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E Carosa, A Sansone and Female 182:6 R101–R116 Review others

MANAGEMENT OF ENDOCRINE DISEASE Female sexual dysfunction for the endocrinologist

E Carosa1,*, A Sansone2,3,* and E A Jannini3

1Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy, 2Centre of Correspondence and , University of Münster, Münster, Germany, and 3Chair in Endocrinology and should be addressed Medical (ENDOSEX), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy to E A Jannini *(E Carosa and A Sansone contributed equally to this work) Email [email protected]

Abstract

Sexual function is an important component of either general health and quality of life in both genders. Many studies have focused on the different risk factors for sexual dysfunctions, proving an association with several medical conditions. Endocrine disorders have been often mentioned in the pathogenesis of female and male sexual dysfunctions; however, particularly in women, sexual function is rarely addressed during clinical, in general, and endocrinological, in particular, consultations. As a thorough diagnosis is required in order to provide an adequately tailored treatment, knowing how each endocrine dysfunction can impair sexual health is of the utmost importance, considering the high prevalence of conditions such as disorders of pituitary, thyroid, adrenal, gonads, as well as metabolic disorders. We performed a thorough review of existing literature on the different mechanisms involved in the pathogenesis of female sexual dysfunctions secondary to endocrine disorders in order to provide an up-to- date reference.

European Journal of Endocrinology

European Journal of Endocrinology (2020) 182, R101–R116

Introduction

Gender development, sexual anatomy, and function, as is unfortunately not fully developed yet well as sexual behaviors, are largely hormone-dependent (1). The presence of endocrine disorders in the principal characteristics of beings. However, unfortunately sexual dysfunctions is rarely searched, just as the presence and surprisingly, the presence of the endocrinological of sexual dysfunction (SD) in endocrine and metabolic science in the new, but growing, field of medical sexology/ diseases (2) is rarely investigated. In clinical practice, little

Invited Author’s profile Emmanuele A Jannini is Full Professor of Endocrinology, Andrology and Medical Sexology at the University of Rome Tor Vergata, was a guest researcher and fellow at the Clinical Endocrinology Branch, NIDDK, and lecturer at St Catherine’s College, Oxford, on courses of the European Academy of Sexual Medicine. Currently, he is also a Visiting Professor of Andrology at the Sun Yat-sen University (Guangzhou), Anhui Medical University (Hefei), and Jiao Tong University (Shanghai). He studies reproductive and sexual endocrinology with particular interest in thyroid hormone receptor, impotence, premature , and female sexual function and dysfunction.

https://eje.bioscientifica.com © 2020 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0903 Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 06:40:02AM via free access

-19-0903 European Journal of Endocrinology https://eje.bioscientifica.com IGF1, thyroid,hypothyroidism,hyperthyroidism,thyroid hyperprolactinemia, prolactinoma,growthhormone,GH, with theBooleanoperatorsANDandOR:, Embase, and Scopus database, using the following terms A literaturesearch wasconducted usingPubMed,Cochrane, Search strategy (FSFI-6) ( Function Index(FSFI)initsfull( validated psychometrictool,suchastheFemaleSexual addressing femalesexualfunctionthroughapopular, well screening, wedecidedtoconcentratemainlyinthestudies well asmetabolicdiseases( pituitary, thyroid,adrenalandgonadaldisorders,as concerning thesexualfunctionofwomenaffectedby sexual QoL(SQoL)andofteneasilytreatable. impacting both, in general, quality of life (QoL) and the However, these disorders are common, quite dramatically no studiesfromrandom,population-basedsamples. this comorbiditycannot be easily assessed, as there are (SD) withendocrinedisorders,theexactprevalenceof studies haveshowntheassociationofsexualdysfunctions dependent inallthephasesoftheirlife.Whileseveral whose sexuality is exquisitely and dramatically hormone- really puzzlingandnoteasytounderstand,inwomen( during endocrinedisorders.Thisisparticularlyevident,but consideration isgiventotheevaluationofsexualfunction health andsexualfunctioninwomen. Endocrine alterationsassociated withimpairmentofsexual Figure 1 Review In this review, we have analyzed the publications 5 ). Fig. 1 others E Carosa,ASansoneand ). Asamethodological 4 ) orabridgedform 3 ),

function iswellknown.AtransientincreaseinserumPRL The linkbetweenprolactin(PRL)levelsandsexual Prolactin Authors (ECandAS)betweenAugustOctober, 2019. Literature search wasconductedindependentlybytwo index, qualityoflife,QoL,sexualSQoL. sexual desiredisorder, HSDD,FSFI,femalesexualfunction dyspareunia,hypoactive vaginismus, vaginaldryness, gout, hyperuricemia,FSD,femalesexualdysfunction, deficiency, ,androstenedione,diabetes, hypogonadism, Turner, estrogendeficiency, hyperaldosteronism, adrenalfailure,hyperandrogenism, congenital adrenalhyperplasia,CAH,hypoaldosteronism, Cushing, Addison, hypercortisolism, hypocortisolism, glucocorticoid, mineralocorticoid, cortisol, DHEA, disease, goiter, Graves,Basedow, Hashimoto,adrenal, but someevidencealsosuggests thatadirecteffectis axis, inhibition ofthehypothalamic-pituitary-gonadal effects ofhyperprolactinemia arepartlymediatedthrough function ratherthantosexual health( they have mainly focused on gonadal and reproductive given thehigherprevalenceinwomenthanmen, reproductive functions have focused on female patients, studies ontheeffectofchronichyperprolactinemia these behavioralparameters( central regulator of and arousal, thus reducing secretion andonthedopaminergicpathway, themain effectofprolactinongonadotropin fact, theinhibitory reproductive dysfunction( been suggestedasaperipheralbiomarkerofsexualand in menandwomen( associated withhypoactivesexualdesiredisorder(HSSD) induce areductionofsexualactivityinanimalsandare It iswellknownthatchronicallyelevatedPRLlevels Hyperprolactinemia ( SD hasbeeninvestigated,suchasinprematureejaculation While thecorrelationbetweenlowlevelsofPRLandmale Hypoprolactinemia period ( ( and distressingactivitiesand,specifically, afterthe bothinmenandwomenmanyeustressing is observed Female sexualdysfunction 8 , 9 ), similarstudiesdonotexistinfemale. 7 6 ). ), probably partly accounting for the refractory ), probably partly accounting for the refractory 10 Downloaded fromBioscientifica.com at10/02/202106:40:02AM ). Forsuchreasons,PRLhas 11 ). Solidevidenceconfirms,in 12 ). Whilethemajorityof 182 :6 11 ). Inmen,the R102 via freeaccess

