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R Pasquali and others ESE Guidelines on Endocrine 182:1 G1–G32 Clinical Practice work-up in obesity Guideline

European Society of Endocrinology Clinical Practice Guideline: Endocrine work-up in obesity

R Pasquali1, F Casanueva2, M Haluzik3, L van Hulsteijn4, S Ledoux5, M P Monteiro6,7, J Salvador8,9, F Santini10, H Toplak11 and O M Dekkers12,13,14

1University Alma Mater Studiorum, Bologna, Italy, 2Department 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, 3Diabetes Centre and Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine and Institute of Endocrinology, Prague, Czech Republic, 4Department of Clinical Endocrinology and Metabolism, University Medical Centre Groningen, Groningen, the Netherlands, 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, 7University 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 and Diabetology, Department of Medicine, Medical University of Graz, Graz, Austria, 12Department of Correspondence Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands, 13Department of Clinical should be addressed Endocrinology and Metabolism, Leiden University Medical Centre, Leiden, the Netherlands, and 14Department of to R Pasquali Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Email [email protected]

Abstract

Obesity is an emerging condition, with a prevalence of ~20%. Although the simple measurement of BMI is likely a simplistic approach to obesity, BMI is easily calculated, and there are currently no data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity. An increased BMI leads to a number of hormonal changes. Additionally, concomitant hormonal diseases can be present in obesity and have to

European Journal of Endocrinology be properly diagnosed – which in turn might be more difficult due to alterations caused by body fatness itself. The present European Society of Endocrinology Clinical Guideline on the Endocrine Work-up in Obesity acknowledges the increased prevalence of many endocrine conditions in obesity. It is recommended to test all patients with obesity for thyroid function, given the high prevalence of hypothyroidism in obesity. For hypercortisolism, male hypogonadism and female gonadal dysfunction, hormonal testing is only recommended if case of clinical suspicion of an underlying endocrine disorder. The guideline underlines that weight loss in obesity should be emphasized as key to restoration of hormonal imbalances and that treatment and that the effect of treating endocrine disorders on weight loss is only modest.

European Journal of Endocrinology (2020) 182, G1–G32

1. Summary of recommendations

The recommendations (R) in this guideline are worded as we classified as very low (+000), low (++00), moderate (+++0) recommend (strong recommendation) and we suggest (weak and strong (++++). See further section ‘Summary of methods recommendation). We formally graded only the evidence used for guideline development’. Recommendations based underlying recommendations for diagnostic strategies. on good clinical practice and/or experience of the panelists The quality of evidence behind the recommendations is were not graded.

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-19-0893 European Journal of Endocrinology https://eje.bioscientifica.com patients usingcorticosteroids. R.3.5. normal valuesareappliedas fornon-obese(+000). R.3.4. considered. (testingfor)hypercortisolismbariatric surgery shouldbe R.3.3. (++00). hypercortisolism biochemicaltestingshouldbeperformed R.3.2. not routinelyappliedinobesity(++00). R.3.1. the thyroidglandirrespectiveoffunction. R.2.9. antibodies, andageshouldbetakenintoaccount. to treathyperthyrotropinaemia,TSHlevel,thyroid R.2.8. obesity withtheaimatreducingbodyweight(++00). (elevated TSHandnormalFT4)shouldnotbetreatedin R.2.7. function (++00). hormones to treat obesity incaseof normal thyroid R.2.6. irrespective ofantibodies(++00). (elevated TSHanddecreasedFT4)istreatedinobesity R.2.5. hormonal valuesareappliedasfornon-obese(+000). R.2.4. of FT3inpatientswithelevatedTSH. R.2.3. (anti-TPO) shouldbemeasured(++00). based onTSH;ifTSHiselevated,freeT4andantibodies R.2.2. tested forthyroidfunction(+++0). R.2.1. obesity. measurements aspartofthehormonalevaluationin supplementsthatinterferewithhormone and dietary R.1.4. emphasized askeytorestorationofhormonalimbalances. R.1.3. are routinelyreferredtoanendocrinologist. R.1.2. especially ifBMI circumference canprovideadditionalinformation sufficient asfirstdiagnosticmeasure.Measuringwaist- For routinecaredefiningobesityasBMI an importantconditionthatoftenremainsundiagnosed. measure weightandheighttocalculateBMI,asobesityis R.1.1. Clinical PracticeGuideline We recommendnot totestforhypercortisolism in We suggest that for patients with obesity the same We recommendthatinpatientsgoing for Inpatientswithclinicalsuspicionof We recommendthattestingforhypercortisolism is We suggest against the use of routine ultrasound of We suggest that for the decision to treat or not We recommendthathyperthyrotropinaemia We recommendthatoverthypothyroidism We suggestthatforobesepatientsthesamenormal We donotrecommendtheroutinemeasurement We recommendthattestingforhypothyroidismis We recommendthatallpatientswithobesityare We recommend taking into account drugs We recommendthatweightlossinobesityis We recommendthatnotallpatientswithobesity We suggestthatforallpatientsitisofvalueto We recommendagainsttheuseofthyroid < 30 kg/m 2 . R Pasqualiandothers > 30 kg/m 2 is of hypogonadism we suggest measuring total and free R.4.2. symptoms/signs ofhypogonadism(++00). patients; wedorecommendinvestigatingkeyclinical hypogonadism isnotroutinelyappliedinmaleobese R.4.1. is notnormalizingBMIinmostcases. R.3.9. hypercortisolism. should beperformedtofindthecause/source ofthe an ACTHshouldbemeasuredandfurtherimaging R.3.8. cortisol. this canbeeither24-hurinecortisolorlate-nightsalivary test ispositive,werecommendasecondbiochemicaltest; R.3.7. test asfirstscreeningtool. recommend a1mgovernightdexamethasonesuppression R.3.6. 17-hydroxyprogesterone and prolactin.Ifthemenstrual testosterone, SHBG,Δ4androstenedione, oestradiol, to assessgonadalfunction by measuringLH,FSH,total R.5.3. chronic anovulation/infertility. patients withobesitymenstrualirregularitiesand R.5.2. with obesity(++00). dysfunction isnotroutinelyappliedinfemalepatients R.5.1. with obesityseekingfertility(+000). a firsttherapeuticmeasureinhypogonadalmalepatients R.4.8. restoration for6–12months(+000). clinical features are notimproving despite biochemical R.4.7. testosterone levelsinthenormalrange(+000). R.4.6. start testosterone(+000). out. Thesolepresenceofobesityisnotenoughreasonto and other causesof hypogonadism should have been ruled individual cases;contra-indicationsshouldbeconsidered treatment with testosterone can be consideredin and ifclinicalbiochemicalhypogonadismpersists, R.4.5. biochemical andclinicalhypogonadism. weight losstorestoreeugonadisminobesepatientswith R.4.4. reference rangesfortestosterone(+000). R.4.3. testosterone (orcalculated),SHBG,FSHandLH. work-up inobesity ESE GuidelinesonEndocrine Inmale patients with obesity withclinical features We recommendthatbiochemicaltestingfor Treatment ofprovenendogenoushypercortisolism Ifthe1mgovernightdexamethasonesuppression Ifhypercortisolism testingisconsidered,we Forevaluationofmenstrual irregularitywesuggest We suggest to assess gonadal function in female We recommendthattestingforgonadal We donotrecommendtestosteronetreatment as We suggeststoppingtestosteronetreatmentif We suggesttreatmentwithtestosteroneaimingat We suggestthatifweightlosscannotbeachieved We recommendemphasizingtheimportanceof Inobesitywesuggestapplyingage-specific Inallpatientswithconfirmedhypercortisolism, Downloaded fromBioscientifica.com at09/30/202103:48:48PM 182 :1 G2 via freeaccess European Journal of Endocrinology have beenreleased( Europeanguidelines medicine, andmultidisciplinary it isimportantforobesityto becomeanintegralpartof called ‘diabesity’andtreated accordingly( 2 diabetes,thecombination ofthetwodiseasesisoften disease and cancer( diabetes, hyperlipidaemia,hypertension,cardiovascular in thedevelopmentofnon-communicablediseaseslike Obesity isanemergingconditionandplaysacentralrole 2. Obesity–ashortintroduction hypertension inobesity. hypertension inthecontextoftherapy-resistant R.6.7. suspicion ofasyndromicobesity. hormones, suchasleptinandghrelin,unlessthereis R.6.6. routinely inpatientswithobesity(+000). R.6.5. D deficiencyinpatientswithobesity(+000). R.6.4. patients withnormalGHlevels(+000). R.6.3. should beperformedasaminimum(+000). with suspectedhypopituitarism;iftestedadynamictest R.6.2. routinely appliedinobesity(+000). R.6.1. reduce bodyweight(+000). in postmenopausalobese women with the sole aim to R.5.8. sole aimtoreducebodyweight(+000). R.5.7. syndrome features(++00). women withPCOSthatadditionallypresentmetabolic R.5.6. glucose. recommend toassessovarianmorphologyandblood T, Δ4androstenedioneandSHBG. We additionally features. We suggesttomeasuretotaltestosterone,free when PCOSisconsideredbasedontheclinical R.5.5. progesterone andprolactin. function to be assessed by measuring LH, FSH, oestradiol, R.5.4. follicular phase. that theassessmentshouldtakeplaceduringearly cycle isirregularbutsomewhatpredictable,wesuggest Clinical PracticeGuideline We causesof suggesttoconsidersecondary We recommendnottotestroutinelyother We suggestnottotestforhyperparathyroidism We suggestnottoperformroutinetestsforvitamin We recommendnottouseGHtreatobesityin We suggest testing for IGF1/GH only in patients We recommendthattestingforIGF1/GHisnot We recommendnottostartoestrogensubstitution We recommendnottostartmetforminwiththe We suggest to initiate metformin treatment in Forevaluationofanovulationwesuggestgonadal We recommendtoassessandrogenexcess 1 3 ). Due to the tight relation with type ). R Pasqualiandothers 2 ). Following, use aBMI-baseddefinitionofobesity(BMI is likely anovertlysimplisticapproach to obesity, we higher ( hormonal, metabolicanddiseaseimplicationsiseven persons, theburdenofunhealthybodyfatwith a substantial amount of normal –and overweight fat and/orincreasedbodyfatnessisalsopresentin and obesity. Ifoneconsidersthatunhealthyvisceral BMI hasbeenusedassingleindicatorofoverweight women ( systematic differenceinprevalencebetweenmenand heterogeneity intheprevalence;thereishoweverno the emergingobesityproblem( the StudyofObesity(EASO)wasfoundedtoaddress tripled since1986whentheEuropeanAssociationfor countries isaround20%( were appointed by the ESE Clinical Committee. Hermann were appointed by the ESE Clinical Committee. Hermann Renato PasqualiandOlafDekkers (methodologicalexpert), of Endocrinology(ESE).The chairsoftheworkinggroup, This guidelinewasdeveloped byTheEuropeanSociety 3.1. Guidelineworkinggroup 3. Methods to focusonsyndromicobesity. hormonal alterations in patients with obesity. We donot we dodiscussthepotentialtherapeuticconsequences of in patientswithobesity;althoughnotitsmainfocus Clinical Guidelineisfocusedontheendocrinework-up are listedin Table 1 The mainhormonalalterationsinobesityareshown throughout thisguideline.Themainreasonisthat of hormonalalterations,isconceptuallyshownin obesity andhormones,ascauseconsequence by bodyfatnessitself.Thetwo-wayrelationshipbetween in turnmightbemoredifficultduetoalterationscaused can bepresentandhavetoproperlydiagnosed–which resistance. Additionally, concomitanthormonaldiseases changes, themostobviousexamplebeinginsulin endocrine work-upinobesity. sophisticated methodsaremoreusefultoguidethe because therearecurrentlynodatashowingthatmore BMI iseasilycalculatedinclinicalpracticeandalso work-up inobesity ESE GuidelinesonEndocrine Prevalence datarevealonlypartoftheproblemas The actualprevalenceofobesityinmostEuropean The presentEuropeanSocietyofEndocrinology Increased bodyfatnessleadstoanumberofhormonal . Different diseases that potentially cause obesity 6 5 ). AlthoughthesimplemeasurementofBMI ). Table 2 . Downloaded fromBioscientifica.com at09/30/202103:48:48PM 3 ). Thenumbershavealmost https://eje.bioscientifica.com 4 ). Thereisaclear 182 :1 > 30.0 kg/m Fig. 1 G3 via freeaccess 2 ) .

European Journal of Endocrinology https://eje.bioscientifica.com with practicalguidancefor theendocrinework-upin The overallpurposeofthisguideline istoprovideclinicians 3.3. Aims obesity. developed withthespecificaimtocoverrareforms of a broadrangeofdoctors.Inline,theguidelineswerenot involved inthecareofpatientswithobesity This guidelinewasdevelopedforhealthcareproviders 3.2. Targetgroup the rationalebehindrecommendations. discussion; minoritypositionsweretakenintoaccountin 2018 andSeptember2018).Consensuswasreachedupon The workinggrouphadtwoin-personmeetings(February and LeonievanHulsteijn(Netherlands,methodology). Toplak (Austria),OlafDekkers(Netherlands,methodology) Severine Ledoux(France),JavierSalvador(Spain),Hermann Ferruccio Santini(Italy),MartinHaluzik(CzechRepublic), Mariana PMonteiro(Portugal),FelipeCasanueva(Spain), consisted of the following experts: Renato Pasquali (Italy), team of theStudyObesity(EASO).Themultidisciplinary Toplak asrepresentativeoftheEuropeanAssociation served Reciprocal interactionsbetweenobesityandendocrinediseases,includingpotentialcontributionoftreatment. Figure 1 Clinical PracticeGuideline R Pasqualiandothers , whichcovers it requires,however, thatstudiescompare different Secondly, grading fordiagnosticstrategiesispossible, when formally grading studies on diagnostics ( the presenceofsuchreference standardiscrucial standard for most endocrine conditions in obesity; for endocrinetestinginobesity:thelackofreference problems hamperedaformalgradingoftheevidence low (++00),moderate(+++0)andstrong(++++).Two low(+000),the recommendationsisclassifiedasvery search (seeSection3.6).Thequalityofevidencebehind (see Section3.5),thesecondasystematicliterature base. Thefirststepwastodefinetheclinicalquestions Development and Evaluation) as amethodological GRADE (GradingofRecommendationsAssessment, detail previously( The methodsusedhavebeendescribedinmore guideline development 3.4. Summaryofmethodsusedfor clinical judgment. Recommendations arethusnevermeanttoreplace but alsotheclinicaljudgmentoftreatingphysician. decisions shouldtakeintoaccounttherecommendations obesity. In clinical practice, diagnostic – and treatment work-up inobesity ESE GuidelinesonEndocrine 11 ). Inshort,theguidelineused Downloaded fromBioscientifica.com at09/30/202103:48:48PM 182 :1 G4 12 via freeaccess ). ).

