>> GOOD MORNING, WELCOME TO THE SECOND DAY OF THE CONFERENCE. I KNOW THAT YESTERDAY WAS A LONG DAY BUT A VERY WORTH WHILE 1. SO I'M THE FIRST SPEAKER TODAY AND I'LL TALK ABOUT PC OS WITH DIABETES AND GLUCOSE INTOLERANCE, GENERALLY THIS IS WHAT I'LL BE TALKING ABOUT TODAY AND THAT IS THE EPIDEMIOLOGY OF GLUCOSE INTOLERANCE AND MATH O GENESIS AND TREATMENT AND SCREENING RECOMMENDATIONS. SO JUST TO BEGIN SO THAT WE'RE ALL ON THE SAME PAGE, THIS IS THE AMERICAN DIABETES ASSOCIATION CRITERIA FOR DIABETES SO THAT NORMAL IS CONSIDERED A FASTING GLUCOSE LESS THAN A HUNDRED WITH A 2 HOUR BLOOD SUGAR LESS THAN 140. --ALL 2 HOUR TESTS WOULD BRING THE GLUCOSE FROM 240 TO 199 AND THIS IS CONSIDERED A MIDDLE RISK AND THEN THOSE INDIVIDUAL WHO IS HAVE A HIGH RISK WOULD HAVE A 1 C-BETWEEN 5.7 AND 6.4. TRUE DIABETES IS DEFINED AS A GREATER THAN 126 ON FASTING, GREATER THAN 200 ON AN ORAL GLUCOSE TOLERANCE TEST. GREATER THAN 6.5 ON AN AC1 CAND A RANDOM GLUCOSE OF GREATER THAN 200 WITH THE CLASSIC SYMPTOMS. SO THE NUMBERS WERE DERIVED FROM REAL DATA AND THIS IS 1 OF MAJOR OUTCOMES THAT WAS USED WAS RETINOPATHYATHY AND JUST TO THE PREDICTION OF RETINOPATHYATHY AND THE TOP HERE IS THE GLUCOSE AND THE FLASH POINT IS AT 115-MILLIGRAMS WHERE THEY TAKE OFF PERCENTAGE FOR DEVELOPING RETINOPATHYATHY. FOR A 2 HOUR BLOOD SUGAR IT'S 255 HERE AND FOR AN O1 C IT'S 5.9%. SO IT'S AN EXAMPLE HOW THIS IS REAL LYE BASED ON REAL DATA. AND WE'RE--OBVIOUSLY CONCERNED ABOUT DIABETES AND WE'RE CONCERNED THEREFORE ABOUT ANYTHING THAT INCREASES THE RISK OF DEVELOPING DIABETES BECAUSE OF THE OVERALL INCREASE DEATH RISK AND THIS SLIDE LOOKS AT THE DEATH RISK FROM CANCER AND HERE IS A MEAN FASTING BLOOD GLUCOSE WITH A HAZARD RATIO OF 1 EQUAL TO A BLOOD SUGAR OF ABOUT 100 IT INCREASES WITH INCREASING BLOOD SUGAR AND THIS IS EVEN MORE PRONOUNCED WITH VASCULAR DEATHS IN WHICH THERE IS A PRONOUNCED INCREASE IN THE DEVELOPMENT OF DIABETES, AND THE DEVELOPMENT OF VASCULAR DEATH IN INDIVIDUALS WITH HIGH BLOOD SUGARS AND ON THE RIGHT IS NONCANCKER NONVASCULAR DEATH. SO THESE ARE ALL SIGNIFICANT REDICKERS PARTICULARLY OF RASCULAR DEATH. SO, WHAT--THIS IS 1 OF THE VERY EARLIEST DESCRIPTIONS OF KNOWING THERE'S AN ELEVATED GLUCOSE AND ELEVATED INSULIN IN WOMEN WHO HAVE WHAT WAS THEN CALLED TCOD. SO THE 1980 REPORT SHOWED THAT THIS IS WOMEN WHO HAD--IN ALL GLUCOSE TOLERANCE TEST, THESE ARE WOMEN WHO HAD IN RED WHERE PC OD PATIENTS AND THESE ARE--THESE WERE CONTROLLED OBESE WOMEN AND ON THE RIGHT SIDE IS THE--YOU COULD SEE IT AS WELL AND HERE IS THE OBESE WOMEN AND HERE IS THE WOMEN WHO HAD PC OD. SO THE QUESTION WAS, WAS IT JUST OBESITY, WAS IT JUST POCD AND FURTHER DATA WOULD SAY THAT IT--IT WAS NOT JUST A MATTER OF BMI, BUT--IT OCCURRED BOTH IN LEAN AND OBESE WOMEN. SO THIS SIDE LOOKS AT INSULIN SENSITIVITY IN BOTH LEAN WOMAN HERE AND OBESE WOMEN HERE SO IF YOU LOOK AT LEAN WOMEN, WOMEN THAT HAVE PCOS, EXCUSE ME HAD DECREASED INSULIN SENSITIVITY COMPARED TO CONTROLS AND THE SAME THING HELD FOR OBESE WOMEN IN THAT OBESE WOMEN HAD LESS INSULIN SENSITIVITY FOR THE SAME AMOUNT OF OBESITY IN A WOMAN WHO DID NOT HAVE PC O S. --PCOS. SO THEN, JUST TO DEVELOP THIS THEME EVEN MORE, THAT IMPAIRED GLUCOSE COLLANCE AND DIABETES IS MORE COMMON AND WOMEN WITH PCOS AND HERE YOU SEE THE PERCENTAGE OF THE POPULATION THAT HAD A NORMAL GLUCOSE TOLERANCE TEST IMPAIRED OR DIABETES AND IT'S DIVIDED INTO 3 GROUPS AND THE 1S IN THE DARK GREEN, WERE PCOS, COMPARED TO A BMI MATCHED COMPARED TO A CONTROL WOMEN AND WOMEN WHO HAVE PCOS WERE MORE LIKELY TO HAVE IMPAIRED GLUCOSE TOLERANCE AND THEY WERE MORE LIKELY TO HAVE DIABETES COMPARED TO EITHER THEIR CONTROLLED WEIGHT OR CONTROL GROUP ENTIRELY. SO, THE OVERALL PREVALENCE OF IMPAIRED GLUCOSE TOLERANCE HAS BEEN DEBATED. THIS IS JUST 1 STUDY THAT WAS RECENTLY PUBLISHED OUT OF ITALY IN WHICH THEY FOLLOW THESE WOMEN PERSPECTIVELY AND THAL SITUATION 21.4% OF WOMEN WITH PCOS HAD EITHER DIABETES OR IMPAIRED GLUCOSE TOLERANCE AND THIS WAS COMPARED TO 4.5 CONTROLS, OF CONTROLS SO WE CAN DEBATE THE NUMBER BUT I DON'T THINK THERE'S REALLY ANY DOUBT THAT THERE'S AN INCREASE PREVALENCE OF IGT AND IN THIS STUDY THERE,'S BEEN A SENSE THAT BETA CELL FUNCTION WAS PRESERVED ALTHOUGH I'LL SHOW YOU DATA THAT MAY BE DEBATABLE AND IN THE EARLY STAGES IT'S ACTUALLY INCREASED AND OF COURSE, THAT IS NATURAL IN„'i THE PROGRESSION OF DIABETES IN TYPE 2 DIABETES IN WHICH FIRST THERE IS INSULIN RESISTANCE, PERIPHERALLY AND THEN THERE'S A COMPENSATORY INCREASE IN THE INSULIN LEVELS AND IT'S SECRETE FRIDAY THE BETA CELLS BUT CERTAINLY AT SOME POINT THIS IS OVERCOME AND THERE'S A DUAL DEFECT. THE OTHER OBSERVATION WE'LL TALK ABOUT IN DETAIL IS THAT THIS IS MORE COMMON IN WOMEN WITH HYPER ANDROGENNISM, SO THE MECHANISM OF INSULIN RESISTANCE IS JUST REALLY NOT KNOWN. THIS DATA THAT IT'S RESISTANCE TO INSULIN MEDIATED UPTAKE IN THE MUSCLE, AND LIM POLARIZED SIS IS ASSOCIATED OFTEN TIMES WITH A NORMAL FASTING GLUCOSE BUT ELEVATED CIRCULATING FREE FATTY ACID AND IT IS MECHANISM HAS BEEN DEBATED FOR--SINCE OZ OZ--ROZIOLO PUBLISHED THE FACT THAT THESE PEOPLE ARE HYPER INSULIN ANEMIC AND IT'S DECREASED WITH THE ASPECT BODIES RECEPTOR OR POST RECEPTOR DEFECT OR A DECREASE IN INSULIN RECEPTOR THAT SITS ON THE TARGET ISSUE AND THERE'S BEEN DATA TRYING TO POINT TO THE ACTUAL MECHANISM AND THERE'S STUDIES THAT ANDREA DID THAT SHOW THAD INCREASED PHOSPHORYLATION OF SORRY UMKC RESIDUES AT THE INSULIN RECEPTOR LEADS TO THIS INSULIN RESISTANCE AND INCREASED PHOSPHORYLATION OF CYP 17 A-1 GENE IS INCREASED IN THIS POPULATION IN WHICH THERE'S AN EXCESS ANDROGEN PRODUCTION. I WANT TO MENTION NOTHING ABOUT THE INDID YOU SIN RESISTANCE AS IT RELATES OUT OF VISCERAL ANAPOSSITY. WE DISCUSSED THAT THE AMOUNT IS SIMILAR BETWEEN WOMEN WITH PCOS AND OBESE WOMEN, BUT IF YOU LOOK AT THE CORRELATION FOR VISCERAL ATA POSSITY AND THE INSULIN RESISTANCE, THE RED DOTS ARE WOMEN WHO HAVE PCOS, WHICH SHOWS THAT THE WOMEN WHO HAVE PCOS HAVE MORE INSULIN RESISTANCE FOR THE SAME AMOUNT OF VISCERAL ATA POSSITY. SO THERE SEEMS TO BE SOMETHING MORE THAN JUST THE AMOUNT OF VISCERAL ATAPOSITY, THAT PREDICTS THE RESISTANCE AND SOMETHING IN THE ACTUAL METABOLISM AND THE STEPS OF THE SITE. THERE ARE OTHER PREDICTERS OF INSULIN RESISTANCE AND PARTICULARLY THAT OF ANDROGENS AND THIS LOOKS AT SOME OF THE VARIABLES THAT ARE MEASURED IN WOMEN WITH INSULIN RESISTANCE AND THIS COLUMN IS HYPER ANDROGENNISM WITH OLIGO MENNORRIA AND THIS IS IT ALONE VERSES CONTROLS. BMI IS CERTAINLY HIGH ARE IN THOSE WOMEN--HIGHER IN THESE WOMEN WHO HAVE HYPER ANDROGENNISM COMPARED TO OTHER GROUPS. FASTING INSULIN WAS SIMILAR BETWEEN THE HYPER ANDROGENNISM AND JUST THE OLIGO GROUP BUT THE SENSITIVITY INDEX WAS LESS IN THE HYPER ANDROGEN LADIES AND THE INSULIN BETA CELL FUNCTION WAS WORSE IN THOSE INDIVIDUALS WHO HAD THE HYPER ANDROGENNISM. AND THIS IS SHOWN IN THIS SLIDE AS WELL, IS THE QUESTION IS, BESIDES THE PERIPHERAL RESISTANCE TO INSULIN, IS THERE A PROBLEM WITH THE BETA CELL. SO WHAT THEY DID HERE IS LOOK AT THIS IS GLUCOSE ON THISICIDE OF THE SLIDE THIS, IS INSULIN ON THIS SIDE OF THE SLIDE AND THESE ARE LEAN AND OBESE, LEAN AND OBESE. THE--IF YOU LOOK AT THE GLUCOSE, THOSE WOMEN WHO HAD THE PCOS, THAT'S P-VERSES CONTROL, LEAN PCOS WOMEN HAD A HIGHER GLUCOSE LEVEL WHICH IS NOT A SURPRISE BUT THEY HAD A LOWER INSULIN LEVEL, OBESE WOMEN, THE SAME THING WAS SEEN. THE PCOS WOMEN HAD A HIGHER GLUCOSE LEVEL COMPARED TO THEIR OBESE CONTROLS. BUT THEY HAD A LOWER INSULIN LEVEL. SO THIS IS SUGGESTING THAT THE DEFECT MAY START OUT AS A PERIPHERAL RESISTANCE BUT THERE'S ALWAYS A BETA CELL DYSFUNCTION THAT IS HAPPENING AT 1 POINT. NOW THE DEVELOPMENT OF TRUE DIABETES CERTAINLY OCCURS IN THE POPULATION OF THOSE WHO HAVE IMPAIRED GLUCOSE TOLERANCE STKPEFT THIS SLIDE LOOKS AT THE HAZARD RATIO FOR DEVELOPING TYPE 2 DIABETES AND WOMEN WHO HAVE WHO ARE CONTROLLED VERSES WOMEN WHO HAVE PCOS, SO THE OVERALL RELATIVE RISK OF DIABETES IN A PCOS POPULATION IS 3.015 AND THEIR RATES ARE 5.7. THIS IS IN A THOUSAND PERSON YEAR VERSES CONTROLS OF 1.7 IN A CONTROL POPULATION. A VERY IMPORTANT PREDICTER OF WHO GOES ON TO DEVELOP DIABETES IS NO SURPRISE IS BMI AND THIS--THIS FIRST OFF BEING PUBLISHED IS THAT BASELINE BMI, NORMAL,OVERWEIGHT, OBESE. AND THIS IS BMI AT THE 2 YEAR FOLLOW UP, NORMAL OVERWEIGHT AND OBESE AND AGAIN, THE RATE OF DEVELOPING TYPE 2 DIABETES IS THE GREATEST IN THOSE WOMEN WHO ARE OBESE AT BASELINE AND OBESE AFTER FOLLOW UP. LOOKING AT AGE STANDARDIZE THE THE--STANDARDIZED AND PREVALENCE IN THE ITALIAN COHORT I MENTIONED. 39.3% OF THE POPULATION BECAME DIABETIC AND THE PREDICTERS WERE BMI, BASELINE FASTING GLUCOSE, GLUCOSE UNDER THE CURVE AND DECREASING SEXUAL BINDING GLOBUE LYNN. SO IN SUMMARYOT EPIDEMIOLOGY, INSULIN RESISTANCE IS INDEPENDENT OF OBESITY, OBESE WOMEN WITH PCOS TEND TO BE MORE INSULIN RESISTANCE THAN NORMAL WEIGHT COUNTERPARTS, OBESITY IS A EMPTY RISK FACTOR FOR GLUCOSE INTOLERANCE AND DIABETES, AND INSULIN RESISTANCE DOESN'T ALWAYS EQUAL GUTMACHERICOSE INTOLERANCE AND 30-40% PREVALENCE OF GLUCOSE INTOLERANCE, TYPE 2 DIABETES AND INSULIN RESISTANCE TENDS TO WORSEN OVERTIME. SO THE PATHOGENESIS IS COMPLICATED. WE DON'T FULLY UNDERSTAND IT. THIS IS 1 OF THE ORIGINAL OBSERVATIONS THAT IT WAS RELATED TO TESTOSTERONE LEVELS SO HERE IS PLASMA TESTOSTERONE AND PLASMA INSULIN LEVELS AND SO THE GROUP TODAY WAS BOTH OBESE AND TCOD SO WHAT YOU SEE HERE IS WITH INCREASE IN TESTOSTERONE LEVELS THERE WAS AN INCREASED LEVEL OF INSULIN. SO WHERE DO ANDROGENS COME FROM? NORMALLY IN A PREMENOPAUSAL WOMAN, HALF COMES FROM THE ADRENAL GLAND AND THIS CONVERSION ABOUT 25%, AND THEN 25-50% COMES ON THE OVARIES, TESTOSTERONE IS METABOLIZED TO DHG AND ESTRO DIAL. NOW I THEN HAS COME UP SEVERAL TIMES OF THE DISCUSSION IS THAT ARE THERE ANY BENEFITS TO NORMAL ELEVATED ANDROGENS AND CERTAINLY IN A NONPCOS POPULATION, THERE'S DATA THAT'S ASSOCIATE WIDE BONE DENSITY AND ROUGH ATOM TEBGZ AGAINST OSTEOPOROSEIS, LEAN BODY MASS, PROTPEBGZ FROM FRAILTY, INCREASED LIAISON BID O AND IMPROVED SEXUAL FUNCTION. IT IS ANOTHER TOPIC BUT THERE HAVE BEEN RELATED SEXUAL FUNCTION IF PCOS WOMAN TO A HIGHER TESTOSTERONE LEVEL AND THE HIGHEST LEVEL WERE THOSE WOMEN WHO WERE IN THE MORE THAN 1 STANDARD DEVIATION ABOVE THE MEAN GREATER THAN 92, THEY HAD HIRE DESIRE GREATER ACEROUSAL AND GREATER ORGAS MIC ACTIVITY. SO THIS IS SOMETHING THAT HALF THE POPULATION, HALF THE WOMAN WE SEE COMPLAIN OF DECREASED LIAISON BID O AND A PCOS MAY COMLINE OF A HIGH--COMPLAIN OF A HIGHER LIBRARY FOUNDATION EDUCATIONAL--LIBIDO. THIS IS DATA FROM A LARGE COHORT WHERE WE LOOK ATATLER O SCLEROSIS AND THESE WERE NON PC OS WOMEN AND WE LOOKED AT THE SEX HORMONES TO INSULIN RESISTANCE AND FOUND THAT THOSE WOMEN WHO HAD HIGHER BIOAVAILABLE TESTOSTERONE HAD INSULIN RESISTANCE. HIGH ESTRO DIAL. THIS DHEA WAS A BIT MIXED BUT A LOWER SHBG ALL ASSOCIATED WITH INSULIN RESISTANCE IN A NONPCOS POPULATION. HOW DOES THAT RELATE TO BMI THIS, IS LOOKING AT THE FREE ANDROGEN INDEX, ACROSS THE CORTILES OF BMI, THE DIFFERENT BIOLOGY FOR IT TO SYMPTOMATIC OR ASYMPTOMATIC WOMEN WITH PCOS, SO THE HIGHER THE BMI, THE MORE LIKELY THEY ARE TO HAVE AN EXCESS FREE ANDROGEN INDEX AND THE HIGHER THE BMI, THE LOWER WILL BE THEIR INSULIN SENSITIVITY. AND THERE'S PROBABLY MANY MECHANISMS FOR THE ELEVATED TESTOSTERONE IN THIS POPULATION, THERE'S AN INCREASE IN CIRCULATING TESTOSTERONE AND INCREASE IN HIDE ROGY PROG, ALL THESE WE HAVE DISCUSSED RECENTLY. SO SOME CLASSIC WORK THAT WAS DONE BY JOHN NESLA, HAS LOOKED AT THE RELATIONSHIP OF INSULIN ON TESTOSTERONE PRODUCTION AND THIS SHOWED THAT WOMEN WHO--THIS IS LOOKING AT INSULIN STIMULATED TEST OFT RON BY O SYNTHESIS, THESE ARE NORMAL WOMEN AND WOMEN WITH PCOS TO MAKE THE POINT THAT TESTOSTERONE PRODUCTION IS GREATER IN THE OVARIAN FECCA CELLS WHEN GIVEN INSULIN. SO THE COMMON PATHWAY HERE IS THAT INSULIN ENHANCED OR IS AN INTRINSIC ABNORMALITY IN THE PULSE GENERATOR. THERE'S LESS SUPPRESSION OF THE LH PULSE BY PROGESTERONE AND INSULIN IS ACTING AS AN AMPLIFIER OF LA STIMULATED INTEROVARIAN EXCESS AND THAT'S I THINK AN IMPORTANT WORD TO USE HERE IS AMPLIFICATION AND THAT THIS'M LIAISONFICATION RESULTS IN OVULATION AND ARREST OF THE FOLLICULAR CELL FORMATION. THIS INTERPLAY THOUGH IS WHERE DOES INSULIN COME IN AND HERE WE'RE SAYING AGAIN THAT IT AMPLIFIES LH ACTION IS ACTS SINNER GESTICLY TO ENHANCE HAND ROUGH ATOM GEN PRODUCTION. IT ALSO WORKS AT THE LEVEL OF THE LIVER AND WE'LL HEAR LATER ABOUT THE RELATIONSHIP OF PCOS TO LIVER DISEASE AND THE FACT THAT THERE IS SHBG WHICH IS A MARKER OF INSULIN RESISTANCE AND THIS IS LOWERED IN WOMEN WHO HAVE PCOS, NOW THE OPPOSITE IS TRUE AS WELL IN THAT--AGAIN THIS ISSUE OF INSULIN AND TESTOSTERONE AND IN THIS SITUATION, THESE SHOW THIS SLIDE SHOWS DECREASE INSULIN STIMULATED GLUCOSE UPTAKE, SO HERE IS GLUCOSE UPTAKE AND HERE IS INCREASING CONCENTRATION OF INSULIN SO NO SURPRISE WITH INCREASING CONCENTRATIONS OF INSULIN, THERE IS AN INCREASED GLUCOSE UPTAKE. HOWEVER IN SOMEONE WHO IN THE SITUATION OF THE ADA POETIC SIGHT IN WHERE THERE'S EXCESS ANDROGEN THERE,'S LESS GLUCOSE UPTAKE FOR THE SAME AMOUNT OF INSULIN AND THIS CAN BE SEEN HERE AS WELL, IS THAT HERE THE INCREASING AND INCREASE IN THE TESTOSTERONE CONCENTRATION AND THAT RESULTS IN LESS EFFECTIVENESS OF THE GLUCOSE. SO BOTH THE INSULIN IS AMPLIFYING AND THE TESTOSTERONE IS DECREASE INDEED THE EFFECTIVENESS OF INSULIN. SO LOOKING AT A SEPARATE PHENOTYPE, THESE ARE WOMEN WHO ARE--WHO ARE HYPER ANDROGENIC AND OLIGO MERRILY RIA, AND HYPER ANDROGENS AND OLIGO, SO THEY HAVE HIGHER TESTOSTERONE LEVELS, MORE INSULIN RESISTANCE, LOWER SHBG, AND MORE LIKELY TO HAVE METABOLIC SYNDROME COMPARED TO THE HYPER ANDROGENS ALONE OR THE OLIGO MENNORRYIC ALONE. SO WE'VE SEEN SOMETHING LIKE THIS A FEW TIMES IN THAT 1 CAN START AT THE TOP OR THE BOTTOM, HERE'S OBESITY, WITH POLYCYSTIC SYNDROME CAUSING INSULIN RESISTANCE, HYPER INSULINNISM AND THIS RESULTS IN INCREASED OVARIAN PRODUCTION OF TESTOSTERONE AND IT'S LIVE WITH THE SEX BINDING GLOBUE LYNN AND THIS IS ANDROGEN STARTING AT THE BOTTOM IN WHICH IT'S AMPLIFYING LH PRODUCTION, AND REDUCING SHBG CONCENTRATIONS. ALL RIGHT SO I'M GOING TO END WITH SOME ISSUES OF TREATMENT AND SCREENING RECOMMENDATIONS THE FIRST AND FOREMOST IS LIFESTYLE MODIFICATION AND THERE'S BEEN GOOD DATA TO SHOW THERE IS A SIGNIFICANT REDUCTION IN METABOLIC PARAMETERS COMPARED WITH LIFESTYLE ALONE COMPARED TO CERTAINLY METAFORM EDUCATIONAL OR KHRO MID, THESE METABOLIC IMPROVEMENTS OCCUR AFTER 4 TO 12 WEEKS WHERE 1 CAN SEE A FULL IN TESTOSTERONE AND INCREASE IN SHBG AND REDUCED WASTE CIRCUMFERENCE AND REDUCED SERUM LEVELS AND IGF 1 AND THIS CAN OCCUR WITH REALLY MODERATE AMOUNTS OF DAILY EXERCISE. JUST TO SHOW YOU INSULIN RESISTANCE, THESE ARE--THIS IS I CONTROL POPULATION PUT ON A LIFESTYLE INTERVENTION AND THIS IS WOMEN THAT HAVE PCOS WHERE THERE'S A NICE DECLINE AFTER 12 WEEKS IN THE INSULIN RESISTANCE. THIS IS THE SAME FOR--HERE'S PCOS WOMEN WHO HAVE A DROP IN TESTOSTERONE LEVELS AFTER 12 WEEKS COMPARED TO A CONTROL GROUP. METAFORMIN HAS BEEN TALKED ABOUT A GREAT DEAL, MECHANISM OF METAFORMIN, IT'S FIRST LINE AND 1 OF THE MOST POPULAR DRUGS FOR TREATMENT OF DIABETES. IT INHIBITS THE OUTPUT OF GLUCOSE, THE DOSE RECOMMEND IS 500-MILLIGRAMS T. I.D. ASK HAS A SIGNIFICANT REDUCTION IN INSULIN LEVELS BUT IN THOSE WOMEN WHO ARE NONOBESE. IT ALSO WILL RESULT IN REDUCED SERUM TESTOSTERONE LEVELS BUT AGAIN PARTICULARLY IN THE NONOBESE POPULATION. IT HAS REALLY VERY LITTLE EFFECT ON INSULIN SENSITIVITY, WEIGHT LOSS OR SERUM LIPIDS AND IT IS ASSOCIATE WIDE GI DISTURBANCE AND IN POPULATIONS OF GENERAL INSULIN GLUCOSE AND TOLERANCE IT WAS NOT AS GOOD AS LIFESTYLE MODIFICATION, WE KNOW THAT FROM THE D PP STUDY AND IN GENERAL I THINK THAT LIFESTYLE MOLLIFICATION HAS TO BE A STRONGER RECOMMENDATION FOR GLUCOSE INTOLERANT PATIENT. NOT TRUE DIABETES BUT FOR WOMEN WHO HAVE IMPAIRED GLUCOSE TOLERANCE AND THIS IS JUST LOOKING AT MINIMAL MODELING, A WAY OF LOOKING AT GLUCOSE SENSITIVITY. AND THIS IS WOMEN IF RED ARE THE BASELINE, WOMEN IN BLUE ARE ASK AFTER METAFORMIN TREATMENT AND THERE WAS ESSENTIALLY NO DIFFERENCE IN THE INSULIN DYNAMICS IN WOMEN WHO WERE GIVEN METAFORMIN. THE INSULIN SENSITIZES. ONE THINKS THAT MIGHT MAKE SENSE, THESE ARE THE GAMMA, IMPROVES ACTION OF INSULINOT LIVER, AND SCALE AND MUSCLE AND ADA POSITEAND IT DOES RESULT IN A FREE TESTOSTERONE BUT THERE ARE RISKS TO THIS, YOU KNOW THAT 1 OF THEM HAS BEEN TAKEN OFF