocrine causesandconsequencesofobesitycouldbe of thestudiesincluded,noformaldistinctionbetween considerable. However, giventhecross-sectionaldesign the prevalence of hypothyroidism and hypogonadism was Whereas theprevalenceofhypercortisolism waslow( the prevalenceofseveralendocrinedisordersinobesity. We performedasystematicreviewandmeta-analysisof Discussion of studies. pooled proportion was estimated given the low number Prevalence ofPCOSrangedfrom9.1to25%,andno Prevalence ofhyperandrogenism TSH levelsinthelowerpart ofthereferencerange( associated withincreasedodds ofobesitycomparedwith line, TSHlevelsintheupper part ofthereferencerangeare leading toincreasedwatercontentofthebody( body fat,andareducedcapacityofexcretingfreewater, and reducedphysicalactivity, leadingtoaccumulation of of weightgainviadecreasedrestingenergyexpenditure classified ashavinghypothyroidism. be notedthatpatientstreatedwithlevothyroxinewere the implementationofiodizedsalt( that ahighprevalenceofendemicgoiterpersistsdespite studies fromIndia( numbers of subclinical hypothyroidism were reportedin various study populations. For example, high prevalence Likely thisisduetodifferentclinicalcharacteristicsofthe hypothyroidism) and1.7-43.7%(overthypothyroidism). considerably andrangedfrom0to58.3%(subclinical reported prevalencenumbersinourreviewdiffered is knowntobehigherinfemales( review is1:4andtheprevalenceofthyroiddisorders should be noted that themale-to-female ratio inour in America,andof3.80.4%Europe( subclinical hypothyroidismandovert numbers of4.3and0.3%arereportedforrespectively numbers inthe general population, where prevalence respectively. Thesenumbersareclearlyhigherthan hypothyroidism in obesitywere14.6and 14.0%, and overt (newly diagnosed or already treated) disorders inobesity Prevalence ofendocrine The pooledprevalenceofsubclinicalhypothyroidism The generalperception isthathypothyroidismacause 21 , Downloaded fromBioscientifica.com at09/29/202111:11:14PM 39 , 40 , 41 ), whereitisreported 4 42 182 ). Furthermore,the ). Lastly, itshould :1 45 ). Inobesity, a 37 , 43 38 < 1%), ). In 16 ). It 44 via freeaccess ). European Journal of Endocrinology care officesintheUnited States ( of 38.7%menaged study previouslyreporteda prevalence ofhypogonadism prevalence 33%).TheHIM (HypogonadisminMales) of biochemical hypogonadism in obese men (pooled or adrenalsource ofhypercortisolism. hypercortisolism); theywerealldiagnosedwithapituitary two patientsrefusedfurtherinvestigationofthesource of obese patientswithprovenhypercortisolism (although review though,imagingwasnegativeinnoneofthe neuroendocrine responsetohypoglycaemia( elevated cortisollevelsoccurredasacounterregulatory axis orthat the hypothalamus-pituitary-adrenal component ofT2DM( negative imagingmayreflectanunderlyinginflammatory hypothesis thathypercortisolism inT2DMpatientswith documented hypercortisolism. Thisledtheauthorsto imagingwasnegativein31%ofpatientswith pituitary T2DM patients( showed a prevalence of 3.4% of hypercortisolism in concerned T2DMpatientsandarecentmeta-analysis of 2–3permillion( by endogenoushypercortisolism israrewithanincidence known, buttheincidenceofCushing’s syndromecaused hypercortisolism inthe generalpopulationarenot of hypercortisolism. Exact prevalencenumbersof followed by imaging studies to determine the source by the Endocrine Society Guideline( for assessmentofhypercortisolism asrecommended All includedstudiesused of hypercortisolism in patientswithobesity( euthyroid didnotchangeBMI( hypothyroid patientswiththyroxineuntilclinically ( bariatric surgery decrease ofTSHlevelsafterweightlossresultingfrom asignificant by thefactthatseveralstudiesobserved between obesityandhypothyroidismisfurthersupported subclinical hypothyroidism.Thisreverserelationship euthyroid range( at maintainingserumthyroidhormoneswithinthe axis,aimed of thehypothalamus-pituitary-thyroid This increaseddisposalratemightpromoteactivation adiposity, since turnover rate is proportional to body size. that therateofthyroidhormonedisposalisincreasedin free thyroxine (FT4) ( TSH wasshown,withaninverserelationtolow/normal positive correlation between measures ofadiposity and Clinical Study Our studyrevealedarelativelyhighprevalence It is important to note that half of included studies The resultsofourreviewrevealedalowprevalence 51 43 10 ). Interestingly, inthatstudyadrenal/ 49 ). Thenetresultwouldbebiochemical , 46 , 14 50 ). A possible explanation could be ≥ , ). 45 years presenting to primary 45 yearspresentingtoprimary 16 52 ≥ ). Importantly, treatmentof ) involvingactivationof 2 ofthebiochemicaltests 47 L TvanHulsteijnandothers , 54 48 ), withanincreased ). 