European Journal of Endocrinology consensus oftheguideline developmentcommittee. ( and experienceofthe panelists werenotgraded Recommendations basedongoodclinicalpractice guideline, butasubstantialnumberwouldnot( most persons would still act in accordance with the the recommendation.Foraweakrecommendation, would want the management in accordance with informed persons(clinicians,politiciansandpatients) recommendation canbestatedasfollows:reasonably (weak recommendation). The meaning of a strong as recommend (strong recommendation) and suggest the panel ( of implementation,etc.),( (patient preferences,goalsforhealth,costs,feasibility and undesirableoutcomes,( ( in obesity. harms ( strategies withrespecttoclinicaleffectivenessand thyroid-stimulating hormone. growth factor;LH,luteinizinghormone;PCOS,polycysticovarysyndrome;PTH,parathyroidSHBG,sexhormone-bindingglobulin;TSH, releasing hormone;GLP,glucagon-likepeptide;GnRH,gonadotropin-releasingHPA,hypothalamic–pituitary–adrenalaxis;IGF,insulin-like hormone; FFA,freefattyacids;FSH,follicle-stimulatingFT4,thyroxine;GH-BP,growthhormone-bindingprotein;GHRH,hormone- 11-HSD, 11 Ghrelin Leptin GLP-1 Aldosterone Renin Insulin PTH 25-OH vitaminD LH/FSH Testosterone (female) Testosterone (male) Prolactin IGF-1 Growth hormone ACTH Cortisol (bloodandurine,salivary) FT4 TSH Hormone Table 1 15 1 Clinical PracticeGuideline ) qualityoftheevidence,( ). Recommendations were derived from majority For therecommendationswetookintoaccount: β 12 Hormonal alterationsinobesity. -hydroxysteroid dehydrogenase;ACTH,adrenocorticotropichormone; CBG,corticosteroid-bindingglobulin;CRH,corticotropin-releasing ). Suchstudieshavenotbeenperformed 13 , 14 ). The recommendations are worded 4 3 ) clinicalexperienceof ) valuesandpreferences 2 R Pasqualiandothers ) balanceofdesirable ↓ ↑ ↓ ↑ ↑ ↑ N or ↓ ↑ ↓ ↑ ↓ ? N or N or N or Altered suppressiontests N or N orslightly N or Levels inobesity LHinwomen inmen ↑ ↓ ↓ ↑ ↑ ↑

↓ 14 ). ).

paper ( review is summarized below, and published as stand-alone (females) was subsequentlyperformed ( secretion, hypogonadism(males)andhyperandrogenism the prevalenceofthyroiddisorders,autonomouscortisol guideline. Aliteraturesearch andsystematicreviewon disorders inobesitytoberelevantasevidencebaseforthe review ontheprevalenceofmostcommonendocrine published. The guidelinepanelconsidered a systematic knowledge ofthepanelnosuchtrialsinobesitywere with the best morbidity and mortality outcome), to the randomized trial(i.e.whatdiagnostictestisassociated Although diagnosticstrategiescanbecomparedin a work-up inobesity, thatis,aboutdiagnosticquestions. The presentguidelineisprimarilyabouttheendocrine endpoint definition 3.5. Clinicalquestions,eligibilitycriteriaand explaining whyspecificrecommendationsweremade. All recommendationsareaccompaniedbytext work-up inobesity ESE GuidelinesonEndocrine ↑ ↑ Insulin resistance Secondary duetovitaminDdeficiency ↓ ↓ Trapping inadiposetissue, Insulin resistance ↑ Insulin resistance(PCOS) ↓ Discordant data Increased intrahepatictriglyceridecontent ↑ ↓ ↑ Hyperactivity oftheHPAaxis ↑ ↑ ↑ ↑ Proposed pathophysiologicmechanism Lack ofghrelindecreaseaftermeals Increased adiposemass,Leptinresistance ↑ Adipokines,renin-angiotensin,leptin Sympathetictone liversynthesis 25OHvitaminDbindingprotein oestrogens/androgens SHBG GHsensitivity GHRH, CRH CRH, disposal peripheralT4disposal leptinandinsulin FFA,microbiota 16 ). ↑ ↑ adipose11-HSD, ↑ aromatase GH-BP, ↑ insulin, ↓ Downloaded fromBioscientifica.com at09/30/202103:48:48PM GnRH ↓ ↓ ↓ SHBG CBG ↓ ghrelin, sunexposure https://eje.bioscientifica.com ↑ 182 somatostatin :1 Table 3 ). This G5 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com PTH, parathyroidhormone;TSH,thyroid-stimulating hormone. luteinizing hormone;MC4R,melanocortin receptor4;ODST,overnightdexamethasonesuppressiontest;PCSK, proproteinconvertasesubtilisin/kexin; ACTH, adrenocorticotropichormone; FSH,follicle-stimulatinghormone;FT4,freethyroxine;GH,growth IGF,insulin-likegrowthfactor;LH, Pseudohypoparathyroidism Type1a Prohormone convertase1/3 Abnormal processingof Primary emptysella MC4R mutation Leptin receptordeficiencyorinactive Leptin deficiency Insulinoma (Severe) hypothyroidism Hypothalamic obesityacquired Hypothalamic obesityassociatedwith Hypopituitarism GH deficiency Ovarian failure(prematureor Drug-induced endocrinedysfunction Cushing’s diseaseor Androgen excess(women) Androgen deficiency(men) Condition Table 2 Clinical PracticeGuideline osteodystrophy) (Albright hereditary mutation) deficiency (PC-1/3)(PCSK1gene mutations Propiomelanocortin (POMC)gene leptin ( (hypothalamic lesionsor,tumors) Genetic Syndromes menopause) antipsychotics, glucocorticoids…) (e.g. lithium,anti-depressants, syndrome 8 Examples ofendocrinediseases/disturbancescausingorcontributingtoobesity. ) R Pasqualiandothers Rare Extremely rare Extremely rare Rare (increase rare Extremely rare Extremely rare Very rare Rare Rare Extremely rare Rare Rare Physiological Premature Common Rare Common Common Prevalence inobesity pressure) intracranial Common (Menopause) uncommon Suspicion ofhypothalamicobesity Hypothalamic orpituitarydisease, Vaginal mucosaatrophy Secondary amenorrheaVasomotor Glucocorticoid therapy Psychiatric disorders Type 2diabetes Hypertension Central obesity Acanthosis nigricans Hirsutism Irregular menses Central obesity Symptoms andsignsof Severe obesity When tothinkaboutit Short stature,shortfourth Multiendocrine disorders, Red hair Severe childhoodobesity female, HTA,SAOSheadache, Severe childhoodobesity Severe childhoodobesity Severe childhoodobesity Hypoglycaemic symptoms Concurrent autoimmunediseases Mixedematous features Possible multipleendocrine Severe hyperphagia Hypogonadism (hypogonadismor Surgery orradiotherapyin surgery orradiationtherapy pituitary orhypothalamic symptoms hypogonadism delay calcifications, developmental metacarpal bones,obesity,s.c. hypothyroidism ( insufficiency and primary hypogonadism,adrenal growth hormonedeficiency, including diabetesinsipidus, menstrual disturbances abnormalities retardation syndrome, mentalandgrow gonadal function.dysmorphic hypergonadotropic) orvariable pituitary region work-up inobesity ESE GuidelinesonEndocrine 10 ) Downloaded fromBioscientifica.com at09/30/202103:48:48PM FT4 TSHLHFSH(testosteroneor Serum IGF-I,GH-stimulating FSH, LH,oestradiol 1 mgODSTtoexcludeCushing 1 mgODST LH FSHoestradioltestosterone LH FSHtestosterone First diagnosticprocedure PTH ACTH MRI ofpituitary Prolactin, FSHLH,testosterone/ Leptin normalor Leptin Leptin 72-h supervisedfast Blood glucose,insulin,C-peptide FT4 TSH Brain CTorMRI Leptin (leptinresistance)( GH stimulationtest ACTH stimulationtest GH IGF-1PRL tests glucocorticoid use) syndrome (exceptin oestradiol, cortisol,IGF-1 genetic testing estradiol) ↑ calcium ↓ ↑ ↓ ( 9 ) 182 :1 ↓ phosphate ↑ 7 ); ↑ G6 via freeaccess European Journal of Endocrinology dexamethasone suppressiontest;TSH, thyroid-stimulatinghormone;TT,totaltestosterone;UFC,urinefree cortisol;WC,waistcircumference. BMI, bodymassindex;FT,freetestosterone; LDDST,low-dosedexamethasonesuppressiontest;LNSC,late night salivarycortisol;ODST,overnight Question 4: Question 3: Question 2: Question 1B: Question 1A: Clinical question Table 3 implemented asappropriatebythepanel. All comments and suggestions were then discussed and field; itwasalsosubmitted forcommentsbyESEmembers. A draftoftheguidelinewasreviewedbyexpertsin other societies 3.7. Reviewprocessandendorsementof hypercortisolism ( included (two studies assessedbothhypothyroidism and potentially relevantpaperswereconsidered;68 different criteria used in included articles). Overall, 3819 abdominal obesity(definitionofenlargementbasedon kg/m For allpapersconsideredobesitywasdefinedasBMI with included, asobesityisnotarareconditionandstudies performed. We only considered papers with A literaturesearch ofelectronicmedicaldatabaseswas 3.6. Descriptionofsearchandselectionliterature Clinical PracticeGuideline obesity? female patientswith hyperandrogenism in prevalence of obesity? male patientswith hypogonadism in prevalence of obesity? hypercortisolism in prevalence of obesity? hypothyroidism in prevalence ofsubclinical obesity? hypothyroidism in prevalence ofovert 2 < and/orlargewaistcircumference asexpressionof 10 patientsprobablysufferfromselectionbias. Clinical questionsandmetricsofthereview. Whatisthe Whatisthe Whatisthe Whatisthe Whatisthe 16