European Journal of Endocrinology both GH-dependentandnon-GH-dependent dwarfism So far, nostudyhasadequatelyaddressed theeffectsof Decreased GH 20 located inbothmaleandfemalegonadsgenitalia( regulation ofsexualfunctions:infact,GHreceptorsare functions. GHisalsosupposedtobeinvolvedinthe metabolism, aswellcardiovascularandothersystems the entirelife,regulatingprotein,glucose,andlipid childhood; however, GHalsoexertsseveralactionsduring is responsible for regulation of linear growth during It istextbookknowledgethatgrowthhormone(GH) Growth hormone sexual dysfunctions. line investigationfor women complaining of all kindsof reasons, prolactin should always be assessed as a first- not justinwomenofreproductiveage.Forthesame should beinvestigatedinallcasesofhyperprolactinemia, premises, itshouldthereforebeclearthatsexualfunction was notinvestigatedviatheFSFI( with reproductivedysfunctions,althoughsexualfunction that macroprolactinemiawasalsofrequentlyassociated however, more recently, Kalsiand colleagues reported to suspectacausativeroleformacroprolactinemiainSD; macroprolactinemia ( sexual desirewastheonlyonenegativelyaffectedby the FSFIwere affected by‘common’hyperprolactinemia, macroprolactinemia and found that, while all domains of also investigatedtheextentofSDinpatientswith of SD in women. Curiously, and colleagues Krysiak colleagues ( therefore reinforcing and thecorrelationfoundbyKrysiak came to thesameconclusion, despite small sample size, total scoreandalldomainscores( forms ofhyperprolactinemiasignificantlyimprovesFSFI with dopaminergicdrugscommonlyusedindifferent score testthancontrols( that womenwithhyperprolactinemiahavelowerFSFI on thistopichavebeenpublishedsofar( physician aswellbymanyendocrinologists.Fewstudies hyperprolactinemia arelargelyunderestimatedbythe in affectedwomen.Sexuallydysfunctionalwomenwith provide additionalexplanationforimpairedsexualhealth these regards, the samemechanismscould theoretically found onsexualdesire( Review ), includingtheoocyte,granulosa,andtesticularcells. 16 ) betweenprolactinlevelsandtheseverity 15 ). Thisishardlyadequateevidence 13 14 ). Despitelackingevidencein , 15 , others E Carosa,ASansoneand 16 ) andthattreatment 18 16 ). Basedonthese , Table 1 17 ). Allstudies ), showing 19 , Female sexualdysfunction

Table 1 Studies reporting hyperprolactinemia (HyperP) and female sexual dysfunction (FSD).

Patients Scores

Studies n Age SFV CTRL HyperP HyperP + Bromo P Comments 14 HyperP = 25 35.72 ± 10.2 FSFI 31.10 (27.55–32.88) 23.40 (17.70–27.30) <0.0001 SD was diagnosed in 88% patients, while only CTRL = 16 34.86 ± 4.88 25% of CTRL women were found to have SD. All FSFI domains scores were lower in women

Downloaded fromBioscientifica.com at10/02/202106:40:02AM with HyperP. The most affected domains were desire and arousal. 15 HyperP = 14 30 ± 5 FSFI 31.67 ± 3.15 27.00 ± 3.10 <0.05 Women with HyperP had lower total scores on

https://eje.bioscientifica.com CTRL = 14 29 ± 5 the FSFI than control subjects. All FSFI domains scores were lower in women with HyperP. Small sample. 182 17 HyperP = 15 32 ± 5 FSFI 32.37 ± 2.18 vs 27.64 ± 2.39 vs 27.36 ± 2.52 vs <0.05 Women with HyperP had lower total scores on HyperP + 32 ± 6 32.25 ± 2.40* 27.19 ± 2.61* 31.26 ± 2.89* the FSFI than control subjects. Bromo :6 Bromo = 15 treatment significantly increase FSFI total CTRL = 14 30 ± 6 score and all domain scores. Small sample.