THE MARKET ENTIRELY. IT MAY INCREASE THE WEIGHT AND AT THIS POINT I WOULD CONSIDER IT ONLY INVESTIGATION. IT'S ALSO CONSIDERED A CATEGORY C DRUG, SO THEREFORE IT WOULD BE CONTRA INDICATED IN PREGNANCY. NOW IT IS INTERESTED IN HOW TO DIABETES DIABETES AND RESISTANCE IN THE POPULATION. IT TURNS OUT THAT THE SCREENING WITH FASTING PLAZA GLUCOSE FAIL TOED IDEBT 41% OF PREDIABETIC WOMEN AND 20% OF THE DIABETIC POPULATION, WE DISCUSSED YESTERDAY IT IS NOT A GOOD TEST EITHER. OGTT AND AC1 C HAD FAIR AGREEMENT. SO THE STANDARD TEST THAT'S OFTEN USE SIDE AN ALL GLUCOSE TOLERANCE TEST WITH 75-GRAMS. THIS SHOULD BE REPEATED EVERY 2 YEARS AND AC1 C IS CONSIDERED A GOOD MARK FOR CARDIOVASCULAR DISEASE RISK AND THERE'S 2 TESTS, THE OTHER ALTERNATIVE WOULD BE DOING 2 TESTS AND THAT WOULD BE THE 2 FASTING BLOOD SUGARS 2 AC1 Cs OR THE 1 ALL GLUCOSE TOLERANCE TEST. SO IN CONCLUSION, IMPAIRED GLUCOSE TOLERANCE AND DIABETES IS COMMON IN WOMEN WITH PCOS REGARDLESS OF BODY WEIGHT, THE MECHANISM FOR THIS INCLUDES A COMBINATION OF HYPER INSULINNISM AND ANDROGENNISM AND EVALUATION SHOULD BE DONE ON ALL WOMEN WITH PC OAND TREATMENT OFFERED STARTING WITH LIFESTYLE MODIFICATION. THANK YOU VERY MUCH. DID [ APPLAUSE ] I WOULD LIKE TO INTRODUCE OUR SECOND SPEAKER FOR THE MORNING, EVELYNTAL--EVELYN TALBOTT FROM THE UNIVERSITY OF PITTSBURGH AND SHE WILL DISCUSS CARDIO VASCULAR DISEASE. >> GOOD MORNING. I'M HAVING A BIT OF ANN VERSERY, IT OCCURRED TO ME THAT IN 1992, DR. DAVID GUZIK, AND SARAH BERGEN AND I BEGAN OUR NIH GRANT TO STUDY PC O, IT WAS NOVEMBER OF 92, SO I'M HAVING 1 OF THOSE SENIOR MOMENT WHEN IS I SAY, OH MY GOD, IT'S BEEN 20 YEARS, AND I BELIEVE THAT IT IS 20 YEARS BUT I'M VERY HAPPY TO BE SMEAR TO TALK ABOUT SOME OF OUR WORK, BUT ALL OF YOUR WORK AS WELL AND THE LONG-TERM HEALTH CONSEQUENCES OF PC O AND SPECIFICALLY CARDIOVASCULAR DISEASE. THE FIRST COUPLE OF THESE SLIDES, I REALIZED THE DAY BEFORE TODAY THAT I WAS ALSO SUPPOSED TO MENTION SOMETHING ABOUT THIS LIP DEEMIA AND METABOLIC SYNDROME WHICH HAS ALREADY BEEN COVERED AND THIS PARTICULAR FIRST COUPLE OF SLIDES ACTUALLY COME FROM THE ANDROGEN EXCESS SOCIETY THAT DID A CONSENSUS STATEMENT AND A LITERATURE REVIEW A FEW YEARS BACK SO I THOUGHT I WOULD START WITH THESE TO BE ALL ENCOMPASSING, THIS LIP DEEMIA WHICH WE TALKED ABOUT, SOME YESTERDAY, AND SOME MORE TODAY, BOTH ABSOLUTE AND RELATIVE IS FREQUENT IN WOMEN WITH PC O, IT'S BEEN ESTABLISHED PRETTY WELL. THIS LIP DEEMIA OCCURS AT A YOUNGER AGE AND IN THE GENERAL PROJECTION NEURONS OR PIONSULATION AND OBVIOUSLY SHOULD BE DETECTED AND TREATED. THE MOST COMMON ABNORMALITY THAT YOU'VE SEEN IN SEVERAL OF THE OTHER PRESENTATIONS IS A LOW HDL AND IT IS PARTIALLY INDEPENDENT OF OBESITY. THE OTHER DISLIP DEEMIA THAT'S BEEN NOTE INDEED NUMEROUS TIME SYSTEM ELEVATED TRIGLYCERIDE FASTING AND POST PLAN DEAL AND LDL CHOLESTEROL INCREASES ALSO HAVE BEEN--HAVE BEEN NOTED. TRIGLYCERIDE ELEVATION IS MORE COMMON IN PC O WOMEN WHO ARE OBESE. AND THEN JUST TO ROUND OUT THE DISLIP DEEMIA, NONHDL CHOLESTEROL ARE RELATIVELY UNCOMMON AND GENERALLY ASSOCIATE WIDE LDL IS TRIGLYCERIDE INCREASE AND THERE'S BEEN SOME NOTATION THERE'S A SHIFT TOWARDS SMALLER LDL AND THE SIZE, AND THE PARTICLES BECOME ELEVATE INDEED LEAN OR OBESE WOMEN WITH PC O, WHEN METABOLIC SYNDROME OCCURS AND WE'VE JUST SHOWN RECENTLY THAT IT CERTAINLY IS MORE PREVALENT IN WOMEN WITH PC O, EVEN MORE CIRCULATING LIPIDS APOETIC LIPOPROTEINS ARE FOUND. DETERMINING MOST COST EFFECTIVE STANDARDIZED MEASURES FOR DISLIP DEEMIA AND WOMEN WITH PC O REQUIRES FURTHER RESEARCH. AND THIS IS JUST A SLIDE AND A SHOWING THAT 2 PCO POPULATIONS 1 IS IN VIRGINIA AND 1 IS SISLY THAT THERE ARE--SICILY AND THERE ARE ALTERATIONS IN LIPIDS AND THEY APPEAR TO VARY BY LOCATION. AND AGAIN THIS COMES FROM THE ANDROGEN EXCESS SOCIETY JUST TO BE COMPLETE SHOWING THAT PREVALENCE, CAN YOU SEEOT RIGHT SIDE--SEE ON THE RIGHT SIDE HAS DEFINITELY SHOWN, BEEN SHOWN REPEATEDLY IN MANY, MANY INVESTIGATIONS. SO THIS BRINGS ME BACK TO THE CARDIOVASCULAR DISEASE, SORT OF OVERVIEW FOR CARDIOVASCULAR DISEASE RISK. WE KNOW WOMEN WITH TCO HAVE ABNORMAL BIOCHEMICAL FUNCTIONAL AND STRUCTURAL MARKERS OF CV RISK, CONSIDERING THE CO EXISTENCE OF OBESITY AND INSULIN, RESISTANCE WITH PCO MOST STUDIES FAIL TO CLARIFY WHAT EXTENT THESE RISK FACTORS ATTRIBUTABLE TO OBESITY RESISTANCE, MOST OF THOSE HAVE EXAMINED ONLY CDRISK FACTORS BUT NOT CBD END POINTS THEMSELVES, AND TO DATE FEW STUDY VS SHOWN HIGHER RATES OF CVD AND MORBIDITY AND MORTALITY IN WOMEN WITH CLINICAL FEATURES OF PCO, SO DURING THIS SESSION WE WILL REVIEW BRIEFLY SOME OF THE SUBCLINICAL MARKERS OF CBD AND INVESTIGATIONS AND OF CARDIOVASCULAR RISK SPECIFICALLY. HERE'S JUST A GENERAL SKAO EPLATA OF--SCHEME ATA OF THE INSIDE OF AN ARTERY WALL AND JUST TO SHOW THE STREAKS THAT BEGIN, THIS IS REALLY THE EVOLUTION OFATLER O SCLEROSIS WITH THE FATTY STREAKS YOU SEE HERE, EARLY ON IS IT BUILDS UP OVER TIME AND THROMBOSIS. SO IT HAPPENINGS OVER A LONG, LONG PERIOD OF TIME AND IT'S SILENT AND--BUT IT IS A COMMON SOURCE EPIDEMIC BASED ON A MYRIAD OF RISK FACTORS INCLUDING DIABETES, INCREASED LDL, DECREASED HDL, AND THE LIKE. SO 1 OF THE FIRST MEASURES STUDIED WAS DECREASE RESPONSE TO BLOOD FLOW AFTER SCHEMIA EQUALS ENDOTHELIAL DYSFUNCTION. LOOKING AT THE 20 STUDIES THAT HAVE BEEN DONE SO FAR EITHER NIH OR RODDER DAM CRITERIA HAS SHOWN A SIGNIFICANTLY LOWER FMD IN WOMEN WITH PCO COMPARED TO CONTROL. THE COMMON LIMITATIONS WE'VE DISCUSSED A LOT YESTERDAY AND ALSO TODAY, MOST OF THESE STUDIES ARE DONE IN WHITE WOMEN WITH SMALL SAMPLE SIZES, DIFFERENT CRITERIA FOR PCO AND DO NOT ALWAYS ADDRESS PHYSICAL ACTIVITY WHICH CAN HAVE AN EFFECT. DUE TO DIFFERENCES IN THE FMD PROTOCOLS, COMPARING FMD ACROSS STUDY SYSTEM CAUTIONED, HOWEVER THAT BEING SAID, THERE IS EVIDENCE THAT WOMEN WITH PCO DO HAVE MORE SUBCLINICAL VASCULAR DISEASE MEASURED BY FMD THAN CONTROLS ADJUSTING FOR AGE AND BMI AND FUTURE RESEARCH SHOULD REALLY INCLUDE LARGER STUDIES THAT USE A MORE STANDARDIZED FMD PROTOCOL. HERE'S THE NEXT MEASURE OF SUBCLINICALATLERATHEROSCLEROSIS WHICH IS CORROT EDUCATIONAL ARTERY IN THE FRONT OF OUR NECKS THE SIDES OF OUR NECKS AND IT'S A FAIRLY EXCELLENT NONINVEIGHSIVE MEASURE OF NONCAROTIDATLER O CHEROSEIS AND IT'S HIGH MORTALITY IN THE LATE 80S AND EARLY 90S SHOWED FIRST IN CHILDREN WHO HAD FAMILIESIAL HYPER LIP DEEMIA IN HEAVY SMOKERS IN HIGH RISK GROUPS, THOSE ARE THE FIRST GROUPS TO SHOW PROOF OF CONCEPT WITH CARDIOVASCULAR, WITH CAROTID IMT AND THAT PROGRESSED FORWARD TO PEOPLE WHO WERE AT RISK OF HEART DISEASE WHO HAD ELEVATED LDL, THESE INDIVIDUALS WERE FOLLOWED AND SHOWN, IT WAS SHOWN THAT AGGRESSIVE TREATMENT OF LIPID LOWERING MEDS DID IN FACT, COULD IN FACT IMPROVE IMT AND SO, IT'S BEEN REALLY--REALLY SOMEWHAT OF AN INDUSTRY GOLD STANDARD, BOTH REGARD TO LOOKING AT RISK OF STROKE AS WELL AS RISK OF HEART ATTACK. IT'S WELL VALIDATED, HIGHLY REPRODUCIBLE MEASURE. HE NOTED THAT 12 OUT OF 21 SHOWED A SIGNIFICANTLY HIGHER IMT IN WOMEN WITH PCO COMPARED TO CONTROLS. THE COMMON LIMITATIONS ARE WHAT WE TALKED ABOUT EARLIER. ALL CAUCASIAN WOMEN, SAMPLE SIZES, DIFFERENT CRITERIA FOR PCO ASK DIFFERENT IMT PROTOCOLS. HOWEVER, THAT BEING SAID, THERE DOES APPEAR TO EVIDENCE THAT WOMEN WITH PCO DO HAVE MORE SUBCLINICAL VASCULAR DISEASE MEASURED BY IMT THAN CONTROLS ADJUSTING FOR AGE AND BMI. AND LARGER STUDIES ARE NEEDED TO LOOK AT PROGRESSION OF IMT OVERTIME. THIS WAS RECENTLY PUBLISHED IN I BELIEVE THE JOURNAL OF HUMAN REPRODUCTION. BY MY STUDENTS AND THIS IS A META-ANALYSIS OF THE 20 STUDIES AND YOU CAN SEE LOOKING AT THE--THE AUTHORS ARE ON THIS ACCESS AND YOU CAN SEE THE ARROW BARS, EVERYTHING OVER 0 IS SHOWING A SIGNIFICANT EFFECT AND YOU CAN SEE THAT PRETTY MUCH THE EVIDENCE APPEARS TO BE THAT THERE IS A GREATER INDICATION OF A GREATER IMT, WOMEN WITH PCO AFTER ADJUSTING FOR AGE AND BMI. AND FINALLY THERE IS CORANNORY CALCIFICATION, THE TIME LINE, I SHOWED YOU WITH THE VESSEL HOW WE START WIDE THE FATTY STREAK AND THEN THERE WAS THE CALCIFICATION THAT WAS THE MIDDLE, LOVELY PICTURE AND THEN THE FINAL THROMBUS AT THE END, WELL CORONARY CALCIFICATION IS NEWER, IT'S NEWER ON THE RESEARCH HORIZON, IT CAME INTO BEING, I WOULD SAY IN THE MID TO LATE 90S AND CERTAINLY HAS GONE ON TO BE--TO BE USED IN MANY STUDIES, 3 STUDIES OF MEASURED CORONARY ARTERY CALCIFICATION AND MAY MARKER OF SOME CLINICALARTLER O SCLEROSIS AND COMPUTED TOMOGRAPHY AND DR. DOMESTIC WHO IS IN THE AUDIENCE AND HIS COLLEAGUE ROSE CRISTIAN WAS 1 OF THE EARLY PEOPLE, AS WAS DAVID GUZIK AND MYSELF. AND THESE STUDIES TO SUGGEST THAT WOMEN WITH PCO HAVE A GREATER PREVALENCE OF CORONARY ARTERY CALCIFICATION. SCHROFF HAD 24 CASES AND 24 CONTROLS AND SHOWED A HAD-LOOKED AT 24 CASES OF OBESE AND MENOPAUSAL, I DON'T HAVE THE EXACT AGE BUT THESE WERE YOUNGER WOMEN AND SHOWED THAT THERE WAS A SIGNIFICANT PREVALENCE OF C. A. C. IN CASES COMPARED TO CONTROLS. DAN AND ROSE CRISTIAN LOOKED TO 36 CASES AND 71 CONTROLS, I BELIEVE THEY WERE AGE AND BMI ADJUSTED AND HE ALSO SHOWED A PREVALENCE AND INCREASED PREVALENCE OF CORONARY ARTERY CALCIFICATION AND ODDS RATIOS ON THOSE, TOO, AND THEN WE ACTUALLY WERE ABLE TO LOOK AT--EXCUSE ME, 149 CASES AND 166 CONTROLS AND OUR WORK CONTINUES AND WE'RE LOOKING--WE ACTUALLY HAVE ANOTHER POINT IN TIME, 3 YEARS LATER TO LOOK AT PROGRESSION IN WHICH WE WILL BE PUBLISHING SHORTLY AND THE--OUR PREVALENCE WAS ALSO VERY SIMILAR TO WHAT THE--WHAT DR. DOMESIK AND DR. CRISTIAN FOUND IN AN ODDS RATIO AROUND 2 AND A PREVALENCE OF ARTERY CALCIFICATION GREATER THAN 10 WAS HIGHER IN WOMEN WITH PCO AFTER AGING BMI AND ADJUSTMENT. AGAIN THE SAME LIMITATIONS MOST STUDIES HAVE BEEN HAMMERED BY SMALL SAMPLE SIZE AND COMMENT ON LACK OF STATISTICAL POWER, PREVALENCE OF C. A. C. IS VERY LOW IN YOUNGER AGE GROUPS, IT GROWS EXPONENTIALLY AND IT SORT OF, IT APPEARS TO BE WHEN YOU DON'T HAVE ANY C. A. C., 0 REMAINS AT 0, BUT WHEN YOU START--WHEN IT STARTS TO APPEAR, IT HAS AN EXPONENTIATION THAT APPEARS TO BE--TO SHOW TO BENEFIT ITSELF AND THEN, REALLY INCREASES QUITE DRAMATICALLY OVER TIME, WE HAVE C. A. C. LEVELS IN SOME WOMEN OVER A THOUSAND. ONE LADY WHO ENDED UP PASSING AWAY FROM CORONARY ARTERY DISEASE CAME IN TO SEE US AND I BELIEVE IT WAS 2000. SHE WAS PART OF A PILOT AND HER C. A. C. SCORE AT THAT POINT WAS 780 AND SHE CLEARLY WENT ON TO HAVE CORONARY ARTERY DISEASE AND PASSED AWAY FROM THAT CONDITION BUT CLEARLY THAT'S 1 CASE AND LARGER PROSPECTIVE TODAYS OF THE PROGRESSION OF C. O. C. ARE--C. A. C. ARE NEEDED AND I SHOULD MENTION, TOO, EARLY EARLY STUDIES BY BIRDSOL, AND BOB WILD, EARLY STUDIES, PREC. A. C. AND IMT THAT LOOKED AT GERONTOLOGYSTSOGRAPH SCHEPEOPLE COME IN WITH AN GUINA PARTICULARLY IN THE EARLY 90S, THERE WEREN'T A WHOLE LOT OF TOOLS BESIDE CORONARY ANGIOGRAPHY. IF YOU HAD CHEST PAIN, YOU TAKE A STRESS TEST, YOU WERE PRETTY MUCH--YOU WERE PRETTY MUCH TOLD THAT YOU NEEDED TO HAVE SOME TYPE OF INTERNAL READING OF OF YOUR ARTERIES AND THAT TYPICALLY WAS A CORONARY ANGIOGRAPHY ALBEIT THAT HAS A 1 PERCENT MORBIDITY AND MORTALITY RATE ASSOCIATE WIDE IT, BUT OFTEN YOU DON'T HAVE A CHOICE. SO IN THIS CASE, THERE 142 WOMEN, 60 CASES THAT COME IN FOR CORONARY ANGIOGRAPHY INDEPENDENT OF PCO, THEY WERE PART OF A CORONARY CARE UNIT AND THEY HAD ASSESSMENT OF CHEST PAIN OR VALVEULAR DISEASE EXCLUDED WERE WOMEN WHO HAD A BILATERAL REFERECTOMY, AND THESE WERE CONDUCTED AND THEY WERE FOUND TO HAVE THE ANGIOGRAPHY, THE OVARIES WAS ALSO CONDUCTED TO DETERMINE IF THERE WAS POLYCYSTIC OVARY, IF THEY HAD POLYCYSTIC OVARIES SO IT TURNED OUT THAT 142, OF THE WOMEN, 60 ACTUALLY HAD POLYCYSTIC OVARIES AND 82 HAD NORMAL OVARIES, AND IT WAS NOTED THAD WOMEN WITH MORE EXTENSIVE CORONARY ARTERY DISEASE WERE MORE LIKELY TO HAVE POLYCYSTIC OVARIES ON ULTRASOUND AND THOSE WITH LESS EXTENSIVE DISEASE SO THIS IS REALLY 1 OF THE FIRST CLUES THAT THERE COULD BE A RELATIONSHIP WITH PCO AND THE CONCOMITANT METABOLIC DERANGEMENTS THAT THEY OFTEN SUFFER AND CHD. WILD, EARLY EARLY THAN THAT HAD LOOKED AT WOMEN UNDER GOING CORONARY CATHETERIZATION AND DID A HE RESITTISM AND IN THIS PAPER NOTE THAD THE PREVALENCE OF IT WAS MUCH MORE COMMON WITH IN WOMEN WITH CONFIRMED CORONARY ARTERY DISEASE UPON CATHETERIZATION BUT HE WAS ESSENTIALLY VERY MUCH AHEAD OF HIS TIME IN NOTING THIS. SO FINE IT COMES DOWN TO THE WIRE WITH THE MORBIDITY, MORTALITY END POINTS. AND TO DATE, I BELIEVE, I BELIEVE WE'RE TALKING ABOUT 9, I THINK WE HAVE 9, 9 STUDIES, WE'LL GO BACK, SORRY. --WE'LL GO BACK, 9 STUDIES THAT HAVE LOOKED AT CARDIOVASCULAR MORBIDITY AND MORTALITY BETWEEN WOMEN APPROXIMATE PCO AND CONTROLS. YOU WILL NOTICE THAT THE MEAN AGE HOWEVER, IF YOU LOOK AT THE MEAN AGE OF MOST OF THESE, IT'S PRETTY YOUNG. LOOKING AT 20-74 IS PROBABLY THE WIDEST RANGE, SOBOLO WAS AN AVERAGE OF 59, THIS IS WILD OF THE PEER POINTS SUBGROUP, I BELIEVE, THAT WAS THE RESECTIONED BUT IT WAS A SOUP GROUP THAT WAS RECONTACTED AND 56.7 AND THEN OUR GROUP, LOOKED AT CHARM 2 WHEN THE WOMEN WERE FAIRLY YOUNG, 43, 42.4 AND 43. AND IN GENERAL IT'S A MIXED BAG, THOSE ARE THE FIRST 4, AND THE LAST 5, THEY WERE 38.7, SHAW WAS ACTUALLY THE--I BELIEVE THESE--THAT WAS THE WISE COHORT OF 390 POST MENOPAUSAL WOMEN THAT RICARDO HAS PUBLISHED WITH LESLIE SHAW AND THEIR RANGE WAS ACTUALLY 62, THAT WAS PROBABLY THE OLDEST, SOLOMON WAS THE NURSES HEALTH STUDY AND ACTUALLY MENTIONED THE NURSES HEALTH STUDY DID NOT--NURSES HEALTH STUDY AND SHAW DID NOT USE RODDER DAM OR NIH, THEY WERE CLARIFIED MORE WITH SELF-REPORT OF OLIGO MENNORRIA ABNORMAL PERIODS AND MENSTRUAL IRREGULARITY. THAT BEING SAID THEY WERE ABLE TO COME UP WITH A REASONABLE NUMBER OF INDIVIDUALS TO THEN DICHOTOMIZE AND MOST RECENTLY, A STUDY EYE IPTACAR, WHICH WAS PUBLISHED A MONTH OR 2 AGO, IF YOU LOOK AT 652 WOMEN, 309 CASES 343 CONTROLS BUT AGAIN, HIS MEAN AGE OF 46.6. AND AGAIN IT'S A COMBINATION OF RODDER DAM, NIH OR RODDER DAM. SO AT THE END OF THE DAY WHEN YOU LOOK AT THESE 9. NINE EPI-BLASTY--9 EPI-BLASTY STUDIES FOLLOWED THE LITERATURE OR NIH CRITERIA FOR PCI DIAGNOSIS AND FOLLOW UP OF PCO CASES FOR CBD END POINTS, THEY WERE EITHER CROSS SECTIONAL, OR PROSPECTIVE HISTORICAL PROSPECTIVE PEER POINT AND WHILED. ASIAN BMI CONFOUNDING, THE PCO CASES WERE BETWEEN 30 AND 74 WITH A MEAN AGE OF ABOUT 50 AND ALL STUDIES WERE AGE ADJUSTED OR AGE MATCHED AND 2 WERE ACTUALLY BMI ADJUSTED. THE FINDINGS ARE REALLY TO DATE, I WOULD SAY INCONCLUSIVE, 2 PREVALENCE STUDIES DID NOTE AN INCREASED RISK OF CBD, THESE WERE YOUNGER WOMEN AND VERY SMALL NUMBERS. REMAINING 5, PURE POINT, WILD AND DALTKPWREPB, NOTED NO SIGNIFICANT INCREASES IN THE EVENTS ALTHOUGH THEY DID NOTE DEFINITE INCREASES IN HYPERTENSION AND INCREASES IN HYPER DIABETES AND WILD ACTUALLY NOTED AN INCREASE IN DEATH OR DISEASE FROM STROKE FROM CEREBRAL VASCULAR DISEASE. SO I WOULD SAY THE YOUNG AGE OF FOLLOW UP, MEAN AGE OF 50 MAY HAVE INCLUDED ONLY THOSE WITH PREMATURE HEART RISK AND SMALL STUDY SAMPLES MAKE RISK ESTIMATES UNSTABLE AND I MENTIONED THE OTHER--THE 2 STUDIES. SO IN CONCLUSION--SORRY ALTHOUGH CONSIDERABLE PREVIOUS REPORTS REPORT THE FINDING OF AN INCREASED RISK OF CHD AND PCO, INVESTIGATIONS TO DATE HAVE BEEN INCONCRUISIVE, THE HEART DISEASE AMONG PRE AND PERIMENOPAUSAL WOMEN HAS BEEN SIGNIFICANT. THERE ARE 7 PER THOUSAND REPORTED IN WOMEN 4445-54, SO IF HAVE YOU WOMEN YOU'RE FOLLOWING UNTIL THE AGE OF 60, HAVE YOU A SMALL CHANCE OF HAVING THE POWER TO DETECT THE INCREASES THAT WE'RE TALKING ABOUT. SO GIVEN THIS SLOW RATE AMONG WOMEN IN THE GENERAL POPULATION IT IS NOT SURPRISING THAT THE STUDY OF RISK MI AND CHG IN WOMEN IS VERY DIFFICULT AT BEST. AND SO AT THIS POINT, I WOULD SAY CONTINUED FOLLOW UP OF ESTABLISHED COHORTS OF WOMEN PUTTING TOGETHER OTHER STRONG GOOD COHORTS THAT ARE NOW IN EXISTENCE, BOTH NATIONALLY OR INTERNATIONALALLY WOULD REALLY BE--WOULD BE INDICATE WIDE AN ASSEMBLY OF LARGER SAMPLES OF WOMEN WITH AND WITHOUT PCO ARE NECESSARY TO ANSWER THIS IMPORTANT QUESTION. AND I JUST WANT TO GIVE ACKNOWLEDGMENT TO THE ANDROGEN EXCESS SOCIETY BECAUSE PART OF THIS WORK WAS BASED ON A PRESENTATION WE GAVE AT THEIR LAST MEETING. THANK YOU. [ APPLAUSE ] >> THE SPH-BGS SPEAKER WILL BE DR. DAVID EHRMANN, FROM THE UNIVERSITY OF CHICAGO AND HE WILL TALK ABOUT OBJECTIVE SLEEP APNEA IN PCOS: CASES AND CONSEQUENCES. EMPLOY. >> GOOD MORNING AND I WOULD LIKE TO EXPRESS MY TKPWRAT--GRATITUDE TO THE MEETING ORGANIZERS AND I WOULD LIKE TO THANK THE DOCTORS FOR INVITING ME TO SPEAK AND SHARE THE RESULTS OF SOME