)). Obese female Obese male Obesepatients Obese patients Population patients patients R Pasqualiandothers Predefined selectioncriteriaandkeyoutcomeparameters Data onhyperandrogenismbased Data onhypogonadismbasedlowTT Data onhypercortisolismbased Data onsubclinical/overthypothyroidism Restriction included articles) test basedoncut-offvaluesusedin raised TTorFT(definitionofpositive articles) on cut-offvaluesusedinincluded or FT(definitionofpositivetestbased articles) cut-off valuesusedinincluded (definition ofpositivetestbasedon cortisol afterODSTorLDDST assay, elevatedLNSC,serum greater thanthenormalrangefor of thefollowingmeasurements:UFC used inincludedarticles) positive testbasedoncut-offvalues based onraisedTSH(definitionof > 10 patients ≥ 30 hyperandrogenism infemales,reportedprevalencesof to 52%,alsosuggestingunderlyingheterogeneity. For prevalence inthe11includedpapersrangedfrom16 found tobe32.7%(95%CI:23.1–43.0);thereported testosterone measurements,thepooledprevalencewas 22 studies.Formalehypogonadism,basedonfree prevalence of 0.9% (95% CI: 0.3–1.6), based on underlying clinicalheterogeneity. ranged considerablybetweenincludedstudies,suggesting and subclinicalhypothyroidism,thereportedprevalence CI: 9.2–20.9),alsobasedon19studies.Forbothclinical of subclinicalhypothyroidismwasfound14.6%(95% (95% CI:9.7–18.9),basedon19studies;theprevalence prevalence ofhypothyroidisminobesitywas14.0% For detailsofthereviewsee( systematic review 4. Summaryofresultsfromthe higher thanexpected( PCOS ranged from 9.1 to 25% (three studies), which is work-up inobesity ESE GuidelinesonEndocrine For hypercortisolism, wefoundanoveralllow ≥ 2 Prevalence of Prevalence of Prevalence of Prevalence of Outcome hyperandrogenism hypogonadism hypercortisolism hypothyroidism subclinical/overt 17 Downloaded fromBioscientifica.com at09/30/202103:48:48PM ). https://eje.bioscientifica.com 16 ). Insummary, the 182 :1 studies included Number of 18 22 27 3 G7 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com we suggestthatinpatientswith morbidobesityareferral conditions canbedifficult todistinguishfromobesity, and becauseclinicalsigns and symptomsofendocrine of endocrinedisturbances is relatedtoobesityseverity, excess inwomen).Inaddition, becausetheprevalence hypercortisolism, hypogonadism in males or androgen suspicion ofanendocrinedisease(e.g.endogenous The endocrinologistshouldbeconsultedincaseofclear compatible withavailableresources inmostcountries. standard referraltoanendocrinologistwouldnotbe Furthermore, theprevalenceofobesityissuchthat by otherendocrinediseasesorhormonaldisturbances. endocrine andmetabolicimbalance,obesityisnotcaused In mostcases,despiteobesitybeingacondition of Reasoning: endocrinologist. to an with obesity are routinely referred R.1.2. We recommendthatnotallpatients plethysmography) measurements( Scans or BOD-POD (air displacement absorptiometry) analysis) measurements,DXA(Dual-energy X-ray phenotyping mayincludeBIA(Bioelectricalimpedance practice thesemeasurescanbeeasilyachieved.Detailed the respectivecut-offsare94and102cm).Inclinical regarded equallyimportantasaBMI is regardednormal,80-88cmaselevatedand waist circumference (inCaucasian femalesawaist fat mass (with sarcopenia) may be suggested by increased Especially insubjectswithBMI of obesityrelatedcomplicationswithmoresevereobesity. IV-VI accordingly( Recently, EASOhassuggestedtogradefurtherwithobesity kg/m ( diagnostic measure. Furthermore, a grading in obesity I an adequateindicatorofobesityandsufficientasfirst associated withhighfatmassandthusBMIisconsidered Obesity, defined by aBMI Reasoning: especiallyifBMI information waist-circumference canprovideadditional sufficient asfirstdiagnosticmeasure.Measuring care definingobesityasBMI that oftenremainsundiagnosed.Forroutine condition BMI, asobesityisanimportant value tomeasureweightandheightcalculate R.1.1. We suggestthatforallpatientsitisof 5.1. Generalrecommendations > Clinical PracticeGuideline 30 kg/m 2 ) isproposedandshouldbeusedinclinicalpractice. 2 ), obesityII( 6 ) becauseoftheincreasingprevalence > 35 kg/m > 30 kg/m < 30 kg/m R Pasqualiandothers 2 3 < ) andobesityIII( ). 30 kg/m > 2 30 kg/m , is in most cases > 2 30 kg/m increasedbody 2 2 > . , inmales 88 cmis < 80 cm 2 > is 40 TSH inobesitywasrecently suggested( among theseconditions( risk, havebeenidentified; interestingly, obesityisnot not recommended ( blood tests.Screeningofthe generalpopulationismostly of obesity. Hypothyroidismcanbeeasily diagnosed by gain) arenonspecific( depression, cramps,menstrualdisturbanceorweight in Europewasestimatedaround5%( 10% ( and thatofsubclinicalhypothyroidismbetween4 Reasoning: evaluation inobesity. ofthehormonal measurementsaspart hormone with supplements that interfere and dietary R.1.4. We recommendtakingintoaccountdrugs following chaptersfordetails). reduction, irrespective of therapeutic strategy (see proper equilibriumisusuallyrestoredfollowingweight For mosthormones (TSH, cortisol. testosterone), the Reasoning: imbalances. is emphasizedaskeytorestorationofhormonal R.1.3. We recommendthatweightlossinobesity bariatric surgery. obesity and /or rapid weight gain and candidates for referral totheendocrinologistincludetherapy-resistant to anendocrinologistisconsidered.Furtherreasonsfor overt hypothyroidismvariesbetween0.2and5.3%( common endocrinediseases.InEurope,theprevalence of of obesity, becausehypothyroidismisone ofthemost Thyroid functioniscommonlyassessed,independently Reasoning: obesity aretestedforthyroidfunction(+++0). R.2.1. We recommendthatallpatients with 5.2. Testingforthyroidfunction ( of varioushormonalaxesaswellwithassays exogenous substancesmayinterferewiththeregulation or preventing cardiovascular events. Some of these weight lossorwell-being,controllingglucosemetabolism taken bypatientswithobesity, withtheaimoffacilitating supplementsarecommonly complications, severaldietary Beside generaldrugsusedtomanageobesity work-up inobesity ESE GuidelinesonEndocrine 2 , 18 Symptoms ofhypothyroidism(suchasfatigue, , 21 19 ); theprevalenceofundiagnosedhypothyroidism ). 24 23 ), although some populations at Downloaded fromBioscientifica.com at09/30/202103:48:48PM ) andcanbeconfusedwiththose 20 , 24 ), buttheusefulnesstotest 182 22 ). 25 :1 ). Furthermore, G8 20 via freeaccess ) European Journal of Endocrinology attempts atloosingbodyweight. 44 profile, andthus,potentially increasesvascularrisk( Hypothyroidism contributes to an unfavorable lipid risk factorsandfeaturesof metabolicsyndrome( potentiates theriskofobesitytodevelopcardiovascular ( of screeningversusnoinobesepopulations hypothyroidism. be differentiatedfromauto-immune-relatedsubclinical hyperthyrotropinaemia associatedwithobesitymust event(seealso 5.2.4)( rather thantheprimary autoantibodies) islikelyanadaptiveresponse( the increaseinserumTSH(inabsenceofthyroid ( bariatric surgery weight lossobtainedbycalorierestriction( abnormal thyroidfunctionusuallyimprovesafter weight (BW)ratherthanthecause( in thyroidhormonesaresideeffectsofincreasingbody However, somelongitudinalstudiessuggestthatchanges loss inducedbydiet( range, maypromoteweightgain( variations ofthyroidhormones,eveninthenormal and BMI( studies have showna positive association between TSH tohypothyroidism.Severalis usuallynotsecondary than 10%)( produces onlyamodestweightloss(usuallyofless ( in hypothyroidism( However, despiteweightgainbeingafrequentcomplaint due toglycosaminoglycansaccumulation( and reducedphysicalactivity, andalsofluidretention, mass, duetomilddecreaseinrestingenergyexpenditure induce weightgainbymeansofbothanincreasingfat energy metabolismandhypothyroidismcouldindeed Certainly, thyroidhormoneshaveanimportantrolein and/or a reasonforresistanceto weight lossefforts. with obesity withthe hope to identify a causeof obesity found 14.6%(95%CI9.4–20.9). 18.9); the prevalence ofsubclinical hypothyroidism was of hypothyroidisminobesitywas14.0%(95%CI9.7– population ( or subclinicalhypothyroidismcomparedtothegeneral Notably, onestudynotedatenfoldincreaseofeitherovert subclinical hypothyroidisminobesityhasbeenshown. obesity beforebariatricsurgery. Ahigherprevalenceof TSH screening is recommended in patients with severe 42 27 Clinical PracticeGuideline ). Finally, untreated hypothyroidismcouldblightthe ). However, if‘true’ hypothyroidismispresent,it ). Inline,treatmentofoverthypothyroidism No studydirectlyassessedthebenefitsandharms Thyroid functionisfrequentlyassessedinpatients 32 26 , 29 33 ). In our meta-analysis ( , ) andsomestudiessuggestedthatsmall 30 21 , , 31 28 36 ), indicatingthatsevereobesity ), itisusuallyoflimitedextent ). Thissuggeststhatinobesity 35 ) or bariatric surgery ( ) orbariatricsurgery R Pasqualiandothers 34 ) orimpairweight 16 37 ), the prevalence ). Furthermore, 38 , 41 39 20 ). Thus, ) orby , 27 36 21 40 43 ). ). ). ). ). ) , ( representing lessthan1%ofcaseshypothyroidism and adisproportionatelylowconcentrationoffT4,israre hypothyroidism, withlow-to-normalTSHconcentrations hypothyroidism.Central is enoughtoruleoutprimary majority ofclinicalsituations,inwhichnormalTSH best screeningtestforthyroiddysfunctionthevast According toAmericanguidelines( Reasoning: be measured(++00). elevated, freeT4andantibodies(anti-TPO)should hypothyroidism isbasedonTSH;ifTSH R.2.2. We recommendthattestingfor assess thyroidfunctioninobesity. and treatmentis inexpensive and safe, we recommend to comorbidities inobesity, andbecauseassessmentissimple prevalent andcouldpotentiateweightgainworsen not usefultodetecthypothyroidism ( Measurement of total or free triiodothyronine (T3) is Reasoning: TSH. measurement ofFT3inpatientswithelevated R.2.3. We donotrecommendthe routine considered. ( weak torecommendtestingforthyroglobulinantibodies in the context of obesity, the evidence is currently too the valueofthyroglobulinantibodies( hypothyroidism ( TPO antibodies is recommended in case of subclinical increased risk to progress ( with TPOantibodieslevels antibodies canpredictprogressiontoovertdisease, In patientswithincreasedTSH,thyroidperoxidase(TPO) determine patientsatriskofdevelopinghypothyroidism. helpful todiagnoseautoimmunehypothyroidismand conflicting results( population ( antibodies are detected in about11%of the general autoimmune thyroiditis.Raisedconcentrationsofthyroid total T4( these situations,freeT4shouldbemeasuredinsteadof symptoms ofhypothyroidismwithnormalTSH( disease, thyroidhormoneresistancesyndrome,or suspected, notablyifthereisasuggestionofpituitary hypothyroidismare or ifdisordersotherthanprimary work-up inobesity ESE GuidelinesonEndocrine 46 50 ). Thus, fT4 hastobemeasured only ifTSHiselevated ); inindividualcases,thyroglobulintestingcanbe The mostcommoncauseofhypothyroidismischronic In conclusion,becausehypothyroidismisrather 45 ). 47 ), whilestudiesinobesityhaveprovided 45 48 ). Althoughthereisdiscussionabout , 49 Downloaded fromBioscientifica.com at09/30/202103:48:48PM ). Thyroidantibodyprofilesare 27 > , 500 IU/mLindicatingan https://eje.bioscientifica.com 49 ). Thus, assessment of 182 45 :1 20 ), TSHisthe 25 ) aslevelsare ), especially 46 G9 ). In via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com specific referencevaluesfor theobesepopulationwould no compellingevidencehas beenprovidedthatusing ( threefold inthemorbidobesity category weight ranges,theprevalence ofhighTSHlevelsincreased category. Thisstudy showed that,byusingthenormal- and0.7–7.5mIU/Linthe morbid obesity category were estimatedas0.6–5.5mIU/Linthenormal-weight Notably, inalargecross-sectionalstudy, TSHranges modifications includeincreasesinleptinandinsulin( obesity. Othermechanismsproposedto explainthese substitutive in obesity, togetherwiththeneedforhigher doses of ( axis activation of the pituitary–thyroid compensatory thyroid hormonedisposalinobesity, causinginturna by an increased plasmatic volume or increased rate of decrease inthyroidhormonesconcentrations,explained described ( BMI andFT3withadecreaseFT4/FT3ratiohavebeen between BMIandFT4apositiverelation with FT3andFT4isinconsistent,butanegativerelation and arecorrelatedwithBMI( in normal-weight,age-andgender-matchedindividuals of thyroidparameters:TSHlevelsareusuallyhigherthan population ( upper limitistypicallyaround4mIU/Linthegeneral specific. This generation TSH assays being laboratory reference ranges( The definitionofhypothyroidismisbasedonstatistical Reasoning: obese (+000). values are applied as for non- hormonal normal R.2.4. We suggestthatforobesepatientsthesame is notstraightforward. ( people, thisbeingmainlyrelatedtothenutritionalstatus has beendescribedtobehigherinobesitythanlean non-thyroidal illnessinobesity( publication suggested that inflammation may increase of non-thyroidal illness inthe obese population but one syndrome’ ( thyroidal illness’,‘euthyroidsicksyndrome’or‘low-T3 conversion of T4 to T3, a mechanism known as ‘non- status andsystemicinflammation)canreducethe chronic extra-thyroidalconditions(involvingnutritional FT3 levelisdifficulttointerpretbecausemanyacuteor functioning thyroidtissuebyelevatedTSH.Moreover, often normalduetohyperstimulationoftheremaining 53 54 Clinical PracticeGuideline ). ThisinterpretationisinlinewithlowerFT4levels ). This shows that the interpretation of FT3 in obesity Some authorsargueforspecificnormsinobesity. 48 51 45 l -thyroxine inhypothyroidpatientswith , ). There are very fewdataontheincidence ). Therearevery ). Obesity is associated with modifications 53 20 ). TheTSHelevationcouldreflect , 45 ), thereferencerangeforthird- 48 R Pasqualiandothers ). TherelationofBMI 52 ). Incontrast,FT3 53 ). However, 27 ). but onlyamodestweightlossisachieved( subsequently adjustedbyperiodicassessmentofserum thyroid hormonelevelsandclinicalsituation( l 0.45–4.12 mIU/Lshouldbeconsidered( specific normalvaluesarenotavailable,aTSHtargetof L-triodothyronine combination( benefits havebeendemonstratedofL-thyroxineand ( with TSH case ofoverthypothyroidism,orinmildhypothyroidism with levothyroxine substitution should be considered in Although theissueisstillcontroversial( Reasoning: ofantibodies(++00). obesity irrespective (elevated TSHanddecreasedFT4)istreatedin R.2.5. We hypothyroidism recommendthatovert need treatment. help toidentifypatientswiththyroiddysfunctionwho as apossiblecauseforfailure of hypocaloric diets. Several in FT3levelsduringcaloricdeprivation hasbeenadvocated hypothyroidism andobesity. Furthermore,thereduction in popularfallacyisoftentranslated intoalinkbetween thyroid hormonesandresting energyexpenditure,which for thismisusestemsfromthewell-knownlinkbetween their use in euthyroid obese subjects ( prescribed, despitespecificrecommendationsagainst from the1890s)andsometimesarestillinappropriately lowering effectofsheep-derivedthyroidextractsdate obesity drugs(thefirstclinicalreportsontheweight- as anti- been extensively employed in the past century Thyroid hormone preparations and their derivatives have Reasoning: thyroid function(++00). totreatobesityincaseofnormal hormones R.2.6. We recommendagainsttheuseofthyroid ( achieved bybariatricsurgery l should notbeadjustedwiththeaimatreducingBMI.The of TSHisthesameasingeneralpopulationand determined by excretion of excessbodywater. The target by a mild increase in restingenergy expenditure ( particularly the elderly and/or with cardiovascular disease. in patientswithlong-lasting,overthypothyroidism, the startingdoseandinescalationshouldbeused for treatmentmonitoring.Cautioninthechoiceof TSH. FT3 and FT4 measurement are not recommended work-up inobesity ESE GuidelinesonEndocrine 45 -thyroxine doseshouldbeassignedonthebasisof -thyroxine doseisusuallytobereducedafterweightloss ). L-thyroxine is the hormone of choice; no additional In obesity, treatmentofhypothyroidismisfollowed > 10 mIU/L, in line with current guidelines Downloaded fromBioscientifica.com at09/30/202103:48:48PM 57 ). 56 182 ). Iflaboratory- 45 :1 ). The rationale 45 55 ). Theinitial ), treatment 29 ), mainly 45 G10 ) and 34 via freeaccess ) European Journal of Endocrinology practitioner tointroducethyroid hormonetreatment. suggestive ofhypothyroidism thatmaypromptthe levels arelessthan0.1mIU/L ( and approximatelyonethird toonehalfoftheseTSH on side effects.Indeed,between10and33%ofindividuals patients treatedwith reported, andlowTSH values arefrequentlyfoundin Harms oftreatmentwerepoorlystudiedandsparsely or qualityoflife ( symptoms such as overweight subclinical hypothyroidism does not improve clinical ( compared withplaceboinsubclinicalhypothyroidism difference in BMI with levothyroxine treatment Randomized controlledtrialsreportednorelevant of have studied the potential benefits and the safety may belowerinobesity( overt hypothyroidismoccursin2–5%( annual progressionofsubclinicalhypothyroidismto estimatedthathypothyroidism. TheWhickhamsurvey own isnotenoughtodiagnoseaconditionofprimary normal FT4isacommonfindinginobesity, andonits A slightlyincreasedTSH( Reasoning: weight (++00). treated inobesitywiththeaimatreducingbody FT4)shouldnotbe (elevated TSHandnormal R.2.7. We recommendthat yet developed( peptides that deliver FT3 specifically in the liver are not rate didnothaveaconclusiveoutcomeandthecombined improve metabolic parameters without affecting heart The developmentofTR which wasalsousedasanargumentforuseinobesity. thyroid hormonealsoimproveshepaticlipidmetabolism, ischemic events( facilitate theonsetofcardiacarrhythmia,heartfailureor obesity alreadyatriskforcardiovasculardiseasemay Furthermore, excessive thyroid hormone in patients with adverse effectsonbonemetabolismandaffectivestatus. indicating lossoffat-freetissuebesidetheoccurrence nitrogenexcretionhasbeenobserved, increased urinary demonstrated onlyminoreffectsintermsofefficacy, while thyrotoxicosis ( loss, without producing adverse effects due to iatrogenic of thyroidhormoneortheiranaloguestofavourweight studies havebeenperformedtoinvestigatetheability 42 Clinical PracticeGuideline ). A recent meta-analysis showed that treatment of l l Patients withobesityoften complainofsymptoms -thyroxine therapyhaveTSHvaluesbelownormal -thyroxine treatmentintheobesepopulation. 62 58 61 ). , ). Apartfromdecreasingbodyweight, 59 , l 60 -thyroxine potentiallycausing β -selective agonistsupposedto < ). Overall,thesestudieshave 10 mIU/L)inthepresenceof 64

