PCOS enigma and challenges. Natural history. Sven O. Skouby, M D, DM Sc

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1 eigma ad challeges Sve O. Skuby, M D, DM Sc Reprductive Medicie Uit Dep. Ob/Gy. Herlev/Getfte Hspital, Faculty f Medical ad Health Scieces Uiversity f Cpehage, Dem ark The NORDIC MENOPAUSE Sciety Disclsures Pharma fudig Pharma Advisry Bards ESC Past Presidet EMAS Past Presidet IMS Bard NOMS Past Presidet Cflicts f iterests: il Herlev/Getfte Hspital Herlev/Getfte Hspital Learig bjectives Learig bjectives Prevalece f : >% The m st prevalet edcrie dysfucti am g fertile Apart frm varia dysfucti cliical peetrati f metablic disturbacies ad CVD risk are liked t phetypes Etilgy: ukw Natural histry

2 Fetal prgrammig f Hrmal iteractis i PCO S Gur EB et al, WJD, 2, 96-2 Natural histry f. has a multifactrial aetilgy that icludes itra-uterie, geetic ad evirmetal factrs which might r might t be iterrelated. Aders Saches de Mel et al. Reprducti 2;:R-R2 2 Sciety fr Reprducti ad Fertility Csequeses f IR Csequeses f IR 2

3 Herlev/Getfte Hspital Herlev /Getfte H Defiiti f phetypes accrdig t the Rtterdam criteria The Rtterdam criteria. Olig-/amerrhea 2. Cliical ad/r bichemical hyperadrgeism. Plycystic varies (PCO) Ad exclusi f ther related disrders Features Phetype Phetype 2 Phetype Olig-/amerrhea Cliical ad/r bichemical hyperadrgeemia Hetergeeity! Phetype Plycystic varies Fauser B.C.et el, Hum Repd 2 Ja;9():-7 8 Herlev/Getfte Hspital ad BMI Metablic assciatis/c-mrbidity -6% BMI > Isuli resistace (IR) Impaired glucse tlerace Dyslipidemia Type 2 diabetes Cardivascular (CVD) 22 Fertil Steril 2; 2:-

4 Assessmet f Cardimetablic Prfile betwee the differet phetypes Obesity (BMI kg/m2), verweight (BMI kg/m2), hypertesi (BP /9 mm Hg), elarged waist circumferece ( 88 cm), hyperglycemia (fastig glucse >6. mml/l), isuli resistace (/HOMA-IR <.7), dyslipidemia (TC. mml/l, TG >.7 mml/l, LDL-C. mml/l, HDL-C <.2 mml/l) ad presece f metablic sydrme (MetS; ATP III criteria, presece f three r mre f ay f the fllwig cliical features: waist 88 cm, fastig glucse.6 mml/l, BP /8 mm Hg, HDL <. mml/l, TG.7 mml/l) Cclusi(s) Wme with hyperadrgeic have a wrse cardimetablic prfile ad higher prevalece f CV risk factrs cmpared with with hyperadrgeic. Fertil Steril 2; 2:- phetypes traslate t differet edcrie ad metablic csequeces - Hwever, fr mst beefical iterveti attempts icrease i isuli sesitivity seems t be pivtal

5 Herlev/Getfte Hspital : CVD i relati t phetypes Tekst starter ude A r e p h e t y p e s f w m e w it h P C O S b a s e d B M I a d i s u l i r e s i s t a c e a r e m r e c a u s a lly a s s c ia t e d w it h d is t i c t C V D r is k p r f ile s h BMI www. AJOG.rg + IR IR + O b e s it y + O b e s it y OLOGY vary sydrme ather risk factr fr veus sm? Uited States, 2 28 rss-sectial aalysis usig Thms bases fr the years 2 thrugh 28. S amg aged 8- years was riable lgistic regressi mdels., was 7.2 fr OS. Cmpared with withut Tekst starter ude e likely t have VTE (adjusted dds IR + IR O b e s it y Ehedes Craig Hper, PhD; Hai K. Atrash, MD; Hussai R. Yusuf, MD; Sheree L. Bulet, DrPH e prevalece ad likelihd f veg with ad withut plycys- IR Ehedes Sted g O b e s it y 2 rati [aor] 8-2 years,.26; 9% cfidece iterval [CI], 2.6.8; aor 2- years, 2.9; 9% CI, ; aor - years, 2.; 9% CI,.8 2.8). A prtective assciati (dds rati,.8; 9% CI,.7.98) with ral ctraceptive use was ted fr. CONCLUSION: might be a predispsig cditi fr VTE, partic- Herlev Hspital ularly amg aged 8-2 years. Oral ctraceptive use might be prtective. D is t r ib u t i f B M I/IR - p h e t y p e s a c c c r d i g t t h e le v e l f E T P a d C R P t h r m b prevalece, g ra m Key wrds: plycystic varyasydrme, veus thrmbemblism er WC, Atrash HK, et al. Is plycystic vary sydrme ather risk factr fr veus thrmbemblism? Uited States, 27:77.e-8. % l C wp R, L ETP w i gh H C P,R H ig ETh P 7 6 (VTE) is icludes DVT) ad itial prederess, itic chest mptms. s, Natial pmetal trl ad y 7, 22; reprt are essarily Ceters fr rest. Epidemic ata, GA, Divisi f Birth ies, veti, ta, GA.7 see that with were times mre likely t have a family histry f veus thrmbsis.2 Mak ad Dkras22 hypthesized that with likely have a icreased baselie risk fr develpig thrmbsis cmpared with ther i the geeral ppulati. Hwever, study has evaluated the prevalece f VTE amg with cmpared with withut. Give the ptetial fr thrmbtic amg with, the purpse f this study was t: () determie the prevalece f VTE amg with ad thse withut ; ad (2) assess the assciati betwee ad VTE. VTE is the third mst cmm cardivascular after mycardial ifarcti ad strke amg the geeral ppehedes 2, ulati. Sted gthe verall aual icidece f VTE is estimated t be -2 per adults per year.-7 These icidet estimates, hwever, might t represet the etireehedes ppulati because VTE ici dece differs by age ad race, ad slightly by sex. VTE is a multifactrial with bth iherited ad acquired risk factrs. I 26-7% f first-time VTE cases, the etilgy is ukw,,8; a pssible predispsig cditi t yet assessed is plycystic vary sydrme (). www. AJOG.rg is the mst cmm edcrie M ATERIALS AND M ETHODS disrder affectig f GYNECOLOGY reprduc- Data surce GENERAL tive age. Estimates f its prevalecevary vary sydrme Is plycystic ather risk factr veusfrm Data fr the study were fr derived 9-2 thrmbemblism? States, 2 28 ad rage frm 6%. Its exact eti- Uited the 2 thrugh 28 Thms ReuEkwutsi M. Okrh, MD; W. Craig Hper, PhD; Hai K. Atrash, MD; Hussai R. Yusuf, MD; Sheree L. Bulet, DrPH lgy is ukw, but it is characterized ters MarketSca Cmmercial datawww. OBJECTIVE: We sught t determie prevalece ad likelihd f2 [aor] 8-2 years,.26; 9% cfidece iterval [CI], 2.6 AJOG.rg by a hetergeeus presetati f hybases. ve- ratithese databases cmprise us thrmbemblism (VTE) amg with ad withut plycys-.8; aor 2- years, 2.9; 9% CI, ; aor - years, tic vary sydrme (). 2.; 9% CI,.8 2.8). A prtective assciati (dds rati,.8; peradrgeism, vulatry dysfucti, lgitudial, deidetified health i9% CI,.7.98) with ral ctraceptive use was ted fr STUDY We perfrmed a crss-sectial aalysis usig Thms GENERAL GYNECOLOGY DESIGN:. MarketSca Cmmercial databases fr the yearssurace 2 thrugh 28. claims data frm large emad plycystic varies.reuters is als asthe assciati betwee VTE ad amg aged 8- years was CONCLUSION: might be a predispsig cditi fr VTE, particis plycystic vary sydrme ather risk factr fr veus assessed usig age-stratified multivariable lgistic regressi mdels. ularly amg aged 8-2 years. Oral ctraceptive sciated with isuli-iduced elevatis plyers ad health plas acrssuse might the be prtective. RESULTS: Prevalece f VTE per, was 7.2 fr thrmbemblism? Uited States, 2 28 f plasmige activatr (PAI)-, Uited States ctai ifrmati ad ihibitr 9.8 fr withut. Cmpared with withut Key wrds:ad plycystic vary sydrme, prevalece, veus, thse with were mre likely (adjusted dds thrmbemblism t have VTE M. Okrh, MD; W. Craig Hper, PhD; Hai K. Atrash, MD; Hussai R. Yusuf, MD; Sheree L. Bulet, DrPH which is a ptetekwutsi ihibitr f fibrilysis. ipatiet admissis, utpatiet While sme studies have fud t visits, ad pharmaceutical claims. The OBJECTIVE: We sught t determie prevalece ad likelihd f ve- rati [aor] 8-2 years,.26; 9% cfidece iterval [CI], 2.6 eus thrmbemblism (VTE) with is ad that times be assciated with crary heart data frm multiple US aor - years, us thrmbemblism (VTE) amg withutare plycys-derived.8; aor 2- years, with 2.9; 9%were CI, ; V a chric cditi that icludes mre likely t have a family histry f 2 (dds rati,.8; vary sydrme ().thrmbsis (DVT) ad VTE is the third mst cmm 2.; 9% CI,.8 2.8). A prtective assciati bth deep vei ad Dkras cardi- veus thrmbsis. Mak risk factrs,-2 ticther studies have shw states that are gegraphically diverse. 