OF OUR RECENT WORK RELATED TO THE IMPACT OF OBSTRUCTIVE SLEEP APNEA AND THE METABOLIC PROTEIN COMPLEXERBATIONS IN WOMEN WITH PCOS. YES, THANK YOU. SO I'M GOING TO FOCUS ON SLEEP APNEA AS IT PERTAINS TO PCOS AND THE NICE THING ABOUT OBLIGATIONS STREBGTIVE SLEEP APNEA AND/OR 1 OF THE NICE THING SYSTEM THAT THERE'S OBSTRUCTIVE SLEEP APNEA AND THERE'S OBSTRUCTIVE SLEEP APNEA SYNDROME BUT WE DON'T HAVE TO HAVE DISCUSSIONS ABOUT THE TERMINOLOGY WAS OBSTRUCTIVE SLEEP APNEA DIFFERS IN THE SYNDROME IS THAT THE SYNDROME IS THE SAME AS OSA, BUT IT REQUIRES THE PRESENCE OF DAY TIME SOMULENCE, SO WE DON'T HAVE NIH CRITERIA AND RODDER DAM CRITERIA FOR SLEEP APNEA, THERE'S ESTABLISHED CRITERIA FOR THIS CONDITION. BUT CLINICALLY, IT'S CHARACTERIZED BY THE PRESENCE OF OF SLEEP FRAGMENTATION AND REDUCED SLOW WAVE SLEEP WHICH IS AN IMPORTANT PHASE OF NONREM SLEEP THAT'S IMPORTANT FOR METABOLIC FUNCTION AND RESTORATION OF METABOLIC DYSFUNCTION AND THE OTHER IMPORTANT COMPONENT OF OBSTRUCTIVE SLEEP APNEA IS INTERMITTENT HYPOXIA THAT OCCURS WITH THE OBSTRUCTIVE EVENTS AND THIS LEADS IN PART TO SOME OF THE CLINICAL OUTCOMES THAT WE'LL GET TO. THE OTHER IMPORTANT COMPONENT OF OBSTRUCTIVE SLEEP APNEA RELATES TO SYMPATHETIC ACTIVATION AND DISRUPTION IN THE PITUITARYY ACCESS WHICH THEN CONTRIBUTES TO, IN PART THE DEVELOPMENT OF INSULIN RESISTANCE AND INSULIN SECRETORY DISFUNCTION AND I THINK YOU CAN SEE WHERE I'M HEADING WITH THIS AND THE OXIDATIVE STRESS THAT OCCURS WITH THE HYPOXIA, ALSO IS ASSOCIATE WIDE LEPTIN RESISTANCE, DEPNECTIN, INCREASED LEVELS OF INFLAMMATION AND IMPAIRED GLUCOSE TOLERANCE AND TYPE 2 DIABETES AND THIS RECOGNITION OF A CONNECTION BETWEEN GLUCOSE INTOLERANCE AND TYPE 2 DIABETES AND OBSTRUCTIVE SLEEP APNEA IS RELATIVELY NEW AND I THINK DR. IVAN ONCOTTER, AND A COLLABORATOR OF MINE DID THE SEMINOLE WORK THAT ESTABLISHED THIS CONNECTION BUT WE'RE STILL LEARNING MORE ABOUT IT. NOW THE SEVERITY OF OBSTRUCTIVE SLEEP APNEA IS READILY QUANTIFIED. AND IT'S QUANTIFIED BY THE NUMBER OF APPLICATIONS NICK EVENTS PER HOUR OF SLEEP AND LESS THAN OR EQUAL TO 5 IS CONSIDERED TO BE ABSENCE OF SLEEP APNEA 5 AND 15 IS MILD, 15 AND 30 IS MODERATE AND GREATER THAN 30 EVENTS OF HOUR IS SEVERE AND THERE IS AN IMPORTANT RELATIONSHIP BETWEEN THE SEVERITY AND THE COMPLIICATIONS OF THIS SYNDROME. WHAT'S BEEN KNOWN FOR MANY YEARS AND THIS IS A SUMMARY OF NOT EVERY STUDY THAT'S BEEN PUBLISHED BUT MANY OF THEM THAT HAVE BEEN IS THAT SLEEP APNEA IS MUCH MORE COMMON IN MEN THAN IN WOMEN. IN FACT IF YOU LOOK AT MOST OF THESE STUDIES, THESE WERE ALL CONDUCTED USING A CLASSIC POLYSYMNOGRAPHY WHICH IS AN IN-HOUSE OR IN-HOSPITAL LABORATORY STUDY THAT QUANTIFYS THESE OVER THE NIGHT TIME PERIOD. YOU CAN SEE THAT IN GENERAL THE PREVALENCE IN MEN IS 2 TO 3 TIMES GREATER THAN IN WOMEN AND THE REASONS FOR THIS THAT WE'RE GOING TO COME TO, MOST OF THE STUDIES HAVE SHOWN THAT THE DISORDER HAS A MAIL PREDOMINANCE. SO WHY WOULD THAT BE. WHAT'S KNOWN ABOUT THE EFFECT OF GENDER AND SLEEP APNEA AND WELL, I JUST TOLD YOU THE PREVALENCE IS HIGHER, TESTOSTERONE LEVELS ARE VERY CRITICAL IN INFLUENCING BOTH THE NEURAL CONTROL OF BREATHING, THE CENTRAL CONTROL OF BREATHING AND THE IMPACT OF HYPER CARPIC DRIVE AND HIPOXIC DRIVE AND ALSO IS IMPORTANT IN INFLUENCING UPPER AIR WAY MECHANICS, SO THE KEY PHYSICAL EVENT THAT OCCURS WITH AN APPLICATIONS NICK EPISODE IS AIRWAY COLLAPSE AND THE INDIVIDUAL TRIES TO TAKE A BREATH AGAINST A CLOSED GLOTTIS AND TESTOSTERONE HAS AN INFLUENCE ON THAT AS ON DO OTHER SEX STEROIDS AS YOU'LL SEE. TRADITIONALLY, YOU'LL SEE THE GENDER DIFFERENCE THAT I JUST SHOWED YOU IS EXPLAINED BY THE INFLUENCE, MAINLY THE THOUGHT OF ANDROGENS, BUT I THINK WE HAVE DATA AT LEAST IN PCOS THAT INDICATE THAT MAY NOT BE THE CASE. THE OTHER THING THAT DIFFERENTIATES SLEEP APNEA AND SLEEP IN GENERAL BETWEEN MEN AND WOMEN IS THAT WOMEN TEND TO HAVE A HIGHER PREVALENCE OR A HIGHER AMOUNT OF SLOW WAVE ACTIVITY WHICH I TOLD SURVEYS PROTECTIVE AGAINST SLEEP APNEA AND THE HIGH LEVEL OF ACTIVITY MAY BE PROTECTING THEM ALTHOUGH THAT'S SOMEWHAT SPEC LATTIVE AND SOMETHING WE'RE INTERESTED THIS STUDYING. NOW, THIS IS THE--THIS IS REALLY WHAT OPENED THE DOOR FOR THOSE INTERESTED IN LOOKING AT THE RELATIONSHIP BETWEEN SLEEP APNEA AND PCOS, AND THIS STUDY WAS CONDUCTED AT--WHOOPS, THIS STUDY WAS CONDUCTED AT THE BRIGHAM AND ANDREA DENATHE WAS INVOLVED IN THESE STUDIES. IT WAS ELEGANT BECAUSE IT RECRUITED 18 WOMEN WITH PCOS AND 18 CONTROLS BUT THE NICE THING ABOUT THIS PARTICULAR STUDY WAS THAT THESE INDIVIDUALS WERE MATCHED NOT ONLY BY AGE BUT BY BMI. SO THERE'S VERY GOOD PAIR MATCHING IN THESE INDIVIDUALS. SO WHAT THEY FOUND WAS THAT THE MEAN APNEA HIGHWAY POXIA INDEX IN WOMEN WITH PCOS WAS 22, PLUS OR MINUS 6 SO THAT'S MODERATE TO SEVERE SLEEP APNEA COMPARED TO 6.7 PLUS OR MINUS 2 IN CONTROLS SO HIGHLY SIGNIFICANTLY DIFFERENT IN WOMEN WITH PCOS EVEN THOUGH THEY'RE OF SIMILAR AGE AND SIMILAR BODY MASS INDEX. AND INTERESTINGLY, WHEN 1 BREAKS DOWN BY SEVERITY OF SLEEP APNEA, THE APNEA INDEX BEING OVER 5, 10 OR 15, IN EVERY CATEGORY, THE PREVALENCE IN PCOS WAS GREATER THAN IT WAS IN THE CONTROLS. USUALLY ABOUT TWICE AS HIGH TO AS MUCH AS 8 TIMES HIGHER. SO THE FACT THAT THESE WOMEN HAD SLEEP APNEA, SOME WOULD SAY, WELL, YOU KNOW IT'S NOT TOO SURPRISING, THEY'RE OVERWEIGHT, IT'S A KEY RISK FACTOR BUT THESE ARE COMPARED TO CONTROL WOMEN WHO WERE ALSO OVERWEIGHT SO THERE MAY BE--IT WAS THOUGHT SOMETHING UNIQUE ABOUT PCOS THAT RENDERED THEM MORE LIKELY TO HAVE SLEEP APNEA, THIS WAS FOLLOWED UP BY A STUDY THAT LEGRO WAS INSROFED IN AT PENN STATE WHO IS A SLEEP RESEARCHER AND RICK RECRUITED 53 WOMEN WITH PCOS. YOU CAN SEE THAT THEIR AGE WAS 32 AS YOU WOULD EXPECT BUT THE BMI WAS MORE IN THE RANGE OF WHAT WE SEE IN CHICAGO AND WHAT RICK SEES IN CENTRAL PENNSYLVANIA, MEAN BMI OF 38 NOW THEY COMSPARED THEIR DATA IT'S PROBABLY HISTORICAL CONTROLS, 452 AND AND PARTIALLY HERE BECAUSE GENERALLY, THE POPULATION WAS NONPCOS WOMEN IS LOWER IN BODY MASS INDEX AND ARE WOMEN WITH PCOS. SO THEY NEEDED TO DO STATISTICAL ADJUSTMENT BUT IN SO DOING THEY STILL HAD VERY IMPORTANT FINDINGS. ONE THAT WAS EVEN AFTER CONTROLLING WITH BMI, WOMEN WERE AT LEAST 30 TIMES MORE LIKELY TO HAVE SLEEP DISORDERED BREATHING AND 9 TIMES MORE LIKELY THAN CONTROLS TO HAVE DAY TIME SLEEPINESS. THIS WAS A NEW FINDING THAT CAME OUT IN THE SAME YEAR THAT THE STUDY FROM THE BRIGHAM CAME OUT. INSULIN RESISTANCE IN THEIR STUDY WAS A STRONGER PREDICTER OF SLEEP DISORDER BREATHING THAN AGE BMI OR TESTOSTERONE. AND FINALLY THE USE--THERE WAS SOME SORT OF SUGGESTIVE EVIDENCE IN THE PAPER THAT USE OF ORAL CONTRACEPTIVES WAS ASSOCIATE WIDE THE PROTECTIVE EFFECT AGAINST SLEEP DISORDERED BREATHING. SO WITH THAT AS THE BACKGROUND AND WHAT WE HAD TO WORK WITH GOING INTO THIS, WE DECIDED TO INVESTIGATOR THIS FURTHER TO LOOK AT WHETHER THERE WERE METABOLIC ASSOCIATES WITH THESE SLIP DISORDERS. SO, PCOS, I DON'T HAVE TO REALLY SUMMARIZE VERY EXTENSIVELY FOR THIS GROUP, IS COMPRISED OF COURSE OF HYPE IRB INSULIN ANEME ALL OF WHICH ARE RISK FACTORS FOR SLEEP APNEA AND AGAIN ISSUES AS I TOLD SURVEYS COMPRISE OF THESE SPECIFIC COMPONENTS. WHAT ARE THE CONSEQUENCES OF OBSTRUCTIVE SLEEP APNEA, WELL IT'S NO 1 KPWO EN THERE ARE PROTEIN COMPLEXERBATIONS IN THE SYMPATHETIC NERVOUS SYSTEM ACTIVITY THAT CAN LEAD TO INCREASED LEVELS OF CATECHOLAMINES, IT'S KNOWN THAT THERE'S DISRUPTION IN THE HYPOALAMILLIOIC ACCESS THAT IN SOME REPORTS INCREASES CORTISOL IN THE CIRCULATION IS ALSO THE DIP LO CITE HAS BEEN IMPLICATE WIDE RELEASE OF A CERTAIN KIND THAT MAY CONTRIBUTE TO SOME OF THE METABOLIC DISTURBANCES. NOW, THE OTHER 2 HORMONES THAT HAVE BEEN KNOWN HISTORICALLY TO INFLUENCE SLEEP APNEA HAD NOT BEEN LOOKED AT IN ANY STUDIES UP UNTIL--WELL, IN 1991 BUT LOW ESTRO DISCIPLINARY OLDER PEOPLE AND LOW PROGESTERONE ARE ALSO IMPORTANT IN CONTRIBUTING TO THE DEVELOPMENT OF OBSTRUCTIVE SLEEP APNEA AND WE KNOW THAT LOW PROGESTERONE IS TYPICAL OF WOMEN WITH PCOS BECAUSE OF THE OVULE LATTERY STATE. SO THESE ARE SUMMARIZING 3 DIFFERENT METHODS THAT HAD BEEN USED TO TRY TO RECAPITULATE THE INDEPENDENT OR INDIVIDUAL ELEMENTS OF OBSTRUCTIVE SLEEP APNEA TO DEEMERGING WHAT THE IMPACT IS UPON INFLUENCE SENSITIVITY BAYOUS OF A FREQUENTLY SAMPLED IVGTT. AND IN THIS STUDY, SHOWN HERE, AT OUR INSTITUTION CONDUCTED A STUDY IN NORMAL INDIVIDUALS AND THEN FRAGMENTED THEIR SLEEP ON 3 CONSECUTIVE NIGHTS, LOWERING THEIR--NOT THEIR TOTAL SLEEP TIME BUT SELECTIVELY ABNORMALITIESROGATING SLOW WAVE SLEEP AND YOU CAN SEE THERE WAS A STATISTICAL REDUCTION IN INFLUENCE SENSITIVITY, JUST IN SO DOING. STAMATAKIS AND PUNJABI, FOUND A REDUCTION IN SENSITIVITY AND MOST INTERESTINGLY INDIVIDUALS WITH NORMAL OXYGEN TENSION DURING THE NIGHT WERE THEN EXPOSED TO INTERMITTENT HYPOXIA AND BECAME MORE INSULIN RESISTANCE. SO ALL OF THESE ARE COMPOPENTS OF SLEEP APNEA AND WHICH 1 IF PARTICULAR OR WHICH COLLECTIVELY CONTRIBUTE TO THE INSULIN RESISTANCE THAT'S ASSOCIATE WIDE OSA, IS AN AREA OF GREAT INTEREST. NOW, THIS IS A LITTLE BIT TANGENTIAL BUT I WANT TO POINT OUT THAT WE'VE BEEN INTERESTED IN THE TISSUE EFFECTS OF SLEEP RESTRICTION AND THESE ARE RESULTS THAT WERE RECENTLY PUBLISH INDEED THE ANNALS AND THESE REPRESENT DOZE RESPONSE CURVES OF INSULIN AGAINST POSFOCUSED ON AKP TO TOTAL AKP. SO INSULIN SIGNALING CULTURED THE DIP LO SIGHTS. AND THESE WERE NORMAL INDIVIDUALS IN A RANDOMIZED CROSS OVER DESIGN AND THEY WERE STUDIED UNDER NORMAL SLEEP CONDITIONS AND SLEEP RESTRICTION. D WHAT YOU CAN SEE IS THAT, WITH SLEEP RESTRICTION, THERE WAS A CHANGE IN A SHIFT IN THE DOSE RESPONSE CURVE OF POSFOCUSED ON AKT TO TOTAL AKT RATIO WHICH IS A MARKER OF IMPAIRED INSULIN SIGNALING SO FOR THE FIRST TIME, IT INDICATE THAD SLEEP RESTRICTION MIGHT MANIFEST AT LEAST IN THE THE DIP LO SITE WITH INSULIN RECESTANCE SO WE'RE TRYING TO GAIN INSIGHT INTO THE MOLECULAR BASES FOR THE INSULIN RESISTANCE THAT'S ASSOCIATE WIDE OBSTRUCTIVE SLEEP APNEA AND RELATED DISORDERS. SO WHAT WE REALLY SOUGHT TO DO WAS TO EXAMINE THE EFFECTS OF SLEEP EFFECTS ON METABOLIC FUNCTION IN WOMEN WITH AND WITHOUT NCOS. --PCOS, WE USED THAT THE FACT THAT THEY HAD HYPER ANDROGENNISM OR ANEMIA, THEY HAD AN ELEVATED FREE TESTOSTERONE, THEY HAD A FULL NIGHT OF POLYSOM NONAPOPTOTIC GRAM AND THEY HAD A MEASUREMENT THE NEXT MORN INCLUDING A GLUCOSE TOLERANCE TEST AND THESE WERE ENROLLED CONSECURATIVELY AND WITHOUT REGARD TO THE PRESENCE OR ABSENCE OF OSA SYMPTOMS AND IN SUBSEQUENT SLIDES I'M GOING TO SHOW THAT YOU POSTDOC WE FOUND SOME OF THESE INDIVIDUALS HAD OVULATED AND BECAUSE WE WANTED TO RESTRICT OUR ANALYSIS TO THE FOLLICULAR PHASE, WE EXCLUDED THOSE WHO WOULD SEEM TO HAVE BEEN IN THE ROUTIAL PHASE AND YOU'LL SEE WHY YEE DID THAT IN A MOMENT. SO WE'VE BEEN FORTUNATE FOCUSED ON STUDY 175 EMPLOYMENT PROGRAMS WITH THIS PROTOCOL, 46 CONTROL WOMEN, 129 WOMEN WITH PCOS, AND THESE ARE THE DEMOGRAPHIC CHARACTERISTICS SO THERE'S SIMILAR IN AGE, ALTHOUGH BY A NOVA THERE ARE DIFFERENCES ACROSS THE 4 GROUPS IN TERMS OF AGE ALTHOUGH THE SRAO EP APNEA WOMEN TEND TO BE SLIGHTLY OLDER AS THEY DO SLIGHTLY HEAVIER AS YOU MIGHT EXPECT, THEY TEND TO HAVE A HIGHER WAIST CIRCUMFERENCE AND THIS IS THE GREG DOWN OF ETHNICITY, AFRICAN AMERICAN AND CAUCASIAN AND WE USE THE CATEGORY CALLED AND AFRICAN AMERICAN AND INDIVIDUALS WERE CONSIDERED TO BE IN THE HIGHER RACE RISK WITH TYPE 2 DIABETES AND THAT WILL ENTER IN JUST A MINUTE. AND LEVELS FOR THE 4 DIFFERENT GROUPS. SO THERE WERE DIFFERENCES BETWEEN THE 4 GROUPS WHICH MEANT WE HAD TO DO A STATISTICAL ADJUSTMENT BECAUSE WE DIDN'T TRY TO PAIR PATCH, WE'VE DONE SO SUBSEQUENTLY BUT THE INTERESTING DATA WAS THAT THE ODDS RATIO FOR SLEEP APNEA AND PCS CONTROLS WAS 2.44 WITH THIS CONFIDENCE IN TRIPLE. EVEN AFTER CONTROLLING FOR AGE BMI AND RACE, NOW IN THE PAST PEOPLE CONTROLLED FOR AGE AND BMI BUT WE ALSO CONTROLLED FOR RACE AND SO THE ODDS RATIO IS SIGNIFICANT IN PCOS. I'LL SHOW IT TO YOU A BIT LATER BUT AS AS YOU MIGHT PREDICT, SEX HORMONE OF GLOBUE LYNN BINDING LEVELS WERE LOWER THAN THOSE WHO ARE MORE OBESE AND PROGESTERONE LEVELS WERE IDENTICAL--NOT WORKING, PROGESTERONE LEVELS WERE IDENTICAL ACROSS THE GROUP, SO SIGNIFICANT DIFFERENCE AND THE FREE TESTOSTERONE WAS SLIGHTLY HIGHER BUT NOT STATISTICALLY HIGHER IN THE OSA POSITIVE VERSES OSA NEGATIVE. IN TERMS OF SLEEP VARIABLES, THE SLEEP TIME AND MINUTES WAS UNCHANGED ACROSS THE GROUP, SIMILAR, ESPEURBS FICIENCY WAS THE SAME, HYPOXIA WAS HIGHER IN THOSE WITH SLEEP APNEA AND THE BREAK DOWN BETWEEN MILD, MODERATE AND SEVERE SLEEP APNEA WAS SIMILAR ACROSS THE 2 GROUPS. NOW THESE ARE THE RESPONSES TO ORAL GLUCOSE CHALLENGE AND THIS IS THE CONTROL GROUP WITHOUT SLEEP APNEA AND THIS IS THE CONTROL GROUP WITH SLEEP APNEA THIS IS THE WOMEN WITHOUT SLEEP APPLICATIONSA AND THESE ARE THE WOMEN WITH SLEEP AMNIA AND BOTH CONTROLS AND PCOS, THE PRESENCE HAD A SIGNIFICANT IMPACT TO A NEURAL GLUCOSE CHALLENGE AND HERE ARE THE VALUES AND SIGNIFICANTS AREAS ON THE CURVE. IF WE LOOK AT GLUCOSE OR INTOLERANT OR COMBINING THEM AND CALLING IT ABNORMAL GLUCOSE TOLERANCE, YOU CAN SEE THAT AS AN INDIVIDUAL WITH PCOS, AND IMPAIRED GLUCOSE ABNORMAL GLUCOSE TOLERANCE AND THIS IS SUGGISTIVE I KNOW I'M GOING OUT ON A LIMB HERE TO INDICATE THAT YOU KNOW ALL OF OUR STUDIES TO DATE WHERE WE SAID WOMEN WITH PCOS HAD A HIGH RISK FOR GLUCOSE INTOLERANCE, A LOT OF THIS MAY BE DRIVEN BY THE PRESENCE OR ABSENCE OF--WHETHER THESE WOMEN HAVE SLEEP APNEA OR NOT. NOW THIS IS THE PROGESTERONE IN THE GLUCOSE IN THE CONTROLS AND IN THE PCOS AND THIS RELATIONSHIP WAS NOT SIGNIFICANT IN THE CONTROLS BUT IT WAS IN THE PCOS TO A MARGINAL DEGREE AND LEVELS ON OGGT, SEEM TO BE INFLUENCED BY SOME EXTENT BY PROGESTERONE, IS AGAIN YOU CAN SEE THAT AS OSA DEVELOPS, THERE'S AN INCREASE IN INSULIN CONCENTRATIONS AND I WANT TO AGAIN STRESS THE DATA THAT THESE ARE AGE AND CONTROL AND BMI FOR ALL OF THE PRESENTATION. THESE ARE THE P-VALUES FOR AREA UNDER THE CURVE. YOU CAN SEE THAT THE INDEX WHICH IS AN ESTIMATED INSULIN SENSITIVITY INDEX IS LOWEST IN THE PCOS WITH OSA AND STATISTICALLY, IT'S SIGNIFICANT BOTH FOR THE PRESENCE OF PCOS, AND ALSO FOR THE PRESENCE OF OSA. NOW HERE'S THE PART THAT WAS SURPRISING BUT CONSIST EPT THROUGH ALL OF OUR STUDIES IS THAT THERE'S NO RELATIONSHIP BETWEEN PCOS AND THE LEVEL OF TEST OFTREASON, SO WOMEN WITH OUT WE'RE AND NO IMPACT ON THE PRESENCE OF SLEEP APNEA, TO SUMMARIZE WOMEN ARE AT RISK FOR HIGHER RISK FOR HAVING SLEEP APNEA THAN WOMAN OUT PCOS WITHOUT CONTROLLING FOR THESE FACTORS, SLEEP APNEA IS A DETERMINANTS AND TYPE 2 DIABETES IN WOMEN AND THE METABOLIC OBSERVED, IN GENERAL MAY BE LARGELY DRIVEN BY WHAT WE'RE THINKING ASK WHAT THOSE SUBTYPES, THOSE THOSE WITH AND OUT SLEEP APNEA, GLUCOSE TOLERANCE IS CORRELATE WIDE PROGESTERONE CONCENTRATIONS WITH THE PCOS. AND I WON'T HAVE TIME TO SHOW YOU THE SLIDES EXCEPT I WANT TO POINT OUT TO YOU THAT IN ANOTHER STUDY, WHERE WE HAVE TREATED THIS WITH 19 WOMEN WITH PCOS, THERE WAS A 24 HOUR SAMPLING PERIOD IT DOESN'T CHANGE, CORTISONE LEVELS WERE THE SAME BEFORE AND AFTER, AND AS WERE LEPTIN LEVELS. SO, FINAL SUMMARY, AND CONCLUSION, TREATMENT OF SLEEP APNEA WHICH I DIDN'T HAVE--I RAN OUT OF TIME UNFORTUNATELY, RESULTS IN IMPROVED MEASURES OF CARDIO METABOLIC FUNCTION AND INSULIN SENSITIVITY AND DAY TIME AND NIGHT TIME SYMPATHETIC ACTIVITY AND DAY TIME FLOOD PRESSURE AND THESE ARE PUBLISHED. AND THERE'S A NUMBER OF USE AND THE CHANGE OF INSULIN SENSITIVITY WHICH IS TRUE THIS OTHER POPULATIONS AS WELL, AND CHANGE IN 24 HOUR EPINEPHRINE LEVELS AND THESE ARE USED TO DETERMINE BENEFITS AND SO 1 OF THE THERAPEUTIC OPTIONS FOR WOMEN WITH PCOS MAY TURN OUT TO BE TREATMENT OF SLEEP APNEA IF THEY INDEED HAVE IT. AND I HAVE A NUMBER OF PEOPLE TO THANK AND THEY'RE LISTED HERE, SOME OF IN THE AUDIENCE AND SPECIFICALLY AS CARTER AND CARLA TEMPLE AND BOB REZONINGEN FELLED WHO CAN IS HERE AND WHEN WE COME TO THE DISCUSSION I'LL BE HAPPY TO TAKE ANY QUESTIONS. THANK YOU. [ APPLAUSE ] >> SO NOW WE COME TO THE LAST PRESENTER OF THE EARLY MORNING SESSION AND THIS IS DR. KURT BARNHART, HE IS FROM THE UNIVERSITY OF PENNSYLVANIA AND HE WILL BE TALKING ABOUT ENDOMEETRIAL CANCER AND OTHER CANCERS IN WOMEN WITH PCOS. >> GOOD MORNING, AND THANK YOU FOR WELCOMING TO THIS CONFERENCE. GIVE ME A MEMORY CLONE MOMENT TO SET THIS UP. I WANT TO GO BACK TO THIS SLIDE, I NOTICED ON THIS PICTURE WHICH THERE IS NO RELATIONSHIP TO ANYTHING REPRODUCTIVE ON THIS SLIDE. NO WHERE AND LET'S REMEMBER THAT AS WE GO