hyperthyrotropinaemia ). Very fewclinicaltrials 66 R Pasqualiandothers ). 63 ) andtherate 65 ). ).

of primary hypothyroidism(e.g.previousradioiodineof primary autoimmunity (see5.2.2),orcoexistenceofothercauses should betakenintoaccount.Thepresenceofthyroid treatment of mild hypothyroidism other considerations benefit islesscertain.Forthedecisiononstarting and whichpatientswithTSHlevelsof4.5–10mIU/L levels above10mIU/Lshouldbetreated( is ageneralagreementthathypothyroidismwithTSH risk ofdevelopinghypothyroidism( A morepronouncedelevationofTSHisrelatedtohigher Reasoning: antibodies, andageshouldbetakenintoaccount. to treat R.2.8. We suggestthatforthedecisiontotreatornot patient seekingappropriatemanagementoftheirobesity. naemia, sinceweightlossisunlikelyandmaydeterthe initiated onlybasedonthefindingofhyperthyrotropi As argued,thyroidhormonetreatmentshouldnotbe first, secondandthirdtrimester, respectively). However, ranges (around2.5mIU/L,3 mIU/Land3.5atthe target rangeforTSHshould be basedontrimester-specific and theirTSHis a pregnancy, ifthey havepositivelevelsofserumTPOAb women ofchildbearingagewhoarepregnantorplanning mIU/L ( inpregnantwomen withTSH and pretermdelivery T-thyroxine therapydecreasestheriskfor pregnancyloss neurocognitive deficitsinoffspring.Thereisevidencethat outcomes, and possibly with an increased risk of an increasedriskofadversepregnancyandneonatal hypothyroidism has been associated with infertility, trial wasperformedinoldobesepersons. with subclinicalhypothyroidism( apparent benefitsonclinicalsymptomsinolderpersons the ‘Trust ThyroidTrial’, levothyroxineprovided no associated withhigherTSHlevels( studies havedemonstratedthatextremelongevityis youngest populationonlyandonthecontrary, cohort inthe heartdiseaseisgenerallyobserved and coronary mIU/L ( for older patients in good health status with TSH ( should directthedecisiontowardafollow-upstrategy in thepresenceofconcurrent(cardiovascular)diseases, treatment. Bycontrast,olderage( or inawomanfertileageshouldprompt destructive thyroiditis),particularlyinayoungsubject oftreatment forhyperthyroidismorahistory work-up inobesity ESE GuidelinesonEndocrine 45 ). Among womenofreproductiveage,subclinical l -thyroxine replacementtherapyisrecommended 70

68 hyperthyrotropinaemia ). TheATA recommendations proposetotreat ). Thelinkbetweenmildhypothyroidism > 2.5 mIU/L( Downloaded fromBioscientifica.com at09/30/202103:48:48PM 45 https://eje.bioscientifica.com ). Duringpregnancy, the > , TSH level, thyroid , TSHlevel,thyroid 70 years)particularly 69 182 68 67 ), butnospecific ). Inaddition,in ). Althoughthere :1 45 l -thyroxine ), whether G11 > > 4.0 10 10 via freeaccess -

European Journal of Endocrinology https://eje.bioscientifica.com solism R.3.1. We recommend that testing for 5.3. Testingforhypercortisolism ultrasound assessmentinobesity. sufficient dataintheliteraturetorecommendsystematic abnormalities and thyroid cancers in obesity, there is no conclusion, despiteagreaterincidenceofmorphological of thyroidcancerinpatientswithobesityarelacking.In systematic ultrasoundassessmentimprovetheprognosis data showingthatearlydetectionofthyroidcancerby aggressiveness hasstilltobedefined( cancer ( thyroidthyroid cancers,butnegativelywithmedullary positively related to papillary, follicular and anaplastic abdominal adiposityincreasedtherisk.Obesitywas greater riskofthyroidcancerandbothgeneral Each 5-unit increase in BMI was associated with 30% greater riskofthyroidcancerinpatientswithobesity. A recentmeta-analysisof21articleshasshowna55% with obesityorinsulinresistancehasbeenreported. arguesforthishypothesis( surgery improvement of thyroid hypoechogenicity after bariatric mediators producedbytheadiposetissue( increased TSHstimulationorincreaseininflammatory as wellthyroidnodules( include increases in thyroid volume and hypoechogenicity the thyroidhavealsobeenassociatedwithobesity. These In additiontobiochemicalchanges,structuralchangesof invasiveandexpensiveacts( can leadtounnecessary years, systematicultrasoundexaminationofthethyroid frequency of thyroidnodules, up to50%bytheage of 60 hypothyroidism ( not requiredneitherinovert( such asabnormalthyroidpalpation,anultrasoundis Generally, intheabsenceofadditionalclinicalindications subclinical tooverthypothyroidisminwomen( predictive valueasTPOantibodiesforprogressionfrom Features ofthyroiditisonultrasoundhavethesame hypoechogenic patternonthyroidultrasonography. Autoimmune thyroiditisisoftencharacterizedbya Reasoning: thyroid function. of ultrasound ofthethyroidglandirrespective R.2.9. We suggestagainsttheuseofroutine ensure thatthesametargetsaretobeachieved. no study was specifically conducted in obese women to Clinical PracticeGuideline An increased incidence of thyroid cancers in patients An increasedincidence of thyroidcancersinpatients isnotroutinelyapplied inobesity(++00). 75 ). The impact of obesity on thyroid cancer 21 ). Inaddition,giventhehigh 27 , 73 R Pasqualiandothers 20 ), whichmaybedueto 74 ) norinsubclinical ). 76 ). Importantly,

hypercorti 27 ). The 72 71 ). ). - also arecommoninobesity ( diabetes, hypertensionordepression appearinCSbut CS ( is associatedwitha95%probability ofadiagnosis as osteoporosis,spontaneous ecchymosesandthinskin The combinationofsomecatabolicmanifestationssuch purple striaeincreasethelikelihoodofCS( spontaneous ecchymoses,proximalmyopathyorwide context, catabolicsignssuchasskinatrophy, osteoporosis, clinical featuressuggestiveofhypercortisolism. Inthis should becarriedoutinsubjectswhoexhibitspecific Screening forCSdiagnosisinpatientswithobesity, Reasoning: (++00). performed estimated 0.9%(95%CI:0.3–1.6)( In ourreviewthepooledprevalenceofCSinobesitywas hypercortisolism R.3.2. Inpatientswithclinicalsuspicionof hypercortisolism besides obesity. in patientswhoexhibitotherspecificfeaturesof ( with obesity, accordingwithpreviousrecommendations lend supportforaroutinescreeningofCSinpatients among patientswithobesity, thereporteddatadonot its multifactorialoriginandthelowprevalenceofCS treatment programhavenotbeenwellestablishedyet. general population( to bemorecommoninpatientswithobesitythanthe ( 2 diabeteswithpoormetaboliccontrolhasbeenshown a higherCSprevalenceof~2–3%inpatientswithtype patients withsevereobesityhavebeenincluded( uncommon,rangingfrom0to0.7%,though been very ( CS of9.3%amongaseries150patientswithobesity CS. Despiteapreviousstudyhasshownprevalenceof central obesity with associated comorbidities from mild a diagnosticperspective,difficultiesarisetodifferentiate life andexpectancyunlessproperlytreated( effects anddevastatingcomplicationsaffectingqualityof endogenous hypercortisolism derivesfromitscatabolic (CS) should be ruled out. The interest of unmasking and/or type2diabetes,adiagnosisofCushing’s syndrome associated cardiovascularriskfactorssuchashypertension obesity ispresent,accompaniedbysomespecificsignsand of so-calledpseudo-Cushingstates( Obesity iscommonlylistedamongthedifferent entities Reasoning: work-up inobesity ESE GuidelinesonEndocrine 87 83 80 ). Therefore,screeningforCSshouldbeperformed ), inmostseriesthediagnosisofCSobesityhas , Assuming theepidemicproportionsofobesity, 88 84 ). Otherfeaturessuchascentral obesity, type2 , 85 ). Moreover, subclinicalCShasbeenreported biochemicaltestingshouldbe 86 ), thoughitsdiagnosticcriteriaand Downloaded fromBioscientifica.com at09/30/202103:48:48PM Table 4 16 77 ). These observations ). Theseobservations ). Ontheotherhand, 182 , 78 :1 ). Whencentral 77 79 , 78 81 ). From G12 , , 88 82 via freeaccess ). ).

European Journal of Endocrinology severe obesity is generally low ( especially sensibleforCSdetection ( severe postoperative complications, making this scenario increased cardiovascular risk may be responsible for Factors suchashypercoagulability, catabolicstateand ifundiagnosed ( severe adverseeffectsaftersurgery have endogenous hypercortisolism that couldlead to may eventually some candidates to bariatric surgery raredisease, frequent inCS.DespiteCSbeingavery metabolic syndrome and type 2 diabetes, which are also obesity-related comorbiditiessuchashypertension, commonly presentwith Candidates tobariatricsurgery Reasoning: should beconsidered. (testingfor) bariatric surgery R.3.3. We recommendthatinpatientsgoingfor manifestations ( and hypokalaemia,thougharelessspecificthancatabolic probability ofCSare nephrolithiasis, frequent infections hypercortisolism ( possibility ofCSandjustifythescreeningfordetection young patients with abdominal obesity may also raise the and/or type2diabetesdespiteconventionaltherapyin diagnosis. Thepresenceofuncontrolledhypertension determine whichpatientsshouldbescreenedforCS underline theimportanceofclinicalassessmentto Weight gainwithgrowth Incidental adrenalmass Depression, insomnia,irritability, Hypertension and/orpasthistory Type 2diabetes Truncal fatdistribution(face, Erectile dysfunction,infertility Hyperandrogenism and/or Peripheral oedema Facial plethoraand Dorsocervical fatpad Osteoporosis Proximal myopathy Thin skin Easy bruising Wide purplestriae Table 4 Clinical PracticeGuideline retardation (children) cognitive impairment,psychosis of cardiovasculardisease neck, abdomen) menstrual abnormalities supraclavicular fullness Although theprevalence of CSinpatientswith Clinical featuresofhypercortisolisminobesity. Table 4 78 ). Otherfeaturesthatmayincreasethe ). 81 R Pasqualiandothers No Often presentinanypatient Often presentinobesitywithout Often presentinobesitywithout Often presentinobesitywithout Often presentinobesitywithout Often presentinobesitywithout Often presentinobesityassociated No No No No No No No No Obesity , associated hypercortisolism associated hypercortisolism associated hypercortisolism associated hypercortisolism associated hypercortisolism with polycysticovariansyndrome 82 90

hypercortisolism , ). 91 ), a study of 16 89 ).