5 ), and if positive, 53 ). Inour < 1%). EJE-19-0666 version ofthisfigureisavailable at Prevalence ofhypogonadismaccording toBMI.Afullcolour Figure 7 liver, whichinturnleadstoalargeramountofTTavailable sex-hormone-binding globulin(SHBG)productionofthe resistance ( increased hepatogenous glucose production and insulin levels ofadiponectinseeninobesitycanalsoleadto and therefore induce insulin resistance ( which downregulatesglucosetransporter(GLUT)4 cause augmentationofestrogenreceptorbetaexpression, of testosteronetoestradiol.Thehigherlevelsestradiol cytochrome P450inadipocytesincreasestheconversion of testosteronebyLeydigcells( concentrations inobesemenmayinhibittheproduction mechanisms have been proposed. Firstly, elevated leptin but also the consequence of obesity ( important toconsiderthathypogonadismcanbethecause accumulation oftotalandvisceralfatmass( well establishedandlowtestosteronelevelspromote correlation betweentestosteroneandBMIinmenis risk inmenwithobesity(oddsratio2.38).Thenegative exact valuesoflowTTlevels.However, bothstudies studies reported cut-off levels for TT but none reported studies inourreviewassessedhypogonadismbyTT. All being withinthenormalrangeislow( dL), in whichcase the probability of FT concentrations below thelowerlimitofnormalrange(e.g. of TTlevelsinobesity, unlessTTconcentrations are far the EndocrineSocietyrecommendstomeasureFTinstead decrease inSHBGandtheconsequentalteredlevelsofTT, for conversiontoestradiolinfattissue.Because of the disorders inobesity Prevalence ofendocrine BM 10 20 30 40 50 60 70 80 90 0 20 I . 58 30 ). Insulinresistancecaninducedecreased 40 Downloaded fromBioscientifica.com at09/29/202111:11:14PM 50 https://eje.bioscientifica.com https://doi.org/10.1530/ 56 ). Secondly, aromatase 6 182 ). Several underlying :1 60 6 57 ). Sixincluded % hypogonadism(FT) % hypogonadism(TT) ). The lower Percentage 55 < 150 ng/ ). Itis 17 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com EJE-19-0666 at paper the of version online the to linked is This Supplementary materials Endocrinology ( Work-up for Obesity Guideline of the European Society of consequences forscreeningwerefertotheEndocrine the underlyingmechanismsarecomplex.For in patients with obesityisconsiderable, although criteria areusedtodefinePCOS)( aged women(9.1–25% vs 6–20%,dependentonwhich almost similartothegeneralpopulationofreproductive- with ourreview:prevalenceofPCOSinobesewomen is with BMI-matchedcontrolwomen( imaging didnotdifferinwomenwithPCOScompared system ( stimulates LH-mediatedsteroidogenesisinthethecacell of androgensisincreasedthroughthefactthatinsulin abdominal obesity( SHBG-bound DHEAandΔ the increasedproductionrateoftestosteroneandnon- therefore causesrelativehyperandrogenism,amplifiedby ( decreased production ofSHBG through insulinresistance obesity infemales,especiallyabdominal,isassociatedwith for biochemicalhyperandrogenismonly. Asinmales, for diagnosingPCOS,butwewereunabletostratifyresults biochemical hyperandrogenismasanessentialcriterion All threestudiesusedthepresenceofclinicaland/or studies investigating prevalence of PCOSwereincluded. hyperandrogenism inwomenwithobesity;onlythree exclusively investigatingprevalenceofbiochemical concentrations withrepeatmeasurement( be large,itis important toconfirm low testosterone variations inserumtestosteroneconcentrationscan prevalence inthisstudywas22.6%.Sinceday-to-day measurements of testosterone ( pre-definition ofhypogonadism,byusingtwoseparate the effectismodest( body mass and fat mass in hypogonadal men, although effect oftestosteronereplacementtherapyonBMI,lean 61 ( isobserved loss resultingfrombariatricsurgery BMI ( increasing prevalenceofhypogonadismwith using TTandstudiesFTshowedthesametrendof 67 Clinical Study ). Conversely, severalstudieshaveshownapositive ). InfemalesthisisbelievedtoincreaseFTfractionand To conclude, the prevalence of endocrine disorders Our literaturesearch didnotidentifystudies Importantly, onlyonestudymetourbiochemical Fig. 7 69 . ). However, visceralfatmassquantifiedby ). ImprovementofTT/FTlevelsafterweight 72 ). 68 62 ). Furthermore,ovarianproduction , 63 4 -androstenedione (Δ , 64 , 65 L TvanHulsteijnandothers 7 , ). 66 70 33 ). , https://doi.org/10.1530/ ). The reported 71 ). Thisisinline 6 ). 4 -A) seenin 59 , 60 , References or editorialprocessforthispaper,onwhichheislistedasanauthor. O M D is on the editorial board of EJE. O M D was not involved in the review Acknowledgements the public,commercialornot-for-profitsector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest

disorders inobesity Prevalence ofendocrine 2 1 9 8 7 6 5 4 3 Garvey WT, Mechanick JI,Brett EM,Garber AJ,Hurley DL, Yumuk V, Tsigos C, Fried M,Schindler K,Busetto L,Micic D, Fierabracci P, Pinchera A,Martinelli S, Scartabelli G, Salvetti G, Nyaga VN, Arbyn M&Aerts M.Metaprop: aStatacommandto Conway G, Dewailly D,Diamanti-Kandarakis E,Escobar-Morreale HF, Bhasin S, Brito JP, Cunningham GR,Hayes FJ,Hodis HN, Nieman LK, Biller BMK,Findling JW, Newell-Price J,Savage MO, Garber JR, Cobin RH,Gharib H,Hennessey JV, Klein I,Mechanick JI, Dekkers OM, Vandenbroucke JP, Cevallos M,Renehan AG, Jastreboff AM, Nadolsky K,Pessah-Pollack R,Plodkowski R& org/10.1159/000442721) management inadults. Association fortheStudyofObesity. Europeanguidelinesforobesity Toplak H &ObesityManagementTask Force oftheEuropean endocrine diseasesinmorbidlyobese patientsscheduledforbariatric Giannetti M, Pucci A,Galli G,Ricco I, Querci G 2014 perform meta-analysisofbinomialdata. 2014 European SocietyofEndocrinology. et al. Franks S, Gambineri A,Kelestimur F, Macut D,Micic D,Pasquali R 00229) Metabolism Society clinicalpracticeguideline. Testosterone therapyin men withhypogonadism:anEndocrine Matsumoto AM, Snyder PJ,Swerdloff RS,Wu FC &Yialamas MA. org/10.1210/jc.2008-0125) Endocrinology andMetabolism an EndocrineSocietyclinicalpracticeguideline. Stewart PM &Montori VM.ThediagnosisofCushing’s syndrome: org/10.4158/EP12280.GL) Association. Association ofClinicalEndocrinologistsandtheAmericanThyroid for hypothyroidisminadults:cosponsoredbytheAmerican Taskforce onHypothyroidisminAdults.Clinicalpracticeguidelines of ClinicalEndocrinologistsandAmericanThyroidAssociation Pessah-Pollack R, Singer PA, Woeber KA &AmericanAssociation journal.pmed.1002742) etiology. studiesof systematic reviewsandmeta-analysesofobservational Altman DG &Egger M.COSMOS-E:guidanceonconducting 1–203. for medicalcareofpatientswithobesity. College ofEndocrinologycomprehensiveclinicalpracticeguidelines American AssociationofClinicalEndocrinologistsand Reviewers oftheAACE/ACEObesityClinicalPracticeGuidelines. The polycystic ovary syndrome:apositionstatementfromthe Thepolycysticovary 72 171 (https://doi.org/10.4158/EP161365.GL) 39. PLoS Medicine P1–P29. 2018 (https://doi.org/10.1186/2049-3258-72-39) Endocrine Practice 103 (https://doi.org/10.1530/EJE-14-0253) 1715–1744. 2019 Obesity Facts Downloaded fromBioscientifica.com at09/29/202111:11:14PM 2008 16 2012 e1002742. (https://doi.org/10.1210/jc.2018- Journal ofClinicalEndocrinology and Journal 93 18 2015 European Journal ofEndocrinology European Journal 1526–1540. 988–1028. Archives ofPublicHealth Endocrine Practice 8 (https://doi.org/10.1371/ 182 402–424. :1 et al. Journal ofClinical Journal (https://doi. (https://doi. Prevalenceof (https://doi. 2016 18