*T0 vs 3 months. R103 Bromo, ; CTRL, controls without hyperprolactinemia; FSFI, Female Sexual Function Index; SFV, sexual function valuation. via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com even whileundergoingspecific treatments. should, hence,becarefully investigatedandaddressed, is presentinmostpatients with acromegalyandthatit of thecause,endocrinologists shouldconsiderthatSD such assexualroutineand advancingage.Regardless attribute sexualdysfunctiontoanyotherdifferentcause, it doesnotseem surprising that many patients could of acromegalytendtodevelopslowly, and therefore FSFI total score was associated with IGF-I levels. Symptoms patients,regressionanalysisshowedthatthe was notdifferentbetweencontrolledanduncontrolled female sexualfunction.AlthoughtheFSFItotalscore confirm adirectinvolvementofGHonregulation of patients withrespecttoFSFIscores:thisresultdoesnot between biochemicallycontrolledanduncontrolled during treatment.Nosignificantdifferencewasfound acromegaly, accordingtoserumGHandIGF1levels patients withacromegaly:controlledanduncontrolled controls ( significantly lowerinacromegalicpatientsthanamong of healthy women,andall FSFI domainsscoreswere in 68%ofpatientswithacromegalycomparedto28% in acromegalypatients( single studyhas investigated femalesexualfunction isolation thatcanbeacauseofSDinitself( dissatisfaction ofbodyimage,andtendencytosocial is associatedwithsevereimpairmentofqualitylife, be reversible,evenwithsuccessfultreatment.Acromegaly utmost importance,aschangesinappearancemaynot common disorders.Earlydiagnosisisthereforeofthe diagnostic delay, assymptomsoftenoverlapwithmore like diabetesarecommon.Acromegalyhasanimportant and visceromegaly;additionally, metabolicalterations features, extremityenlargement,softtissueswelling, clinical featuresofacromegalyarechangeinsomatic in acromegaly, whenoccurringinadulthood.Themain be foundingigantism,whenoccurringchildhood,and Increase ofGHandIGF-1isaclinicalconditionthatcan Increased GH health andimpairsexualfunction. and ( also associatedwithreducedstrength,depressedmood, affected subjects;additionally, GHdeficiencyinadultsis less severe forms, can become a psychological burden to SQoL itself.Itissafetoassumethatdwarfism,eveninits relational andintrapsychiclifeand,asaconsequence,the this gap, being evident that hypostature must affect the on femalesexualfunction.We tofill arecurrentlytrying Review 22 21 ). Two groupswereidentifiedamong ) –allsymptomswhichcanworsensexual 22 ) usingFSFI.SDwaspresent others E Carosa,ASansoneand 10 ). A found inmen( and SDinwomen( all studiesshowtheassociationbetweenthyroiddisease patient selectedpopulations.Despitealltheselimitations, small, random,population-basedsamplesderivedfrom ( effects ofthyroiddiseasesonwomen’s sexualfunction males, fewstudiesusingtheFSFIhaveevaluated are largelymorepresentinwomenatallagesthan and SQoL.Althoughthyroidhyper-hypofunctions dysfunctions affectgeneralhealth,aswellsexualhealth symptoms toovert,life-threateningcrises( manifestations, rangingfrommild,hardlyidentifiable Both conditions,infact, have awiderangeofclinical dysfunctions arethemostprevalentendocrinedisorder. is unknown,itgenerallyassumedthatthyroid While theexactprevalenceofhypo-andhyperthyroidism Thyroid and SD.Themechanismofaction throughwhichthyroid association betweenclinically-evident thyroidpathology they allshowedthesameresult, thereforeconfirmingthe limitation isthefactthat these aresmallstudies,but control studies( between and SD in women with case In thelastfewyears,differentpapersshowedacorrelation Hyperthyroidism impairing reliabilityoftheresults. consider levelsofsexhormonesorprolactin,therefore these twostudies,bothperformedusingtheFSFI,donot which caninducehyperprolactinemia.Additionally, TSH levelscommonlyreportedinoverthypothyroidism subclinical hypothyroidismfailstoachievetheelevated solid explanationsforthisinconsistency, onlystatingthat found byAtis( association betweensub-clinicalhypothyroidismandSD studies performed on Asian women ( are foundinsubclinicalhypothyroidism:fact,two compared tocontrols( significant reduction of FSFI scores in hypothyroid women association betweenhypothyroidismandSDwitha All studieslistedin 44–60% –inhyperthyroidism( around 22–46%( impact. The prevalence of SD in hypothyroid women is Female sexualdysfunction Tables 1 and 2 28 ). Mostofthesestudieswerebasedon 25 29 ). However, theauthorsdonotprovide 26 , , 25 ), althoughwithdifferentclinical 27 30 ), confirmingthesameassociation 27 , Table 2 , Downloaded fromBioscientifica.com at10/02/202106:40:02AM 28 , 31 28 ), whereasitishigher–around , , 30 35 29 demonstratedastrong , ) ( 31 , 30 Table 3 , 33 182 32 , 31 , ). Differentresults 34 :6 ). 23 ) contradict the ). Theirmajor , 24 ). Thyroid R104 via freeaccess European Journal of Endocrinology Review

Table 2 Studies concerning hypothyroidism (HypoT) and FSD.

Patients, n Scores Sub- Sub- Sub- Reference CTRL HypoT HypoT HypoAU Eu-Has Method for SFV CTRL HypoT Sub-HypoT HypoAU Eu-Has P Comments 32 36 24 FSFI; 30.3 ± 0.76 18.2 ± 2.41 <0.05 All FSFI domains are No SD >30; impaired in HypoT Middle SD: 23–29; women respect to Severe SD <23 the controls. Small sample. others E Carosa,ASansoneand 28 20 25 25 FSFI; SD <26.55 32.31 ± 3.50 23.92 ± 5.81 From 29.20 to 26.03 <0.001 All FSFI domains are impaired in HypoT women respect to the controls. Small sample. 30 30 17 FSFI Single FSFI – Direct correlation of domains FSFI scores and FT4 scores are was observed in lower in HypoT women. HypoT Small sample. women

31 53 22 FSFI; SD <23.0 25.7 ± 5.2 20.7 ± 6.9 – Compared with Female sexualdysfunction control, there was a significant decrease of desire, arousal and lubrication scores in HypoT women. Small sample. 33 948 138 FSFI; SD <26.55 23.8 (20.2–27.5) 24.4 (20.6–27.6) No effect Sub-HypoT is not a risk factor for SD in Korean women. Downloaded fromBioscientifica.com at10/02/202106:40:02AM 27 18 17 17 16 FSFI; SD <26.55 31.52 ± 2.75 27.87 ± 3.62 23.74 ± 4.00 27.98 ± 3.25 <0.05 Thyroid failure and autoimmunity is associated with SD.

https://eje.bioscientifica.com Small sample. 34 951 168 FSFI 25.7 ± 3.9 25.8 ± 3.9 No effect Sub-HypoT is not a

risk factor for SD in 182 Chinese women. :6

CTRL, healthy euthyroid females without thyroid autoimmunity; Eu-Has, euthyroid women with Hashimoto’s thyroiditis; FSFI, Female Sexual Function Index; SD, sexual dysfunction; SFV, sexual function valuation; Sub-HypoAU, women with autoimmune subclinical hypothyroidism; Sub-HypoT, nonautoimmune subclinical hypothyroidism. R105 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Review Table 3 Studies reporting hyperthyroidism (HyperT) and FSD.