may alsobeinvolvedand haircortisolmeasurement, tissue ( of 11-beta hydroxysteroid dehydrogenase in adipose glucocorticoid feedbacksensitivity andincreasedactivity response tophysicalandpsychological stimuli,reduced with abdominalobesity, includingexcessive cortisol dysregulation intheactivityofHPA axisinsomepatients Some experimentalandclinicaldatapointsto a Reasoning: non-obese (+000). valuesareapplied asfor the samenormal R.3.4. We suggestthatforpatientswith obesity following surgery. surgical complicationsoradverseclinicaloutcomes suspicious clinicalsignsisneededtopreventpotential specialattentiontoruleoutCSinpatientswith surgery patients iscontroversial( preoperative screening for CS in all severe obesity features arepresent( rule outadiagnosisofCS,especiallyifsuspiciousclinical to paid topatientswhoarecandidatesbariatricsurgery ( surgery control aswellintenseweightregainafterbariatric expected improvementinhypertensionanddiabetes suggesting thatCSmayberesponsibleforlessthan diagnosis, persistenceorrecurrencewasunrecognised, hasshownthatCS patients operatedofbariatricsurgery work-up inobesity ESE GuidelinesonEndocrine Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Hypercortisolism Yes Not always 94 92 ). However, otherfactorssuchaschronic stress ). Therefore,particularattentionshouldbe Hypercortisolism effectsonthebrain Increased circulatingvolumeand Hyperglycaemic effect Fat redistribution Gonadotrophin inhibition Gonadotrophin inhibitionand Increased fluidreabsorption Fat redistribution Fat redistribution Catabolic effect Catabolic effect Catabolic effect Catabolic effect Catabolic effect Mechanisms GH inhibition,effectsongrowthplates Potential originofCushingSyndrome Table 4 catecholamine sensitivity increased androgensecretion and fatredistribution Downloaded fromBioscientifica.com at09/30/202103:48:48PM 93 ), incandidatestobariatric ). Althoughbiochemical https://eje.bioscientifica.com 182 :1 G13 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com substantially improve the sensitivity of the test, even in substantially improvethesensitivity ofthetest,evenin dexamethasone dosetobody weightdoesnotseemto ( 2 mgvs1suppression test inpatientswithobesity recent study did not find significant advantage of using or equivalentmethod-dependentcut-offvalue( of postdexamethasonelevels sensitive toruleouthypercortisolism withthethreshold (92% inarecentstudy)( still relativelyhigheveninpatientswithsevereobesity severely obese patients is increased, but the specificity is previous studies( simple, wellstandardizedandusedinthemajority of A 1mgovernightdexamethasonesuppressiontest is Reasoning: suppression testasfirstscreeningtool. dexamethasone we recommenda1mgovernight R.3.6. If on thediagnosticpossibilityofendogenousCS. ofHPAon theimpairmentorrecovery functionratherthan corticosteroid therapy, themaininterestisusuallyfocussed potential endogenousCS( glucocorticoid treatmentbeforestartingevaluationfor recommend investigating whether patients are on and suppressed endogenous HPA axis activity. Guidelines axis assessment, by inducing cushingoid clinical features Exogenous corticosteroidtherapyinterfereswithHPA Reasoning: hypercortisolism R.3.5. We recommendnottotestfor HPA functionparametersinpatientswithobesity. cortisolorotherfunctional evaluate nocturnalsalivary there arenoreasonstoconsiderdifferentcut-offs from thoseconsideredinnormalbodyweight.Likewise, to usedifferentmethodologyorinterpretationcriteria diverse dexamethasonedoses,thereisnosolidevidence tested differentcut-offpointsforcortisolsuppressionand potential falseresults( that maydisturbdexamethasonemetabolismleadingto attention shouldbepaidtothesimultaneous use ofdrugs acceptable performance toruleoutCS( vast majorityofauthorsconsiderthatthistestshowsan may displaylesscortisolsuppressioninsomecases,the obesity. Despitethatsubjectswithabdominalobesity suppression asthescreeningmethodtodetectCSin samples( cortisol exposurethanplasmaorsalivary when available, may offer a better reflection of chronic 97 Clinical PracticeGuideline ). In line, a study has shown that adjustment of the ). Inline,astudyhasshown thatadjustmentofthe Most studiesrelyon1mglate-nightdexamethasone

hypercortisolism 79 inpatientsusingcorticosteroids. ). The risk of false-positive tests in ). Theriskoffalse-positivetestsin 78 78 ). Althoughsomestudieshave , 81 87 ). This test is sufficiently ). Thistestissufficiently testingisconsidered, ≤ , 95 50 nmol/L( R Pasqualiandothers ). In cases of exogenous ). Incasesofexogenous 78 , 87 , ≤ 95 1.8 µg/dL) 1.8 µg/dL) ). Special 96 95 ). A ). A ).

and obstructivesleep apnoea ( benign orpotentiallymalignant typeofadrenalmass todistinguishbetween choice) arenecessary primary appropriate imagingmethods (non-contrastCTas In casesofACTH-independent hypercortisolism the hypercortisolism andguidethetherapeuticapproach. examinations willhelptoestablishtheexactcauses of of hypercortisolism. These further measurements and ( ACTH measurements,whicharenotalteredbyobesity Reasoning: circumference andUFC ( studies haveshownarelationshipbetweenBMIandwaist elevated inpatientswithobesity( cortisolvaluesareinconsistently Mind thaturinary-free out thediagnosisofendogenoushypercortisolism. cortisol are measured to establish or rule night salivary cortisol(UFC)or/andlate- suppression test,urinary-free We suggestthataftera1mgovernightdexamethasone comorbidities suchasdepression( suppression testcanbeinfluencedbythepresenceofother The positivityof1mgovernightdexamethasone Reasoning: cortisol. orlate-nightsalivary urine cortisol second biochemicaltest;thiscanbeeither24-h suppression testispositive,werecommenda dexamethasone R.3.7. Ifthe1mgovernight would beexpectedaccordingtoincreasingBMI( the progressivelygreatersuppressibilityofHPA axisthat women, abdominalfatdistributionmaypartiallycounteract dexamethasone metabolism.Ontheotherhand,atleastin which maybedependentondifferencesinbothcortisoland HPAthe of axis,anddexamethasonelevelshasbeenfound, post-dexamethasone cortisolconcentrations,suppression doses areadministered. In addition, an effect of sex on individuals withobesity, particularlywhennear-maximal the cause/sourceof tofind imagingshouldbeperformed and further hypercortisolism R.3.8. Inallpatientswithconfirmed recommended bytheEndocrineSocietyguidelines( the combinationofdifferenttestsadrenalfunctionas Confirmation ofendogenoushypercortisolism requires of adrenalincidentalomaforfurtherinformation( nmol/L (1.9–5.0 µg/dL) (see ESE guideline management cortisol postdexamethasonelevels(between51and138 tests are needed in particular in patients with borderline patients withobesity. Therefore,additionalbiochemical work-up inobesity ESE GuidelinesonEndocrine 103 ), shouldbeperformedtoinvestigatethecause , an ACTH should be measured Downloaded fromBioscientifica.com at09/30/202103:48:48PM 102

hypercortisolism ). 101 ) that are common in 99 182 ), alcoholism( 94 :1 ), thoughsome 98 . ). G14 96 100 78 via freeaccess )). ). )

European Journal of Endocrinology obesity, hypogonadism, type 2 diabetes and metabolic 115 its pathophysiology( inflammation, oxidativestress andtype2diabetesin such asobesity, visceralfatexcess,insulinresistance, reflecting theparticipationofseveralmetabolicfactors hypogonadism mayalsoapplytothiscondition hypogonadism and dysmetabolic hypogonadotrophic hypogonadism ( obesity is listed as a cause of functional secondary value lowerthan12.1nM/L( havehypogonadismonthebasis ofatestosteronesurgery of patientswithclassIIIobesitywaitingforbariatric higher prevalenceofhypogonadism( such asmetabolicsyndromeortype2diabetesexhibit a ( impairs spermconcentration,motilityandmorphology of 32.7%(95%CI:23.1–43.0)( hypogonadism based onfree testosterone measurements ( to 45%ofpatientswithmoderate-to-severeobesity testosterone concentrations)hasbeenreportedinup hypogonadism(lowplasmaMale obesity-secondary Reasoning: (++00). key clinicalsymptoms/signsofhypogonadism obese patients;wedorecommendinvestigating hypogonadism isnotroutinelyappliedinmale R.4.1. We recommendthatbiochemicaltestingfor 5.4. Testingforhypogonadisminmales factor ratherthanasolecauseofobesity. hypercortisolism isinmostofthepatientsacontributing ( lead to normalization of BMI in the majority of patients doesnot gain, itstreatment(surgicalorconservative) endogenous hypercortisolism contributestoweight hypercortisolism hasthehighestpriority. Although In case of confirmed hypercortisolism, treatment of Reasoning: solism R.3.9. Treatment ofprovenendogenous vsectopicorigin( pituitary should beperformedtodifferentiateCushing’s diseaseof MR and in some cases inferior petrosal sinus sampling in patientswithconfirmedhypercortisolism pituitary ( 105 104 108 107 Clinical PracticeGuideline ). Therearemultilateral relationshipsbetween , ). When normal or high ACTH values are detected ). Patientswithobesityandassociatedcomorbidities ); inourreview, wefoundapooledprevalenceof 106 is not normalizing BMIinmostcases. isnotnormalizing ). Thesefindingssuggestthatendogenous 111 ). Othertermssuchaslate-onset 107 78 , 108 ). 110 R Pasqualiandothers , 16 ). Accordingly, severe 111 ). Moreover, obesity 109 , 112 ). Infact,75%

hypercorti , 113 , 114 - , obesity-secondary hypogonadismdiagnosis. *Indicate somenon-specificsymptoms thatarerelevantformale Other symptoms/signsofanterior pituitarydysfunction Gynaecomastia andreducedtesticular volume Decreased androgenicbodyhair Sleep disturbances* Cognitive impairment Changes inmood,fatigue* Infertility* Osteoporosis* Hot flushes* Gynoid fatdistribution* Muscle weakness* Reduction inleanbodymass Reduced sexualdesire* Weakness ofmorningerections* Erectile dysfunction* Table 5 investigating routinelykeyclinicalsymptoms/signs hypogonadism ( clinical featurescreatetheneedforinvestigating with obesity, andtestingshouldbeconsideredwhen male hypogonadismisnotrecommendedinpatients population ( reduced testosteronelevels( a roleingonadotrophininhibitionand,consequently, functional hypercortisolism inobesitymayalsoplay axisinducingof thehypothalamic–pituitary–adrenal well asoestradiolbloodlevels( inhibit LHsecretionandreducetestosterone( testosterone intooestradiol,mayalsocontributeto activity inadiposetissue,responsibleforconverting and type2diabetes( values areassociatedwithobesity, metabolicsyndrome and, ontheotherhand,lowtestosteroneplasma commonly accompanied by low testosterone values syndrome. Thus,obesity-associatedcomorbiditiesare testosterone plasma concentrations represent the initial Once clinicalsuspicionhasbeenestablished,total Reasoning: FSH andLH. total andfreetestosterone(orcalculated),SHBG, features ofhypogonadismwesuggestmeasuring R.4.2. Inmalepatientswithobesityclinical picture issuspiciousofhypogonadism( the presenceofhypogonadismespeciallyifclinical insulin resistanceand/ortype2diabetesaretestedfor that obesepatientswithmetabolicsyndromeand/or proper testicularsizeassessment.Inline,wesuggest of hypogonadisminallmenwithobesity, including work-up inobesity ESE GuidelinesonEndocrine Clinical symptoms/signsofmalehypogonadism. 111 ), a routine hormonal screening for Table 5 116 Downloaded fromBioscientifica.com at09/30/202103:48:48PM ). Therefore,werecommend ). Theincreaseinaromatase 94 https://eje.bioscientifica.com ). Asforthegeneral 109 182 ). Adysregulation :1 113 , 118 117 ). G15 ), as via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com to beconsidered. is negativeleptinassessment andgeneticevaluationhave needed inselectedpatients ( region by MRI may also be the hypothalamic–pituitary confirmed biochemically, morphologicalexplorationof ( associated withhypogonadotrophichypogonadism syndromic orhypothalamicobesityarefrequently hyperprolactinaemia, leptin signaling abnormalities, attributing thehormonaldisordertoobesity;especially hypogonadismshouldbeexcluded before secondary hypogonadism hasbeendiagnosed,othercauses of gonadotrophins areelevated.Oncehypogonadotrophic ( in somecaseswithpredominanceofFSHoverLH with lowplasmagonadotrophinconcentrations,and ( hypogonadism andsecondary distinguish betweenprimary demonstrated, FSHandLHmeasurementsareusefulto diagnosis ( hypogonadism for aformalmaleobesity-secondary dysfunction andreducedmorningerectionsisrequired hypogonadism suchasdecreasedsexualthoughts,erectile of lowtestosteronelevelswithclinicalfeatures testosterone concentrations.Ingeneral,acombination values ( are commonlyassociatedwithlowSHBGcirculating obesity, sincebodyfatexcessandinsulinresistance ( binding globulin(SHBG)andalbuminconcentrations testosterone byusingtestosterone,sexhormone- available, itmaybepreferabletocalculatebioavailable free testosterone(equilibriumdialysis)isnotwidely diagnosis ofmalehypogonadism( concentrations determinebiochemicalbasisforthe ( is foundtobenearthelowerlimitofnormalrange measure freetestosteronelevelswhentotal testosterone levels ( separate daysinfastingstate,sincefoodintakesuppresses should be confirmed by taking morning samples in two increasing age( pulsatile LHandtestosteronepatterntendtoflattenwith ( h orwithin3afterwaking-upincaseofshiftworkers should betakeninthemorningbetween0700and1100 a circadian rhythmoftestosteronesecretion,thesample tool forinvestigatinghypogonadism( 111 111 119 111 107 111 Clinical PracticeGuideline Once lowtestosteroneconcentrationshavebeen However, sincethegold standard procedure to measure , ). Inthosesituations,SHBGandfreetestosterone ). Ontheotherhand,dailycircadian rhythmand ). When secondary hypogonadismhas been ). Whensecondary hypogonadism, where ), in contrast with primary hypogonadismisassociated ). Maleobesity-secondary 123 111 117 ). Thissuggestionappliesespeciallyto , 116 ). 120 ), complicatingtheinterpretationof ). Lowtestosteroneconcentrations 111 , 119 111 ). It is recommended to ). Ifimagingexploration R Pasqualiandothers 121 , 111 122 ). Sincethereis ).