22 via freeaccess

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22 21 20 19 18 17 16 15 14 13 12 11 10 Jankovi Clinical Study Rotondi M, Leporati P, LaManna A,Pirali B,Mondello T, Fonte R, Saluja M, Pyasarbadi P, Jelia S,Chittora S,Swami Y&Vimlani H. Ghazali SM &Abbiyesuku FM.Thyroiddysfunctionintype2 Resta O, Pannacciulli N,DiGioia G,Stefàno A,Barbaro MP&De Szomstein S, Avital S, Brasesco O,Mehran A,Cabral JM& Raftopoulos Y, Gagné DJ,Papasavas P, Hayetian F, Maurer J,Bononi P Moulin deMoraes CM,Mancini MC,Melo ME,Figueiredo DA, Michalaki MA, Vagenakis AG, Leonardou AS,Argentou MN, Janssen IM, Homan J,Schijns W, Betzel B, Aarts EO,Berends FJ& Gómez-Zamudio JH, Mendoza-Zubieta V, Ferreira-Hermosillo A, Chikunguwo S, Brethauer S,Nirujogi V, Pitt T, Udomsawaengsup S, Alhambra Expósito MR,Tenorio Jiménez C,MolinaPuerta MJ, org/10.1530/EJE-08-0734) ofEndocrinology European Journal morbid obesity:isitenoughtodiagnose subclinicalhypothyroidism? Magri F &Chiovato L.Raisedserum TSHlevelsinpatientswith Practice associations withitscomponents. Study ofthyroiddysfunctioninmetabolicsyndromeand ofPhysiologicalSciences Nigerian Journal diabetics seenattheUniversityCollegeHospital,Ibadan,Nigeria. 4753(04)80051-6) Diseases disordered breathing. hypothyroidism inobesepatientsreferredtoasleepclinicfor Pergola G. Highprevalenceofpreviouslyunknownsubclinical org/10.1381/096089204772787365) and short-termoutcome. replacement therapyforsubnormalthyroidfunction–prevalence Rosenthal R. Laparoscopicgastricbypassinpatientsonthyroid 509–513. Roux-en-Y gastricbypassformorbidobesity. & Caushaj PF. Improvementofhypothyroidismafter laparoscopic org/10.1381/096089205774512537) gastric bypass. and improvementafterweightlossinducedbyRoux-en-Y of subclinicalhypothyroidisminamorbidlyobesepopulation Villares SM, Rascovski A,Zilberstein B&Halpern A.Prevalence Thyroid Kyriazopoulou VE. Thyroidfunctioninhumanswithmorbidobesity. Habeos IG, Makri MG,Psyrogiannis AI,Kalfarentzos FE& soard.2015.02.021) and RelatedDiseases patients beforeandafterRoux-en-Ygastricbypass. de Boer H.Subclinicalhypothyroidismanditsrelationtoobesityin (https://doi.org/10.1016/j.arcmed.2016.10.007) with extremeobesity. andcardiovascularmarkersinpatients increase proinflammatory Peralta-Romero J & Cruz M. Highthyroid-stimulating hormone levels Molina-Ayala MA, Valladares-Sálgado A, Suárez-Sánchez F, deJesús soard.2007.07.011) Diseases loss onthyroidhormonelevels. Chand B &Schauer P. Influenceofobesityandsurgicalweight (https://doi.org/10.3305/nh.2014.29.5.7256) is itreallynecessary? Moreno MÁ. ScreeningforCushing’s syndromeinobesepatients; Manzano García G, PriorSánchez I,MuñozJiménez C&Gálvez 0545-4) Obesity Surgery onendocrineandmetabolicparameters. effects ofbariatricsurgery Prevalence ofendocrinedisordersinmorbidlyobesepatientsandthe Schifferl M, Hofer A,Langer F, Prager G,Ludvik B,Gessl A org/10.1007/s11695-010-0297-6) beyonddiabetes. surgery: 2018 2006 ć 2004 2007 D, Wolf P, Winhofer Y, Anderwald CH, Promintzer- (https://doi.org/10.1381/096089204323013514) 8 16 14 3 2012 3–7. Obesity Surgery 631–635;discussion635. 73–78. 248–253. 2015 (https://doi.org/10.1016/j.cmrp.2017.11.010) 22 Nutricion Hospitalaria Nutrition, Metabolism,andCardiovascular Archives ofMedicalResearch 62–69. (https://doi.org/10.1089/thy.2006.16.73) 11 Obesity Surgery Obesity Surgery (https://doi.org/10.1016/S0939- 1257–1263. 2005 (https://doi.org/10.1007/s11695-011- 2009 Surgery forObesityandRelated Surgery Current MedicineResearch and 15 L TvanHulsteijnandothers 1287–1291. 160 2010 2004 2011 (https://doi.org/10.1016/j. (https://doi.org/10.1016/j. 403–408. 2014 25 Obesity Surgery 14 21 173–179. 29 95–97. 2016 54–60. (https://doi. Surgery forObesity Surgery 1020–1023. (https://doi. 47 (https://doi. (https://doi. 476–482. et al. 2004