Patients, n Scores Graves’ Toxic Method Graves’ Toxic References CTRL HyperT disease adenoma for SFV CTRL HyperT disease adenoma P Comments 30 30 22 FSFI* – All FSFI domains were significantly impaired in HyperT women. After restoration of euthyroidism, a significant improvement was observed in all domains, with the exception of orgasm. Small sample. 29 40 40 FSFI; 29.0 ± 10.4 24.2 ± 9.96 0.0001 HyperT women had lower FSFI score in all SD <26.55 domains compared with age-matched others E Carosa,ASansoneand controls. Small sample. 31 53 18 FSFI; 25.7 ± 5.2 19.5 ± 7.6 – Compared with control , there SD <23.0 was a decrease of desire score in the HyperT women. Small sample. 35 34 31 30 FSFI; 32.03 ± 3.41 26.42 ± 3.89 28.85 ± 3.26 0.001 HyperT women had lower FSFI score in all SD <26.55 domains compared with age-matched controls. Small sample.

*The FSFI’s total scores have not been published for this study. SFV, sexual function valuation. administration ofglucocorticoids ( axisfollowinglong-term hypothalamic-pituitary-adrenal adrenal diseaseortodrug-induced dysfunctionsofthe failure arecurrentlyattributed toeitherautoimmune the hypothalamus,respectively. Mostcasesofadrenal gland,or dysfunction –theadrenalcortex,pituitary insufficiency aredefinedbasedonthesource of Primary, secondary, formsofadrenal and tertiary –Addison’sdisease response. with theandrogenreceptorandthereforeelicitsignaling secretion fromtheadrenal,asglucocorticoidscaninteract true alsoforconditionsnotdirectlyaffectingandrogen the adrenalmightinfluencefemalesexualhealth.Thisis both impairedandexaggeratedhormonereleasefrom and itisthereforeunsurprisingthatconditionsresulting different questionnaires, suchastheSF-36, highlighted female sexualfunction.Nevertheless,otherstudiesusing on the effects autoimmune thyroid disease has on conflicting results,nodefiniteconsensuscanbereached with worseFSFIscores( thyroid peroxidaseantibodyserumtiters–wasassociated investigated whetherthyroidautoimmunity–thatis, neglected by literature. Only afew studies, in fact, The issueofautoimmunethyroiddiseaseislargely Autoimmune thyroiddisease receptors inthegenitals( supported onthebasisofpresencethyroidhormone thyroid hormones( ( hypothalamic thyroid axiswhich alters prolactin levels hypotheses arerelatedeithertothedysfunctionof diseases induceSDisnotknown:themostreliable gland isthemajorsource forandrogensinwomen( parts oftheadrenalgland.Moreindetail, impaired orexaggeratedhormonereleasefromdifferent . Differentclinicalscenariosareassociatedto release of glucocorticoids, mineralocorticoids, and adrenal The adrenalglandisinvolvedintheproductionand Adrenal gland which theydescribedasthyroid-related( more frequentlyself-reportingsexualhealthimpairments, that youngwomenwithautoimmunethyroiddiseaseare Female sexualdysfunction 25 ) ortoadirecteffectrelatedthelevelsofcirculating 30 ). Thissecondhypothesiscanbe 27 Downloaded fromBioscientifica.com at10/02/202106:40:02AM 36 , , 31 37 ). Asthesestudiesbrought ). 40 182 ). Women affected :6 38 ). R106 39 via freeaccess ), European Journal of Endocrinology CYP21A2 genotype),twoforms ofCAHarecommonly deficiency. Depending onthegeneticbackground(the and hypoaldosteronismresulting from21-hydroxylase features suchashyperandrogenism, hypocortisolism, hyperplasia (CAH)isaclinical syndrome,including the consequenthyperandrogenism.Congenitaladrenal have alargeeffectonfemalesexualitymostlythrough Congenital and acquiredadrenalhyperplasiasortumors Hyperandrogenism possible ( hormone supplementationsshouldbestartedasearly as did not confirm these results,suggesting that theadrenal ( reduced thecomorbiditywithSDrespecttoplacebo women andthatDHEAreplacementtherapysignificantly adrenal insufficiency isassociated toSD insexuallyactive results( contradictory was alsostudiedonsexualfunctioninwomenwith both QoLandSQoL( elderly womenhasbeenassociatedwithimprovementof decline inolderwomen( in peripheraltissues( women bytheconversiontotestosteroneendestrogen the total sexhormone amount and biological activity in of SD.Infact,DHEAandDEAScontributesubstantiallyto in adrenalinsufficiencycanbeassociatedwiththepresence Dehydroepiandrosterone (DHEA)anditssulfate(DHEAS) 50% ofandrogenproduction( source ofandrogeninthe female,accountingforalmost As previouslystated,theadrenalismostimportant Adrenal insufficiency–hypoandrogenism failure usingtheFSFI. no studyhasinvestigatedsexualfunctioninginadrenal pleasure andlowerdiscomfortduringintercourse. Sofar, as sexuallyactivehealthycontrols,withhighersexual with Addison’s diseaseandconcludedthatpatientswere the SexualActivityQuestionnaire)inacohortofwomen in fact,Erichsen ( production inthefemalebodystemsfromadrenal of adrenal failure, given that almost 50% of women withandrogeninsufficiency –acommonfeature with theSQoL.Lossoflibidohasbeenreportedin Surprisingly, adrenal failures have rarely been correlated decrease ofQoLcomparedwithgeneralpopulation( adrenalinsufficiencyreporta orsecondary by primary 39 45 Review ). However, otherstudiesinolderwomen( ). However, reportsintheseregardsareinconsistent: 46 , 47 ). t al et 44 42 Table 4 . assessedsexualfunction(using ). TheeffectofDHEAreplacement ). Additionally, DHEAandDHEAS 43 ) andreplacementinnormal ). Artl others E Carosa,ASansoneand 39 et al ). Thereductionof . demonstratedthat Table 4 41 ). ) Female sexualdysfunction Table 4 Studies concerning adrenal function and FSD.