used. Mostavailabletestosteroneassaysareimmunoassays be consideredwheninterpretingatestosteroneresult. intra-individual variations( by chronicdiseases,medications,genetics,lifestyle,and ( confirm thebiochemicaldiagnosisofhypogonadism hypogonadism, noadjustmentsforBMIareusedto obesity isassociatedwithanincreasedprevalenceof and circannual testosteronerhythms.Although single morning samples, disregarding pulsatile, diurnal ( reduction seemstobelowerthanpreviouslythought recent reportssuggestthatthemagnitudeoftestosterone Male testosteronelevelsdecreasewithage,though Reasoning: reference rangesfortestosterone(+000). R.4.3. In obesity we suggest applying age specific to the presence ofthreesexual symptoms ( 11 nmol/L(3.2ng/mL)todefine hypogonadismassociated Study hassuggestedacut-off valueoftotaltestosterone reference toobesepeople( withoutspecific years measuredbymass-spectrometry aged 21-35yearsand6.4-25.7nmol/Lformen70-89 of Australiaconsidersarange10.4-30.1nmol/Lformen men aged19 Endocrine Societyproposes9.2 assays used(seeforreview( binding ofSHBGandalbuminontheaccuracy of is good,butresultsdependondissociationconstantsfor with measurementsperformedequilibriumdialysis calculation offreetestosteronebyaformula.Correlation most guidelinesrecommenddirectmeasurementsor and technicallychallenging.Forpracticalreasons, method tomeasurefreetestosteronebutisexpensive impact onvariability( handling ofthesampleaswellcalibrationalsohavean LC-MS rangesfrom ( become progressivelyadoptedshowingbetterprecision (LC-MS)has chromatography tandemmassspectrometry and requiresregularcalibration.Nevertheless,liquid obtained bymassspectrometry, whichismoreexpensive immunoassays. However, theiraccuracyislowerthanthat most reference ranges have been established using which arerapid,simpleandinexpensive.Moreover, (RIA, enzymeimmunoassayorfluoroimmunoassay), work-up inobesity ESE GuidelinesonEndocrine 107 124 118 Testosterone resultsalsodependontheassaytechnique Regarding normal reference ranges for testosterone, the Regarding normalreferencerangesfortestosterone,the Equilibrium dialysisrepresentsthegoldstandard ). Moreover, testosterone measurements are affected , , 125 125 , ). Nevertheless,thesestudiesarebasedon 126 − 39 years( ). Variability betweenimmunoassaysand − 14 to+19%,( 126 125 Downloaded fromBioscientifica.com at09/30/202103:48:48PM ). 128 ), whereas the Endocrine Society ), whereastheEndocrineSociety 126 126 ). The European Male Aging ). TheEuropeanMaleAging )). ). Alltheseaspectsshould − 31.8 nmol/L in healthy 31.8 nmol/Linhealthy 127 182 ). Preparationand :1 118 ), which ), which G16 via freeaccess European Journal of Endocrinology levels andsymptoms/signs ofhypogonadismdonot In caseweightlossisnotachieved and/oriftestosterone Reasoning: testosterone (+000). enough reasontostart out.Thesolepresenceofobesity isnot been ruled and othercausesofhypogonadismshouldhave cases; contra-indicationsshouldbeconsidered testosterone canbeconsideredinindividual hypogonadism persists, treatment with be achievedandifclinicalbiochemical R.4.5. We suggestthatifweightloss cannot that spermcharacteristicswillalsoimprove( the improvementingonadalfunction,thisisnowarranty more weightthaneugonadalmen( arereportedtolose obesity submittedtobariatricsurgery weight loss( function besidesachievingsignificantandsustained ofthehypothalamic recovery effective meansofincreasingtestosteronelevelsand patients withfunctionalmalehypogonadism( isnotrecommendedin along withlifestyleinterventions along with the potentialrisks, testosterone therapy common. Given the limited evidence for benefits very isrelativelysmall,asweightregainalso interventions benefits afterweightlossachievedthroughconservative ( loss maybeinsufficienttonormalizetestosteronelevels modification, dietandexercise, achieving 5%weight withlifestyle interventions aware thatconservative in obesity. However, healthcarepractitionersmust be approach aimingtoreversefunctionalmalehypogonadism significant impactonBMI( with androgen deficiency ( reduced fat free mass is a common feature among men further promoteadiposity. Indeed,increasedfatmassand male hypogonadism,whilehypogonadismcan of aviciouscyclewhereobesitycanleadtofunctional There iscompellingevidencehighlightingthepotential Reasoning: hypogonadism. obese patientswithbiochemicalandclinical tance ofweightlosstorestore R.4.4. We recommendemphasizingtheimpor population includingpatientswithobesity. is probably applicable for thegeneralmale European 131 Clinical PracticeGuideline In severely obese patients, bariatric surgery is a very isavery In severelyobesepatients,bariatricsurgery Weight lossshouldbethefirst-linetherapeutic ). Besides,theabilitytosustainmalegonadal 134 , 135 ). In addition, hypogonadal men with ). Inaddition,hypogonadalmenwith 129 130 ), although rarely having a ). − R Pasqualiandothers pituitary gonadal axis gonadalaxis pituitary 136

). However, despite eugonadism 137 132 , 138 , 133 ). in ). - Severe cardiacfailure Severe lowerurinarytractsymptoms duetoprostatic Severe sleepapnoea Active desiretoachievefertility Male breastcancer Prostate cancer Haematocrit Table 6 for 3 months. Transdermal testosterone application is of intolerance,sincetheeffectswillbemaintained injection andduetoitslongdurationofactionincase at theinjectionsite,rarecasesofcoughfollowing to itslargevolumeofinjectionthatcaninducepain testosterone plasma levels.Disadvantages are related as treatmentofhypogonadismbecauseitleadstosteady 12weeks)iswidelyusedundecanoate (1000mgevery ( growthofprostateorbreastcancererythrocytosis, and adverseeffects.PotentialsideeffectsofTRTinclude patients shouldbewellinformedonpotentialbenefits medicalteam,andthe contextofamultidisciplinary to weightloss.Itisadvisabletakethisdecisionin orientedTRT shouldbeaddedtolifestyleintervention potential benefits,sideeffectsandrisks.Inthatcase, can beconsideredonanindividualbasis,considering excluded, testosteronereplacementtherapy(TRT) improve andothercausesofhypogonadismhavebeen hypothalamic is not indicated for men with obesity and normal ineugonadalsubjects.Therefore, TRT is observed improvement, no evidenceof this beneficialeffect is associatedwithweightlossandbodycomposition administration ( also representtestosteronefor contraindications tractsymptoms sleep apnoea,heartfailureandurinary therapy ( is considered as a contraindication for testosterone on growthofmetastaticprostatecancer, prostatecancer effectoftestosterone Nevertheless, giventhestimulatory prostate cancerdevelopmentisnotwellestablished. reported ( association betweenTRTandsleepapnoeahasbeen drug ( to otherpersonsbyphysicalcontactwiththeapplied induce skin irritation and can transfer hormonal effects also associatedwithstablecirculating levels,butcan work-up inobesity ESE GuidelinesonEndocrine 111 enlargement Although TRTgiventomenwithhypogonadism Table 6 , 111 116 Contraindications fortestosteronetherapy. 111 , ). The injectable preparation of testosterone 140 116 depicts contraindications for TRT ( > 54% ). Highhaematocrit,breastcancer, severe ); theexactrelationshipbetweenTRTand − ). pituitary gonadalfunction. pituitary 111 , 141 Downloaded fromBioscientifica.com at09/30/202103:48:48PM ). https://eje.bioscientifica.com 182 :1 139 G17 ). An via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com hypogonadism desirefertility overthenextyear monotherapy whenmales withhypogonadotrophic spermatogenesis and,therefore, iscontraindicatedas of gonadotrophinsecretion andsuppressionof Testosterone administrationisfollowed byinhibition Reasoning: (+000). fertility hypogonadal treatment asafirsttherapeuticmeasure in R.4.8. We donotrecommendtestosterone should beconsideredtopreventpotentialsideeffects. after 6 improvement ofthesymptoms/signshypogonadism BMI ( as improvementsininsulinresistance,lipidprofileand and anincreaseinleanbodymassareexpectedaswell to recover( Erectile dysfunction may require 6 months of treatment mood maybeevidentfromthefirstmonthoftherapy. after 3weeksoftreatment,whereastheimprovementin of treatment. lead toreductionoftestosteronedoseortermination of breast cancer ( worsening ofsleepapnoea,gynaecomastia,andgrowth balding, prostaticgrowth,reducedspermproduction, androgenic manifestationssuchasacneandmalepattern (haematocrit higher than 54%), such as erythrocytosis ( re-evaluated regularlytomonitortheefficacyofTRT All symptoms/signsofhypogonadismshouldbe Reasoning: biochemical restorationfor6 if clinicalfeatures are notimproving despite R.4.7. We suggeststoppingtestosteronetreatment after startingTRTtomonitorpotentialsideeffects. the cardiovascularsituationshouldbeevaluatedregularly of aspecificage.Haematocrit,prostatehealthstatusand to restoretestosteronevaluesthemid-normalrange concentration thatshouldbeachieved,theobjectiveis there arenosufficientdatatoestablishthetestosterone attributed to testosterone deficiency ( The mainaimofTRTistoreversethesymptomsandsigns Reasoning: range (+000). aiming attestosteronelevelsinthenormal R.4.6. We suggesttreatmentwithtestosterone 111 Clinical PracticeGuideline The effectsofTRTonsexualdesireareusuallyevident , 116 142 − 12 monthsoftreatment,stoppingtestosterone ). TRTmaybeassociatedwithdiversesideeffects ). IncasethatTRTisnotassociatedwithan 139 malepatientswithobesityseeking ). FollowingTRT, areductioninfatmass 111 ). Appearance of these signs may R Pasqualiandothers − 12 months(+000). Table 5 ). Although

obesity ( syndrome (PCOS)occursin29%offemalepatientswith Nevertheless, itshouldbenoticedthatpolycysticovary infertility orsymptoms/signsofhyperandrogenism. clinical suspicion,suchasmenstrualabnormalities, patients isnotrecommendedunlessthererelevant Routine testingforgonadaldysfunctioninfemaleobese Reasoning: patients withobesity(++00). dysfunction is not routinely applied in female R.5.1. We recommendthattestingforgonadal 5.5. Testingforgonadaldysfunctioninfemales recover spermatogenesis( should bethefirst-linetherapy, inordertoensureor spermatogenesis. Thereforetreatmentwithgonadotropins care mustbetaken,sincetestosteronetreatmentmayhalt ( show multilateralrelationships thatjustifytheinterest visceral obesity, insulin resistanceandhyperandrogenism action topreventthemetabolic consequences( with PCOS in order to confirm insulin resistance and take concentrations should becarriedoutinobesewomen measurement of fasting glucoseand insulin plasma affect women across the lifespan( dyslipidaemia andcardiovascularriskfactorsthatcan resistance andmetabolicsequelae,suchastype2diabetes, excess, PCOSisfrequentlyassociatedwithinsulin ultrasound ( chronic anovulationandpolycysticovariesasassessedby two out of three criteria including hyperandrogenism, Rotterdam consensus, which requires thepresence of the presenceofPCOSisestablishedaccordingto ( manifestations ofobesity-relatedgonadaldysfunction of recurrent miscarriages can also be clinical history sensitivity ( effects ofinsulinonsteroidogeniccellsthatretain mechanisms remain unclear, these are likely related to the hyperandrogenaemia ( adolescence inwhathasbeendefinedasobesity-related in determining female hyperandrogenaemia, especially in alopecia arepresent. In fact, obesity playsamajorrole symptoms orsignssuchasacne,hirsutism,androgenic should undergofurtherevaluationwhensuggestive relative functionalhyperandrogenism( obesity ( work-up inobesity ESE GuidelinesonEndocrine 111 149 Particularly whenaccompaniedwithvisceralfat , ). Fromaperspectiveofdiagnostic characterization, 143 144 145 ). In those men seeking to conceive, additional ). In those men seeking to conceive, additional 146 150 ) reachingupto36%ofwomenwithsevere ). Obesityinfemalescanbeassociatedwith , ). 148 ). Inaddition,infertilityandamedical 146 Downloaded fromBioscientifica.com at09/30/202103:48:48PM 143 , 148 ). ). Althoughtheprecise 151 182 ). Inthis context, 146 :1 , 147 17 ); women ). Thus, G18 via freeaccess European Journal of Endocrinology We recommendhormonal assessmentstobepreferably be includedtoruleout21-hydroxylase deficiency( to PCOS,plasma17-hydroxyprogesterone shouldalso adrenal hyperplasiamaypresent clinicalfeaturessimilar less common,sincepatients withlate-onsetcongenital in symptomaticadolescentwomenwithobesity. Although 153 and biochemicalcharacteristicsofthissyndrome( PCOS, since obesity is commonly associated with clinical measurements areprimarilyaimedtoestablishorexclude oestradiol, 17-hydroxyprogesteroneandprolactin.These LH, FSH,totaltestosterone,SHBG,Δ4androstenedione, function tobeassessedbymeasuringcirculating levelsof For evaluationofmenstrualirregularity, wesuggest gonadal Reasoning: phase. should takeplaceduringtheearlyfollicular predictable, wesuggestthattheassessment butsomewhat cycleisirregular menstrual 17-hydroxyprogesterone andprolactin.Ifthe SHBG, Δ4androstenedione, measuring LH,FSH,totaltestosterone, we suggesttoassessgonadalfunctionby irregularity R.5.3. Forevaluationofmenstrual specific clinicalfeatures. hypercortisolism, which can be responsible for additional of hyperprolactinaemia,thyroiddysfunctionand endocrine evaluationshouldalsoincludeassessment In the presence of menstrual disorders or infertility, the insulin resistance,adrenaldisordersandiatrogenicfactors. excluded, suchascongenitaladrenalhyperplasia,severe excess otherclinicalentitiesapartfromPCOSshouldbe causes offemalegonadaldysfunction.Incaseandrogen PCOS andinsulinresistance,aswellothersecondary confirm orexcludehyperandrogenaemia,anovulation, investigated withadequateendocrinetestsaimingto presence ofirregularperiods,infertilityshouldbefurther insulin resistanceandlow-gradeinflammation( factors maymediatethesephenomena,whichinclude formal diagnosisofPCOS( increased riskofmiscarriages,evenintheabsencea Obesity isassociatedwithfertilityimpairmentand Reasoning: andchronicanovulation/infertility.irregularities female patientswithobesitymenstrual R.5.2. We suggest to assess gonadal function in dysfunction inpatientswithsuggestiveclinicalfeatures. to beassessedinthecontextofobesity-inducedgonadal Clinical PracticeGuideline ). Thisbiochemicalprofileshouldalsobeinvestigated 149 R Pasqualiandothers ). Diversepathological