disorders inobesity Prevalence ofendocrine 29 28 27 26 25 24 23 38 37 36 35 34 33 32 31 30 Alhayek AA, Khader YS,Jafal S,Khawaja N&Ajlouni K. Leibowitz G, Tsur A, Chayen SD,Salameh M,Raz I,Cerasi E& Baid SK, Rubino D,Sinaii N,Ramsey S,Frank A&Nieman LK. Abraham SB, Rubino D,Sinaii N,Ramsey S&Nieman LK.Cortisol, Cardoso EM, Arregger AL,Monardes G&Contreras LN.Anaccurate, Lima N, Cavaliere H&Medeiros-Neto GA.Aretrospectivestudy Duntas L, Hauner H,Rosenthal J&Pfeiffer EF. Thyrotropinreleasing Gamendia Madariaga A,SantosPalacios S, Guillen-Grima F& Hollowell JG, Staehling NW, Flanders WD,Hannon WH,Gunter EW, Kaplan SA, Lee JY, O'Neill EA,Meehan AG&Kusek JW. Prevalence Rabijewski M, Papierska L,Zgliczy Kapoor D, Aldred H,Clark S,Channer KS&Jones TH.Clinical Ganesh HK, Vijaya Sarathi HA,George J,Shivane VK, Bandgar T, Dhindsa S, Miller MG,McWhirter CL,Mager DE,Ghanim H, Dhindsa S, Prabhakar S,Sethi M,Bandyopadhyay A,Chaudhuri A Chandel A, Dhindsa S,Topiwala S, Chaudhuri A&Dandona P. 2265.1996.737558.x) Endocrinology cause ofpoorglycaemiccontrolinobesediabeticpatients. Gross DJ. Pre-clinicalCushing’s syndrome:an unexpectedfrequent jc.2008-2766) and Metabolism andobesepopulation. overweight Specificity ofscreeningtestsforCushing’s syndromeinan (https://doi.org/10.1002/oby.20083) subjects andreviewoftheliterature. obesity, andthemetabolicsyndrome:across-sectionalstudyofobese steroids.2013.02.005) populations. non-invasive approachtodiagnoseCushing’s syndromeinat-risk SH Ingbar, JMMcKenzie&GFFenzi.Boston,MA:Springer, 1987. population. In of thyroidautoimmunityandhypothyroidisminarandomobese ofObesity Journal International hormone (TRH)immunoreactivityandthyroidfunctioninobesity. Galofre JC. Theincidenceandprevalence ofthyroiddysfunction Clinical EndocrinologyandMetabolism (NHANESIII). Health andNutritionExaminationSurvey antibodies intheUnitedStatespopulation (1988to1994):National Spencer CA &Braverman LE.Serum TSH,T(4),andthyroid 0.3109/13685538.2013.844786) prostatic hyperplasia. tract symptoms associatedwithbenign men withlowerurinary of lowtestosteroneanditsrelationshiptobodymassindexinolder 767496. men inPolishpopulation. incidence ofhypogonadotropichypogonadismintype2diabetic dc06-1426) adiposity. 2 diabetes:correlationswithbioavailabletestosteroneandvisceral and biochemicalassessmentofhypogonadisminmenwithtype Practice type 2diabetesmellitusinanAsianIndianstudygroup. Menon PS &Shah NS.Prevalenceofhypogonadisminpatientswith (https://doi.org/10.2337/dc09-1649) and nondiabeticobesemen. Chaudhuri A &Dandona P. Testosterone concentrationsindiabetic 0804) Metabolism hypogonadism intype2diabetes. & Dandona P. Frequentoccurrenceofhypogonadotropic Care Testosterone concentrationinyoungpatientswithdiabetes. Mellitus prevalence andassociatedfactor. Hypogonadism amongJordanianmenwithtype2diabetes: 2008 2009 2015 (https://doi.org/10.1155/2013/767496) Diabetes Care 31 2004 1996 2013–2017. Steroids 15 3 31–36. 2009 Thyroid Autoimmunity 513–520. 89 44 5462–5468. 2013 94 717–722. Aging Male (https://doi.org/10.1016/j.ijdm.2011.01.003) 2007 3857–3864. (https://doi.org/10.2337/dc08-0851) (https://doi.org/10.4158/EP09035.ORR) 78 Downloaded fromBioscientifica.com at09/29/202111:11:14PM BioMed Research International Diabetes Care 476–482. 30 1991 911–917. (https://doi.org/10.1046/j.1365- (https://doi.org/10.1210/jc.2004- 2013 International Journal ofDiabetes Journal International ń Journal ofClinicalEndocrinologyand Journal Journal ofClinicalEndocrinology Journal ski W &Pi 15 https://eje.bioscientifica.com , pp591–593.EdsAPinchera, 2002 (https://doi.org/10.1210/ Obesity 83–87. 16 (https://doi.org/10.1016/j. 169–172. 2010 (https://doi.org/10.2337/ 87 182 2013 ą 489–499. tkiewicz P. The :1 33 21 1186–1192. (https://doi.org/1 E105–E117. 2013 Endocrine Journal of Journal Clinical Diabetes 2013 19 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com