9%ifarcCI,.7.98) withthat ral ctraceptive use was ted fr pulmary emblism (PE). Iitial pre- vascular after mycardial hypthesized with Cite this article as: Okrh EM, Hper WC, Atrash HK, et al. Is plycystic vary sydrme ather risk factr fr veus thrmbemblism? Uited States, Am J Obstet Gyecl 22;27:77.e STUDY DESIGN: We perfrmed a crss-sectial aalysis usig Thms setati might be leg pai, tederess, ti ad strke amg the geeral pp- likely have a icreased baselie risk fr. Reuters MarketSca Cmmercial frchest the years 22,thrugh 28.aual icidece develpig thrmbsis cmpared with shrtess f breath, databases r pleuritic ulati. The verall pai, r there be amg symptms. i the ppulati. The assciati betwee VTEmight ad years was CONCLUSION: might be geeral a predispsig cditi fr VTE, particfaged VTE8- is estimated t be -2 per ther NOVEMBER 22 America Jural f Obstetrics & Gyeclgy study has years. evaluated adults per year.-7 These icidet esti- Hwever, assessed usig age-stratified multivariable lgistic regressi mdels. ularly amg aged 8-2 Oralthe ctraceptive use might mates, hwever, might t represet the prevalece f VTE amg with Frm the Divisi f Bld Disrders, Natial be prtective. etirefrppulati because VTE ici- cmpared with withut RESULTS: Prevalece VTE per, was 7.2 Ceter Birthf Defects ad Develpmetal dece differs by age ad race, ad slightly. Give the ptetial fr thrmdisabilities, Ceters fr Disease Ctrl ad ad 9.8 fr withut. Cmpared with withut Key wrds: plycystic vary sydrme, prevalece, veus Preveti, Atlata, GA. by sex. VTE is a multifactrial btic amg with,, thsereceived with mrejuly likely t havewith VTEbth (adjusted dds thrmbemblism May 2,were 22; revised 7, 22; iherited ad acquired risk the purpse f this study was t: () de- 77.e accepted August, 22. factrs. I 26-7% f first-time VTE termie the prevalece f VTE amg,,8 The fidigs ad cclusis i this reprt are risk withfactr ad thse withut ; cases, is ukw ; a ps- ather Cite this article as: Okrh EM, Hper WC, Atrash HK, et the al. etilgy Is plycystic vary sydrme fr veus thrmbemblism? Uited States, thse f the authrs ad d t ecessarily sible predispsig cditi t yet as- ad (2) assess the assciati betwee Am J Obstet Gyecl 22;27:77.e-8. represet the fficial psiti f the Ceters fr sessed is plycystic vary sydrme ad VTE. Disease Ctrl ad Preveti. (). The authrs reprt cflict f iterest. is the mst cmm edcrie AND M ETHODSwith were times Preseted rally at the 6th Aual Epidemic eusitelligece thrmbemblism (VTE) is disrder affectig f reprduc- M ATERIALSthat Service Cferece, Atlata, GA, Data surce a chric cditi that icludes tive age. Estimates f its prevalece vary Data fr the mre likely t have April -, 2. study were derived frm a family histry f Ekwutsi M. Okrh, MD, Divisi ad rage frmthird 6%.mst Itscmm exact eti- the bth deep Reprits: vei thrmbsis (DVT) adf VTE veus 2 thrugh 28thrmbsis. Thms Reu- Mak ad Dkras is the cardibld Disrders, Natial Ceter Birth lgy is ukw, but it is characterized ters MarketSca Cmmercial datapulmarydefects emblism (PE). Disabilities, Iitial pre- vascular after mycardial ifarchypthesized that with ad Develpmetal by a hetergeeus presetati f hy- bases.2 These databases cmprise Ceters fr Disease Ctrl ad Preveti, setati might be leg pai, tederess, ti have a icreased baselie risk fr ad strke amg the geeral pp- likely peradrgeism, vulatry dysfucti, lgitudial, deidetified health i6 