THROUGH, AND WE'RE FOCUS ON THE GOING TO TALK ABOUT GENERALLY WHAT'S CALLED REPRODUCTIVE CANCERS SOME ON CANCER, SOME ON OVARIAN CANCER AND OTHER GUIN ONICOLOGGIC CANCERS AS WELL AND WHAT I'LL DO IS GIVE YOU THE WHOLE LECTURE HERE IN 2 SLIDES AND THEN I'LL GO INTO A LITTLE MORE DETAIL. SO WOMEN WITH OVARY SYNDROME HAVE ABOUT 2.7 OR 2.8 FOLD INCREASE, AND THAT CONCLUSION IS BASED ON FAIRLY MODERATE AMOUNT OF DATA, FAIRLY MODERATE QUALITY SO WE HAVE SOME CONFIDENCE IN THAT WOMEN WITH POLYCYSTIC OVARY SYNDROME HAVE A 2 AND HALF FOLD INCREASE IN OVARIAN CANCER AND THAT IS BASED ON LIMITED DATA SO WE HAVE LIMITED CONFIDENCE IN THAT CONCLUSION. THERE IS LIMITED EVIDENCE TO SUPPORT THAT THERE IS NO ASSOCIATION BETWEEN PCOS AND BREAST CANCER AND THAT IS BASED ON LIMITEDDED DATA AND THAT IS ASSOCIATION IS BASED ON PCOS, RATHER THAN ANY OTHER SUCH AS VAGINAL, VULVACOR CERVICAL. I MEANT TO BE PRECISE IN MY WORDS BUT I DIDN'T MEAN TO BE PULLING THE WOOL OVER MY EYES, LET ME TELL YOU WHY I USE THOSE QUALIFIERS. NOW THIS IS COMPLEX AND CONFOUNDED AND THE DATA ISN'T ALL THAT TERRIFIC BECAUSE IT TAKES SUCH A LONG SERIES AND A LOT OF PEOPLE TO MAKE THESE CONCLUSIONS, SO IN GENERAL IT'S VERY DIFFICULT TO SEPARATE THE RISK FOR A WOMAN THAT HAS HCOS, HOWEVER WE DEFINE IT FOR MANY OTHER RISK FACTORS WE KNOW ARE ASSOCIATE WIDE CANCER AND LIKE INFERTILITY, TREATMENT OF INTERTILITY AND OVULATION IN ITSELF AND A LOT OF WORK THAT OBESITY IS RELATED INDEPENDENTLY TO A NUMBER OF CANCERS. SO WE ALSO HAVE TO REALIZE IT WILL BE SENSITIVE TO A NUMBER OF THINGS. IT'S A SMALL NUMBER WE WILL REVIEW FOR YOU IN OVARIAN CANCER AND IT'S ALSO A SMALL NUMBER OF WOMEN BOTH EXPOSED OR UNEXPOSED OR CASES OR CONTROLS, OF COURSE THAT'S FURTHER COMPLICATED BY THE DEFINITION OF PCOS ITSELF I WILL NOT REVISIT THE DEFINITION WE WOULD LIKE TO MAKE BUT WE WILL CONFOUND IT BY THE FACT THAT MANY OF THESE DON'T EVEN CARE WHAT THE DEFINITIONS WERE MAKING, THE SELF-REPORT OR SOMETHING TO DO WITH THE OVARY OR OVARIAN DYSFUNCTION, WE'RE FOCUS ON THE EVEN SURE THESE WOMEN HAD PCOS TO BE SURE AND OF COURSE IT'S LIMIT TO THE COMPARISON POPULATIONS THEMSELVES. SOME OF THESE AS WAS MENTIONED YESTERDAY, SOME OF THEM EXCLUDE WOMEN IN INFERTILITY, SOME INCLUDE THEM, SOME EXCLUDE THOR VALID AND RELIABLIAN CONDITION AND SOME INCLUDE THEM AND IT MAKE ITS TOO HARD LOOK AT THE POPULATION. SO LET ME LOOK AT ENDOMETRIAL CANCER, WOMEN WITH ANAOVULULATION THEY ARE AT RISK FOR HYPER PLACE WHAT AND ENDOMETRIAL CANCER AND PCOS WAS 1 OF THOSE CLASSIC RISK FACTORS WITH AMENORIA OR OLIGO MENNOR YEA WHICH HAS HYPER PLASSIA AND CANCER. IT'S GENERALLY ACCEPTED BUT THERE ISN'T A LOT OF EVIDENCE TO PROVE IT. MOST OF THE EVIDENCE COMES FROM HORMONE REPLACEMENT THERAPY AND HYPER PLACIA AND WE MADE THE CONNECTION THAT IS PREMENOPAUSAL SYNDROME THAT HAS IT, THERE ARE A NUMBER OF CASE REPORTS, I'M NOT DISPUTING THAT AND VERY WELL KNOWN FINDING BUT QUANTIFY TAG RISK IS MORE DIFFICULT. LUCKILY WHEN YOU INCLUDE THOSE CASE REPORTS AND LOOK AT SPECIFIC EXAMPLES, MOST OF THOSE ARE WELL DIFFERENTIATED AND HAVE GOOD PROGNOSIS AND THERE'S NO HISTOLOGICAL DIFFERENCE NOTE INDEED ENDOMETRIAL CANCER IN SOMEONE WITH OR WITHOUT PCOS. THE RISK IS THOUGHT TO BE ESTLO GEN RELATED BUT THERE ARE A LOT OF HYPOTHESIS THAT SAY MAYBE NOT, MAYBE THE RISK OF INDEPENDENT AND OTHER FACTORS, THIS IS JUST 1 PROPOSED SOLUTION THAT ENDOMETRIAL CANCER RISK IS DUE TO ANDROGEN, THAT IT'S ANDROGENS AND NOT ESTROGENS. THIS GOES THROUGH, WE COULD DO IT IF YOU WANT BUT IT GOES THROUGH OBESITY, THROUGH SOMEHOW PERIPHERAL AND ROAM ANISATION AND ESTROGENS, IT'S IT'S GOING THROUGH INSULIN AND IGF1 AND IT'S BINDING PROTEIN ON ENDOMEET REUMKC ITSELF AND THEREFORE PERHAPS INCREASING THE RISK AND ENDOMETRIAL CANCER WHICH LEADS TO ME TO A QUESTION WHEN WE TALK ABOUT EPD O MEETRIAL CANCER WHAT I DON'T SUNDAY WHETHER THIS RISK IS ONLY ASSOCIATED WITH THE AN-OFULATION, AND THE IMMEDIATE RISK OF CANCER OR ARE WE SAYING 1 MORE PCOS IN YEARS AND RISK FOR CANCER MOST MENOPAUSALLY OR LATER DUE TO SOME OTHER MECHANISM AND THAT WILL BE HARD TO TEASE OUT, HOWEVER, THE BEST RISK THE BEST RISK SEEMS TO BE 2 OPINIONED 7 HA CONFERENCE CENTER OF 1, WHICH MEAN ITS TOUCHED NULL SO WE COULDN'T CONCLUDE THERE WAS A RISK. SOMEONE REDID THIS META-ANALYSIS THIS JUST THIS YEAR AND THEY GOT A 2.89 AND A CONFERENCE INTERVAL THAT SAYS IT'S TPHAOU NOT DUE TO CHANCE. THE PROBLEM IS THERE'S CASE REPORTS 200 OR 300 CASE REPORTS, IT BOILS DOWN TO 20 GOOD IS IT STUDIES ONLY OF WHICH 4 WILL PUT IN FOR META,AINAL SIS AND IN THIS PARTICULAR CASE, THE RELATIVE RISK FOR THE INDIVIDUAL STUDIES RANGES FROM NO ASSOCIATION AT ALL TO RISK AS HIGH AS 6. IN PARTICULAR THE META-ANALYSIS LOOKED AT 4 STUDIES AND ONLY WOHAD A SIGNIFICANCE AND 1 HAD NO RISK AND TALKING ABOUT YOU KNOW 666 WOMEN OF CANCER OF WHICH 29 WOMEN HAD PC OS, AND ABOUT 3000 CONTROLS AGAIN WITH A RELATIVELY LOW INCIDENCE OF PCOS, THE DIFFERENCE IN THE META-ANALYSIS THE 1 THAT MAKE ITS SIGNIFICANT IS THE LATTER 1 INCLUDE INDEED 1991 STUDY AT THE FORMER 1 EXCLUDED AND THIS IS THE PROBLEM, THE 1 THEY EXCLUDED AND THEN SUBSEQUENTLY PUT BACK IN SHOWS AN ODDS RATIO OF 4.2 BUT IT'S WOMEN WITH INFERTILITY ASSOCIATED FACTORS. SO WE'RE NOT SURE, THAT'S PCOS, 1 AUTHOR SAID SAID I'LL TAKE IT OUT BECAUSE WE'RE NOT FUR SURE THE OTHER SAID I'LL PUT IT IN BUT THE OTHERS GIVES US CONFIDENCE. THERE'S OTHER STUDYS THAT SHOW WILD RISK AND THIS IS JUST A SECOND AGO SHOWS A RISK AS HIGH AS 5 AND 6 IN OBESE WOMEN LEADING TO THE QUESTION ARE CERTAIN WOMAN WITH PCOS AT HIGHER RISK THAN OTHERS AND I WOULD LEAVE THAT OUT THERE BECAUSE IT'S VERY POSSIBLE IF NOT LIKELY BUT I WON'T BE ABLE TO TELL THAT YOU ANY ANY CERTAINTY. NOW IF WE TRANSALATE THE POPULATION RISK, WE TALK ABOUT AN ABSOLUTE RISK INCRETESSING WOMEN WITH ENDO MEETRIAL CANCER FROM ABOUT 17 PER HUNDRED THOUSAND TO ABOUT 46 PER HUNDRED THOUSAND. A LIFETIME RISK THAT'S INCREASE PROGRESS 3% TO 9%. BUT REMEMBER THIS IS A GOOD PROGNOSIS CANCER, 86% 5 YEAR SURVIVAL RATE. ARE THERE GUIDELINES AND PRESENSION STRATEGIES TO AVOID THIS? WE ARE ALL TAUGHT THAT HYPERTENSION CAN REVERSE THIS RISK, THERE'S THAT EVIDENCE BECAUSE ORAL CONTRACEPTIVE PILLS ARE PROGESTERONE DOMINANT THAT THEY WILL WORK AS WELL AS CYCLIC PROJESTIN. THERE'S NO EVIDENCE THAT THAT SAYS 1 WORKS BETTER OR WORSE IN TERMS OF CANCER RISK OR ANY HEALTH BENEFIT FORS A WOMAN WITH PCOS. NOW, THERE'S A DEBATE OR MAYBE BETTER TO SAY, NOT A TRUE CONSENSUS FOR HOW WE SURVEILL THESE WOMEN. WE ALL AGREEN CELLS THERE SHOULD BE SOME SURVEILLANCE IN THE WOMAN THAT'S AMENORA THE 3 MONTH SURVEILLANCE OR AT LEAST HAVE A PERIOD BRAWN EVERY 3 MONTHS IS AT BEST GOOD CLINICAL PRACTICE AND REALLY ISN'T BASED ON EVIDENCE, EXCEPT FOR MAYBE THE HORMONE REPLACEMENT LITERATURE AS WELL. WHEN WOULD YOU BIOPSY SOMEBODY? I THINK WE HAVE DEFERRED GOOD CLINICAL PRACTICE, THERE ISN'T A CONSENSUS ON THAT. SOME PEOPLE HAVE SUGGEST GREATER THAN 10-MILLIMETERS BUT TRULY EVIDENCE BASE AND I CAN'T ADDRESS THE FACT THAT WELL THERE IS LITERATURE THAT SAYS ENDOMETRIAL THICKNESS UNDER 4 IS AT RISK FOR CANCER BUT I DON'T KNOW IF THAT'S FOR ALL WOMEN OR FOR 4 OR EXCLUDE WOMEN WITH PCOS. LET'S SWITCH TO OSOARIAN CANCER FOR A SECOND. WHY WOULD SOMEBODY--WHY WOULD WE BE WORRY BODY OVARIAN CANCER WITH PCOS, THERE'S THE THEORY ABOUT INCESS ANT OFULATION, MAYBE INCREASE THE RISK FOR OVACKIAN CANCER IT MAY BE TUBAL FUNCTION OR MEN SIS THROUGH THE TUBES AND RETROGRADE MENSE SIS, I THOUGHT ABOUT THAT LAST NIGHT AND I CAN'T TILE IT TO PCOS BUT MAYBE SOMEONE IN THE AUDIENCE CAN GIVE IT A FACTOR. LACK OF PARITY, LACK OF BREAST FEEDING AND SOME HYPER RISK MAY BE DUE TO INCREASED ANDROGENS AS WELL. NOW THERE'S OLD LITERATURE THAT WE ARGUE ABOUT A BIT BUT LET'S KEEP IN THE BACK OF OUR MIND THERE,'S BEEN REPORTS THAT CHROMA DUCE MAY BE ASSOCIATE WIDE CANCER ASARILY AS 19 NORAND A MORE RECENT STUDY WHO SAY THAT WOMEN TREAT WIDE IVFETAL COMPARTMENT ARE AT GREATER RISK FOR OVARIAN CANCER, AND THAT WAS DOMINATED BY BORDER LINE CANCER BUT THAT ALSO SHOULD BE IN THE BACK OF THEIR MIND THAT IT MIGHT BE DUE TO INFERTILITY TREATMENT AS WELL, THAT MIGHT BE DRIVING THIS RISK: SOET BEST ESTIMATE IS A INN CREASE OF 2.5 AND--INCREASE OF 2.5 AND IF YOU CHECK WITH WOMEN WHO TOOK ORAL CONTRACEPTIVES, IT WOULD NO HIGHER THAN 10. THIS IS STUDY IS FROM THE HORMONE STUDY AND 7 CASES WITH PCOS THAT HAD OVARIAN CANCER OUT OF 4000 CONTROLS WITH WOMEN. NOW IF THAT STUDY WAS TRUE IT WOULD TRANSLATE OUT OF 17 OUT 700,000 WOMEN INCREASING WOMEN AND AGAIN WE HAVE LIMITED CONFIDENCE IN THAL? WHY? IT WAS ONLY 1 STUDY IN 7 SUBJECTS BUT ALSO IF YOU LOOK AT THE PREVALENCE OF PCO AND BOTH CANCER GROUP AND NONCANCKER GROUP WE'RE TALKING ABOUT PREVALENCE OF 1.5 AND LESS THAN 1%. SO I DON'T KNOW IT WOULD BE INCLUDE THE ROBUST POPULATION WHERE WE MIGHT EXPECT A 5 OR 8% PREVALENCE OF PCOS. NOW INTERESTINGLY, PEER POINT REHEARD ABOUT DID SOMETHING CALLED STANDARDIZED MORTALITY RATES AND YOU LOOK AT THE MORTALITY RATE OF 1 MORE PCOS, COMPARE TO WHAT YOU EXPECT, IT'S ABOUT 1. WE HEARD THAT BEFORE. BUT IF HAVE 1 WITH PCOS AND OVARIAN CANCER YOU HAVE A BETTER SURVIVAL. 70% MORE LIKE HOE TO SURVIVE SO IT'S A GOOD THING TO HAVE OVARIAN CANCER WHEN YOU HAVE PCOS. NEVER A GOOD THING TO HAVE CANCER BUT THE MORTALITY RATE IS LOWER AND IT DOES LEAD TO THE SITUATION WHERE IT'S A CLEAR AS OPPOSE TO METASTATIC OR EPITHELIAL CANCERS. THERE ARE GUIDELINES OR STRATEGIES FOR THIS RISK? NO, NOT REALLY. WE KNOW THAT ORAL CONTRACEPTIVE REDUCES BY 30-50%. WE KNOW THAT PARITY REDUCES THE RISK OF CANCER BY 50%, SO 1 STRATEGY WOULD BE IF A WOMAN OF INFERTILITY THAT WE CAN TREAT HER, AND THE OTHER STAT EDGE SETHAT HE DOES HAVE AMENORIA WE TREAT HER WITH ORAL CONTRACEPTIVE PILLS AND WE DON'T KNOW IF THE RISK IS THE SAME OR THE PROGESTERONE IS THE SAME OR NOT, IT'S THE STRATEGY TO SURVEILL A WOMAN THAT OVARIAN CANCER WITH OR WITHOUT PCOS. WHAT ABOUT BREAST CANCER, THE RISK OF BREAST CANCERS ARE COMMON WITH PCOS AS WELL, OBESITY, PARITY, I'VE SEEN RECENT LITERATURE THAT LEPTIN IS ALSO ASSOCIATE WIDE IGF AND BREAST CANCER LEVELS ARE ASSOCIATE WIDE IT AND WE SHOULD LOOK FOR AN ASSOCIATION. IT MAY BE THE PROLONGED ESTROW ZYGOUS GEN USE, I HAVE TROUBLE WITH THAT WHOLE BREAST CANCER PROLONGED ESTROGEN USE BECAUSE IT'S SO GROSS IN ITS DEFINITION. YOU KNOW EARLY MENY, LATE MENOPAUSE BUT IT DOESN'T TALK ABOUT THE QUALITY OF OVULATION, JUST REPRODUCTIVE AGE AND IF SOMEONE IS AT OVULATION, IS GOOD OR BAD, DID CREASE OR INCREASE RISK? I DON'T HAVE AN ANSWER BUT I THOUGHT IT WOULD THROW IT OUT THERE. NOW REMEMBER, OBESITY IS A RELATIVELY STRONG PRODETECTEDDIVE FACTOR FOR PREMENOPAUSAL BREAST CANCER WHILE IT'S A RELATIVELY STRONG RISK FACTOR FOR BREAST CANCER POST MENOPAUSALLY AND I CAN'T EXPLAIN THAT EITHER. SO WHAT'S THE EVIDENCE FOR PCOS, WELL, LUKELY IT'S TPHUL, ABOUT PUBLICITY 9, IT'S BASED ON 3 STUDIES, 1 STUDY SAID HAD A TREND 1 STUDY SAID NO RISK AND 1 SAID PRODUCTIVE. WE'RE TALKING ABOUT LARGER CASES. IF YOU BELIEVE THIS RISK WERE TRUE, YOU WOULD HAVE A REDUCTION IN BREAST CANCERS FROM 121 TO A HUNDRED THOUSAND, TO ABOUT 106 BYE-BYE BUT STUDY WAS CRISTICIZEED AGAIN BECAUSE OF THE LOW PREVALENCE RACE OF PCOS AND LESS THAN 1% TO 1.3% IN THE WOMEN THAT WERE STUDIED. INTERESTINGLY IF YOU LOOK AT THE PEER POINT STANDARD MORTALITY. A WOMAN WITH PCOS GETS PWRAFT CANCER, HE HAS A HIGH MORTALITY RATHER THAN THERE'S A NOT WIDE LEVEL AND NOT SIGNIFICANT. SO SHOULD WE CHANGE OUR GUIDELINES AND PREVENTION FOR WOMEN WITH PCOS? AGAIN I DON'T SEEM TO HAVE TOEFDZ DO THAT. WE KNOW THE PARITY WILL ISSUE RISK OF BREAST CANCER, WEIGHT LOSS WILL REDUCE THE RISK FOR BREAST CANCER AND THERE ISN'T SEEM TO BE RISK WITH ORAL CONTRACEPTIVE PILLS AND BREAST CANCER SO WE'RE NOT AFFECTS BEHAVIOR ALL THAT MUCH AND THERE'S NO RECOMMENDED ACCEPTED SCREENING THAT'S DIFFERENT WITH THE HISTORY OF PCOS THAN ANY OTHER WOMAN. AS I MENTIONED BEFORE, THERE'S INSUFFICIENT DATA TO LOOK AT VULSA OR OTHERS CONDITIONS. WHERE DOES THIS TAKE US? I TOOK THESE OUT OF AMSTERDAM PCOS WORKSHOP THAT BART HA USER ORGANIZED SO THERE'S QUALITY DATA SORT THAT WOMEN WITH PCOS HAVE A 2.7 OR 2.4 FOLD INCREASE IN THESE CANCERS AND HAVE DIFFERENTIATED AND GOOD PROGNOSE ESTIMATE THAD. SECOND 1 TO QUOTE THE CONSENSUS DOCUMENT, THERE EVIDENCE TO SUGGEST THAT PCOS ARE NOT AT RISK FOR OVARIAN CANCER. I DON'T KNOW HOW THAT GOT CHANGED BUT THAT'S NOT ACCURATE. THE TEXT SAYS THERE'S ON NO RISK AND THE CONCLUSION SAID THERE'S NO RISK AND I WANT TO CORRECT THAT. THERE'S DATA TO JUGGEST THAT WOMEN WITH PCOS DO NOT HAVE A RISK FOR BREAST CANCER. THERE'S SUBTYPESLEY IN THE LANGUAGE THERE BUT IT'S IMPORTANT. THIS IS AN AREA WE NEED TO TALK ABOUT, THERE IS NO OPTIMAL MORTALITY TO HOW TO MONITOR THESE WOMEN FOR HYPER PLASSIA OR CANCER SO, THE DECISION OF WHEN YOU ULTRASOUND SOMEBODY OR BIOPSY SOMEBODY IS BASED ON GOOD MEDICAL PRACTICE SUCH AS LENGTH OF AMENORA AND THE ENDOMEET RIIUM, THICKNESS, CHARACTER, SO THERE ISN'T GREAT STANDARD RECOMMENDATIONS WE CAN GIVE YOU OTHER THAN PRACTICE GOOD MEDICINE. SO WHERE DO WE GO FOR THE GAPS IN RECOMMENDED RESEARCH? ONE OF THE GAPS IS DIFFICULT TO SEPARATE THE PCOS CANCER RISK INDEPENDENTLY, FROM THOSE OTHER RISK FACTORS I MENTIONED, PARITY AND FERTILITY AND OVULATION AND OBESE ETICS AND AGAIN TO SUMMARIZE AT THE SAME TIME, LACK OF PRECISION IN THESE ESTIMATES AND THE RISK OF ENDOMETRIAL CANCER ESPECIALLY IN THE SUBGROUPS. I DON'T KNOW WHETHER WOMEN WITH HYPER ANDROGEN ROUGH ATOM NEMIA HAVE A HIGHER RISK THAN SOMEONE THAT HAS POLYCYSTIC OVARIES. IT'S LIMITED IN THE COMMENTS IN THE ASSOCIATION WITH OVARIAN CANCER AS I MENTIONED BUT THERE'S A STUDY THAT SHOWS A RISK AND CANCER STUDIES AND PCOS NEED TO INVOLVE MORE SUBJECTS, MORE CLARITY ON THE PHENOTYPE AND THE COMPARISON POPULATIONS NEED TO BE BETTER. SO MY 9AL SLIDE AND SUGGESTS FOR FUTURE RESEARCH ARE SIMPLY THAT WE DO NEED LONGITUDINAL STUDY OF THE ASSOCIATIONS OF PCOS AND OVARIAN BREAST CANCER WHILE CONTROLLING FOR THESE FACTORS I HEARD GOOD -FZ EVIDENCE THAT WE THESE STUDIES WHICH WERE ONGOING WHICH IS GRIT BECAUSE THE GOAL HERE OF COURSE IS TO IDENTIFY HIGH RISK SUBJECT, SUBSETS OF OF WOMEN WHO MAY NEED DIFFERENT SURVEILLANCE FOR CANCER THAN JUST A NORMAL WOMEN. AND RIGHT NOW, I CAN'T SAY, THAT WE HAVE SUCH A PARADIGM OTHER THAN RECOGNIZING THAT ANOFOVULATION IS ASSOCIATE WIDE THE CANCER IN THE IMMEDIATE SHORT OUTCOME AND ALONG TERM RISK IS NOT YET KNOWN. SO THANK YOU VERY MUCH. [ APPLAUSE ] >> WE WILL TAKE A BREAK NOW. LET'S START IN 15 MINUTES AT 10:15. THANK YOU VERY MUCH. WELCOME BACK PLEASE TO THE MORNING SESSION. THIS IS AS YOU RECALL SESSION 3, THE LONG-TERM HEALTH CONSEQUENCES OF PCOS AND I WOULD LIKE TO INTRODUCE OUR FIRST SPEAKER FOR THIS SECOND HALF. THIS IS DR. SILVA ARSLANIAN, SHE IS FROM THE UNIVERSITY OF PITTSBURGH AND HER TALK IS ON NONALCOHOLIC FATTY LIVER DISEASE. THANK YOU. >> THANK YOU. >> I THANK THE ORGANIZERS FOR THE INVITATION TO WORK IN THIS WORKSHOP BUT MORE IMPORTANTLY I THANK THEM FOR ASSIGNING ME THIS TOPIC BECAUSE IT PROMPTED ME TO LOOK INTO A DATA SET WE ACQUIRED A WHILE BACK AND NEVER HAD THE OPPORTUNITY TO PUT IT TOGETHER. SO, THIS IS WHAT I'M GOG TRY TO COVER--GOING TO TRY TO COVER IN THE 14 MINUTES AND LET'S START WITH NONALCOHOLIC FATTY LIVER DISEASE, THE DEVELOPMENTAL ENDOCRINOLOGY MISSION IS WHEN THERE'S MORE THAN 5 PERCENT FATTY INFILTRATION OF THE HEPATOCYTE. IN THE PRESENCE OF LESS THAN 20-GRAMS OF ALCOHOL COMSUMPTION PER DAY AND AFTER EXCOLLIDINGING OF OTHER CAUSES OF HEPATIC DISEASE AND THIS AMOUNT EXCEEDS THE 95th PERCENTILE OF AN OTHERWISE NORMAL HEALTHY, NORMAL WEIGHT INDIVIDUALS. SO, IT'S BELIEVED THAT FATTY LIVER IS PRESENT IN UP TO 75% OF OBESE INDIVIDUALS AND AS HIGH AS 95% OF MORBIDLY OBESE ADULTS AND IT'S ESTIMATED THAT NONALCOHOLIC FATTY LIVER DISEASE WHICH FROM NOW ON I'M GOING TO REFER TO AS NFLD, AND IT EFFECTS 20% OF THE WORLD'S POPULATION. SO HERE'S A PATIENTS IN THE CLINIC IRB OF THE GROWTH FINDING OF A NORMAL LIVER THIS, IS THE FATTY LIVER, [INDISCERNIBLE], THIS IS THE HISTOLOGY OF A NORMAL LIVER AND THE HISTOPATHOLOGY OF HEPATIC SIGNIFYITOSEIS, YOU CAN APPRECIATE THE FAT DROPLETS IN THE HEPATOCYTES. AND THESE ARE THE VARIOUS STAGES OF FATTY LIVER DISEASE, PROGRESSING FROM NORMAL TO HEPATIC OR NFLD, AND NONALCOHOLIC STEREO HEPATITIS WHERE THERE IS EVIDENCE OF HEPATOCYTE BALLOONING, FIBROSIS AND INFLAMMATION. AND AROUND 20-30% OF THIS INDIVIDUAL OR INDIVIDUALS WITH THIS TYPE OF PATHOLOGY OVER A 10 YEAR PERIOD WITH PROGRESS