Patients Scores Pl. vs Control, Method for Studies n DHEA, age n SFV Parameters Values P Comments Adrenal insufficiency 45 24 23–59 Four VAS Frquency of sexual thoughts 27 ± 19 vs 42 ± 23 0.01 The DHEA replacement therapy (50 mg) resulted in a Degree of sexual interest 27 ± 20 vs 45 ± 22 significant improvement in SD and also in reduction of Mental satisfaction with sex 36 ± 30 vs 55 ± 25 and after four months of treatment. Physical satisfaction with sex 34 29 vs 51 26 Downloaded fromBioscientifica.com at10/02/202106:40:02AM ± ± 46 39 18–70 McCoy’s SSQ Desire 8.3 ± 2.4 vs 8.3 ± 2.2 No effect The DHEA replacement therapy (25 mg) does not have a Problems 5.3 ± 2.3 vs 4.8 ± 2.9 major impact on subject health status or sexuality. Satisfaction 19.2 ± 4.6 vs 18.8 ± 3.4

https://eje.bioscientifica.com 47 15 61.5 ± 1.7 ESF Fantasies 2.20 ± 0.43 vs 2.13 ± 0.45 No effect The DHEA replacement therapy (50 mg) did not affect Libido 2.27 ± 0.33 vs 2.20 ± 0.37 sexual functions Satisfaction 3.07 0.25 vs 3.20 0.22