55 54 53 52 51 49 48 47 45 44 43 42 41 40 39 50 46 Clinical Study Ng Tang Fui M,Hoermann R,Cheung AS,Gianatti EJ,Zajac JD Mulligan T, Frick MF, Zuraw QC,Stemhagen A&McWhirter C. Davis SN, Mann S,Briscoe VJ,Ertl AC&Tate DB. Effectsofintensive Donath MY &Shoelson SE.Type 2diabetesasaninflammatory Steffensen C, Pereira AM,Dekkers OM&Jørgensen JO.Diagnosisof Steffensen C, Bak AM,Rubeck KZ&Jorgensen JOL.Epidemiologyof Lee SY, Braverman LE&Pearce EN. Changesinbodyweightafter Pinkney JH, Goodrick SJ,Katz JR,Johnson AB,Lightman SL, Portmann L &Giusti V. Obesityandhypothyroidism:mythor Taylor PN, Razvi S,Pearce SH &Dayan CM.Clinicalreview:areview Santini F, Marzullo P, Rotondi M,Ceccarini G,Pagano L,Ippolito S, Tandon N,Marwaha RK, Gupta N,Karak AK,Verma K & Verma A, Jayaraman M,Kumar HKVS&Modi KD.Hypothyroidism Gupta H, Sheth SP&Vaishnav B. Associationofsubclinical Sudhakar MK,Singh M,Senthil N&Rajendran A.The Agarwal G, Lindholm J, Juul S,Jorgensen JOL,Astrup J,Bjerre P, Feldt- de MouraSouza A&Sichieri R.AssociationbetweenserumTSH & Grossmann M.Obesityandageas dominantcorrelatesoflow (https://doi.org/10.1111/j.1742-1241.2006.00992.x) HIM study. Prevalence ofhypogonadisminmales agedatleast45years:the 701–709. responses tohypoglycemiaintype2diabetes. therapy andantecedenthypoglycemiaoncounterregulatory org/10.1038/nri2925) disease. 0434) Endocrinology patients: asystematicreviewandmeta-analysis. endocrine disease:prevalenceofhypercortisolism intype2diabetes 117–123. based study. Incidence andlateprognosisofCushing’s syndrome:apopulation- Rasmussen U, Hagen C, Jorgensen J, Kosteljanetz M, Kristensen L (https://doi.org/10.1159/000314297) Cushing’s syndrome. Practice hypothyroidismwithlevothyroxine. treatment ofprimary org/10.1038/sj.ijo.0801316) Metabolic Disorders and hyperthyroidism. sympathetic influencesonplasmaleptininhypothyroidism Coppack SW, Medbak S&Mohamed-Ali V. Thyroidand of Endocrinology concentration withinthenormalrangeandadiposity. reality? 2013 the referencerange. of theclinicalconsequencesvariationinthyroidfunctionwithin R137–R152. health anddisease. between thyroidglandandadiposetissue:signalintegrationin Chiovato L &Biondi B.Mechanismsinendocrinology:thecrosstalk 2265.2003.01895.x) Endocrinology iodine status,thiocyanateexposureandautoimmunity. Kochupillai N. Residualgoitreinthepostiodizationphase: 1135–1138. and obesity, causeofeffect? Research from Western India. hypothyroidism withmetabolicsyndrome:across-sectionalstudy 5 Metabolic Syndrome. prevalence ofthyroiddysfunctionamongSouthIndianwomenwith Metabolism in Europe:ameta-analysis. 213–216. 98 2014 Revue MedicaleSuisse 2016 Nature Reviews:Immunology 3562–3571. (https://doi.org/10.1210/jcem.86.1.7093) (https://doi.org/10.2337/db08-1230) 2014 International Journal ofClinicalPractice Journal International (https://doi.org/10.1530/EJE-14-0067) Journal ofClinicalEndocrinologyandMetabolism Journal 2003 2016 20 9 2011 265–269. 1122–1128. 99 2000 175 59 European Journal ofEndocrinology European Journal 923–931. Journal ofClinicalEndocrinologyandMetabolism Journal Asian Journal of Pharmaceutical andClinical ofPharmaceutical Asian Journal 165 (https://doi.org/10.1210/jc.2013-1315) Neuroendocrinology 672–681. Journal ofClinicalandDiagnosticResearchJournal International Journal ofObesityandRelated Journal International R247–R253. 24 11–15. (Supplement2)S165–S166. Journal ofClinicalEndocrinologyand Journal 2007 Saudi MedicalJournal (https://doi.org/10.4158/EP14072.OR) (https://doi.org/10.1210/jc.2013-2409) (https://doi.org/10.1046/j.1365- (https://doi.org/10.1530/EJE-11-0261) 3 2011 859–862. (https://doi.org/10.1530/EJE-16- L TvanHulsteijnandothers 2010 11 98–107. 92 Diabetes European Journal of European Journal (Supplement1)1–5. 2008 2006 2014 European Journal European Journal (https://doi. 2009 29 60 (https://doi. Clinical