INTO CIRRHOSIS AND ANOTHER 4-27% WE PROGRESS FROM CIRRHOSIS TO HEPATOCELLULAR CARCINOMA. SO WHAT IS THE PATHOGENESIS OF NFLD, IT'S TRULY AN IMBALANCE BETWEEN FAT ACQUISITION BY THE LIVER AND REMOVER. THE ACQUISITION OF FAT BY THE LIVER IS FROM DIETARY SOURCES, BOTH FAT AND GLUCOSE, PARTICULARLY FRUCTS ON WHICH ENHANCES LIPO GENESIS BUT SOME FAT IN GENERAL, THE STANDARD AMERICAN DIET WHICH DELIVERS AROUND A HUNDRED GRAMS OF FAT A DAY, 20-GRAMS OF IT WILL END UP IN THE LIVER. AND THEN THERE IS TISSUE LIAISON POLARIZED SIS WHICH GENERATE 3 FATTY ACIDS GOING INTO THE LIVER AND BEING RESCERTIFIED AND THEN DE NOVO SYNTHESIS. THE REMOVAL OF FAT THROUGH THE LIVER IS THROUGHOXIDATION, RECERTIFICATION AND SECRETION AFTER INCORPORATION IN THE LDS AND HERE'S A GRAPHIC REPRESENTATION OF THAT, THE SOURCE OF LIPIDS IN THE LIVER THROUGH DIET, MICROHYDROLYSIS AND PREFATTY ACIDS, AND THEN CERTIFICATION OF TRIGLYCERIDE FROM THE TISSUE HIPWOL SIS, AND THE LIVERS ANOTHER 20-GRAMS, SO BETWEEN THE DIET AND THE TISSUE LIAISON POLARIZED SIS, WE GET PER DAY, THE AMOUNT OF LIVER FAT THAT WE'RE ALLOWED TO HAVE, SO AS THIS INCREASES THE OF COURSE THE DELIVERY OF PREFATTY ACIDS AND THE INFLUX OF FAT INTO THE DELIVER INCREASES, AND THE REMOVAL OFOXIDATION AS I MENTIONED, WITH THE RECERTIFICATION. NOW A FEW OBSERVATIONS ABOUT NFLD, THE PREVALENCE INCREASES WITH INCREASING OBESITY. MEN ARE AFFECTED MORE THAN WOMEN BEFORE 60 YEARS OF AGE BUT WOMEN MORE THAN MEN THEREAFTER, HISPANICS ARE AFFECTED MORE THAN CAUCASIANS, MORE THAN AFRICAN AMERICANS. THERE IS FAMILIESIAL CLUSTERING WITH THE HERITABILITY OF AROUND 39% FOR NFLD, IT IS STRONGLY ASSOCIATE WIDE INSULIN RESISTANCE, METABOLIC SYNDROME, TYPE 2 DIABETES, THERE ARE WELL KNOWN IDENTIFIED AND STUDIED GENETIC MUTATIONS, AMONG THE POPULATION LEVEL, THE NEURINE GENE, PLP A 3, IT ACCOUNTS FOR ALMOST SEFBT% OF THE RACIAL DISPARITY IN RISK FOR NAFLD. THERE ARE INDIVIDUALS MUTATIONS THAT EVEN THOUGH THERE ARE ASSOCIATE WIDE INCREASED HEPATIC SERRAITOSEIS, THE STUDIES SHOW THAT THEY ARE NOT ASSOCIATED WITH HEPATIC OR PERIPHERAL INSULIN RESISTANCE. WHAT ARE THE DIAGNOSTIC METHODOLOGIES? I HAVE LISTED SOME OF THE REFERENCES FOR EACH DIAGNOSTIC METHODOLOGY, WE DON'T HAVE TIME TO GO THROUGH THEM BUT HERE I HAVE COMPILED THEM. LIVER ENZYMES ARE TYPICALLY THE 1 DETECTED BECAUSE YOU KNOW YOU'RE DEALING WITH AN OBESE PATIENT WHETHER OR NOT THAT PERSON AS PCOS OR A PATIENT WHO COMLINES OF OF SOME GI DISCOMFORT, YOU DELIVER ENZYMES THAT ARE ABNORMAL, THE NEXT THING YOU REFER THEM FOR A SEWNOGRAM WHICH IS THE MOST FREQUENTLY UTILIZED IMAGE IT IS METHODOLOGY IN CLINICAL PRACTICE. MIND YOU, THE AUTOSEWNOGRAM OR SONOGRAM OF THE LIVER ONLY DETECTS THE SERRAITOSEIS ONCE IT'S ABOVE 30%. SO IT'S PRETTY LATE IN THE COURSE OF HEPATIC SERRAITOSEIS. CTOF THE LIVER CAN BE USED TYPICALLY AS A RESEARCH METHOLOGY WHERE YOU USE THE ATENUATION, BASED ON THE UNITS WITH THE SPLEEN AS INTERNAL STANDARD BECAUSE THERE ARE DIFFERENCES BETWEEN THE DENSITY OF THE LIVER AND SPLEEN AND CAN YOU COME UP WITH A FATTY LIVER INDEX WHICH I'LL DISCUSS LATER. MRIs ARE NOT A METHODOLOGY, MRS PROVIDES QUANTITATIVE ESTIMATE AND YOU CAN MEASURE LIVER FAT AS LOW AS 3, 4, 5%. AND FINALLY LIVER BIOPSY, WHICH IS REALLY THE ONLY METHOD TO STAGE AND GREAT NAFLD, BECAUSE IT'S ONLY WITH LIVER BIOPSY YOU CAN DETECT INFLAMMATION, BALLOONING FIBROSIS. OTHERWISE, THE ONLY THING THAT CAN YOU DETECT WITH OTHER METHODOLOGIES IS JUST THE PRESENCE OF FAT. NOW LET'S COME TO THE CRUX OF THE TALK NAFLD AND PC RS, NOW I WOULD LIKE TO REMIND YOU THAT THE INTEREST IN THIS FIELD GOES BACK PROBABLY AROUND 6 OR 7 YEARS SO I TRY TO GET 1 EXAMPLE EVERY YEAR TO POINT OUT WHAT THE ADVANTAGES OR DISADVANTAGE OF THAT STUDY WOULD BE BUT OVERALL, THE STUDIES ARE FRAUGHT WITH THE PROSPECTIVE NATURE OF VIEWS, INADEQUATE CONTROL, INADEQUATE POWER, VARIOUS DEFINITIONS OF PC Rs AS WE DISCUSS IN LENGTH YESTERDAY AND VARIOUS APPROACHES TO DETECT FATTY LIVER PRESENCE. SO HAVING SAID THAT, LET ME START WITH 2005, WITH THIS STUDY THAT TRIBUTE MEDICAL RECORDS OF 73 WOMEN SEEKING PERTILITY TREATMENT IN THE KISER PERMANENTE SYSTEM AND OF COURSE LIVER FUNCTION TEST AND THEY WERE FOUND TO HAVE ELEVATED ALD 30% AFTER PCOS AND PLUS 30% ELEVATED ALST, AND NOT SURPRISINGLY WOMEN WITH HIGHER HAD HIGHER BMI, TRIGLYCERIDES, CHOLESTEROL AND QUICK INSULIN RESISTANCE. YOU HAVE SEEN ALL THE STUDIES AND MEASURED A SURROGATE ESTIMATE OF INSULIN SENSITIVITY EITHER WHO THEY ARE OR QUICKIE. SO OKAY, IT'S NOT SURPRISING THAT THE ASSOCIATION AND COMPONENT WITH THE INSULIN RESISTANCE. SO THE CONCLUSION IS THAT IT EXPENDS THE HIGH RATE OF ALT AND PC RS, AND THIS IS ANOTHER RETROSPECTIVE CHART IN REVIEW IN 2006, 275 CHARTS WERE REVIEWED WITH NICD WITH THE OS, BETWEEN 99 AND 2004, AND 207 WOMEN HAD ASCAD DOCUMENT INDEED THE RECORD OF THOSE WOMEN 171 HAD NORMALLY ALTS, 29 HAD ELEVATED ALASD AND THE VARIETY OF THEM 5 HOLIDAY, AND 13 BOAT AND THEN 16 OF THEM, OF THE 29 UNDER WENT IMAGING STUDIES AND SO YOU CAN SEE THE WEAKNESS OF THE RETROSPECTIVE CHARTS REVIEW STUDY DESIGN. BUT WHAT THE--BUT AMONG THOSE 29 WOMEN WHO HAD THE ELEVATED ALTASD, 6 HAD PERSISTENT ELEVATIONS AND UNDERWENT LIVER BIOPSY THAT SHOWEDS THE PRESENCE OF NASH. SO WHAT THEY DID WAS COMPIE THOSE 6 WOMEN, ONLY 6 WHO HAD PRESENT NASH SO THE 171 WOMEN WHO HAD NORMAL ASDALT, MIND YOU THESE WOMEN DID NOT HAVE BIOPSY SPECIMEN, I SAID THAT AROUND ONE-THIRD OF JUST SIMPLE SIMPLE HEPATITIS EITOSEIS COULD HAVE IN EVIDENCE OF EVIDENCE OF NASH. IF 1 BIOPSIES THEM SO AGAIN, THE WOMEN WHO HAD NASH HAD THIS COMPONENTS THAT WAS DIFFERENT FROM THE WOMEN WHO DID NOT HAVE NASH, HIGH FASTING AND ASDLT, PLEASE NOTICE THAT BMI WAS 6 BMI UNITS HIGHER IN THE NAS GROUP THAN THE NO-NASH GROUP BUT THIS WAS NOT SIGNIFICANT NOT BECAUSE TRULY THIS IS NOT SIGNIFICANT IN MY OPINION IS CLINICALLY SIGNIFICANT BUT THERE WAS A POWER ISSUE THERE. NOW THE NEXT STUDY WAS A PROSPECTIVE STUDY THIS TIME, OF 41 WOMEN IN 2007 BUT THEY WERE MATCHED FOR AGE, BMI AND PLEASURE WHICH IS AN ADVANCEMENT ON THE TRIBE STUDIES, THE METHOD OF ASSESSMENT THAT NAFLD WAS ULTRASOUND AND THEY DID METAPWOLIC STUDIES AND PC RS WOMEN HAD ALT, FASTING INSULIN AND GLAUCOMA, NOTHING NEW SO FAR. BUT THIS WAS--THIS WAS A FINDING THAT AROUND 41% OF THE WOMEN WITH PCOS HAD% OF THE CONTROL WOMEN, AND 39% HAD ABNORMAL ALT VERSES 3.2%. AGAIN, BRINGING HOME THE MESSAGE THAT NOT EVERYBODY WITH EVIDENCE OF NAFLD WOULD HAVE ELEVATION THAT ENZYME LEVELS INCREASES WHETHER THEY'RE PCOS OR CONTROLS AND THAT'S OF COURSE, THE PREVALENCE OF INSULIN RESISTANCE MEASURES BY IRIN THE STUDY WAS HIGH AND THE COMPARED TO THE CONTROLS. SO THE CONCLUSION WAS THAT NAFLD WAS FREQUENTLY IN THE WOMEN AND PCOS SHOULD BE SCREENED FOR LIVER DISEASE. THIS IS YET ANOTHER RETROSPECTIVE STUDY THIS TIME IN 2007. OF THE CONSECURATIVE WOMEN, BUT THE ADVANTAGE WAS THAT IT LOOKED AT THE SPECTRUM OF BMI FROM LEAN TO OOH BEES WOMEN, BUT, 64% WERE ON A VARIETY OF TREATMENTS, OCPs, MET FORMIN, COMBINATION OF OCP AND MED FORMIN AND THE ASSESSMENT WAS ABDOMINAL ULTRASOUND AND AS YOU CAN APPRECIATE AS GUTMACHER FROM LEAN TO OVERWEIGHT TO OBESE, THE PERCENT WITH HEPATIC SER ONITOSEIS INCREASES UP TO 70% AND THE SEVERITY IN THE DARK BARS, THE PERCENT OF THE SEVERE HEPATIC STEREOITOSEIS INCREASES AND THE HATCH BARS ARE HISTORICAL CONTROLS FOR THE PREVALENCE OF HEPATICSTERATOSEIS IN NONPCOS WOMEN. SO 70% OF OBESE PCOS WOMEN IN THIS STUDY HAD EVIDENCE OF NAFLD, INTERESTINGLY, OCP USERS HAD LOWER NAFLD 38% VERSES 64% NONOCP USERS BUT THERE WAS NO DIFFERENCE BETWEEN MET FORMIN USERS OR NONUSERS. SO I'VE ALREADY SHOWN YOU THE 70% EVIDENCE OF THE NAFLD, AND THE 19% OF THOSE OBESE WOMEN HAD EVIDENCE OF ELEVATED ALT. THEN THEY DIVIDED ACCORDING TO INSULIN, AND THE HIGHEST WHICH IS THE WORST IN THE CORTI, AGAINST 70% OF WOMEN WITH RESISTANCE COURSE HAS EVIDENCE OF NAFLD. NOW IN STUDY LOOKED AT THE QUESTION, THE BACK DOOR APPROACH. THEY LOOKED AT FEIGN OF THESE WOMEN WHO HAD EVIDENCE NONALCOHOLIC FATTY LIVER DISEASE, 7 OF THEM WITH ULTRASOUND AND 7 WITH BIOPSY AND THEY CREEPED THEM FOR PCOS, AND THEY FOUND THAT 71% MATCHED THE ROTTER DAM CRITERIA. OKAY, SO, THE CONCLUSION WAS DESPITE LIMITATIONS OF THE STUDY, DUE TO SAMPLE SIZE, 2009, WOMEN WITH NAFLD SHOULD BE ROUTINELY SCREENED FOR PRESENCE OF PCOS, WITH THE SAME WAY WOMEN WITH PCOS SHOULD BE SCREENED FOR THE PRESENCE OF NAFLD. NOW THIS IS A LARGER STUDY PROSPECTIVE STUDY, PCOS WOMEN LEAN TO OBESE, DIAGNOSE WITH ANDROGEN EXCESS CRITERIA IN COMPARISON TO 60 MATCH CONTROLS, AGAIN, HERE YOU SEE THAT 35% OF PCOS WOMEN HAVE NAFLD BY SINNOGRAPHY COMPARED TO ANOTHER 70% IN A STUDY I SHARE WIDE YOU AND AROUND 20% HAVE ABNORMAL ALT ELEVATION. BUT THEY WENT A STEP FURTHER TO DECIDE WHAT ARE THE DETERMINANTS OF HEPATIC STEREO APOPITOSE AND I GUESS IN MULTIPLE REGRESSION ANALYSIS, THEY FOUND WAS THAT AN INDEX OF INSULIN RESISTANCE, HDL CHOLESTEROL, GLOBUE LYNN AND ANDROGEN INDEX AND PCOS STATUS, HAVING OR NOT HAVING IT TO ALL SIGNIFICANT CONTRIBUTORS IN THE MODEL BUT HBMI AND RACE FACTOR WERE NOT. THIS STUDY LOOK AT ONLY LEAN PCOS WOMEN, VERSES 17 CONTROL P.M. AND SOMEHOW THE LIVER ULTRASOUND OR CTOF THE LIVER AND IRRESPECTIVE WHICH METHOD THEY LOOKED AT, THERE WERE NO DIFFERENCES BETWEEN PCOS WOMEN AND CONTROL WOMEN. SO THEY CONCLUDED THAT YOUNG LEAN WOMEN WITH PCOS AND INSULIN RESISTANCE DO NOT HAVE EVIDENCE OF NAFLD, NOW THIS CONTRA DICKS WITH THE DATA I SHOWED WUTHE RETROSPECTIVE REVIEW OF 88 INDIVIDUALS WHERE THE LEAN PCOS WOMEN HAD 30% PREVALENCE OF NAFLD. NOW, THIS STUDY THEY EXTRACTED THE INDIVIDUALS FROM THE EPIDEMIOLOGY OF FATTY LIVER DISEASE, 35 PCOS, OR 34 PCOS WOMEN AND 32 MATCH CONTROLS IN WHOM LIVER BIOPSY SPECIMENS WERE PRESENT FOR 25 IN EACH GROUP. AND THEY FOUND THAT 44% OF PCOS WOMEN HAD NASH, VERSES 20% BUT UNFORTUNATELY DUE TO POWER ISSUES THIS DID NOT TURN OUT TO BE SIGNIFICANT. THE P-WAS APPROACHING SIGNIFICANT. THERE WAS NO PHYSICAL O BIOCHEMICAL DIFFERENCES IN THE CONTROL, BUT THE PCOS WITH NASH HAD AGAIN YET ANOTHER TIME, HIGHER BMI, ATM OR LOWER HDL OR COMPOPENTS. --COMPONENTS. THE WEAKNESS OF THE STUDY WAS THAT P-VALUES WERE APPROACHING SIGNIFICANCE AND THE CLINICAL DEFINITION OF PCOS, ONLY BASED ON THE CLINICAL DEFINITION WITH NO BIOCHEMICAL DOCUMENTATION. THIS IS THE LARGER STUDY FROM CHINA 117 CHINESE PCOS WOMEN WITH THE WIDE SPECTRUM OF BMI, AGAIN, AUTOSOM NONAPOPTOTIC GRAPHIC DETERMINATION OF LIVER FAT BUT IN ADDITION THEY LOOK ABDOMINAL AND MESOTERRIC FAT, TO DEDETERMINANT AND THEY FOUND AROUND 1559.2% FATTY LIVER BY ALTASD RASOUBD AND WHEN THEY COMPARE THE FATTY LIVER IN THE INDIVIDUALS WHO ARE FATTY LIVER VERSES THOSE WHO DO NOT HAVE FATTY LIVER, YET FOR ANOTHER TIME, YOU APPRECIATE THAT ALL THE METABOLIC SYNDROME COMPONENTS ARE SIGNIFICANTLY HIGHER IN THE FATTY LIVER IN INDIVIDUALS THAN THE NONFATTY LIVER INDIVIDUALS. MORE OVER MEAS MESENTERIC FAT AND THE FATTY LIVER WERE HIGHER COMPARED TO NO FATTY INDIVIDUALS. THIS STUDY HAS ADVANTAGE THAT THE 45 PC RS OBESE WOMEN WERE AGE MATCHED WITHIN 3 YEARS, WITH A CONTROL, AGAIN LIVER ULTRASOUND AND AMONG THE PCOS 73% HAD EVIDENCE OF NONALCOHOLIC FATTY LIVER DISEASE VERSES 46%. FINALLY, A STUDY THAT USES THE MRS, ENOUGH TO DETECT NAFLD, IN ADDITION THEY DECIDED THE POPULATION TO THOSE WHO ARE NORMAL ANDROGEN ROWGENIC WITH THE 3 ANDROGENICS OF 7 AND HYPER ANDROGENIC ABOVE 7 AND YOU CAN APPRECIATE THAT WITH MRIDICULOUS --MRS, IS SIGNIFICANTLY HIGHER IN THE HYPER ANDROGENIC AND COMPARED TO NORMAL AND CONTROL. EVEN AFTER ADJUSTING FOR THAT, OR AFTER THE ADJUSTING FOR HORMONE INSULIN RESISTANCE. NOW LET'S COME TO PC RS NAFLD AND TREATMENT. THERE ISN'T MUCH INFORMATION IN THE LITERATURE, THIS IS AN OPEN LABEL STUDY OF MEDFORMIN, OVERWEIGHT WOMEN WHO HAD A BASELINE 57%, HAD NAFLD AT BASELINE BUT UNFORTUNATELY, AND AT THE END OF THE YEAR, ASTLD, ALL IMPROVED SIGNIFICANTLY, BUT 33% DROPPED OUT OF THE STUDY BESIDES THE FACT THIS WAS AN OPEN LABEL STUDY AND LIVER ULTRASOUND, SORRY AND LIVER ULTRASOUND WAS NOT REPEATED AT THE END OF THE INTERVENTION. THIS IS A RANDOMIZED DOUBLE BLIND CROSS OVER STUDY OF OMEGA 3 FATTY ACIDS, PLACEBO FOR 8 WEEKS OR TREATMENT, 8 WEEKS OF [INDISCERNIBLE] AND 8 WEEKS OF TREATMENT, BUT THE PATIENTS REMAINOT LIPID OF HYPERTENSION TREATMENT, IGT AND TYPE 2, THERE WERE A LOT OF CO VARIANTS THAT WERE NOT ACCOUNTED FOR, MRS WAS NOT PERFORMED AT BASELINE BUT THIS IS WHAT THE DATA SHOWED THAT WHILE ON PLACEBO, 10% LIVER FAT OR 8.4% LIVER FAT. I'M NOT DONE BECAUSE THE TIME IS BLINKING SO I WILL NOT BE ABLE TO DISCUSS THIS DATA WHICH I ARE IMPORTANT BUT NOT IN PCOS. AND TO GO OVER OUR DATA THAT A WHILE BACK WE HAD SHOWN THAT OBESE PCOS ADOLESCENCE MATCHED TO NONOBESE, HAD HAD 50% LOWER INSULIN SENSITIVITY WITH THE HYPER INSULIN TO MAKE THE GLYCEMIC PLAN TO HAVE EVIDENCE OF INSULINi] RESISTANCE AND THESE ARE COMPENSATED BY FASTING FIRST PHASE AND SECOND FACE DURING THE HYPER GLYCEMIC CLUMP SO WE THOUGHT THAT WAS THE PERFECT POPULATION TO LOOK FOR FATTY LIVER DISEASE, NOT ONLY THEIR OBESE BUT SEVERELY INSULIN RESISTANCE SO THIS WAS 30 ADOLESCENCE OF PCOS AND DECIDE THERE'S CLINICAL CHARACTERISTICS THATEE USED LIVER FAT ASSESSMENT BY CT SCAN AND YOU TAKE THE LIVER TO SPLEEN RATIO AND THE RATIO OF LESS THAN 1 IS SIGNIFICANT FOR FATTY LIVER DISEASE AND IT CORRELATES VERY WELL WITH HEPATIC FAT WITH BIOPSY AND OF THE 30 ONLY 2 GIRLS HAD A FATTY LIVER INDEX LESS THAN 1. BUT THE CORRELATION WAS WITH AGE AS THE AGE INCREASE, THE FATTY LIVER INDEX WORSENED AND IT IMPROVED WITH IMPROVING GLUCOSE INSULIN STIMULATED GLUCOSE UPTAKE AND I HAVE TO RUN. IT ASSOCIATED WITH ABNORMALITIES DOLLINAL DEPOSITED, THE WORST ABDOMINAL [INDISCERNIBLE] THE WORST FATTY LIVER INDEX AND IT ASSOCIATE WIDE LDL SUBCLASS CONITRATIONS BUT IN A MULTIPLE REGRESSION IT WAS AGE THAT WAS CONTRIBUTING TO THE VARIANTS IN FATTY LIVER INDEX. AND I DON'T HAVE TIME TO SHOW THIS COMPARISON BETWEEN THESE 2 INDIVIDUALS, BUT, SINCE THEN WE'VE BEEN ABLE TO DEVELOP AN MRS METHODOLOGY AND IN ANOTHER STUDY WE HAVE SHOWN THAT EXERCISE INTERVENTION CAN LESSEN THE LIVER FAT WITH MRS TECHNOLOGY SO THE QUESTIONS REMAIN ACTUALLY IN PC RS--PCOS POPULATION, ARE PCOS WOMEN AT INCREASE RISK FOR HEPATIC STEREO APOPTOSIS BY THE MERE FACT THEY HAVE PCOS OR TO THE DEGREE OF INSULIN RESISTANCE. WHAT IS THE NATURAL HISTORY OF THIS, AND WHAT IS THE IMPACT OF PCOS TREATMENT ON NAFLD. THANK YOU AND A,POLOGYIZE FOR--AND I APOLOGIZE FOR THE--[ APPLAUSE ] >> THE NEXT SPEAKER FOR THE MORNING WILL BE DR. NATALY RASGON, SHE IS FROM STANDIFORD UNIVERSITY AND HER--STANFORD UNIVERSITY AND HER TOPIC WILL BE ON MENTAL HEALTH. >> GOOD MORNING. I WILL SWITCH GEARS AND TALK ABOUT MENTAL HEALTH. WE WILL NEED THAT. SO LET ME GET MY--NEXT SLIDE IS NOT LOADING SOMEHOW. OKAY, SO WHY DOES A PSYCHIATRIST COME TO THIS WONDERFUL MEETING AND TALK ABOUT MENTAL HEALTH AND POLYCYSTIC OVARIAN SYNDROME? WELL 1 OF THE REASON SYSTEM THAT THERE IS A SIGNIFICANT OVERLAP ACTUALLY IN THE CLINICAL PRESENTATION IN DISORDERS AND REPRODUCTIVE FUNCTION, METABOLIC FUNCTION AND WOMEN WITH PCOS, SO THAT WAS 1 OF THE INTERESTS OF MINE AND I AM VERY GRATEFUL FOR THE DOCTOR WHO WAS PROVIDING HER SUPPORT ANG GUIDANCE IN MY RESEARCH FOR OVER THE LAST 20 YEARS AND INVITED ME HERE SO I WILL BE SHARING WITH YOU SOME DATA, HISTORICAL DATA WE SHOWED IN THE PAST AND SHARE SOME NEW DATA WHICH HAS NOT BEEN PUBLISHED. SO I'M GOING TO SKIP THIS SLIDE FOR THE SAKE OF TIME BECAUSE IT'S ALL WELL KNOWN AND GO TO THE PURPOSE OF THE TALK WHICH IS TO REALLY LOOK AT THE COMMON CHARACTERISTICS AND POTENTIAL BIOLOGICAL CORRELATES BETWEEN THE MOOD DISORDERS AND PCOS, OR IN THE MORE BROADER PROBABLILY CONTEXT, DISEASES OF THE INSULIN RESISTANCE, SO, DEPRESSIVE DISORDERS VERY MUCH LIKE MANY OTHER ILLNESSES ARE DISEASES IN THE SPECTRUM AND WE KNOW THAT WOMEN WITH POLYCYSTIC OVARIAN SYNDROME HAVE A NUMBER OF PSYCHOLOGICAL DISTURBANCES AND THERE'S AMPLE LITERATURE ON THAT, I'M NOT GOING TO BE TALKING ABOUT THAT, I WILL BE FOCUSING ONLY ON THE DIAGNOSED CLINICAL DISORDERS OF THE EFFECTIVE CIRCULATION SPECIFICALLY, UNIPOLAR DEPRESSION AND BIPOLAR DISORDER, BUT EVEN THOSE ARE ALSO KNOWN ON I SPECTRUM AND THEREFORE CUMULATIVELY, THEY CONSITUTE A VERY SIGNIFICANT PROPORTION OF POPULATION. I DELIBERATELY DID NOT PUT THE NUMBER IN THERE BECAUSE IT WOULD BE QUITE DISTURBING FOR PEOPLE TO SEE BUT ACCORDING TO THE LAST NATIONAL SURVEY, EPIDEMIOLOGICAL SURVEY, THE LIFETIME PREVALENCE OF DEPRESSIVE DISORDERS IS ABOUT 30%. SO, AND THIS