± ± 182 Problems with lubrification 1.60 ± 2.60 vs 2.47 ± 0.36

Problem with orgasm 1.70 ± 0.27 vs 2.10 ± 0.31 :6 Pain 1.30 ± 0.21 vs 1.40 ± 0.16 Cushing’s Syndrome 58* 29 30 FSFI 16.6 (5–23) <0.0001 According to FSFI 24 women (88%) with Cushing had an SD 26.8 (25.5–30.4) R107 *Age: 34–42. via freeaccess Pl, placebo; SFV, sexual function valuation; SSQ, sex scale questionnaire; VAS, visual-analogue scales. European Journal of Endocrinology https://eje.bioscientifica.com 29 CS women had a SD.Moreover, arousal, lubrication, scores withrespecttohealthy controls,24(88%)outof study thatshowed women withCShadlowerFSFI presence ofSDinthecase CS( syndrome (CS)( circulating levelsofglucocorticoidsresultinCushing’s based onthekindofhormoneproduced.Excessive adrenal glandresultsindifferentclinicalphenotypes, Exaggerated productionofsteroidhormonesfromthe Hypercortisolism his/her clinicalhabit in theinterestof patient’s health. abridged form,shouldconsiderthepossibilitytochange addressing sexualfunctionwithFSFI,atleastinits is managingfemalepatientswithadrenaldiseaseswithout health inaffectedpatients. that hyperandrogenismfromCAHcouldimprovesexual evidence fromcurrentliteraturesupportsthenotion treatment with transdermal testosterone ( proving improvementofsymptomswhileundergoing androgen levels( sexual desiredisorder(HSDD)isassociatedtolower compared to the general population. Although hypoactive of homosexualityandbisexualityamongaffectedwomen of patientswithCAH,reportinganincreasedprevalence studiesonthesexual orientation reviewed observational distress ( CAH havelowersexualfunctionaswellhigher forms ofCAH,concludingthatwomenwithnon-classical recently, Schernthaner-Reiter of sexualdysfunction and depression symptoms. More higher BDI-IIscores,suggestiveofprevalence women withnon-classicalCAHalsohadlowerFSFIand controls ( with lowerscoresinallFSFIdomainscomparedtohealthy sexual functionisseverelyimpairedinthesepatients, studied sexualfunctioninclassicalCAH,suggestingthat long psychosocialdifficulties( differentiation resulting in ambiguous genitalia and life- Classical CAHisalsoassociatedwithdisordersofsexual minor extent,withbisexual/homosexualorientation( of childhoodbehaviorwereassociated,althoughtoa CAH, bothprenatalandrogenizationandmasculinization and isoftendiscoveredlaterinlife( non-classical, late-onset form of CAH is clinically milder virilization ofexternalgenitalia;ontheotherhand with salt-wastingcrisesand,inwomen,prenatal reported: the classical form is more severe and manifests Review In conclusion, a contemporary endocrinologistwho In conclusion,acontemporary 48 51 ). Additionally, Gondim ); likewise, Krysiak ); likewise,Krysiak 57 53 ). Onlyasinglestudyanalyzed the , 54 ), withdatafromclinicalstudies t al et 50 t al et 58 others E Carosa,ASansoneand ). Gastaud ). Thisisacasecontrol . compared the two 48 . havereportedthat ). Inbothformsof t al et 55 . ( , t al et 52 56 ) have ), little . have 49 ). showing a relationship between HH and SD, most likely FSFI thancontrolsubjectsin allanalyzeddomains,thus Furthermore, womenwith HH hadlowerscoresonthe reported SD–comparedtoonly 30%inthecontrolgroup. in thebloodwasbelow50 pg/mLand68%ofpatients aged 22–41years;intheHHgroup,levelsofestrogen study recruitingsexuallyactivewomenwithHHand sexual function.Barut a bettermodeltoseetheeffectofestrogenonfemale with hypogonadotropichypogonadism(HH)areprobably FSFI scoresinestradiol-treatedwomen( obtaining thesameresult:asignificantimprovement of 4-year prospectivestudyon727postmenopausalwomen, analyzed theeffectofestrogentherapyvsplaceboin a women inearlypost-( improvement of sexual functions when performed in treatment with induces statistically significant and the partner’s sexual health ( general healthstatus,theclinicalandobstetrichistory, by the effects of aging and other related factors, like the However, studyingSDduringmenopauseiscomplicated the effectsofestrogendeficiencyonsexualfunction. menopause was,infact,usedasamodelforexploring hypothalamic .Theeffectoflowestradiol hypothalamic pituitary premature ovarianfailure,Turner’s syndrome,and Estrogen deficiencycanhavevariouscauses:menopause, Estrogen likely.considered very image induced by thedisease or bythesyndrome is tobe and SQoLbecauseofthespecificalterationinbody sexual drive (despite a relative hyperandrogenism) the possibilitythatCushingpatientsmayhavereduced on glucosemetabolism,orothersystems.Moreover, a directeffectofcortisolexcessonotherhormonalaxes, effect ofcortisolonsexhormones.We mayhypothesize the hypothesisthatSDmaybecorrelatedtoinhibitory correlation betweenFSFIscoresandLHlevels,supporting significantly lowerinpatientswithCS.Thereisapositive orgasm, andsatisfactionsubdomainsofFSFIwere menopausal women is high, between 68% and 86% ( effects onsexualfunction.TheprevalenceofSDinpost- known to regulate mood and desire, which may also have of serotonergicfunction,affectingregionsthebrain onset ofsexualdisorders.Estradiolisalsoamodulator ( accompanied bysymptomsofvulvovaginalatrophy anddyspareunia,often levels resultsinvaginaldryness Female sexualdysfunction 50 ). Thesesymptomssignificantlycontributetothe Downloaded fromBioscientifica.com at10/02/202106:40:02AM t al et . performedacase-control 60 , 61 62 182 ). Systemic or local ). In2017,Taylor 63 :6 ). Young women R108 59 via freeaccess ): European Journal of Endocrinology female sexualdysfunctions. Table 5 tenderness, andbreastendometrialcancerwasnot incidence of vaginal bleeding, endometrial cancer, analysis ofavailablecontrolledstudiesshowedthatthe with theotherlocalestrogentherapies( significantly greateradherenceandpersistencecompared ( dependent pain women experience with fragile, resultinginareductiontheamountofGSM- which selectivelymakesvaginaltissuethickerandless ospemifene hasanestrogenagonist/antagonistactivity in others(antagonism,suchasthebreast).Hence, such asinvagina)andblockadeofthesamepathways of theestrogenicpathwaysinsometissues(agonism, which bindstoestrogenreceptorsandresultsinactivation interesting selectiveestrogenreceptormodulator(SERM) definition byPortman tractinfections’(citingthe dysuria andrecurrenturinary symptomsofurgency,impaired function;andurinary symptoms oflacklubrication,discomfortorpain,and burning, and irritation; sexual symptoms of dryness, decrease, andincludes,‘butisnotlimitedto,genital describes thesyndromewhichisassociatedwithestrogen ( justified orunmotivatedfearofneoplasticconsequences the hormonereplacementtherapy(HRT)becauseof many women,mostlyinthelattergroup,donotaccept syndromeofmenopause, failures, suchasgenitourinary due tocongenital,acquired,orage-dependentovarian administration remainsthebesttreatmentoffemaleSD correlated withspecifichormones. controls, butthepoorsexualfunctioningmaynotbe and patientswithOCHscoredlowerrespecttothe subjects and the OCH group were found in FSFI domains, hormone replacementtherapy. NodifferencesbetweenTS estrogen levelsbecauseallwomenwerereceiving (OCH) andTurner’s syndrome(TS)withoutconsidering the sexualfunctionincaseofcongenitalhypogonadism after therapy( The bigger limitation of this study was the absence of data due to the effects of reduced levels of ovarian hormones. 68 66 Review ). Interestingly, patientstreatedwithospemifene have syndromeofmenopause(GSM) ). Genitourinary While systemic (or at least local) estrogen While systemic (or at least local) estrogen Sexual functiondomains(accordingtotheFemaleFunction Index(FSFI))andendocrinediseasesassociatedwith Pain Satisfaction Orgasm Lubrication 64 ) ( Table 5 t al et ). Anotherpaper( . ( 67 others E Carosa,ASansoneand )). Ospemifene is a new )). Ospemifeneisanew 69 Diabetes andestrogendeficiency Diabetes andhypercortisolism Diabetes andhypercortisolism Hypothyroidism, diabetes,and hypercortisolism Hyperprolactinemia, diabetesand hypercortisolism Hyperprolactinemia, hypoandrogenism,diabetes,andestrogen deficiency ). Arecentmeta- 65 ) analyzed frequently diagnosed endocrine affections in females syndrome(PCOS)isamongthemost Polycystic ovary Polycystic ovarysyndrome deficiency. few data are available for young women with estrogen impair sexualhealthandfunction( devastating psychologicalburdenandpossiblynegatively hyperandrogenism: boththeseconditionscanhavea menstrual irregularities,suchasoligomenorrhea,and abnormalities ( morphology, dysfunction,andmetabolic ovulatory of reproductiveageandfeaturespolycysticovarian estrogen orospemifeneinGSMduringmenopause( however, while many reports recommend the use of improve sexualfunctioninyoungandoldwomen; estrogen therapies. who arenotcandidatesforsystemicnorlocalvaginal severe symptomaticGSMinpost-menopausalwomen of theendocrinologistfortreatmentmoderateto findings, ospemifene appears as anew tool in thehands respect togeneralpopulation( significantly differentinospemifene-treatedpatientswith self-esteem. In adulthood, PCOS can lead to obesity, when occurring in adolescencebynegatively influencing mild tosevere,whichcanalsoaffectsexualdevelopment a variableclinicalentity, withsymptoms ranging from These findings,however, requiresomecaution:PCOSis for the arousal and lubrication domains were reported. not increasetheriskoffemaleSD,althoughlowerscores using differentquestionnaires,concludedthatPCOSdoes included theaforementionedstudies,aswellothers review andmeta-analysisbyZhao pain, andsatisfactioninPCOSwomen.Asystematic study ( no significant difference in all domains, whereas a single by usingtheFSFI;fivestudies( investigated femalesexualdysfunctioninPCOSpatients Female sexualdysfunction In conclusion,thesedatasuggestthatestrogens 79 ) reportedworsescoresforarousal,lubrication, 72 , 73 ). Mostaffectedpatientsdevelop Downloaded fromBioscientifica.com at10/02/202106:40:02AM 70 74 https://eje.bioscientifica.com ). On the basis of all these ). Onthebasisofallthese , 75 72 182 , t al et ). Sixstudieshave 76 :6 , 77 . ( , 80 78 ) which ) found R109 71 via freeaccess ),