171

762–769. 2001 Endocrine 58

2011

86 et al.

disorders inobesity Prevalence ofendocrine 68 64 69 67 66 65 63 62 61 60 59 58 57 56 Bergh C, Carlsson B,Olsson JH,Selleskog U &Hillensjö T. Regulation Pasquali R, Gambineri A&Pagotto U. Theimpactofobesityon syndrome. Ehrmann DA. Polycysticovary Pexman-Fieth C, Behre HM,Morales A,Kan-Dobrosky N& Behre HM, Tammela TL, Tolrá JR, Arver S, Bonifacio V, Lamche M, Srinivas-Shankar U, Roberts SA,Connolly MJ,O’Connell MD, Isidori AM, Giannetta E,Greco EA,Gianfrilli D,Bonifacio V, Wang C, Swerdloff RS,Iranmanesh A,Dobs A,Snyder PJ, Samavat J, Facchiano E,Lucchese M,Forti G,Mannucci E,Maggi M Pellitero S, Olaizola I,Alastrue A,Martínez E,Granada ML, Hammoud A, Gibson M,Hunt SC,Adams TD,Carrell DT, Michalakis K, Mintziori G,Kaprara A,Tarlatzis BC &Goulis DG. Cohen PG. Obesityinmen:thehypogonadal-estrogenreceptor Baldelli R, Dieguez C&Casanueva FF. Theroleofleptinin 323–331. like growthfactorIandinsulin. of androgenproductionincultured humanthecalcellsbyinsulin- 113 syndrome. reproduction inwomenwithpolycystic ovary NEJMra041536) of Medicine 09/13685538.2013.858113) testosterone 1%gel. desire, andbodyproportionsinhypogonadalmentreatedwitha studyofenergy,Miller MG. A6-monthobservational sexual 0.3109/13685538.2012.699562) open-label follow-up. symptoms ofandrogendeficiencyover6monthswith12 with hypogonadaltolow-normallevelsofserumtestosteroneand gel onbodycompositionandhealth-relatedquality-of-lifeinmen A randomized,double-blind,placebo-controlledtrialoftestosterone Kelly J, Hiemeyer F, EuropeanTestogel® StudyTeam, Giltay EJ Metabolism blind, placebo-controlledstudy. in intermediate-frailandfrailelderlymen:arandomized,double- strength, physicalfunction,bodycomposition,andqualityoflife Adams JE, Oldham JA&Wu FC. Effectsoftestosteroneonmuscle (https://doi.org/10.1111/j.1365-2265.2005.02339.x) 2000 aged men:ameta-analysis. composition, bonemetabolismandserumlipidprofileinmiddle- Isidori A, Lenzi A&Fabbri A.Effectsoftestosteroneonbody in hypogonadalmen. function, mood,musclestrength,andbodycompositionparameters Gel StudyGroup.Transdermal testosteronegelimprovessexual Cunningham G, Matsumoto AM,Weber T, Berman N&Testosterone 2014 surgery inmalemorbidobesity? surgery & Luconi M.Hypogonadismasanadditionalindicationforbariatric (https://doi.org/10.1007/s11695-012-0734-9) reversed afterbariatricsurgery. Hypogonadotropic hypogonadisminmorbidlyobesemalesis Balibrea JM, Moreno P, Serra A,Navarro-Díaz M,Romero R org/10.1210/jc.2008-1598) Endocrinology andMetabolism on thesexsteroidsandqualityoflifeinobesemen. Kolotkin RL &Meikle AW. Effect ofRoux-en-Ygastricbypasssurgery metabol.2012.08.012) and Experimental and reproductiveaxis:anarrativereview. The complexinteractionbetweenobesity, metabolicsyndrome 2008 relationship anditseffectonglucosehomeostasis. 