oestradiol 149 ). The 154 152 ). , , dysfunction isduetohypothalamicdysfunction,patients hypogonadism. Although obesity-associated gonadal ovarianfailureandcentral distinguish betweenprimary These hormone measurements should help to Reasoning: FSH, gonadal functiontobeassessedbymeasuringLH, R.5.4. Forevaluationofanovulationwesuggest the establishedRotterdamCriteria( (PCOm) inordertoenablePCOSdiagnosisbyapplying considered to define polycystic ovarian morphology ovarian ultrasoundscan(US)evaluationshouldbe hormonal assessmentscanbeperformedatanytime. amenorrhoea andunpredictablemenstrualcycles,these reference values have been established. In the presence of cycle (1stto5thdayofthemenstrualcycle),whenmost performed intheearlyfollicularphaseofmenstrual clinical features. We suggest to measure total excess whenPCOSisconsidered basedonthe R.5.5. We recommend toassessandrogen stress, eatingdisordersorsevere chronicsystemicdiseases. leading tobiochemicalcentralhypogonadismarechronic out tumours;otherfunctionaldisturbancespotentially hypothalamic hormonal axisshouldbeinvestigatedandimagingofthe of hypothalamic central hypogonadism, a possible global impairment the menstrualcycleshouldalsobeperformed( measurement ofprogesteroneinthemid-lutealphase of investigated. When ovulation assessment is the objective, causes forhyperprolactinaemiashouldbefurther concentrations shouldbemeasuredandthepotential anovulation and infertility. Therefore, prolactin plasma androgen imbalance( orinducedbyperipheral dysfunction, eitherprimary with PCOSasaconsequenceofhypothalamic hypogonadism, but may also be present in somepatients In contrast, high LH values are characteristic of primary PCOS presentationaswellincentralhypogonadism. ovarianfailure,whereasitislowinatypical primary should be paid to FSH, which is differentially high in where lowgonadotrophinvaluesarise.Specialattention are foundincontrastwithcentralhypogonadism, hypogonadism,highlevelsofFSHandLH In primary ovarianfailuremayalsodevelopobesity.with primary work-up inobesity ESE GuidelinesonEndocrine We suggestthatgynaecologicalassessment,including When hormonalevaluationiscompatiblewith Hyperprolactinaemia isarecognizedcauseof

oestradiol − pituitary regionmaybeneededtorule pituitary , progesteroneandprolactin. − pituitary functionaffectingother pituitary 153 Downloaded fromBioscientifica.com at09/30/202103:48:48PM , 155 ). https://eje.bioscientifica.com 155 182 ). :1 153 − pituitary pituitary ). G19 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com approach toenablerestoration ofhormoneimbalancein ovarian dysfunction,metformin canbeatherapeutic related hyperandrogenaemia andhypothalamic Provided thatinsulinresistance playsaroleinPCOS- risk factors,menstrualabnormalitiesandfertility. muscle andadiposetissue,thusimprovingcardiometabolic increasing insulin sensitivity predominantly in liver, resistance inpatientswithPCOS.Metforminactsby Metformin iscommonlyusedformanaginginsulin Reasoning: metabolic syndromefeatures(++00). in women with PCOS that additionally present R.5.6. We treatment suggesttoinitiatemetformin these patients( paid tothepossiblepresenceofmetabolicsyndromein under debate,nonethelessspecialattentionshouldbe is associatedwithanincreasedcardiovascularriskstill to characterizeglucosetolerancestatus.WhetherPCOS insulin resistance. HbA1c measurement maybeuseful opportunity tocalculatetheHOMA-IRindexevaluate ( and inthosepatientswithriskfactorsfortype2diabetes to performanoralglucosetolerancetestinobesepatients should bemeasuredandtheAE-PCOSSocietyrecommends and increasedriskfortype2diabetes.Fastingglucosevalues are presentsupportingthediagnosisofPCOS( radiologist, isneededtoconfirmwhetherRotterdamcriteria ultrasonography, assessedbyanexperiencedgynaecologist/ SHBG and albumin ( based on plasma concentrations of total testosterone, of freetestosteronecanbecarriedoutbyusingformulas biochemical hyperandrogenaemia( Δ 4androstenedioneshouldbemeasuredtoconfirm testosterone (ifmeasuredbyequilibriumdialysis),SHBG, Androgen plasmalevelsincludingtotaltestosterone,free the diagnosisofPCOSaccordingwithRotterdamcriteria. ovaries (PCOm)needtobeinvestigated,inorderconfirm anovulation andultrasonographicfeaturesofpolycystic PCOS, hyperandrogenism(eitherclinicalorhormonal), infertility andobesity. Ifthereisclinicalsuspicionof nigricans, menstrualabnormalities,oligo-anovulation, acne, hirsutism,androgenicalopecia,acanthosis Clinical featuresthatraisePCOSsuspicioninclude Reasoning: ovarian morphologyandbloodglucose. SHBG. We additionallyrecommendtoassess testosterone, freeT, Δ4androstenedioneand 157 Clinical PracticeGuideline PCOS isfrequentlyassociatedwithinsulinresistance ). Additionally, fastinginsulinmeasurementgivesthe 153 , 155 123 ). ), see for details 5.4.3. Ovarian ), see for details 5.4.3. Ovarian R Pasqualiandothers 152 , 156 ). An estimation ). Anestimation 155 − ). pituitary pituitary with thesoleaimtoreducebodyweight(+000). R.5.7. We metformin recommend not tostart substitution inpostmenopausalobesewomen R.5.8. We recommendnottostart ( andcanbeusedtopromoteweightloss interventions available forobesitytreatmentasadjuvantstolifestyle loss. Othermedications,suchasliraglutideororlistat,are using metforminwiththesoleaimofpromotingweight obesity treatment.Accordingly, werecommendagainst weight reduction,itcannotbeconsideredasadrugfor Although metforminmayinducemildappetiteandbody Reasoning: patients withPCOSexhibitinginsulinresistance( metformin represents apreferential option to treat profile. Therefore,inadditiontolifestyleintervention, additional benefitofimprovingthepatient’s metabolic patients withobesityandgonadaldysfunction,the with thesoleaimtoreducebodyweight( is notrecommendedinpostmenopausalobesewomen thromboembolism doesexist( rare,apotentialriskofvenous and althoughvery most formulationscontaininglowdosesofoestrogens levels inwomenwithPCOS( Oral contraceptivescanbeusedtoreduceandrogenblood Reasoning: with thesoleaimtoreducebodyweight(+000) GH discharge,suchasGHRH, arginineorinsulin-induced stimulation tests,i.e.administering factorsthatelicita evaluating thesomatotrope axis.Thatrequirestheuseof 24-h variations,thenbasal GH levelsarenotusefulfor Growth hormone(GH)secretionispulsatilewithstrong Reasoning: GHlevels(+000). obesity inpatientswithnormal R.6.3. We recommendnottouseGH totreat minimum (+000). as a tested a dynamic test should be performed patients withsuspectedhypopituitarism; if R.6.2. We suggesttestingforIGF1/GH onlyin not routinelyappliedinobesity(+000). R.6.1. We recommendthattestingforIGF1/GHis 5.6. Otherhormones is questionable. potential negativeimpactonmetabolicissuesandcancer work-up inobesity ESE GuidelinesonEndocrine 158 ). Downloaded fromBioscientifica.com at09/30/202103:48:48PM 160 159 ). Oestrogentreatment ). However, despite 182 :1