European Journal of Endocrinology https://eje.bioscientifica.com associated withfrequencyof masturbationanddesire. , desire,andarousal. DHEASwaspositively of testosteronewasnegatively associatedwithfrequencyof frequency ofmasturbation and desirethe lower quartile 6 months.Testosterone waspositivelyassociatedwith frequently theyengagedinmasturbationtheprevious were asked to report how often they felt desire and how Women’s HealthAcrosstheNation(SWAN) ( reported sexualfunctioninparticipants in the Study of sex steroidsandfollicle-stimulatinghormoneself- dysfunctional women. androgen deficit has not been demonstrated in supplementation shouldbeinformedthatanabsolute ( of thetwoprecursorsteroidsDHEASandandrostenediol sexual desire,buttheyfoundsignificantlylowerlevels reduced androgenactivityinwomenwithhypoactive In apreviousstudy, Bassonandcolleaguesdidnotfind who were not using systemic . associated with sexual desire in women 25 to 44 years old and freetestosterone, androstenedione, and DHEASwere with sexualdesireinwomen19to24yearsold,andtotal age. Freeandtotaltestosteronelevelswereassociated sexual desireintheentiregroupafteradjustmentfor and androstenedioneweresignificantlyassociatedwith desire wasmeasuredbytheFSFI.Bothfreetestosterone were measuredbyliquidchromatographyandsexual women 19to65years old ( and sexualdesirewasinvestigatedin560healthyDanish RIA ( function. Inthisstudy, androgensweremeasuredwith single androgenlevelispredictiveoflowfemalesexual sectional Australianstudyhasdemonstratedthatno the lowerendoffemalerange.Infact,alarge,cross- limitations, as the precision of the assay was scarce at of RIA against ahighlysensitivetestosterone assay have low accuracy. Evenstudiesthatvalidatedtheaccuracy as commercial testosteroneradioimmunoassayshave In women,testosteronedeficiencyisdifficulttodefine Testosterone deficiency transition toovertdysfunction. identify and treat any subclinical SD before its eventual investigating sexualfunctioningissuggestedinorderto not suggestasubstantialeffectofPCOSonsexualhealth, affect sexual health ( depression, andinfertility, allofwhichcannegatively 83 Review ). Theyconcludedthatwomenreceivingtestosterone Randolph 81 ). Recently, theassociationbetweenandrogens et al . investigated the associations between . investigatedtheassociationsbetween 80 ). Evenifcurrent evidence does 82 ). Inthisstudy sex steroids others E Carosa,ASansoneand 84 ). Women However, fewgynecologistsandendocrinologists very for the HSSDin women with precocious menopause ( The hormonewasindeedapprovedaspatchesof300µg vascular, endocrine,andpsychiatricare potentially ( communicable chronicdiseases affectingsexuallife Diabetes isknowntobeone ofthemostdiffusenon- Diabetes encouragingresults. with preliminary doses oftestosteronegelonthepostmenopausalclitoris the woman( maintains itsfullresponsivitytotestosteroneatallages of clear thattheclitorisitself,differentlyfrompenis, the vaginalpenetration( , whichisthetriggerofsexualpleasureduring anatomical structuresnamedclit-urethra-vaginal(CUV) to befoundinthe androgen DHEAinthemenopausalvaginaisprobably dyspareunia ( improve SDinpost-menopause,suchasmoderatetosevere trials havedemonstratedthatlocalvaginalDHEAmay future: somedouble-blind,placebo-controlledclinical ( difficulties indosinglowlevelsoftestosteronewomen ofhormones,andthementioned based publicworry sexual medicine,theoftenirrationalandnotevidence- in femalesexualdesire,theabsenceofspecificculture due toseveralfactors,suchasthelackofmedicalinterest symptom inmenopause.This‘testosteroneWaterloo’ was frequentsexual despite theevidencethatHSDDisavery fewpatientsrequestedthistreatment, prescribed itandvery for testosteronetherapyinpost-menopausalwomen( treatment ofHSDDistheonlyevidence-basedindication International SocietyofEndocrinology, clearlystatesthat the InternationalSocietyforSexualMedicine,and International MenopauseSociety, theEndocrineSociety, societies studyingfemalesexualhealth,amongwhichthe testosterone. Apositionstatementissuedin2019byseveral treating female SD, is the transdermal and topical use of may provideinteresting data fortheendocrinologist function ( women with low desire from women with normal sexual the cutofflevelforandrogenthatwilldistinguish toestablish in women,butmorestudiesarenecessary between androgenlevelsandsexualinterestarousal Female sexualdysfunction 2 87 ); its complications, neurological, micro- and macro- ). The local administration of androgens could be the A new interesting avenue of research, which Taken together, allthesestudiesdemonstraterelations 81 ). 90 88 ), wearecurrentlyexploringtheuseoflow ). Therationaleoftheuseweak bona fide Downloaded fromBioscientifica.com at10/02/202106:40:02AM 89 androgen-dependence of the ). Moreover, havingmade 182 :6 R110 86 85 via freeaccess ). ).