Clift Rd., Mailstp E6, Atlata, GA 2, shrtess. f breath, r pleuritic chest ulati. develpig cmpared with ad plycystic varies. aual is als as-icidece Ekrh@cdc.gv. The verall surace claims data frm thrmbsis large em2-978/free sciated plyers health plas acrss the geeral ppulati. pai, r there might be symptms. f i the VTEwith is isuli-iduced estimated televatis be -2 per ad ther 22 Msby, Ic. All rights reserved. f plasmige activatr ad ctai ifrmati -7ihibitr (PAI)-, Uited StatesHwever, study has evaluated the adults icidet which is a per ptetyear. ihibitr fthese fibrilysis. estiipatiet admissis, utpatiet prevalece claims. f VTE mates, hwever, might represet While sme studies have fudt t visits,the ad pharmaceutical Theamg with Editrs Cmmetary, see Frm the Divisi ffr Bld Disrders, Natial be assciated with crarybecause heart are derived multiple US frm cmpared with withut etire ppulati VTEdataiciCtets Ceter Birth Defects ad Develpmetal risk factrs,-2 ther studies have shw states that are gegraphically diverse.2 dece differs by age ad race, ad slightly. Give the ptetial fr thrmdisabilities, Ceters fr Disease Ctrl ad btic amg with, Preveti, Atlata, GA. by sex. VTE is a NOVEMBER multifactrial 22 America Jural f Obstetrics & Gyeclgy 77.e V Received May 2, 22; revised July 7, 22; accepted August, 22. The fidigs ad cclusis i this reprt are thse f the authrs ad d t ecessarily represet the fficial psiti f the Ceters fr Disease Ctrl ad Preveti. The authrs reprt cflict f iterest. Preseted rally at the 6th Aual Epidemic Itelligece Service Cferece, Atlata, GA, April -, 2. Reprits: Ekwutsi M. Okrh, MD, Divisi f Bld Disrders, Natial Ceter Birth Defects ad Develpmetal Disabilities, with bth iherited ad acquired risk factrs. I 26-7% f first-time VTE cases, the etilgy is ukw,,8; a pssible predispsig cditi t yet assessed is plycystic vary sydrme (). is the mst cmm edcrie disrder affectig f reprductive age. Estimates f its prevalece vary ad rage frm 6%.9-2 Its exact etilgy is ukw, but it is characterized by a hetergeeus presetati f hy- the purpse f this study was t: () determie the prevalece f VTE amg with ad thse withut ; ad (2) assess the assciati betwee ad VTE. M ATERIALS AND M ETHODS Data surce Data fr the study were derived frm the 2 thrugh 28 Thms Reuters MarketSca Cmmercial data2 2 BMI 2-IR BMI 2+IR M I> 2 B - IR M I> 2 B + IR BMI/IR phetypes Geeral Gyeclgy Exclusi f ther cditis We excluded wh met the criteria fr ay f the phetypes ad had! f the fllwig cditis: adreal hyperplasia (2. r 2.9), hyperprlactiemia (2.), r thyrid disrder (2., 2., 2.2, 2., 2.8, 2.9, 22.9, r 22.9). Cmbiatis f these cditis were used t create mutually exclusive phetypes based the available criteri recmmedatis (Natial Istitutes f Health, Rtterdam, ad Adrge Sciety). Wme with phetype A, r classic, were defied by the presece f hyperadrgeism (7., 76. r 76., r 7.x) ad vulatry dysfucti (626., 626., 626.2, 626., 626., 626., 626.6, 626.7, 626.8, r 626.9); but plycystic varies (26.), adreal hyperplasia (2. r 2.9), hyperprlactiemia (2.), ad A, W m e w ith c li ic a l h y p e r a d r g e is m ; a d m e s tr u a l r v u la t r y thyrid disrder (2., 2., 2.2, 2., 2.8, 2.9, 22.9, r 22.9) d y s fu c ti A,, Wme r b th. B, W m e w ith h y p e r a d r g e is m a d p ly c y s tic v a r ie with cliical hyperadrgeism; ad mestrual r vulatry dysfucti, r bth. B, s. C, W m e w ith m e s tr u a l r v u la t r y d y s fu c ti, r b th ; a d p ly c y s tic were abset. Defiitis f the remaiwme with hyperadrgeism ad plycystic varies. C, Wme with mestrual r vulatry dysig phetypes are fud i the adc plycystic v a r ie s. D, fucti, W m erbth; w ith li ic a l hvaries. y p e r ad, Wme d r g ewith iscliical