IS NOT AGAIN, NOT A PSYCHOLOGICAL DISTURBANCE. SO THESE ARE A VERY PREVALENT ILLNESSES AND PREDOMINANT IN THE ISSUE OF 221 REGARD TO THE PREVALENCE OF SPECIFICALLY MADE UNIPOLAR DEPRESSION AND MULTIPLE SUBTYPES OF BIPOLAR ILLNESS. AND I WILL BE PRESENTING TODAY, BASICALLY DATA LOOKING AT BOTH ENDS OF THE SPECTRUM, SO THE--WHAT IS KNOWN ABOUT DEPRESSIVE DISORDERS IN WOMEN WITH A PRIMARY DIAGNOSIS OF PCOS VERSES WHAT ARE THE ENDOCRINE SIGNALLURES AMONG WOMEN WHO HAVE PRIMARY DIAGNOSIS OF MOOD DISORD AND ARE TREATED FOR THAT. SO IN TERMS OF THE PREVALENCE OF PSYCHIATRIC ILLNESS IN THE WOMEN WITH POLYCYSTIC OVARIANCE SYNDROME, NOT THAT MUCH IS KNOWN AGAIN LOOKING AT THE FULL SYNDROME ASK 1 OF THE STUDIES I AM SHOWING HERE IS STUDIED BY ROSSIE. I AM GOING AGAIN THE WRONG WAY, LOOKING AT 72 WOMEN WITH A POLYCYSTIC OVARIAN SYNDROME WHERE 50--57% OF THOSE HAD A PSYCHIATRIC DIAGNOSIS BEING DONE BY STRUCTURED CLINICAL INTERVIEW OF THOSE, ABOUT 26% HAD UNIPOLAR DEPRESSION AND ABOUT 11% HAD BIPOLAR DISORDER. IT'S VERY CONSISTENT FOR THE DATA IN THE GENERAL POPULATION ON THE PREVALENCE OF PSYCHIATRIC ILLNESS. SIMILARLY WE LOOKED AT IN EARLY STUDY STUDIES WHICH I WAS AT UCLA AND IT WAS DONE IN THE PATIENTS NEWLY DIAGNOSED WITH THE PCOS IN THE ENDOCRINOLOGY CLINIC, THERE WERE CONSECUTIVELY RECRUITED AND WE SAW THAT 16 WOMEN OUT OF 32, WHICH IS 50% HAD DIAGNOSIS OF UNIPOLAR DEPRESSION AND LOOKING AT THE BIOLOGICAL CORRELATES OF THAT DIAGNOSIS WE FOUND THAT ACTUALLY UNLIKE WHAT WE THOUGHT, AND THAT IS A COMMON UNDERSTANDING THAT WHEN A WOMAN IS OVERWEIGHT OR OBESE, OR HAS ALOPECIA, IT IS MOSTLY SHE IS DEPRESSED BECAUSE OF HER APPEARANCE. WELL, THAT WAS NOT THE CASE AT ALL AND THE ONLY CORRELATION WE HAD WAS INSULIN RESISTANCE AND PBI. --BMI. WHAT WE ALSO FOUND WHICH WAS OF INTEREST WAS WOMEN RECEIVING TREATMENT FOR PCOS WITH ORAL CONTRACEPTIVES WERE LESS DEPRESSED THAN WOMAN NOT RECEIVING TREATMENT AND THAT WAS AN INTERESTING FINDING KIND OF GIVING US A LITTLE BIT OF THE COMMON GROUND BETWEEN THE EFFECTS OF HORMONES ON MOOD IN VARIOUS CLINICAL POPULATIONS. SO WHAT IS KNOWN ABOUT MOOD MENSTRUAL PSYCHE WILL RELATED MOOD CHANGES NOW IN WOMEN WITH THE PRIMARY MOOD DISORDERS, THERE ARE A NUMBER OF DATA COMES FROM DATA STUDIES AND MOST OF THEM ARE OR PRESENT LIMITED LEVEL OF EFZ BECAUSE THOSE WERE ALL--EVIDENCE BECAUSE THOSE WERE ALL CROSS SECTIONAL SAMPLE STUDIES BUT OVERALL INCLUDING OUR STUDY, WE AND OTHERS SUGGESTED HIGH% OF WOMEN SO IF YOU LOOK AT THE LEFT PART OF THE SLIDE, YOU SEE THE PERCENT OF WOMAN WHO EXHIBITED COMPLETE, EXHIBITED MOOD CHANGES IN RELATION TO THE MENSTRUAL CYCLE PHASE. IN OUR STUDIES THEY WERE CONSECUTIVELY MONITORED FOR ALMOST 6 MONTHS. SO SO THESE ARE FAIRLY LONG STUDIES, THEY'RE NOT HUGE NUMBERS BUT OVERALL QUESTION THEN BECOMES, WHAT IS THE ASSOCIATION BETWEEN THE EFFECTIVE CIRCULATION WHICH IS MOSTLY SITUATED IN THE OLYMPIC SYSTEM AND CORTICALE PREFRONT AT REGIONS AND THE PITUITARYY OR AGREENAL ACCESS REGULATION SO IT'S WELL KNOWN BEEN ESTABLISHED 40 OR 50 YEARS AGO THAT THERE IS A SIGNIFICANT PRESENCE AND THE RECKULATION THAT AND BIPOLAR DEPRESSION, THERE'S ALSO SIGNIFICANT PREPONDERANCE OF RECEPTORS IN THE SAME REGIONS WHERE THE CORTISOL RECEPTORS ARE AND THERE'S A DEFINITE BETWEEN THE KORT VOWEL AND CMS, THERE'S ALSO AND THIS IS CLINICAL EVIDENCE OF THE CO-MORBIDITY WITH THE CARDIOVASCULAR DISEASE AND EARLY MORTALITY IN PEOPLE OVER THE--WHAT WE CALL ACCESS 1 LARGE MAJOR PSYCHIATRIC ILLNESSES AND BY POLAR ILLNESS AND SCHIZOPHRENIA. SO WHAT IS ALSO OF INTEREST IN THE CLINICAL PSYCHIATRY FOR THE LAST, I WOULD SAY 20 OR 15 YEARS NOW IS THE QUESTION OF THE HETEROGENIC EVOLUTION OF THE PCOS LIKE SYNDROME AMONG WOMEN TREATED FOR MOOD DISORDERS AND THAT IS SPECIFIC TO CERTAIN TYPES OF MEDICATION WHICH IS WE USE AND AS PROBABLY YOU KNOW, WOMEN OR PATIENTS WITH MOOD DISORDERS ARE TREATED INDEFINITELY, SPECIFICALLY PATIENTS WITH BIPOLAR ILLNESS, IT'S AN ILLNESS THAT REQUIRES UNRUPTED TREATMENT FROM THE TIME OF DIAGNOSE FOR THE DURATION OF LIFE. SO THE QUIET IS IF WOMEN SPECIFICALLY ARE MORE SENSITIVE TO THE WEIGHT GAIN ON CERTAIN MEDICATIONS OR HYPER ADODGEANISM SO ASSOCIATED WITH CERTAIN MEDICATIONS AND THAT WAS SHOWN FOR THE DEPRIVATION COAT WHICH IS 1 OF [INDISCERNIBLE] ACID WHICH IS 1 OF THE ANTICONSULS ANT MEDICATIONS. AND VERY WIDELY USED IN PHAOD DISORDER TREATMENT OF THESE PATIENTS SO HOW DANGEROUS MIDDLE --TKAEUFRPLGEROUS IT IS FOR A WOMAN'S METABOLIC FUNCTION. SO FOR A NUMBER OF STUDIES I'M SHOWING YOU THE BIGGER SAMPLE, THE PILOT STUDY WAS ON 22 WOMEN AND WE FOUND AT THAT TIME HOE DIFFERENCES IN PREVALENCE OF ABNORMALITIES OR ENDOCRINE CHARACTERISTICS IN THE WOMEN BEING EXPOSED TO MONOTHERAPY OF DEPRIVATION COAT OR LITHIUM. THIS IS THE LARGER STUDY WHERE WE LOOKED AT 80 WOMAN, ALL WOMAN WERE TREATED AT THE TIME OF THE EVALUATION, IT'S A CROSS SECTIONAL 6 SITE STUDY THERE WERE 2 FROM CHILL--CHILE, AND THE ENDOCRINE CHARACTERISTICS LOOKING AT EARLY FOLLICULAR PHASE OF LEVELS OF REPRODUCTIVE HORMONES AND THE WAY WE CLUSTERED THOSE MENSTRUAL ABNORMALITIES WERE ACCORDING TO THE TIME OF DIAGNOSIS OF BIPOLAR ILLNESS, SO IF WE THINK THAT IT IS POTENTIALLY HETEROGENIC PHENOMENON, THIS PCO OS LIKE PICTURE IN WOMEN WITH MOOD DISORDERS, THE QUESTION WAS, DOES IT EVER MANIFEST BEFORE WOMAN WAS DIAGNOSED AND THEREFORE TREATED AND IN FACT WE DID FIND AND THIS IS A SECOND STUDY I WILL SHOW YOU NEXT STUDY WHERE THE SAME AMOUNT, ABOUT 50% OF WOMEN CLOSE TO 50% OF WOMEN WITH MOOD DISORDERS SAY THEY HAD MENSTRUAL ABNORMALITIES ALONG BEFORE THEY WERE DIAGNOSED WITH BIPOLAR ILLNESS SO THE QUESTION OF CHICKEN VERSES EGG COMES TO MIND AND THE TYPE OF ABNORMALITIES YOU COULD SEE THE TYPE OF PAPER, YOU COULD SEE THEY POLYMENNOR YEA AND AMENERRIA AND DURING THE TREATMENT THOSE WHO WERE RECEIVING TREATMENT HAD NO SIGNIFICANT DIFFERENCES IN THE PREVALENCE OR TYPE EVER MENSTRUAL ABNORMALITIES. NOW AGAIN I WANT TO MAKE A POINT BECAUSE I WILL COMING BACK TO THAT, THOSE WERE BASED ON THE SELF-REPORT. THIS IS ON THE HOME DAYA, THIS IS THE--THIS IS THE DATA, THIS IS THE STUDY I JUST SHOWED,--I DON'T KNOW WHY IT'S NOT WORKING, THE MARKER. LONGITUDINAL STUDY OF 25 WOMEN, SEPARATE SUBJECTS WHICH WE FOLLOWED FOR 2 YEARS, JUST MEASURED THEIR HOME IR, MEASURED BMI REKORTY CORDED ALL THE ABNORMALITIES AND CLINICAL CHARACTERISTICS AND THEN MEASURED AGAIN THERE ARE METABOLIC CHARACTERISTICS SO YOU COULD SEE THAT THE HAUL MARK LONGITUDINALLY INCREASES WITH AGE AND WITH DURATION OF TREATMENT WE HAD SIMILAR CHANGES AND TOTAL DISTORTION AND WILL LOOK AT THE EFFECT OF THE [INDISCERNIBLE] SODIUM OF THE DEPRIVATIONA COAT WITH REGARD TO THE EXPOSURE LENGTH AND THE VALUES AND WE FOUND THAT THERE WAS A SIGNIFICANT POSITIVE CORRELATION BETWEEN THE TESTOSTERONE AND THE DURATION OF TREATMENT. SO YES INDEED BEING ON THAT MEDICATION MAY NOT BE GOOD FOR WOMEN FROM THIS STANDPOINT OF THE REPRODUCTIVE FUNCTION AND THE METABOLIC FUNCTION AND YOU DO NEED TO TREAT MENTAL ILLNESS. SO WHAT DO YOU DO? SO THE QUESTION GOES BACK TO HOW TO IDENTIFY THE CHICKEN VERSES EGG IN ORDER TO MAYBE MAYBE INDIVIDUAL ICE THE TREATMENT OPTION FOR WOMEN WHO ARE PRONE OR SUSCEPTIBLE TO DEVELOP MENTAL OR METABOLIC DISFUNCTION AS A RESULT OF TREATMENT. SO IN ORDER TO UNDERTAKE THIS, WE START WITH THE PROSPECTIVE CONTROLLED STUDY, THE CLINICAL INTERVIEW, CAN YOU SEE THE EXCLUSION CRITERIA, I'LL AVOID DISCUSSING IT AND THE PATIENTS WERE CONSECUTIVELY RECRUITED FROM THE CLINIC SO WE'RE KIND OF OVERSAMPLED AND NEVER NEEDED THAT MANY WOMEN WITH BIPOLAR BUT THEY WERE VERY EAGER TO BE EVALUATED FOR THE METABOLIC AND METABOLIC FUNCTION. WE HAD 36 MATCHED CONTROLS. LET ME SHOW YOU THE DEMOGRAPHIC CHARACTERISTICS SO THEY WERE VERY WELL MATCHED FOR AGE, VIRTUALLY IDENTICAL FOR AGE AND BIPOLAR WOMEN WERE HEAVIER THAN THE CONTROLS BUT THE YOU COULD SEE THE MAIN BMI WAS 27, THIS REFLECTS INVERT VERSES OTHER PARTS OF THE COUNTRY, AND EVEN PATIENTS, OVERWEIGHT PATIENTS ARE VERY FIT AND WE HAVE SIMILAR BMIs IN VARIOUS STUDIES SO THE DIAGNOSIS OF PC OS, NOW THIS IS A DIAGNOSIS BY SELF-REPORT. BY THE MEDICAL RECORDS WAS MADE IN 5 WOMAN OUT OF AND NO CONTROL AND AS YOU CAN SEE, THERE WERE A NUMBER OF WOMEN WHO REPORTED CENTRAL AMEN OREA AND SO HERE IS THE DISTRIBUTION SIMILAR IDEA AGAIN LOOKING AT THE ABNORMALITIES AMONG THESE WOMEN NOW IN COMPARISON TO AGE AND BMI MATCHED CONTROLS ON THE QUESTION OF OF WHAT IS GOING ON RIGHT NOW WITH THEIR FUNCTION AND YOU CAN SEE THAT ABOUT 8.7% OF WOMEN WITH BIPOLAR DISORDER HAD OLIGIO MENNORRIA VERSES 5.5% OF CONTROLS WE HAD 7% OF WOMEN WHO WERE BIPOLAR WHO HAD CURRENT AMEN OR YEA AND SIMILAR AMOUNT WHO HAD PAST HISTORY OF OLIGIO MENNOREA AND AGAIN NO DIFFERENCES IN TERMS OF THE PREVALENCE OR WEIGHTS OF MENSTRUAL ABNORMALITIES BETWEEN WOMEN WITH DISEASE AND CONTROLS. HERE ARE THE ENDOCRINE DATA WHICH WE FOUND AND ALSO IN ADDITION TO MEASURING THEIR ENDOCRINE LEVELS THE HORMONE LEVELS IN THE EARLY FOLLICULAR PHASE, WE ALSO DID TRACKING OF OVULATION WHICH WAS FOR 3 CONSECURATIVE MENTAL CYCLES WITH A MIDROUTIAL PROGESTERONE CHECK. ARE THEY REALLY TRULY UNOVULEATORY BECAUSE LITERATURE COULD SUGGEST THAT THERE COULD BE DISFUNCTION BEING PRESENT AND WE WANT TO MAKE SURE. SO YOU COULD SEE THAT WHAT WE FOUND WAS VERY MUCH CONFUSING TO US IN TERMS OF IN TERMS OF HOW TO DECLARE THAT ABNORMALITY PICTURE. WE HAD DEFINITE CHANGE IN THE BMI, WE HAD SIGNIFICANT DIFFERENCES IN FASTING PLASMA INSULIN, DHES, AND 17 OHP. WE DID NOT HAVE ANY DIFFERENCES IN OVULATION AND JUST TO TELL YOU, WE DID NOT HAVE ANY DIFFERENCES IN TESTOSTERONE LEVELS IN TOTAL TESTOSTERONE. SO HERE YOU GO. WE HAVE SIGNIFICANT PREPONDERANCE OF ABNORMALITIES DIAGNOSIS OF PCOS AND YET UPON PROSPECTIVE CONTROLLED EVALUATION, THERE'S NO DIFFERENCE BETWEEN WOMEN WHO HAVE ILLNESS, PSYCHIATRIC ILL RESPONSE THOSE WHO DON'T. THEN WE STARTED LOOKING AT THE EFFECTS OF MEDICATIONS. SO AMONG THAT SAMPLE WE HAD WOMEN WHO WERE ON VARIOUS TYPES OF MEDICATIONS, I AM AGAIN NOT GOING TO TALK ABOUT THAT, FOR THE SAKE OF TIME. BUT WE DID LOOK AT THOSE WHO WERE TREATED AND HAD A SMALL SUBSAMPLE, 15 WOMEN WHO WERE NOT TREATED BY ANY MEDICATIONS. AND THAT THOSE TREATED CLEARLY HAD MANY MORE ABNORMALITIES. WE ALSO LOOK AT THE SEVERITY OF ILLNESS, SO SEVERITY OF ILLNESS IN PSYCHIATRY MEANS THERE'S MORE MEDICATIONS, THE DOSES ARE HIGHER AND THE COMBINATIONS COULD BE EVEN MORE PROVOCATIVE REGARD TO ENDOCRINE DISFUNCTION AND WE FOUND AGAIN THERE'S NO SIGNIFICANT DIFFERENCES OR RATES OF ABNORMALITIES AND AND A NUMBER OF WOMEN WITH PILOT PROJECT BOWLAR ILLNESS REPORTED HYPER THALAMIC AMENORIA WHICH WAS INDUCED BY STRESS OR EXERCISE OR BEEN ASSOCIATE WIDE AN EATING DISORDER WHICH AS YOU PROBABLY KNOW IS MORE PRESENTATIVE OF ANY OTHER SOURCE OF AMENORIA SO IT'S POSSIBLE WE'RE LOOKING AT THE POPULATION OF WOMEN WHO HAVE MORE OF A CENTRAL DYSFUNCTION AND CENTRAL AMENORIA DRIVEN RATHER THAN THE OVARIAN SOURCE. SO I WILL FINISH ON A MOST INTRIGUING FINDING THAT WAS REPORTED 3 YEARS AGO WHEN WE LOOK AT FAMILY HISTORY OF VERY PRODUCTIVE AND METAPWOLIC DYSFUNCTION AMONG THAT SAMPLE AND A NUMBER OF WOMEN IN BOTH CONTROLS AND BY POLAR WOMAN HAD FAMILIESIAL HISTORY AND THAT WAS SPECIFIC TO THE FEMALE FIRST DEGREE RELATIVE WITH THE WOMEN OF BIPOLAR ILLNESS WHO HAD DIABETES AND WE WILL LOOK AT THE HISTORY OF DIABETES UNDERLIES POTENTIAL DIFFERENCES IN THE METABOLIC MARKERS. I CAN TELL YOU THERE'S NOTHING IN THE BIOMARKERS BUT YOU COULD SEE THAT WOMEN FOR THE FAMILY HISTORY HAD SIGNIFICANTLY HIRE BMI, AND EVEN MORE INTERESTINGLY IN THE GTD AND ALL THESE SUBJECTS WENT THROUGH THE 2 HOUR GLUCOSE TOLERANCE TEST, WE HAD SIGNIFICANT DIFFERENCE IN THE END OF THE CURVEOT INSULIN, AND RESULTED BY DIAGNOSIS AND THE EURPT ACTION WITH THE FAMILY HISTORY. SO IN SUM RYE I WOULD SAY INSULIN PREVALENCE IS QUITE THERE FROM THE POLYCYSTIC SYNDROME AND THE FAMILIESIAL HISTORY OF DIABETES TYPE 2 MAY BE 1 OF THE VULNERABILITY BIOMARKERS AND THEREFORE WORKED ARE BEING ASCERTAIN INDEED THE CLINICAL POPULATION AND WHAT IS EVEN MORE I THINK PROVOCATIVE IS THAT ACTUALLY DURATION AND TYPE OF TREATMENT OF PSYCHE TAUPIC MEDICATIONS WAS NOT TRULY ASSOCIATED WITH INSULIN RESISTANCE OR ABNORMALITYS SO IN THAT REGARD WE'RE STAYING WITH THE EGG RATHER THAN THE CHICK EXTEN THERE'S MORE RESEARCH NEEDED. THANK YOU. [ APPLAUSE ] SO THE LAST SPEAKER FOR THIS MORNING'S SESSION IS DR. RICHARD LOBO AND HE WILL DISCUSS WOMEN WITH MENOPAUSE AND PC OS. IN THE MEAN TIME WE WILL BE SENDING OUT CARDS FOR PEOPLE TO RIGHT QUESTIONS, BECAUSE DR. LOBOS TALK WILL BE FOLLOWED BY THE OPEN DISCUSSION. >> OKAY SO I'M GOING TO GO OVER WHAT WE WILL GO ABOUT MENOPAUSE AND PCOS AND THIS SLIDE REALLY DEPICTS OUR GAPS AND KNOWLEDGE, VERY FEW STUDIES VIRTUALLY ALL THE STUDIES ARE CROSS SECTIONAL RATHER THAN LONG NUDEINAL, MOST DATA PERTAIN TO CLASSIC DEFINITION SO AND WE DON'T HAVE INFORMATION ABOUT PHENOTYPES AND OTHER DEFINITIONS AS USED BY ROTTER DAME SO THE RISK FACTORS ARE AN AGING PHENOMENON AND THE THINGS WE'RE CONCERNED ABOUT IS CARDIOVASCULAR DISEASE AND METABOLIC AND CANCER HAVE BEEN POORLY STUDIED AND AS KURT AND OTHERS ALLUDED TO AND RELATE TO THE CLASSICALLY DIAGNOSED WOMEN SO WE DON'T HAVE COMPLETE INFLAMMATION IN THIS AREA. SO FIRST OF ALL, AGE OF MENOPAUSE. AGAIN, THERE ARE NO CLEAR DATA, BECAUSE THERE ARE VERY FEW IF ANY LONG NEWSINAL STUDIES SO THE PRECISION AROUND THE AGE OF MENOPAUSE IS NOT KNOWN. IT'S SOME ASSUME IS IT IS LATER AND THERE'S SUGGESTING IT AND THERE'S MORE STUDIES THAT SUGGEST THAT IS LATER IF YOU WILL SEE WITH THE AMH DATA IF YOU EXTRAPOLATE THAT IT SHOULD ALSO BE LATER. BY THE TIME OF MENOPAUSE, MANY FEATURES FOR THE DIAGNOSIS WILL HAVE BEEN LOST SO THERE IS A POINT WHEN YOU CAN NO LONGER OFFICIALLY MAKE A DIAGNOSIS OF PCOS AND I WILL SHARE SOME LONGITUDINAL DATA ON THAT POINT WITH YOU. THERE'S NO SPECIFIC PHENOTYPE KNOWN, THERE ARE CHARACTERISTICS AND PARTICULARLY THE WOMEN WHO HAVE BEEN CLASSICALLY DEFINED AND I WILL GET INTO THAT IS A LOT OF THESE CHANGES REALLY ARE A FUNCTION OF AGE. SO IT'S AN AGING PHENOMENON RATHER THAN SOMETHING ABOUT PCOS WHICH CHANGESSA THE TIME OF MENOPAUSE AND THIS SLIDE ILLUSTRATES A LOT OF THE KINDS OF DAT A WILL SHOW. THIS IS A RATHER FAMOUS SLIDE ON TESTOSTERONE WITH AGE. THIS IS 24 HOUR MEANS TESTOSTERONE, IT GOES DOWN IN WOMEN AS IT DOES IN MEN AS A FUNCTION OF AGE AND ALL THE ANSWER ANTIGENS ACROSS THE BOARD GO DOWN AND IT DOES IN PCOS AS WELL. SO ANDROGEN DECLINED. WE KNOW THAT THE OVARY SIZE DECREASES AND THIS IS TRUE OF PCOS AND I'LL SHOW YOU DATA ON THAT. AND INCREASINGLY, WE ARE AWARE ALREADY SUCK JEST INDEED THE PREVIOUS TALKS THAT THERE IS A PREVALENCE OF MORE NORMAL MENSE ISOTOPE AS WOMEN GET OLDER WHICH I ALWAYS THOUGHT WAS SOMEWHAT PARADOXICAL BUT IT'S ABSOLUTELY THE TRUTH. THERE'S CROSS SECTIONAL DATA, A TREND FOR LHTO GO DOWN AS DO THE ANDROGEN PARAMETERS AND THIS IS AN AGING PHENOMENON AS I ALLUDED TO, THIS IS THE STUDY BY WINTERS AND YOU CAN SEE THIS IS GROUPING AGE GROUPS AND AGAIN CROSS SECTIONAL AND TESTOSTERONE DECLINES AND I HAVE A GRAPHIC OF THIS NEXT. AS CAN YOU SEE HERE BY THE FOURTH DECADE, YOU NO LONGER HAVE A STATISTICALLY SIGNIFICANT TESTOSTERONE LEVEL AND STUDIES VARY HERE SO YOU CAN PERHAPS GET 1 PARTICULAR CUT THAT IT'S SLIGHTLY INCREASED SO THIS DOWNWARD TREND ALMOST GETS TO THE POINT WHERE IF YOU MATCH CONTROLS CAREFULLY, YOU DON'T SEE A SIGNIFICANT INCREASE ANYMORE. AND WE SO THESE WITH TIME THAT U. I.D CAN--YOU CAN SEE THE CYCLE DECREASES. MEN SISSER CLOSER TOGETHER OR TEND TO BE REGULAR AND THIS CORRELATES WITH SOMETHING ABOUT THE FOLLICULAR COHORT WHICH DECREASES WITH AGE. SO IF YOU SEE THE SLIDE, THE DARK BARS ARE THE PERCENTAGE OF REGULAR CYCLES, YOU SEE THE INCREASING PREVALENCEULENCE AS WOMEN AGE, STARTING REALLY AND INTO THE FOURTH DECADE HIGHER PREVALENCE, NOT A HUNDRED% BUT MORE PERCENTAGE OF THE WOMEN WHO ATTAIN REGULAR CYCLES AND MOST OF THESE ARE OVULE LATTERY, NOT ALL. AND AS YOU CAN SEE WHAT THE CHARACTERISTICS OF THIS AS YOU BREAK DOWN WOMEN INTO THOSE WHO HAVE REGULAR AND THOSE WHO HAVE IRREGULAR CYCLES, THOSE WHO HAVE REGULAR CYCLES IN A NUT SHELL HAVE A DECREASED FOLLICULAR COHORT. SO THEY HAVE A SLIGHTLY HIGHER SSH, AGAIN WITHIN THE NORMAL RANGE AND LOWER ANDROGENS AND LOWER HICK AND B AND THIS IS A BASELINE AND IF YOU CHALLENGE THEM, LOOK AT THE FOCUSED ONICLES THE FOLLICULAR COUNTS ARE LESS. THESE ARE WOMEN WHO ATTAIN NORMAL CYCLES AND IF YOU STIMULATE THEM WITH GENATROPIN, SO YOU SEE WHAT THE MAXIMUM PRODUCTION OR