oestrogen 161 153 ). The G20 ). via freeaccess

European Journal of Endocrinology synthesis ( low vitaminDintake,sun avoidanceandlowerskin true vitamin D deficiency such as malnutrition with a other obesity-related factors may also contribute for a vitamin Dbioavailabilityduetobodyfatsequestration, D stores can be adequate. In addition to decreased attributed toavolumetricdilutioneffect,whilevitamin so the lower 25OHD levels in obese individuals can be vitamin Ddeficiency. Vitamin Disafat-solublevitamin, obesity andwhetherthisindicatesaclinicallysignificant mechanisms underlyingthelower25OHDlevels in ( frequent inobesityandwasreportedtooccur55–97% low serum25-hydroxyvitaminD(25OHD)levelsisvery Vitamin Ddeficiencydefinedbasedonthepresenceof Reasoning: (+000). for vitaminDdeficiencyinpatientswithobesity R.6.4. We routinetests suggestnottoperform option forthetreatmentofobesity. obese patients,norshouldGHtreatmentbeconsideredan or stimulatedGHshouldbemeasuredwhenevaluating 168 is GHdeficiencyamajorcontributorforobesity( obesity cannot be attributed to GH deficiency these minoreffectsarereversibleafterGHreplacement, increase adiposetissueanddecreasemusclemass, ( weight lossachievedbybariatricsurgery severe obesity, after wasobserved butcompleterecovery in patients with reduction in IGF-I levels areobserved innon-obesechildren.Slight greater thanthatobserved GH secretionhaveanormalgrowth,oreven,sometimes obese subjects,and(d)childrenwithsuchabsent symptoms ofadultGHdeficiencyispresentin normal in obesity ( normal subjectsofsimilarage( are ingenerallowbutmostlysimilartothatofnon-obese negative, basedinthefollowingdata:(a)basalGHlevels per se ledsomescientiststodebatewhetherobesity observations loses weightorreturnstonormal( Moreover, suchablockadevanisheswhenthepatient in adultsandchildrenwithexcessofweight( that stimulated GH secretion is blocked the observation hypoglycaemia. TheinterestforGHinobesityaroseafter may notalwaysreflectaclinical problem. 25-hydroxyvitamin D ( loading dosesofvitamin D toachieve the sameserum 169 Clinical PracticeGuideline ). For all of the above, neither basal IGF-I nor basal Although true GH deficiency tends to modestly , isastateoftrueGHdeficiency. Theconclusionwas 170 ). However, itis important to understand the 171 ). Patientswithobesityalso needhigher 165 172 ), (c) only few of the signs and ). Therefore, low 25OHD levels 164 R Pasqualiandothers ), (b)IGF-Ilevelsare 162 166 , ). 163 per se ). These 162 nor 167 ). , vitamin Dsupplementationwiththesolepurposeof incidence ofcardiovascularevents( effects onglucosehomeostasis( to prevent these metabolic disorders ( trials to support that optimization of 25OHD levels is able of conclusiveevidence from randomizedcontrol clinical improvement oftheseconditions.However, thereisalack that re-establishingvitaminDadequacycouldleadtothe resistance andmetabolicsyndrome,whilehypothesising deficiency wasariskfactorforobesity, T2D,insulin studiessuggestedvitaminD numerous observational and lipidmetabolism( plays anindirectbutimportantroleincarbohydrate multitude offunctionsvitaminD,whileD distributed ubiquitouslyinalltissuessuggestinga D receptors and the 1-alpha hydroxylase enzyme are has beenconsideredlikelybasedofthefactthatvitamin diabetes, insulinresistance,andmetabolicsyndrome sHPT inobesityisnotwell established. biologic functions( different allelescanhave substantialimpactonits are amongthemostpolymorphic proteinsknownand but unchangedvitamin-D bindingproteins,which associated withreductionsintotalandfree25OHD incompletely understood.Foraninstance,obesity is other mechanismsaffectingPTHregulationthatare vitamin D–calciumhomeostasis,obesitymayinvolve variable ( threshold forparathyroidstimulationcanbewidely to 71%dependingonvitaminDstatus( reported tobeover20%( (sHPT) relatedtovitaminDdeficiencyinobesity was hyperparathyroidism The prevalenceofsecondary decrease bonemineraldensityisclinicallyrelevant. extent thatwilldriveanincreaseinboneturnoveror osteoporosis ( density and increase in the risk of osteopenia and the skeleton, leading to a decrease in bone mineral increases bone turnover and calcium mobilization from riseinparathyroidhormone(PTH),which compensatory calcium homeostasis.Vitamin Ddeficiencyelicits a Vitamin Disessentialforbone-mineralhealthand Reasoning: roidism routinelyinpatientswithobesity(+000). R.6.5. We suggestnottotestforhyperparathy conditions cannotberecommended. related co-morbiditiesorimproveongoingmetabolic promoting weightloss,decreasingtheriskofobesity- work-up inobesity ESE GuidelinesonEndocrine The relationship of vitamin D deficiency withobesity, 179 , 177 180 ). Thus,vitaminDdeficiencytothe ). Inadditiontodisturbancesinthe 181 , Downloaded fromBioscientifica.com at09/30/202103:48:48PM 173 182 169 ). Inthepasttwodecades, ). Therefore,theetiologyof https://eje.bioscientifica.com , 175 178 ) orresultsinalower 182 ) andincreasedup 174 :1 176 ), has beneficial 171 ). Therefore, ), whilethe G21 via freeaccess - European Journal of Endocrinology https://eje.bioscientifica.com that include resection of gastric fundus decrease ghrelin that includeresectionofgastric fundusdecreaseghrelin weight ( tend tonormalizeinpatients abletorecoveridealbody with obesitycomparedto normalsubjectsandthey development (inmajorityofpatients)( deficiency (in some patients) and lack of normal pubertal hypothyroidism (lowFT4andTSHlevels),growthhormone receptor genemutationsareassociatedwithhypothalamic for thedegreeofobesity( their serumleptinconcentrationsareusuallyappropriate a similarphenotypetoleptingenemutationpatientsbut ( function abnormalitieswithhigherratesofinfections compared tohealthychildren),andT-cell numberand with extremehyperphagia(foodintake3–5-foldhigher leading to severe obesity (mean BMI SDS: 5.8–7.8) along with rapidweightgaininthefirstmonthsafterdelivery of missenseleptingenemutationsarenormalbirthweight circulating leptinlevels ( mutations areextremelyrareandleadtoundetectable to rule-outmissenseleptingenemutations( should onlybeconsideredinsevereearly-onsetobesity fat content( with simpleobesityandcorrelatesBMIbody Serum leptin concentration is increased in patients Reasoning: there issuspicionofasyndromicobesity. suchasleptinandghrelin,unless hormones, R.6.6. We recommendnottotestroutinelyother needs tobeconfirmed( against weightlossinducedboneandfracturesstill whether vitaminDsupplementationactuallyprotects the obeseorbariatricpopulationsareunknown.Moreover, replacement therapyandtarget25OHDconcentrationsin decreased absorption( supplements inhigherdosagesarerequiredtoovercome levels are attained ( it is recommended to ensure that sufficient 25OHD In addition,inordertopreventorattenuateboneloss in patients 2 years after bariatric surgical interventions. toincreaseup50% The prevalenceofsHPTwasobserved patients withobesitysubmittedtobariatricprocedures. measurement of25OHDandPTHshouldbemadefor such as hypercalcaemia, osteoporosis and nephrolithiasis. which leadtotheclinicalsuspicionofhyperparathyroidism, assessed inobesepatients,unlessthepresenceofsigns 188 Clinical PracticeGuideline Circulating ghrelinlevelsaredecreasedinpatients Still, itshouldbenoticedthatanexceptionforroutine Notwithstanding, PTH levels should not be routinely ). Patients with leptin receptor gene mutations have ). Patientswithleptinreceptorgenemutationshave 190 ). Bariatric surgery in particular the operations inparticulartheoperations ). Bariatricsurgery 185 ). Measurements of serum leptin levels ). Measurementsofserumleptinlevels 171 183 ), bearing in mind that vitamin D 184 187 ). However, theidealvitaminD 189 ). ). Typical featuressuggestive ). Bothleptin-and R Pasqualiandothers 186 , 187 186 , 189 ). These ). These ). functions thataffectnot only thegonadotropicaxis Pregnancy inducesprofound changesinendocrine 5.7.1. Pregnancy 5.7. Specificconditions increased prevalenceofobesity. in obesity;nevertheless,thesearenotcharacterizedby Other causesofendocrinehypertensioncanbepresent There are some endocrine disorders associated with There aresomeendocrinedisordersassociatedwith Reasoning: inobesity.hypertension inthecontextoftherapy-resistant hypertension R.6.7. We causes of suggest to consider secondary not bedoneinroutineclinicalsettings. patients haslittleadditionaldiagnosticvalueandshould testing. Therefore,measuringghrelinlevelsinPrader–Willi on clinical features, hormonal abnormalities and genetic The diagnosisofthissyndromecanbeestablishedbased hypogonadism, sleepdisturbancesandotherabnormalities. childhood, significantlyincreasedappetite,GHdeficiency, patients typically present with significant weight gainin patients with Prader–Willi syndrome ( and couldpotentiallycontributetoweightgainare syndrome whereincreasedghrelinlevelsweredescribed ghrelin concentration( levels while diet-induced weight loss usually increases for upto1%ofcasesdiastolichypertension( in hypothyroidism is usually diastolic and may account none oftheseconditionsisusuallysevere.Hypertension accompanied bybothobesityandhypertensionalthough (chapter 5.3fordetails).Hypothyroidismcanbe or symptomsconsistentwiththisclinicalpresentation should beperformedinpatientspresentingwithsigns majority ofpatients( with obesityincludingthepresenceofhypertensionin or presenceofobstructivesleepapnoea( orearly-onsethypertension,adrenalincidentaloma history aldosteronismsuchashypokalemia,family of primary three antihypertensivedrugsandothersuggestivefeatures with persistinghighbloodpressuredespitetreatment aldosteronismshouldbeconsideredinpatients primary patients isoftenassociatedwithobesity( aldosteronism mayaccountfor5–10%ofhypertensive Cushing syndromeandhypothyroidism.Primary aldosteronism, These include in particular primary endocrinehypertensionshouldbeconsidered. secondary both hypertensionandobesity( work-up inobesity ESE GuidelinesonEndocrine Cushing syndromehasmanyoverlappingfeatures 79 Downloaded fromBioscientifica.com at09/30/202103:48:48PM ); testingforCushingsyndrome 191 ). The only specific obesity ). Theonlyspecificobesity 193 182 ) where testing for ) wheretestingfor 195 :1 194 ). 192 ). Testing for ). These ). These G22 196 via freeaccess ). European Journal of Endocrinology factor; LH,luteinizinghormone;TSH, thyroid-stimulatinghormone. ACTH, adrenocorticotropichormone; DHEA,dehydroepiandrosterone;FSH,follicle-stimulatinghormone;GH, growthhormone;IGF,insulin-like Ghrelin Vitamin D Growth hormone Adrenal glands Gonads Thyroid Endocrine gland/hormones Table 7 heavy consequencesonfoetaldevelopment( during pregnancy, whilemostendocrinedisordershave lead tofalseinterpretationofhormonalassessments glands suchastheadrenalandthyroidglands.Thiscan chorionic gonadotropin: HCG), but also other endocrine prolactin) andplacentalhormones(notablyhuman hormones oflactation (increase in oxytocinand (increase inoestrogens,progesteroneandandrogens), Clinical PracticeGuideline Hormones, agingandobesity. Decreased ghrelin( Risk ofosteoporosisand Aggravates thedeficitinducedby Decreased vitaminD( Role insarcopenialinkedtoage Decline ofGHandIGF1with Increased riskofdepression, Reduction ofmineralocorticoidand Increased releaseofACTHand Increased riskofabdominal Increased riskofsarcopenia,but In women,decreasedoestradiol Associated withincreasedriskof In men:Decreasedtestosterone No specificstudiesinoldobese Controversial roleof Increased cardiacrisk( Decrease insymptoms( Increased incidenceof hormone productionwithage Reduced thyroid Alterations sarcopenia obesity and increasefrailty( aging ( frailty ( sarcopenic obesityand glucocorticoid receptors Cortisol. DecreaseofDHEA( cancer inobesity( increased riskofendometrial unhealthy obesity( less bonelossinobesity( FSH-LH ( and progesteroneincreased loss inobesity( increase inBMI,butlessbone sexual andcognitivefunction, sarcopenia andfrailty,declinein (Increased aromataseandSHBG) secretion ( people hyperthyroidism indementia hypothyroidism and longevity inoldpeople increased TSHisassociatedwith hypothyroidism ( R Pasqualiandothers 215 215 208 ) 208 ) ) ) and bioavailability 209 20 208 211 ) 210 ) 208 216 207 ) 206 ) 197 ), ) ) ) but ) 209 ). The 208 ) ) TSH increaseswithagebut TSH onlyasafirststep(see Need toassess No indication No specific recommendation No indicationinelderly No specificnorminelderly No indicationinelderly No specificnormsinobesity Age associatednorm( No indicationinelderly No specificnormsinobesity Age associatednorm( Only ifsymptoms(see5.4) ( no specificnormsforage chapter 5.2.4) in oldobesepeople 5.3) and obesity(seechapter symptoms unless abnormal (see chapter5.5) unless symptoms concentrations decreaseofapproximately10–15%,and levels andadecreaseinTSH.Later, serumfreehormones HCG inducesatransientincreaseinfreethyroidhormones pregnancy onendocrinefunctions. reported theeffectsofinteractionsbetweenobesityand been widelydescribed( deleterious effectsofobesityonpregnancyoutcomeshave work-up inobesity ESE GuidelinesonEndocrine 45 ) orforobesity Concerning thyroid function, during the 1st trimester, 208 212 ). ) 198 Downloaded fromBioscientifica.com at09/30/202103:48:48PM No specificityforobesityinelderly Only ifoverthypothyroidism( Need totreat No specifictreatment Systematic supplementationinold Effect oftreatmentunclearin Promote physicalactivity No specifictreatmentinoldobese No indicationforDHEA No recommendationsinoldobese Oestrogen/progesterone therapy No recommendationsinoldobese More cardiovascularsideeffectsin Only iflowforageand with goodhealthstatus or TSH obese subjects people elderly andnodatainoldobese people substitution ( women endometrial cancer( decreases theriskof body composition( may partlypreventchangein men elderly ( on metabolicdisturbances( symptomatic ( ). However, fewstudieshave https://eje.bioscientifica.com > 214 10 mIU/Linpatients 182 ) 215 :1 212 ) ). Feweffects 210 211 ) and ) G23 21 213 ) via freeaccess ) European Journal of Endocrinology https://eje.bioscientifica.com change with aging and are often less pronounced, which system. Furthermore,thesymptoms ofendocrinedisease secretions withvariableamplitude foreachendocrine Ageing isassociatedwith alterationsofhormonal 5.7.2. Theelderly growth inthispopulationhasbeenshown( ( surgery calcium supplytothefoetus,notablyafterbariatric but the decrease of bioavailable vitamin D may impact the impactofobesityonPTHregulationduringpregnancy, No specificdataisavailableintheliteratureconcerning trimester ofpregnancy, neededforbonemineralization. calcium is transferred to the foetus, especially in the last calcium andvitamin D demand( are notknown. Obesity canfurtherdecreaseGH,buttheconsequences because ofplacentalgrowthhormoneproduction( preeclampsia ( in thethirdtrimesteraredecreasedobesewomenwith women. Itwasnotablyshownthatlevelsofaldosterone preeclampsia thatismoreprevalentinobesepregnant axis havebeenincriminatedinthepathophysiologyof normal valuesforpregnancy( biochemical testresultsmustbecorrelatedwiththe pregnancy, urineandplasmaaldosteroneincrease, increase extracellularfluidvolume.Because,during during pregnancy to compensatevasodilation and to difficulty tointerpretusualtestsduringpregnancy. not recommended,butobesitycanfurtherincreasethe systematic assessmentofcortisolduringpregnancyis foetal complications,includingmacrosomia( is reducedinobesepregnancythatcouldcontributeto easy tointerpretduringpregnancy. HPA axisactivity increase infreecortisol( threefold increaseofplasmacortisollevelsandalesser CRH. The increase in CBG ( large amountsofsteroidandpeptidehormonesincluding adrenal (HPA) axis.Thefoeto-placentalunitproduces induce activationinmaternalhypothalamic–pituitary– During pregnancy, a number of endocrine changes are nospecificrangesforobesepregnantwomen( hormones and TSH throughout pregnancy. However, there recommend specificreferencerangesforfreethyroid TSH returnstonormal.Thus,mostscientificsocieties Clinical PracticeGuideline PTH increasesduringpregnancyinfaceofincreased GH decreasesduringpregnancybutIGF1increases Renin-angiotensin-aldosterone (RAA)axisisactivated Glucocorticoids arevitalfornormalfoetalgrowth. 204 ) andalinkbetweencalciumstatusfoetal 202 ). 197 ). Theusualtestsarenotas 200 197 R Pasqualiandothers ), result in a two to 203 ). AlterationsofRAA ). Around30gof 205 201 ). 199 ). The 197 ). ). ohigr nehi, l Lly Jhsn Jhsn Medtronic, Johnson, & ofgrants/ P: Receipt Johnson M Takeda. Lilly, Sanofi, Nordisk, Novo Eli Mundipharma, Ingelheim, AstraZeneca, Amgen, panel/lectures: Boehringer member/advisory Board Lilly, Eli BMS, AstraZeneca, support: Research H: M Committee. Executive Society Novo Nordisk, Orexigen, Pronokal, Janssen, Ipsen, Pfizer, Member Pituitary from: fees, board advisory or lecturing and grants research Receiving C: F Declaration ofinterest provided in in elderlyandpotentialinteractionswithobesityis by ageinobesepeople.Thedetailsofendocrinechanges specifically studiedthehormonalmodificationinduced hormonal changes.Unfortunately, nostudyhas less favourable. is also different,becausethe benefit torisk ratiomay be cardiovascular functions).Finally, theindicationtotreat greater healthrisks(notablyformusclemassand of endocrinediseasescanalsochangeinelderlywith can leadtomissingofthediagnosis.Theconsequences References for Endocrinology of valuable andcriticalcomments. Society European the of members additional and The authors of the guideline would like designated experts for their review Acknowledgements The guidelinewassponsoredbytheEuropeanSocietyofEndocrinology. Funding author. Theotherauthorshavenothingtodisclose. in the review or editorial process for this paper, on which he is listed as an Sanofi. Olaf Dekkers is on and the editorial board of EJE. Olaf Dekkers was Novonordisk not involved Novartis, MSD, Ingelheim, Boehringer from studies Amgen, clinical for fees and institutional received Sanofi also has T Novonordisk, H Takeda. Novartis, Mylan, Boehringer-Ingelheim, MSD, Amgen, Gebro, from Cheplapharm, boards Bruno advisory and NovoNordisk, lectures for companies: honoraria T: H Pharmaceuticals. pharmaceutical Damor Bioitali, Aegerion, Farmaceutici, following the for S: F Esteve. Janssen, meetings to participation boards, advisory Lilly, studies, profit grants, research Nordisk, Novo for Consultant fees S: lecture J and activities Nordisk. Novo and Ingelheim MSD, Boehringer bureau: AstraZeneca, speaker’s sponsored company Novo a in and Participation Ingelheim Nordisk Boehringer AstraZeneca, MSD, fees: consultation or honoraria of Receipt Serono. Merck AstraZeneca, supports: research work-up inobesity ESE GuidelinesonEndocrine 2 1 Leitner DR, Fruhbeck G,Yumuk V, Schindler K,Micic D,Woodward E Fruhbeck G, Toplak H, Woodward E, Yumuk V, Maislos M,Oppert JM Facts for combinedtreatmentstrategies– EASO canleadtheway. & Toplak H. ObesityandType 2diabetes:twodiseaseswithaneed org/10.1159/000350627) challenge inEurope. position statementonarisingpublichealth,clinicalandscientific Study ofObesity. Obesity:thegatewaytoillhealth –anEASO & ExecutiveCommitteeoftheEuropeanAssociationfor Obesity mayaltertheconsequencesofage-related 2017 10 Table 7 483–492. . Obesity Facts (https://doi.org/10.1159/000480525) Downloaded fromBioscientifica.com at09/30/202103:48:48PM 2013 6 117–120. 182 :1 (https://doi. 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