m ; m hyperadrgeism; e s tr u a l r mestrual v u la t r yr d y s fu c ti vulatry, r b dysfucti, th ; a d r p ly cad y s tic v a rvaries. ie s. Ay # Wme with ay plycystic vary Appedix. bth; plycystic Due t the hetergeic ature f sydrme () phetype (A-D). N # Wme withut ay phetype (A-D). ad its cmplex presetati ad VTE, veus thrmbemblism. defiiti, we als assessed the prevaokrh. Plycystic vary sydrme ad veus thrmbemblism. Am J Obstet Gyecl 22. lece f assciated cditis see amg with (eg, besity I 28,! milli idividuals were CM) cdes were used t idetify these [278., , 78., r V77.8]; erlled, icludig emplyees ad cditis i the database. Each cdi- ifertility [628. r 628.9]; sydrme X r metablic sydrme [277.7]; ad ditheir depedets wh were aged "6 ti was defied as fllws. years ad gegraphically distributed Cliical hyperadrgeism was abetes [2., 2.2, 2.9, r thrughut the Uited States.2 defied as the presece f ICD-9-CM 2.92]) t prvide additial ifrmathis cmmercial database has met r cdes fr ace (76. r 76.), alpe- ti the frequecy f these cditis exceeded requiremets f the US Health cia (7.x), r hirsutism (7.). Ele- withi the differet phetypes. Isurace Prtability ad Accutabil- vated teststere, ather character- Fr all cditis related t, diagity Act f 996 ad, accrdigly, des t istic f cliical hyperadrgeism, was ses reprted ipatiet claims were require specific patiet cset t partic- t icluded because ICD-9-CM csidered valid; diagses based slely utpatiet claims required that the ipate i the study.2 cdes were available fr this labratry diagses were reprted!2 claims value i the database. that ccurred! days apart. Ppulati Ovulatry dysfucti was defied Wme with pssible VTE durig the We restricted the aalysis t by the presece f ay f the ICD- study perid als were idetified usig 8- years f age. The upper limit f age 9-CM cdes fr the 626 series, which are ICD-9-CM cdes fr DVT (67.x, was set at years t keep withi the age limit used by ther prevalece studies.- cdes dealig with disrders f mestru- 67.x, 67.x, 67.9x,.,.9, Wme with were defied by the ati ad ther abrmal bleedig frm.2,.8,.9,.,.2, presece f hyperadrgeism, the pres- the female geital tract: 626., 626.,.-.2,.8, r.9), PE FIGURE Prevalece f VTE durig study perid, 2 thrugh 28

6 CVD i Classical fllw up studies Ucertaity Remais i Wme with Regardig the Icreased Icidece f Cardivascular Disease Later i Life, Despite the Idisputable Presece f Multiple Cardivascular Risk Factrs at a Yug Age Authr Patiets Iterm ediate Dahlgre 92 N= Pierpit 98 Wild 22- yrs fllw up N=986, diagsed betwee N=2 diagsed befre ctrls utcmes Mre diabetes Mre hypertesi Mre cerebral Mre Diabetes CVD Outcmes SMR.9 (9% CI.7-.2) Similar CHD mrbidity ad mrtality Bart C. J. M. Fauser, a d Philippe Buchard Abstract Sed t J Cli Edcril Metab. 2 Dec;96(2):67-7. di:.2/jc Eltig N=6 2-2 yrs fllw up Mre diabetes Mre hypertesi CVD NS Screeig 2 yrs later (6-79 yrs = vs 2 C) Screeig 2yrs later (=; Dahlgre 992) Stei Levethal, wedge resecti

7 The selecti f studies icluded (=92) May 22, 26 Meta-aalysis f the assciati betwee ad CVD CHD; OR:. P=, MI; OR:. P=.9 Take hme message: Take hme message:. Plycystic vary sydrme () is a cmplex ad hetergeeus that ivlves reprductive ad metablic elemets 2. The Rtterdam critria are t valid fr CVD predicti. There shuld be tw ames fr the phetypes: thse with primarily reprductive csequeces, ad thse with imprtat metablic csequeces. icreases DVT risk depedet phetype ad liked metablic disturbacies 2. Life-lg metablic disturbacies exaggerates CVD risk accrdig t all validated risk markers. Ucertaities t whether per se icreases cliical CVD shuld prbably be explaied by differeces i metablic impact mdulated by phetypes ad medical iterveti. 7