STIMULATED THOSE ARE FROM THOSE WHO REMAIN IRREGULAR LA IF YOU LOOK AT STEROIDS AND PROTEINS THIS, IS THE INCREMENT, THEY HAVE A LOWER INCREMENT TO STIMULATION AND THEY HAVE OBVIOUSLY LESS FOLLICLE COUNT SO IT'S A LOWER FOLLICULAR POOL THAT CORRELATES WITH THE INDENSE OF MORE REGULAR CYCLES. AS WOMEN AGE. THIS WAS ANOTHER STUDY WHICH WAS A FOLLOW UP WOMAN OF OVARIAN VOLUME AND CAN YOU SEE THIS IS VERY DIFFICULT WITH A SCATTOGRAM BUT YOU CAN SEE A DOWNWARD TREND IN PCOS AND CONTROLS AND THEY HAVE SOME POLYCYSTIC POST MENOPAUSAL OVARIES HERE AND BECAUSE OF THE--BECAUSE OF THE DECREASE SIZE IT'S VERY DIFFICULT TO REALLY MAKE SENSE OF THIS, BUT YOU WOULD ALSO SUGGEST THE OVARIES STAY, ALTHOUGH THEY'RE MUCH SMALLER, THEY STAY SLIGHTLY BIGGER THAN IN THE PREMENOPAUSAL POPULATION. SO THIS THIS IS MOREAVE CROSS SECTIONAL STUDY AND THE TIME POINTS WERE NOT COMLITELY VALIDATED BUT IF YOU LOOK AT THE CHANGE IN TIME, AS I'VE SUGGESTED, THE LA CHANGES AND ALL GO DOWN AS I FUNCTION OF TIME TO THE POINT THAT YOU LOSE YOUR NORMAL MARKERS FOR PCOS, HOWEVER, YOU CAN SEE, BMIGOES UP AND AS WE'LL SEE LATER THAT SOME OF THE PARAMETERS OF METABOLIC DYSFUNCTION IF YOU WILL DO PERSIST WHICH WAS NOT SHOWN IN THE STUDY AND THIS IS MY CONCERN, IT WAS NOT REALLY RIGIDLY PROSPECTIVELY DONE. AMH AS A TOTAL NUMBER OF FOLLICLES REDECS IN FUNCTION OF TIME AND DECREASES IN PCOS AS WELL. NOW THIS IS THE BEST STUDY, I THEN IS PART OF BART'S GROUP THAT LOOKED AT CONTROLS AND OBVIOUSLY IT'S HIGHER, THIS IS WHO 2--WHO2 WHICH IS LARGELY PCOS, IT'S OBVIOUSLY HIGHER BUT IT DECREASES ALSO WITH AGE AS IT DOES IN THE CONTROLS BUT IF YOU DO THE REGRESSION LINES YOU CAN SEE THAT THE SLOPES ARE DIFFERENT, SUGGESTING THAT THERE'S LESS OF A RAPID DECLINE WITH A HIGHER FOLLICULAR POOL AND THE HIGHER AMH AND PCOS AND WHO2 COMPARED TO CONTROLS AND SO IT'S BEEN SUGGESTED TH-D ANOTHER STUDY, ALSO CROSS SECTIONAL BUT IT SUGGESTS THAT PCOS MIGHT MAINTAIN SOME REPRODUCTIVE FACTORS WITH A LARGE POETIC LICKULAR COHORT AND HIRE MHLEVELS AND SUGGESTING AGAIN THAT DECLINE ARE DIFFERENT SO THAT THERE ARE MORE MAINTAINED IN PCOS. NOW THIS IS A PROSPECTIVE LONGITUDINAL STUDY THIS, IS A STUDY I DID IN COLLABORATION WITH ITALY THIS CONTINUES, IT'S ABOUT 200 PATE VS BEEN FOLLOWED NOW FOR 20 YEARS, WOMEN STARTED IN THEIR 20S AND NOW IN THEIR 40S SO THEY HAVEN'T QUITE REACHED MENOPAUSE YET, CAN YOU SEE HERE THERE A A DECLINE IN TESTOSTERONE, CAN YOU SEE A INCREASE IN WAIST SER CUM FERENCE, WE ARE HARD PRESSED TO SEE CHANGES AND BMI. WE HAVE INTERESTING METABOLIC CHANGES THAT ARE UPCOMING AND THESE ARE THE TRENDS OVER 20 YEARS AND IN THIS POPULATION FOR 20 YEARS ALL THESE WOMEN WERE DIAGNOSED BY ROTTER GRAM CRITERIA, SO THE OVULEATORY PHENOTYPE WAS SEEN IN BASELINE AT 26% OF THE POPULATION, OKAY? SO NOW 20% OF THESE ARE OVIEW LATTERY, AT 20 YEARSATE% OF THE ORIGINAL POPULATION LOST THE DIAGNOSIS OF PCOS, WE COULD NO LONGER DIAGNOSE PCOS BASED UPON THIS. THIS IS AMH AND THIS IS A TIME SET OF THE FIRST EVALUATION AND THE SECOND EVALUATION OF WHAT HAPPENED WITH AMH, THESE WOMEN HAVEN'T REACHED MENOPAUSE YET BUT THESE REMAINED AND THOSE WHO BECAME OVULE LATTERY AND THIS IS OVULATION DOCUMENTED BY PROGESTERONE LEVELS YOU CAN SEE IN THE SALMON COLOR THE AMH LEVELS ALTHOUGH THEY DECLINE WITH TIME WERE HIGHER THAN THOSE WHO REMAINED INOVULEATORY AS THOSE WHO BECAME REGULAR AND SO WE SUGGEST SOMEWHAT OF A CUT OFF OF ABOUT 4 NANO GRAMS PER MILL, THOSE WOMEN AT INITIAL EVALUATION THAT HAD HIGHER LEVELS AND ABOUT 4 OR EVEN 5 NANO GRAMS WERE MILL ARE LIKELY TO REMAIN INOVULE LATTERIORY OPPOSE TO TOEZ WHO HAVE DECREASE IF TIME AND A LOT OF THOSE WOMEN WILL BECOME OVULEATORY.„i AS I SAID, THE METABOLIC DATA SEEMED TO TEASE OUT ACCORDING TO OVULE LATTERY STATUS AS WELL. SO IT'S BEEN SUGGESTED WITH THE AMH DATA THAT THESE WOMEN MAY MAINTAIN FERTILE SO THIS IS A NORWEGIAN COHORT WITH THE RETROSPECTIVE DATA THAT SUGGEST SAID AS WE WELL KNOW, CONTROL WOMEN IN THIS CASE, WOMEN WITH TUBAL FACTOR, THEIR FERTILITY STATUS DECREASES WITH TIME. BUT IT SEEMED TO BE MAINTAINED IN PCOS, AS SUGGESTED BY THIS, AND HUMAN REPRODUCTION, THE LIVE BIRTH RAY AS FUNCTION OF TIME, AND TUBAL FACTOR NONPCO IS AND SEEMS TO BE MORE MAINTAINED IN WOMEN SUGGESTING AND PRESERVATION IN A WAY, SO TURNOVERS AS WE GET INTO WOMEN APPROXIMATE MEN IN MENOPAUSE, METABOLIC CONCERNS WHICH WE SPENT PART OF TODAY PAWKING ABOUT AS THESE WOMEN AGE, THESE ARE THE CONCERNS AND YOU'VE SEEN THIS DATA, THESE ARE THE FEW AND PCOS WOMAN, THEY HAVE A DECREASED CARD QUO VASCULAR DETH WITH 3 SURVIVAL TIME AND I THINK THEY SHOW TH-D YESTERDAY, EVEN THOUGH TESTOSTERONE IS LOWER AND FREE RADICALS TESTOSTERONE LOWER THIS THERE'S SOME CORRELATION WITH THEATURE TILES AND CORTILES OF INCREASE PRETESTOSTERONE OF CARDIO CARDIOVASCULAR OR RISK FACTOR. SOME OF THIS STILL MAINTAINS, WHAT HAPPENS METABOLICALLY WITH TIME. THAL STIMULATED ANTIGEN STAT US SUGGESTS, THIS IS INTERESTING, THAT ANDROGEN ROSINEI IS DECREASED AND THIS IS IN MENOPAUSE SO THIS IS NOT STATISTICALLY SIGNIFICANT SO IT GOES DOWN TO THE POINT THAT WE LOOSE IT COMPARED TO CONTROL BUT IF YOU STILLULATE THEM IT'S ON BOARD WITH PCOS, AND HOWEVER, AS WE SUGGESTED THE METABOLIC FACTORS MAINTAIN SO THEY, AND PART OF THIS IS--YOU KNOW THEY START OUT WITH THESE RISK FACTORS AND WEIGHT GAIN THAT HAPPENS WITH AGE, SO EVEN THOUGH ANDROGENS GO DOWN, THE METABOLIC FEATURES OR RISK FACTORS ARE MAINTAINED, THERE'S STATISTICALLY SIGNIFICANT ON BOTH PANELS AND THE POST MENOPAUSAL PCOS SUBJECTS. A RECENT PAPER FROM ELIZABETH CONNOR AND THIS IS THE CO HORD OF POST MENOPAUSAL WOMEN, THESE WOMEN ARE READY IN THE 70th DECADE AND THIS IS A ROTE SPECTIVE DIAGNOSIS OF PCOS, BUT THEY SUGGEST THAT THE 15EE TYPE OF THE PCOS PATIENT IN MENOPAUSE RESEMBLE THE PREMENOPAUSAL WOMAN IN THAT THEY HAVE HIGHER LEPTIN AND LOWER ADPEN ECTOMYOSININ. ONE OF THE WEAKNESSES OF THE STUDY IS THAT THIS IS NOT A WEIGHT MATCHED POPULATION AND WE KNOW LEPTIN PER SE IS INCREASED PCOS BECAUSE OF WEIGHT, IF YOU WEIGHT IN THOSE PATIENTS LEPTIN IS NOT INCREASED, HOWEVER, ADA TPHREPB ECTOMYOSININ IS DECREASED IF YOU WEIGHT MATCH. SO WHAT THEY DID IS IN DETERMINING THIS POST MENOPAUSAL PHENOTYPE, THESE WOMEN ARE QUITE MUCH OLDER NOW, 74, THEY MADE THE DIAGNOSIS BASED ON HAVING 3 OR MORE COMPONENTS OF WHAT THEY OCCURRED BE IMPORTANT FOR PCOS, THE INFERTILITY OF THIS HISTORY AND OBESITY AND RESISTANCE. SO IT GETS 3 OR MORE OF THESE CONSIDER TO HAVE THEM THE PCOS PHENOTYPE, HIGHER LEPTIN, AND LOWER, AND THEY SHOWED AS A FACTOR OF HOW MANY COMPONENTS YOU HAVE, THE MORE COMPONENTS HAVE YOU, THE LOWER AND THE HIGHER THE LEPTIN. SO, THE LAST THING I'M GOING TO SHOW, THE ONLY LONGITUDINAL DATA THAT WE REALLY HAVE WITH VERY SMALL NUMBERS ARE THE--EITHER DAHLGREN'S COHORT THAT ARE NOW IN THE SEVENTH DECADE SO THERE ARE ONLY 32 WOMEN LEFT AND THIS IS THE SUMMARY STATEMENT OF WHAT THEY FOUND. IT'S A GREATER PREVALENCE OF [INDISCERNIBLE] DOESN'T PERSIST, IT DOESN'T GO AWAY AND WE THAN CLINICALLY THAT SOMETHING VERY DIFFICULT TO GET RID OF EVEN IF ANDROGEN LEVELS GO DOWN, AND THIS REFERS TO THE OLDER PCOS PATIENTS AND MORE VAGINAL DRYNESS, NO DIFFERENCES IN WAIST HIP BECAUSE THEY OBSERVE THE CONTROLS GAINED A LOT OF WEIGHT. SO THE REFERENCE CONTROLS, ELIMINATED ANY POTENTIAL CHANGES IN WAIST-HIP AND COWERIOUSLY LOWER PREVALENCE OF HYPOTHYROIDISM. NOT SURE WHAT THAT MEANS. AND THE STEROID DATA LEVELS, THESE IS THE SEVENTH DECADE SO THINK OF A WOMAN IN HER 70S WITH PCOS, SHS LEVELS ALTHOUGH ELEVATED ARE LESS THAN THE CONTROLS. TEST ON OFTOWN GOWN AND THESE WERE NOT--DOWN AND THESE WERE NOT SUG95 CANT ANYMORE. --SIGNIFICANT ANYMORE. FREE ANDROGEN INDEX WAS LOWER, STILL HIGHENER THE PCO IS AND THEIR 70S COMPARED TO THE CONTROLS. AND SO FINALLY THIS IS THE LAST SLIDE THE AGE OF MENOPAUSE IS LIKELY TO BE LATER, MANY FEATURES, THE ANDROGENS ARE VOLUME AND THE FREQUENCY OF IRREG CYCLES IMPROVE WITH AGING. THE METABOLIC FEATURES PROBABLY PERSIST AND PARTICULARLY BECAUSE OF WEIGHT GAIN AT LEAST THAT'S MY VIEW. THERE'S LITTLE ININALLATION ON CHANGES AND DIFFERENT PHENOTYPES OF PCOS, SO EVERYTHING WE TALK ABOUT IS WHAT WE KNOW ABOUT THE CLASSIC PATIENTS WHO THEN TRANSITION WITH AGE, MAJOR CONCERNS ARE METABOLIC CARDIOVASCULAR AND CANCER RISKS AND IT'S LARGELY IN MY VIEW, AN AGING PHENOMENON. THANK YOU. [ APPLAUSE ] STPHR-RBGS THANK YOU ALL TO THE SPEAKER-- >> THANK YOU ALL TO THE SPEAKER THIS IS MORNING AND I WOULD LIKE TO INVITE THEM UP TO THE OPEN SESSION NOW. I WILL FIRST GOING TO ASK WHETHER OR NOT THERE ARE ANY QUESTIONS FROM THE PANELISTS? THERE'S ALSO INDIVIDUALS WALKING AROUND WITH CARDS TO WRITE QUESTIONS ON IF YOU WOULD PREFER THAT. YES, PANELIST, DR. JOHNSON? >> THANK YOU FOR YOUR EXCELLENT PRESENTATIONS I'M INTERESTED IN KNOWING WHAT THE DATA IS ON THERAPY FOR THE LIVER DISEASE THAT YOU DESCRIBED. THERE WAS A FAIRLY HIGH PREVALENCE AND I'M WONDERING WHAT EVIDENCE THERE IS TO SUGGEST THAT THERE'S EFFECTIVE TREATMENT THAT CAN AFFECT THE OUTCOME. >> THE DATA THAT I JUMPED OVER WAS THE TONIC TRIAL WHICH IS REALLY NOT IN PCO IS WHICH IS IN KIDS 8-17 YEARS OF AGE WHO HAD BIOPSY EVIDENCE OF NAFLD, THEY WERE RANDOMIZED AROUND 55 TO EACH GROUP TO MEDFORMIN MILLIGRAMS A DAY, VITA MEAN E, 800 I. U. D. AND PLACEBO AND THE OUTCOME WAS A CHANGE IN ALTASD AT 92 DAYS OF TREATMENT ASK THERE WERE ABSOLUTELY NO DIFFERENCES AMONG THE 3 GROUPS, SO THERE WAS THE PRIMARY OUTCOME. BUT IN THE SECONDARY ANALYSIS HA THEY FOUND WAS THAT THE PATHOLOGIC CHANGES OF BALLOONING IMPROVED 40% IN THE MEDFORMIN AND 40% IN THE VITAMIN E AND 20% IN THE PLACEBO AND THIS WAS THIS SIGNIFICANTLY DIFFERENT. BUT THESE ARE NOT PCOS KIDS BUT I THOUGHT IT WAS NICE PROSENT IT TO GIVE AN IDEA IF THIS IS THE 1 OF THE PURPOSES OF THIS WORKSHOP IS WHERE DO WE HAD AFTER THIS. BUT THE ONLY TRY I FOUND IN PCOS WAS THAT OPEN LABEL MEDFORMIN AND OMEGA 3 FATTY ACID TRIAL. >> SO I GUESS EVER YESTERDAY'S DISCUSSION, OUR PROBLEMS DEFINING PCOS, I'M A BIT CONCERNED ABOUT THE LIVER BIOPSIES THAT ARE GOING TO BE HAPPENING ALL ACROSS THE COUNTRY IF WE HAVE EXPANSIVE DIAGNOSIS. SO I MEAN, IS IT 1--IF YOU DIAGNOSE, HELP ME THINK THROUGH WHAT IT WOULD LOOK LIKE, IF WE HAD A MAJOR NATIONAL PROGRAM TO IDENTIFY THIS DISEASE, HOW MANY BIOPSIES WOULD EACH OF THESE NEED DURING THE COURSE OF THEIR LIVES FOR US TO IDEBTIFY WHAT WAS GOING ON AND WHAT WOULD BE COSTS OF BOTH THE RISKS AND THE FINANCIAL CLASS B AND DO WE HAVE ANY--I MEAN SINCE WE DON'T HAVE DATA BENEFIT, WE DON'T KNOW IF THEY CAN BE WORTH IT. >> OF COURSE I CAN SPEAK BUT WE HAVE SOMEBODY IN PITTSBURGH WHO COULD SPEAK ABOUT THAT. IN THE COURSE OF SOMEBODY'S LIFE SPAN HOW MANY BIOPSIES 1 WOULD NEED, I WOULD SUGGEST THAT I MEAN, BASED ON THE VERY LIMITED DATA RIGHT NOW, KWROUPBS INDIVIDUALS DON'T SEEM TO HAVE. BUT MAYBE IF WE HAD DONE AN MRS INVESTIGATION WE MIGHT BE ABLE TO SEE SMALL FATTY DEPOSITS IN THE LIVER IN TEENAGERS. IT'S POSSIBLE. BUT IF YOU'RE GOING TO DO A NATIONAL EURBT VENTION, MULTICENTER, NATIONAL PCOS INTERVENTION FOR FATTY LIVER DISEASE, THEN PARTICIPANTS SHOULD HAVE A BASELINE BIOPSY EVALUATION AND END OF STUDY BIOPSY EVALUATION JUST LIKE THE TONIC STUDY, NOW REMEMBER, THE TON INCREASE IN BODY WAS IN CHILDREN AND THEY WERE ABLE TO DO IT. SO I THINK WOULD BE EASIER TO HAVE ADULT WOMEN PARTICIPATE WHO HAVE A CONDITION. YOU KNOW THE CHILDREN IN TONIC 7 THEY WERE ONLY OBESE. NOW ALL OF THE MRS IS NONINVEIGHSIVE BUT IT'S QUITE EXPENSIVE, MUCH MORE THAN A BIOPSY. YES THE RISKS ARE MUCH LESS BECAUSE WE BIOPSY, THERE IS ACTUALLY A VERY, VERY, SMALL RISK OF DEATH MOST BIOPSIES AND AROUND 2 OR 3% RISK OF SOMEWHAT PO BIOPSY ADMITTING TO THE HOSPITAL. SO I MEAN I THINK IT ALL DEPENDS ON WHAT THE INTERVENTION IS GOING TO BE. >> LET ME TRY TO CLARIFY SO I ASSURE THESE THERAPIST IS IN THE GI LITERATURE, BUT, WHY DON'T EVEN QUESTION BEGIN TO WORK UP FOR AN ADULT NORMAL FATTY LIVER DISEASE UNLESS THERE ARE SLTs NOW IF YOU DO MRS OR POLYSYMNOGRAPHY, A LARGER NUMBER OF PATIENTS HAVE IT BUT STANDARD CLINICAL PRACTICES AND I DON'T KNOW DAVID IF YOU WANT TO ELABORATE ON THIS IF THEY ARE--HAVE NORMAL LIVER FUNCTION TESTS, YOU DON'T GO ANY FURTHER. THE PERCENTAGE OF WOMEN IN MY PRACTICE WITH ABNORMAL LYMPHOCYTES, I SCREEN THEM ALL WITH LFTs IS REALLY VERY WELL, AND IF YOU LOOK AT THE TRI GLUTEZONE TRIAL WHICH WAS AT BASELINE GOT LSTs IN ALL THE PATIENTS ONLY 2 TO 3 PERCENT OF THOSE PATIENTS WERE RUN OF I MILL ABOUT PCOS, AND IT WAS ONLY ABOUT 4 IN THE TRI GLUTEZONE, SO THE ABNORMAL LIVER FUNCTION TASKS IS REALLY QUITE LOW. I THINK SOME OF THESE SMALL STUDIES ARE BIASED AND AGAIN, I THINK WE'RE ALSO TALKING ABOUT THE AN-OVULEATORY PHENOTYPE WHICH IS THE INSULIN RESISTANT PHENOTYPE. I DON'T THINK THE PROBLEM IS GOING TO BE AS LARGE AS YOU KNOW SOME OF THESE DATA MIGHT LEAD YOU TO BELIEVE. >> I THINK--I SOMEWHAT DISAGREE WITH YOU BECAUSE THE AWARENESS ABOUT FATTY LIVER DISEASE IS FAIRLY NEW, PROBABLY THE LAST 8 TO 10 YEARS, OKAY. SO THEREFORE, THE DATA IS STARTING TO APPEAR ON 2004, 2005, IF WE WAIT UNTIL YOU SEE ELEVATION IN ENZYMES, IT'S ALREADY LATE BECAUSE THAT HAPPENS ONLY WHEN THERE IT'S THERE FOR HEPATITIS WHICH PRECEDES KH-RBGS IS PRECEDED BY THE NAFLD, THE STAYATOSEIS, AND EVEN TPHAOEUGZINIZEATION--ORGANIZATIO N YOU DO--SIN FLAPPATION SO IN CLINICAL PRACTICE WE DON'T DO IF UNLESS THEY'RE COMPLAINING OF GI DISCOMFORT OR SOMEBODY IN THE FAMILY HAS LIVER DISEASE AND THINGS LIKE THAT WHICH TRIGGERS THE CURIOSITY OR THE SUSPICION TO DO IT. SO THE QUESTION IS REAL ARE WE LOOKING AT THIS AS A CONSORTED RESEARCH EVALUATION WHERE CAN YOU SAY THIS IS ON THE LARGEST SCALE WHERE THEY CAREFULLY DEFINE DIAGNOSIS WITH THE SENSITIVE METHOD TO LOOK AT WHAT IS THE PREVALENCE AND WHAT ARE THE RISK FACTORS, WHAT ARE THE UNDERLYING GENETIC THINGS BECAUSE IF BLACK WOMEN IT WILL BE A LOT LESS BY THE MERE FACT THAT BLACKS ARE TYPICALLY AFFECTED LESS AND THIS IS NEW RESILIENCEALATED, ET CETERA--NEWLY RELATED, ET CETERA OR IS IT THAT WE'RE DEVELOPING A CLINICAL APPROACH TO DIAGNOSING AND MANAGING THESE PATIENTS. REMEMBER THE MANAGEMENT OF IT, IS REALLY LIFE SIZE CHANGE, NUTRITIONAL COUNSELING, WEIGHT LOSS, ET CETERA, ET CETERA. I THINK THIS IS REAL A DIFFICULT PROBLEM BECAUSE THERE'S AN EPIDEMIC OF THIS, IN OBESITY IN THE GENERAL POPULATION AND MANY GASTROENTEROLOGISTS DON'T KNOW WHAT TO DO WITH THAT EITHER, BI OPPOSITING THOUSANDS OF PEOPLE AND WITH A TREATMENT BESIDES WEIGHT LOSS IT DOESN'T USUALLY BRING ANY APPROXIMATE FRUITION SO I WOULD THINK BIOPSIES WOULD BE QUITE AGGRESSIVE. NUBUT I MINE THE CLINICAL APPROACH IS DIAGNOSIS WHEN YOU HAVE ELEVATED ENZYMES AND THE NEXT THING PEOPLE DO IS SEND THEM TO THE GI DOCTOR WHO BIOPSIES THEM AND SAYS OKAY THIS IS NONALCOHOLIC FATTY LIVER DISEASE. >> SO I GUESS MY QUESTION IS SHOULD THE RECOMMENDATION BE THE BIOPSIES SHOULD BE RESTRICTED TO RESEARCH PROGRAMS AND I'M JUST A LITTLE BIT CONCERNED THAT SUDDENLY PCOS WILL BE [INDISCERNIBLE] AND EVERYBODY AROUND THE COUNTRY WILL BE BIOPSYING PATIENTS WITHOUT ANY REAL GOOD EVIDENCE [INDISCERNIBLE] PCOS AT THIS MEETING IS 2 AREAS. ONE WE'RE TALKING ABOUT RESEARCH ISSUES SHOULD BE AND WE'RE ALSO TRYING TO ADDRESS WHAT SHOULD PRACTICE BE FOR PEOPLE ACROSS THE COUNTRY AND I MEAN I GUESS I'M--I WOULDN'T HAVE VOLUNTEERED FOR THIS, GIB WHAT I HEARD TODAY. --GIVEN WHAT I HEARD TODAY. >> I'M NOT SURE AS A PEDIATRIC ENDOCRINOLOGYST, I WANT TO MAKE A RECOMMENDATION FOR LIVER DISEASE, [INDISCERNIBLE] I SPORTSMANSHIP THEY WILL MORE AGGRESSIVE THAN YOU AND I IN BIOPSY THE LIVER, BUT AS I SAID ONCE HAVE YOU EVIDENCE OF ELEVATED ENZYMES YOU KNOW THAT IT'S AT LEAST EVIDENCE OF INFLAMMATION AND MAYBE SOME FIBROSIS, HOW EXPENSIVE IT IS. YOU CAN'T TELL FROM THE DEGREE OF ELEVATION. >> DR. REZA. >> ONE OF THE PROBLEMS IS THAT YOU CAN DO WHAT'S MRI FOR .99 VIBEIVATION, WHEN YOU THESE METHODS ARE HIGH CORRELATED THAT DON'T HAVE TO BE BIOPSIES BUT THEN BECOMES A RESEARCH METHOD BECAUSE 1 OF THE KEY QUESTIONS HERE IS THAT WE'RE ALL GOING BACK AND FORTH IS THAT MANY PEOPLE GO TO AH TOPS WEB CONNECTED A LIVER FULL OF FAT AND THEY'RE JUST FINE. SO THE QUESTION COMES AS PERSPECTIVE, USING SUCH AS [INDISCERNIBLE] I CAN'T SAY IT, ARE THERE CHANGES IN TIME THAT DIFFER FOR WOMEN WHO DON'T HAVE PCO AND CAN'T BE CHANGED BY INTERVENTIONS AND THAT'S A GOOD RESEARCH QUESTION BUT IT'S NOT A [INDISCERNIBLE] QUESTION. >> THE OTHER QUESTION IS THE TREATMENT, ARE THE OCPs MAKING IT BETTER OR WHATEVER,. >> RIGHT. >> BUT YOU THINK EVER THE RESEARCH AGENDA THERE ARE NONINVEIGHSIVE METHODS