European Journal of Endocrinology and amongdiabeticpatients, depressionisseemingly severely affectedbydiabetes anditscomplications( diabetes shouldnotbeunderestimated: qualityoflifeis SD. Intheseregards,thepsychological consequencesof of themultifactorial involvement ofdiabetesinfemale sexual functioning( presence ofhypertensionarealsoassociatedwithworse of diabetes,insulinandantidepressanttherapy, and impaired in type 2 diabetes: older age, longer duration all domainsofthefemalesexualresponsearesignificantly and .Additionally, Tuncel and satisfaction ( such levelnegativelyaffectarousal,lubrication,orgasm, oxygen tension,provingthatvasculardysfunctions at clitoral tissue perfusion measured through transmucosal on youngwomen,Coppola in reducedperipheralarousal( engorgement of clitorisandvagina, ultimately resulting Reduced bloodflowtogenitaltissuescanleadimpaired effect relationshipcannotbetakenforgranted( explanation forsuchassociation,althoughadirectcause- female genital tissues couldprovideapathophysiological factors andfemaleSD:endothelialdysfunctioninthe investigating theassociationbetweencardiovascularrisk recently, Maseroli lubrication, satisfaction, orgasm, and pain ( compromised intype1diabetes,includingarousal, 2006, provedthatmostdomainsofsexualfunctionare of SD in female diabetic patients. Salonia sexuality inrecentyears( suggesting increasedawarenessconcerningfemale prevalence offemaleSDoverthelast15years,possibly Meta- analysishasalsosuggestedanincreased diabetes andsignificantlyassociatedwithdepression( high overallprevalence( investigating thistopichaveproventhatfemaleSDhas demonstrated ( compromised in diabetes ( diabetes. However, sexualfunctioninbothsexesislargely considered inclinicaltrialsinvestigatingcomplicationsof in maleSD,femalesexualfunctionisnotfrequently large bodyofevidencesupportingarolefordiabetes with worseningerectilefunctioning( status, atherosclerosis,andoxidativestressareassociated syndrome anddiabesityinwhichtheinflammatory prominently featuredinconditionssuchasthemetabolic affect erectilefunction( both vascularandneurologicalimpairmentultimately debilitating and might severely impair the SQoL. In men, Review Many factorsarelikelyinvolvedinthepathogenesis 94 101 ). Infact,recent meta-analysis studies ), even after adjusting for age, BMI, t al et 102 95 95 ), providingadditionalproof 91 93 ), beingfeaturedinalltypesof . havereviewedliterature ). et al ); additionally, maleSDis ), as pioneering studies have 99 . havecorrelatedFSFIand others E Carosa,ASansoneand , et al 100 . havereportedthat ); inarecentstudy 92 ). Despitethe 97 t al et ). More 103 ., in 96 98 ). ), ). different domainsofsexual healthseemtobeaffected for psychologicalaswell organic reasons.Additionally, thyroid disease–seemstoimpair sexualfunction,possibly a cases, the presence of an underlying condition – even and sexualfunctionthroughhyperprolactinemia.Inmost effects on reproductive adrenal diseases, and inhibitory in diabetes,impairedandrogenactionorsecretion in identified, suchasmicro-andmacro-vascularalterations Several mechanismsaffectingsexualhealthhavebeen sexual alterations are associated to endocrinediseases. studies, but their conclusions indicate that, frequently, increased. Mostofthemweresmallplacebo-controlledpilot sexual functioninwomenwithendocrinediseases In lastfewyears,thenumbersofstudiesthatevaluated Conclusion in goutpatients. underlines thatsexualhealthisanoften-neglectedaspect inventories forassessmentofsexualfunction,thisstudy Despite thesmallsamplesizeandlackofstandardized burden on relationship in bothmenand women ( intimacy werecompromisedbygout,withasignificant both thephysicalandemotionalcomponentsof without theuseofFSFI:authorsconcludedthat between goutandsexualfunctioninwomen,although Surprisingly, asinglestudyhasaddressedtheassociation joints andtendons.Goutisassociatedwithasignificant inthe accumulation ofuricacidanditscrystallization Gout isacommonmetabolicdiseaseresultingfrom Gout this chronicandworseningdisease. the lifestyleandtodifficulttherapies,characteristicsof increase thecompliancetochallengingadjustmentsin how addressing SD in diabetic patients of both sexes may satisfaction ( of theFSFI,mostnotablyonsexualdesireand has alsoshownpositiveeffectsonthedifferentdomains metformin treatmentaimedtoimproveglycemiccontrol correlates withtheFSFIscore( scale,negatively via theBeckDepressionInventory depression indiabeticandpre-diabeticpatients,measured more prevalentinfemales( disability ( impairment in QoL, mostly resulting from pain and Female sexualdysfunction minor condition,suchasinthe case ofautoimmune 110 109 ); however, SQoL is also affected ( ). We arecurrentlyevaluatingifand Downloaded fromBioscientifica.com at10/02/202106:40:02AM 104 https://eje.bioscientifica.com , 107 105 , 182 , 108 106 :6 ). Interestingly, ). Furthermore, R111 112 111 via freeaccess ). ). European Journal of Endocrinology https://eje.bioscientifica.com References article. review this of content intellectual the to contributed equally S A and C E Author contributionstatement the public,commercial,ornot-for-profitsector. This research did not receive any specific grant from any funding agency in Funding following authors havenothingtodisclose. the for speaker paid and/or consultant companies: Bayer, Ibsa, Lundbeck, Menarini, Otsuka, and Pfizer. The other been has or is J A E Declaration ofinterest matter theirageortheconcomitantillnesses. guarantee asatisfyingsexualfunctiontoallpatients,no and therapeutic support should be provided in order to part ofQoL,andtherefore,inallcasespsychological worth mentioningthatsexualhealthisafundamental female endocrinepatients,anSDispresent.Italso for evaluationandtreatmentif,asfrequentlyoccursin validated psychometrictoolsandofferthemalternatives daily clinical practice old ( patients about their personal sexual function, using in the sexual disorder. Theendocrinologistshoulddiscusswith a closecorrelation between hormonal alterations and the sexualfunction,strengtheninghypothesisof cases, hormonal therapy has led toan improvement in the caseofhyperthyroidismorGHdeficiency. Insome endocrine diseasescanimpairsexualfunction,asin the unexplainedmechanismsthroughwhichseveral affected patients.Futureresearch shouldaimtoidentify and symptoms accompanying sexual dysfunction in should guidethediagnosticprocess,basedonsigns never suggested. Indeed, clinical judgment and suspicion pathologies arecomplex.Blindlyprescribingbloodtestsis studies aresmallandpartlybecausethecausesofsexual directly linked to hormonal alterations, partly because difficult tounderstandwhetherthesexualdisorderis by differentconditions( 3 2 1 Review Studd J &Schwenkhagen A.Thehistorical responsetofemale Jannini EA. SM Jannini EA &Reisman Y. MedicineWithout sexualmedicineisnot maturitas.2009.02.015) sexuality. doi.org/10.1016/j.sxmr.2017.04.002) dependent manner. medicine forfacingnon-communicable diseasesinagender- 943–945. political anduniversityauthorities. medicine: anMJCSMandESSMpetitiononsexualhealthtothe (https://doi.org/10.1016/j.jsxm.2019.04.001) Maturitas =

SM: theinterfaceofsystemsmedicineandsexual 2009 Sexual MedicineReviews 63 107–111. Table 5 113 , Journal ofSexualMedicine Journal 114 others E Carosa,ASansoneand (https://doi.org/10.1016/j. ). Itis,therefore,often ) and new ( 2017 5 349–364. 115 2019 (https:// ) well 16

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