2002 reproduction: experimentalandclinicalaspects. 906–912. testosterone inmenirrespectiveofdiabetesstatus. 1148–1159. 85 70 34 171 2839–2853. 358–360. 5–18. 555–560. (https://doi.org/10.1016/s0015-0282(16)55675-1) (https://doi.org/10.1111/j.2047-2927.2013.00124.x) 2005 2010 (https://doi.org/10.1080/078538902317338599) 2013 352 (https://doi.org/10.1111/j.1471-0528.2006.00990.x) 95 (https://doi.org/10.1016/j.mehy.2007.05.020) (https://doi.org/10.1530/EJE-14-0596) 639–650. Aging Male 1223–1236. (https://doi.org/10.1210/jcem.85.8.6747) Aging Male Journal ofClinicalEndocrinologyandMetabolism Journal 62 457–478. Downloaded fromBioscientifica.com at09/29/202111:11:14PM Clinical Endocrinology 2009 (https://doi.org/10.1210/jc.2009-1251) 2014 Obesity Surgery European Journal ofEndocrinology European Journal Fertility andSterility Fertility 2012 Journal ofClinicalEndocrinologyand Journal (https://doi.org/10.1056/ 94 (https://doi.org/10.1016/j. 17 1329–1332. 15 1–11. 198–207. Metabolism: Clinical New England Journal New EnglandJournal 182 2012 (https://doi.org/10.31 :1 2005 Annals ofMedicine (https://doi. Medical Hypotheses Andrology 1993 22 (https://doi.org/1 Journal ofClinical Journal 1835–1842. 63 280–293. 59 BJOG et al. 2013

et al. 2006

1 via freeaccess

European Journal of Endocrinology

71 70 Clinical Study Mannerås-Holm L, Leonhardt H,Kullberg J,Jennische E,Odén A, Barber TM, Golding SJ,Alvey C,Wass JA, Karpe F, Franks S& Adipose tissuehasaberrantmorphologyandfunctioninPCOS: Holm G, Hellström M,Lönn L,Olivecrona G,Stener-Victorin E (https://doi.org/10.1210/jc.2007-2117) ofClinicalEndocrinologyand Metabolism Journal syndrome. distribution characterizeswomenwithpolycysticovary McCarthy MI. Globaladiposityratherthanabnormalregionalfat L TvanHulsteijnandothers 2008 93 999–1004. et al.

Accepted 24October2019 Revised versionreceived17October2019 Received 28August2019

disorders inobesity Prevalence ofendocrine 72 Pasquali R, Casanueva F, Haluzik M,vanHulsteijn L,Ledoux S, ESE guideline:endocrinework-upinobesity. Monteiro MP, Salvador J,Santini F, Toplak H &Dekkers OM. doi.org/10.1210/jc.2010-1290) Endocrinology Clinical EndocrinologyandMetabolism sex steroids,arestronglyassociatedwithinsulinresistance. enlarged adipocytesandlowserumadiponectin,butnotcirculating 2020 182 G1–G32. Downloaded fromBioscientifica.com at09/29/202111:11:14PM (https://doi.org/10.1530/EJE-19-0893) https://eje.bioscientifica.com 2011 96 182 European Journal of of European Journal E304–E311. :1 (https:// Journal of Journal 21 via freeaccess