WHICH ARE HIGHLY SPECIFIC, HIGHLY VALIDATED THAT CAN ACTUALLY LOOK AT THESE QUESTIONS. >> I MEAN THE MRS IS VERY GOOD BECAUSE WE USE IT IN OBESE BOYS AND WE SHOW THAT 3 MONTHS OF EXERCISE INTERVENTION DOES RESULT IN SIGNIFICANT DECLINES IN MRS DETECTED LIVER FAT. >> RIGHT. >> WE LOOK AT FIBROSIS AND SMALL AMOUNTS, IT'S BEEN VALIDATE WIDE BIOPSIES. >> OKAY. >> ANOTHER QUESTION? >> IT'S JUST A COMMENT BECAUSE I THINK WE HAD SO LITTLE TIME ON THE DIABETES INSULIN RESISTANCE TO JUST SORT OF REVIEW FOR THE PANEL WHAT WE DO KNOW ABOUT IT BECAUSE WE DO KNOW QUITE A LOT. AND THAT IN MANY, MANY POPULATIONS, THE INSULIN RESISTANCE IS INDEPENDENT OF OBESITY, INDEPENDENT OF BODY COMPOSITION SO, IF YOU EXPRESS THE PROLEAN BODY MASS THESE WOMEN ARE ABOUT 40 TO 50% DISCIPLINARY CREASE COMPARED TO NORMAL WOMEN BUT THERE ARE SOME POPULATIONS THAT APPEAR TO HAVE COMPLETELY NORMAL INSULIN SENSITIVITY AND SO IN THE SCANDINAVIAN POPULATION, IF YOU CORRECTLY EXPRESS INSULIN RESISTANCE OR INSULIN SENSITIVITY TO INSULIN SECRETION EVEN THOUGH THE INSULIN LEVELS ARE HIGHER, THEY'RE INAPPROPRIATELY LOW FOR THE DEGREE OF RESISTANCE SO BETA CELL DYSFUNCTION IS FIRST SHOWN ELEGANTLY BY DAVID EHRMANN, IT'S CHARACTERISTIC AND IT'S A VERY EARLY CHARACTERISTIC AND THERE'S BROAD CONSENSUS THAT THE METABOLIC DEFECT AND TISSUES WITH THE POST SIGNALING TRANSDUCTION SO IT'S NOT THE SORT OF WAVE YOUR HAND, WE DON'T KNOW WHAT IT IS. IT'S VERY SPECIFIC. IT'S RIGHT IN THE EARLY STEPS OF SIGNALING, THAT'S BEEN SHOWN IN MUSCLE AND DIFFERENT SITES, SEVERAL GROUPS HAVE CONFIRMED THAT THERE'S ACCESSIVE PHOSPHORYLATION OF THE INSULIN RECEPTOR AND OF IRS 1 AND THERE'S EVIDENCE THAT THERE'S CONSIT WITTIVE ACTIVATION IN SKELETAL MUSCLE OF THE MAP OR KINASE PATHWAY AND THAT'S 1 OF THE KINASES RESPONSIBLE FOR THE SERINE PHOSPHORYLATION AND THERE ARE TISSUE DIFFERENCES AND STEVE FRANKS AS SHOWN THAT THE GRANULOSEIS CELLS WERE RESISTANT METABOLICALLY, BUT STILL RESPOND TO INSULIN STEROID GENICALLY SO CAN HAVE RESISTANCE TO SOME OF THE INSULIN WITHIN THE TISSUES BUT STILL, NORMAL INSULIN ACTION ON SOME OF THE OTHER METABOLIC PATHWAYS FASTING GLUCOSE LEVELS HAVE BEEN KNOWN FOR A LONG TIME ARE POOR SCREENING FOR DIABETES AS IS HEMOGLOBIN AC1 C BECAUSE THEY'RE SO INSULIN RESISTANT IS THE GLYCEMIA SO THAT'S IMPORTANT IN THE RECOMMENDATIONS THAT WE CAN'T DO OUR SORT OF TYPICAL SCREENING FOR DIABETES, THAT THEY NEED THE FULL GLUCOSE TOLERANCE TEST TO BE SCREENED AND THE HEMOGLOBIN AC1 Cs ALSO AREN'T A GOOD SCREENING TOOL AND THAT'S BEEN COBERATED IN SEVERAL STUDIES NOW. SO I THINK THERE'S SPECIFIC FEATURES ABOUT PCOS, AND DIABETES THAT DIFFER A LITTLE FROM OUR RECOMMENDATIONS IN THE GENERAL POPULATION AND WE ARE GOING TO HEAR ABOUT LIFESTYLE BUT CERTAINLY IN THE SETTING OF INFERTILITY OF LIFESTYLE BECAUSE THESE WOMEN ARE MOTIVATED IS QUITE AFFECTED, I WOULD SAY THOSE OF US WHO AREN'T ENDOCRINOLOGYST FIND LIFESTYLE, IT'S VERY HARD AND THAT METFORMIN ENDS UP BEING A VERY GOOD AGENT FOR DIABETES PREVENTION IN THIS POPULATION. NOW UNFORTUNATELY THERE'S NEVER BEEN A TRIAL IN PCOS SUBSET TO LOOK AT DIABETES PREVENTION THE WAY THERE HAS BEEN LIKE IN FORMER GUESTATIONAL DIABETICS. >> I THINK THIS BRINGS UP A THE QUESTION OF WHAT SHOULD BE MONITORED AND DIFFERENCE FOR RESEARCH STUDY VERSES CLINICAL PRACTICE. AND YOU KNOW AC1 Cs AT THE CELLS AND THE GENERAL POPULATION IS BEING--REPLACING THE OGTT CLINICALLY AND IN MANY WAYS THAT MAKES SENSE BECAUSE WHAT ARE YOU GOING TO DO WITH THE INFORMATION CLINICALLY. SO THERE IS INSULIN RESISTANCE FROM A CLINICAL POINT OF VIEW, THE RECOMMENDATION WILL NOT BE MET FORMIN IN MOST SITUATIONS IT WILL BE LIFESTYLE. SO WHERE DO YOU THINK THERE'S THE EXTRA BANG FOR THE BUCK. >> THE OGTT? >> I THINK NUMBER 1 THE PATIENT THAT HAS PREDIABETES IS MORE MOTIVATING TO BE ADHERENT TO LIFESTYLE, NUMBER 2, IF LIFESTYLE FAILS, YOU WOULD COUNCIL FOR MET FORMIN, THE AADSAEUZ RECOMMENDS FOR PATIENTS WITH COMBINED FASTING AND HYPERGLYCEMIA BUT THAT'S A VERY LATE EVENT IN PCOS, WE CERTAINLY NEED THE STUDIES TO SEE IF THEIR PCOS SPECIFIC OUTCOME BUT I THINK IN GOOD CLINICAL PRACTICE, RATIONAL CLINICAL PRACTICE WOULD AAGREES TRYING TO HAVE DIABETES PREVENTION IN THE WOMAN WITH IMPAIRED GLUCOSE TOLERANCE BECAUSE WE KNOW THAT AT LEAST 8% PER YEAR IN THE GENERAL POPULATION AND COMPARED GLUCOSE TOLERANCE PROGRESS TO TYPE 2 SO WE HAVE A RESEARCH QUESTION IS IT THE SAME DIABETES PREVENTION MODALITY, BUT KNOWING ABOUT IT, YOU CAN'T KNOW ABOUT IT, WITH HEMOGLOBIN AIRCRAFT 1 C, I THINK THAT'S WHAT'S IMPORTANT FOR THE FASTING GLUCOSES. >> IF I COULD JUST UNDERSCORE SOME OF THE POINTS THAT ANDREA MADE. A NUMBER OF PEOPLE UPDATE BUT ANDREA AND MYSELF, IF YOU LOOK AT FASTING GLUCOSE AS A PREDICTER, ALL BETS ARE OFF. IF YOU LOOK AT HEMOGLOBIN AC1 C, THE GENERAL VALUE OF WHEN THEY HAVE IGT IS BETWEEN 5 AND HALF AND 7, 5.7 RATHER IF YOU WAIT UNTIL THE AC1 C GETS ABOVE THE THRESHOLD AND THE DIABET AND I CAN THE HORSE IS OUT OF THE BARN SO WHAT WE TRY TO DO IS IDENTIFY THEM EARLY AND 35% OF THESE WOMEN IN THEIR MID20S WILL PRESENT WITH IMPAIRED GLUCOSE TOLERANCE AND WE LEARNED NOW FROM SO MANY TRIALS THAT EARLY INTERVENTION IS THE ONLY WAY TO PREVENT CONVERSION FROM IGT OR PREDIDN'T TO TYPE 2 DIABETES. SO I THINK SCREENING OGGT ON A YEARLYY BASIS ARE NEEDED. >> OKAY. >> WE WILL HEAR AN ENDOCRINOLOGYST WHICH WAY WILL YOU GO. >> CAN I PRESENT A DISSENTING VIEW FROM THAT. >> NO. >> [LAUGHTER] >> OF COURSE, NO, PLEASE DO. >> OKAY. >> SO I SHOULDN'T ADMIT THIS BUT I CHAIRED THE STUDY SESSION OF DPP CONTINUED AND THE PROBLEM IS WHAT WE KNOW, THE ENDOCRINOLOGYST KNOW THIS, THE PROBLEM IS YOU KNOW UNQUESTIONABLE WHEN YOU LOOK AT THE CRITERIA FOR DIABETES THAT YOU WILL LOOK AT AC1 C IT DOES FOCUS ON THE PREDICT PEOPLE WITH DIABETES DIAGNOSED WITH THE GLUCOSE TOLERANCE TEST, THAT'S Q. E. D. BECAUSE YOU'RE USING THE Q. I.D. AS THE STANDARD AND I WILL GUARANTEE YOU THAT 2 R GLUCOSE TOLERANCE TEST WOULD NOT PREDICT AC1 C. THE PROBLEM IS, YOU KNOW IN EVERY ENDOCRINOLOGYST INVOLVED AND WE'VE ALL BEEN INVOLVED IN THIS, IS INTERVENTION, IT'S YOUR QUESTION, DOES INTERVENTION IN THE PRESENCE OF MILD 2 HOUR ELEVATION GLUCOSE ALTER OUTCOMES OVER A LIFETIME? OR IF YOU TREAT, BLOOD LIPIDS, BLOOD PRESSURE, FITNESS, DO YOU FACTOR THAT IN WITH THE SAME LONG-TERM OUTCOMES WITH OR WITHOUT TREATMENT EARLY AND WE PRACTICALLY, WE KNOW THIS BUT THE REST OF THE ROOM NEEDS TO KNOW THAT. WE DON'T KNOW THAT ANSWER AND THAT'S A VERY IMPORTANT ANSWER, THAT'S THE FUNDAMENTAL QUESTION AND WHAT THE ADA RECOMMENDS FOR THE TOLERANCE IS THAT'S ACCEPTABLE BUT NOT NECESSARILY RECOMMENDED FOR TREATING. BECAUSE FRANKLY WE DON'T KNOW WHAT THE HARD OUTCOME IS. IT MAY WELL BE TRUE, IN PARTICULARLY IN THIS POPULATION, THIS MAY WELL BE SOMETHING THAT'S IMPORTANT FOR EXAMPLE, WOMEN HAVE LOWER FASTING GLUCOSE AS THAN M EN BECAUSE THEY HAVE LARGER BRAINS AND THEY HAVE A GREATER GLUCOSE UPTAKE OVER TIME, YOU WILL ALWAYS FIND HIGHER 2 HOURS AND OF OVERFASTING FOR WOMEN. IS THAT ABNORMAL? WELL NOT REALLY DIFFERENT IN AGE WOMEN, IF THEIR BODY MASSES ARE MATCHED SO YOU GET INTO THIS CONUNDRUM BUT YOUR POINT IS TAKEN. THE CLINICAL QUESTION VERSES THE RESEARCH QUESTION AND SOME PEOPLE MAY KNOW BUT I FRANKLY DO NOT KNOW AND I THINK THAT'S 1 OF THE CRITICAL QUESTIONS WE NEED TO FIGURE OUT OVER THE LONG RUN. >> I WOULD AGREE WITH THAT, ESPECIALLY SINCE THERE ARE CONFLICTING DATA ABOUT CONVERSION RATES FROM IGT TO FULL BLOWN DIABETES AND FCOS, SOME STUDY VS SHOWN, RICK HE'S HERE, YOUR STUDIES SHOW THAT THERE REALLY WAS NOT AN INCREASED CONVERSION RATE BUT THERE ARE SOME--THERE ARE STUDIES THAT SHOW AN INCREASED CONVERSION RATE OVER SHORT PERIODS AND UNTIL WE KNOW THAT, DEFINITIVELY, I THINK-- >> AND EVEN MORE FUNDAMENTALLY IF I TREAT YOU OR YOU TREAT ME BECAUSE I'M GETTING OLDER SO I'M THE 1 TO GET DIABETES, IF YOU TREAT ME WHEN I FIRST DEVELOP DIABETES WHEN MY BLOOD SUGAR IS 126 VERSES 125, DO I HAVE ANY DIFFERENT OUTCOME THAN IF YOU TREATED ME 5 YEARS EARLY FOR GLUCOSE NOW, NOT WITH THE BLOOD PRESSURE, BUT WE DON'T KNOW THAT EITHER, AND THAT'S A VERY, THAT A PRESSING QUESTION AND WE GET A WHOLE VARIETY OF PEOPLE TREATED BUT WAITING PLAY BE BAD BUT IT MAY BE REASONABLE, FRANKLY WE DON'T KNOW. >> EARLIER THE DEFICIENCIES, THE BETTER OUTCOME THE THE--THIS RICKLY THE OUTCOME WOULD BE. >> THERE'S AN ARTICLE IN PRY COLLEAGUE DR. BUTLER THAT LOOK AT PETA CELL MASS OVER AGE. IT DOESN'T CHANGE 1 IOTA. THIS IS YOUNG WOMEN AND AND NOT SIMPLE IT'S THE CRUX OF THIS ALCOHOL QUESTION, AND THOSE HIGH ANDROGENS PCO WHATEVER THE SYNDROME IS ALTER THE NATURAL HISTORY. I DON'T KNOW. TO DO THE RISK GOES VERY WELL INTO THE C-RANGE SO MAYBE YOU'RE AT MUCH HIGHER RISK IF YOU'RE A WOMAN WITH PCO THAN A WOMAN WITHOUT BUT AGAIN I DON'T KNOW THE ANSWER TO THAT QUESTION. >> I DO KNOW I WOULD STAY LEAN TO FIT IF I DIDN'T HAVE PCO. >> YOU ARE MAKING A BODY POINT IS THAT AC1 KR-Z PREDICTS CARDIOVASCULAR DISEASE, AND IF THAT'S THE OUTCOME, THAT'S A GOOD TEST. I WANT TO TAKE A SHOW HANDS, SOME PEOPLE DISCUSS DURING OGT ONCE A YEAR, ARE PEOPLE DOING THAT CLINICALLY? >> [INDISCERNIBLE] >> RIGHT. OKAY. TWICE EVERY 2 YEARS. AT THE TIME OF DIAGNOSE I GUESS, I THINK IT WILL BE IMPORTANT IT WILL BE TAKEN IN THE RISK FACTORS THE PATIENT MAY HAVE FOR DIABETES, BODY HISTORY, DISTRIBUTION AND SO ON. BUT I THINK THE POINT I WAS TRYING TO MAKE IS THAT IF YOU ARE GOING TO RELY ON A FASTING GLUCOSE AND WHAT WE TYPICALLY SEE REFERRED INTO US AND ANDREA CAN PROBABLY COBERATE THIS, WE WILL GET A MEASURE FASTING INSULIN AND SAID YOUR INSULIN RESISTANCE BUT YOUR BLOOD SUGARS ARE NORMAL SO YOU'RE NOT AT RISK AND THEN WE DO AN OGGT AND THE GLUCOSE IS 184. >> SO WITH SO MUCH AGREEMENT THAT THE REAL LIFE EVENTS AT THE END OF LIFE ARE NOT WELL ESTABLISHED SO THERE IS GOING TO BE A GREATER NEED FOR LOOKING FOR SUBCLINICAL DISEASE AND DR.TAL BOT ELEGANTLY REVIEWED THE LITERATURE ON INT AND ET CETERA SO I HAVE A GENERAL QUESTION ABOUT THE VALIDITY OF SUCH METHODS. BECAUSE NOW THERE'S MORE AND MORE FOCUS ON GENDER DIFFERENCES ANDET ETIOLOGY, PATHOPHYSIOLOGY OF CARDIOVASCULAR DISEASE AND THESE MEASURES THAT YOU MENTIONED THEY USUALLY APPLY IN MEN AND TESTED IN MEN. SO DO WE ALL BELIEVE THAT THEY'RE EQUALLY USEFUL IN WOMEN? AND IF SO, THEN WHAT WOULD BE THE PREFERRED TEST TO DO? BECAUSE I THINK FOR THE PANEL, FOR ME, THIS IS CRUCIALLY RELEVANT BECAUSE YOU KNOW YOU NEED REALLY LONG-TERM FOLLOW UP STUDY TO GET TO REAL LIFE EVENTS SO SWRAOE TO FOCUS ON SUBSTITUTE OUTCOMES, SO WOULD YOU-- >> WELL THAT'S A VERY GOOD QUESTION, I WILL SAY THAT--THERE ARE MANY--CAN YOU HEAR ME, IN THE PAST, I GUESS SINCE MID90S EARLY 200S, THERE'S THE WOMEN'S HEALTH INITIATIVE, THERE'S A SWAN WHICH IS A--WHICH IS A LARGE--THROUGH THE TESTING BUT IMT HAS BECOME MORE OF A GOLD STANDARD IN WOMEN, I MEAN BECAUSE THERE HAVE BEEN MANY BECAUSE THERE ARE SO MANY STUDIES NOW WHERE THEY'RE FOLLOWING WOMEN WITH CAROTID ULTRA SOEUPBD AS YOU--ULTRA SOUND AS YOU PROBABLY KNOW. WHEN I LOOK AT THE LITERATURE, THE RELIABILITY, REPRODUCIBILITY IS REALLY WITH NEW ULTRASOUND MACHINES COMING OUT ALL THE TIME IS ACTUALLY, ACTUALLY PRETTY GOOD. IT'S VERY GOOD. AND--IN MEN AND WOMAN. >> I HEAR MORE CARDIOLOGIST SAY THAT PLAQUE FORMATION IN WOMEN VERSES MEN VERY VERY, VERY, DIFFERENT AND DELIVER, IS IMT INDEED THE MOST RELATIVE TEST? I DON'T KNOW THE ANSWER. >> WELL THE BLACK I HAVE TO SAY, WE HAVE LOOKED AT A NUMBER OF PLAQUES AND JUST THE WALL AND THICKNESS JUST INDEPENDENT OF PLAQUE AND PLAQUE IS PART OF THE YOU KNOW THE CALCULATION BUT, I CAN JUST SPEAK FOR THE STUDIES THAT I KNOW AND I DO THINK THEY'RE QUITE GOOD, I BELIEVE THEY'RE HIGHLY--AS I SAID THE REPRODUCIBILITY THE VALIDITY, THE ACRASE MODEL SEACTUALLY QUITE GOOD, I WOULD SAY, THAT I ALSO LIKE THE CORONERY CALCIFICATION, THE AEBCT, THE PROBLEM WITH IT IS THAT YOU ALL KNOW IS THAT IT'S COMPUTER POMMOGRAPHY TDOES HAVE RADIATION, IT DOES HAVE RADIATION RISK, I DON'T KNOW WHETHER YOU WANT TO SUBJECT SOMEBODY, SUBCLINICALLY DOESN'T HAVE PROBLEMS TO REPEATED MEASURES OF THAT OVERTIME, THE OTHERS THERE, WE KNOW IT'S NONINVEIGHSIVE AND DOES NO HARM THAT WE KNOW OF. TO ME, THAT'S REALLY THE WAY TO GO. FMDs, THE FLOW MEDIATED VASE O DILATION DOES HAVE QUIRKS IF YOU HAVE EATEN A HALF HOUR BEFORE YOU HAD THE TEST, YOU KNOW IF THERE'S PHYSICAL ACTIVITY, BIAS, RELATED TO KNOWING WHEN THE LAST TIME SOMEBODY EXERCISED. THERE'S OBESITY ISSUE RELATED TO JUST--JUST ACCURATE MEASUREMENTS THROUGH MANY THICKNESSS OFADDA POST TISSUE, SO, FOR MY DOLLAR, I THINK IMT IS STILL DEFINITELY THE GOLD STANDARD. >> RELATED TO THAT, DR. TALBOT, SHOULD THERE BE ROUTINE MONITORING FOR ATHEROSCLEROSIS OR ONLY BASED ON CLINICAL INDKAEUZS. >> BEBOY THAT'S SUCH A GOOD QUESTION. >> YOU'RE ASKING ME? >> YEAH I'M ASKING YOU. >> I--IT'S NOT A VERY INCREDIBLY EXPENSIVE TEST AND MORE AND MORE CENTERS DO HAVE THIS, AND IF WAS MY NICKEL, I KNOW I'VE HAD MINE DONE AND I WILL WILL SAY TO YOU, THAT BASED ON THE IMT WORK THAT WE'VE DONE HERE IN PITTSBURGH WHEN WE LOOKED AT THE IMTs OF PCO WOMEN OVER45, THEY REPRESENTED IMTs THAT ARE MORE CLEARLY IN WOMEN, NORMAL WOMEN WHO ARE 10 YEARS OLDER. SO I WOULD ARGUE, YES. >> IT SHOULD BE DONE AT BASELINE IN ALL WOMEN WITH PC RR. >> OKAY. >> MY ANSWER-- >> I JUST WANT TO PUT A DIFFERENT PERSPECTIVE. NOT MY AREA OF EXPERTISE BUT I LEARN AID LOT FROM SCREENING TESTS, AND BEFORE YOU ADVOCATE A SCREENING TEST, I WOULD BE CAUTIOUS IN MAKING A STATEMENT ABOUT ADVOCATING ROUTINE SCREENING THAT WE HAVEN'T FULLY UNDERSTOOD YET. >> OKAY AND WITH A LOT OF VARIABILITY AND READING THE IMTs ON LOCAL MACHINES. YES, QUESTION IN THE BACK, PLEASE. >> A COMMENT AND A QUESTION, ABOUT-- >> COULD YOU STKPWRAOUS STKPWRAOUS--INTRODUCE YOURSELF. >> YES, A COMMENT ABOUT THE DEBATE IN PCOS ABOUT MEASURING FASTING GLUCOSE OR HBAC1 C OR OGGT, WITH GLUCOSE INTOLERANCE WE'RE DEALING WITH WOMEN PRECONCEPTION AND THERE'S VERY CLEAR EVIDENCE THAT THE GLUCOSE LEVEL EARLY CONCEPTION AND THROUGHOUT PREGNANCY IMPACTS PREGNANCY OUTCOMES AND MANY PEOPLE SHOULD KNOW THAT ABOUT AS WELL AS ME AS AN ENDOCRINOLOGYST BUT IF WE PUT EMPLOYMENT PROGRAMS THAW FERTILET TREATMENT, WE REALLY NEED TO KNOW WHAT THEIR GLUCOSE TOLERANCE IS, AND THAT'S REALLY IMPOR UT FOR OUTCOME. BUT PROBABLY MORE THAN ANYTHING, WE NEED A SCREENING ALEGORITHMS WHICH IS ESTABLISHED ACROSS ETHNICITIES AND LARGE NUMBERS OF WOMEN THAT MAY BE ABLE TO GIVE US A POINT OF FASTING GLUCOSE AND BELOW THIS LEVEL WE DON'T NEED TO LOOK FURTHER AND BELOW THIS WE NEED TO GO ON TO INVEIGHSIVE TESTING, BECAUSE OGTT ARE COSTLY, REDUCE PARTICIPANT INGAUGEMENT AND HAVE AN ECONOMIC IMPACT. SO WE NEED A SCREENING ALEGORITHMS BUT A PLACE TO CONSIDER THE FACT THAT PREGINANCE SCHEGLUCOSE IN PREGNANCY IS A DIFFERENT POINT HERE IN PCOS BECAUSE WE'RE DEALING WITH YOUNG WOMEN, NOT NECESSARILY WOMEN WHO ARE OLDER AND THE DIAGNOSIS OF BOTH PREDIABETES AND DIABETES IS MORE CRITICAL. >> YES, I WOULD LIKE TO ADDRESS THE SUBCLINICAL ATHEROSCLEROSIS THAT WAS RAISED. UNFORTUNATELY I HAD TO MISS SOME OF THE PRESENTATION, I WAS A CONFERENCE CALL, WE HAVE DONE SOME OF THE IMT MESA STUDIES AND CORKACCT CAROTID CHANGE REQUIRES A LAB, EDUCATION, CLOSE TRAINING I WOULD NOT RECOMMEND THIS AS A SCREENING TEST FOR YOUNGER WOMAN. BECAUSE ALTHOUGH IT'S ASSOCIATE WIDE ABNORMAL GLUCOSE TOLERANCE LO SCLERICOSE AND I GUESS OVER THE LONG-TERM STUDIES IT IS A VERY VERY SMALL CHANGE THAT COMPARED TO NORMAL AND I THINK WE'RE NOT REALLY LOOKING FOR STROKE RISK HERE WHICH IS WHAT IS USED FOR IN THE CLINICAL SETTING. SO SIMILAR FMD IS NOT A CLINICAL TEST, THE MUTATED IT'S USE OF VARIABILITY THAT CORONY CALCIUM, AS YOU SAY IS RADIATION IN THE MESA WE USE IT AND IT PREDICTS OUTCOMES BUT THEY'RE MUCH OLDER POPULATION SO AGAIN, I THINK THAT UNTIL YOU KNOW THAT CARDIOVASCULAR RISK IS INCREASED IN THE PC OS GROUP, I WOULD SAY IT'S A RELY GOOD MEASURE FOR RESEARCH FOR THE LONGITUDINAL STUDIES I. I WOULD INCLUDE IT BUT NOT USE IT IN A CLINICAL SETTING. >> CAN I MAKE A RESPOND TO THAT. YEAH, AGAIN I'M SPEAKING VERY QUICKLY, I THINK THAT YOUNGER WOMAN, PERHAPS AN OLDER GROUP OF PCO WOMAN THAT WE'RE HAVING SYMPTOMS AND IT WAS REALLY CONCERN ABOUT NOT JUST SOMETHING SUBCLINICAL BUT SOMETHING THAT MIGHT HAVE A CLINICAL RELEVANCE TO IT. THAT WOULD BE THE MORE APPROPRIATE 1. >> OKAY, QUESTION PLEASE. >> CAN YOU INTRODUCE YOURSELF, I DON'T SEE IT WELL. >> I'M MOVING TO A DIFFERENT TOPIC, ROB PROMAN, ARE YOU WANTING TO TALK ON THE SAME TOPIC? OKAY WE'VE ALL BEEN EDUCATED TO COME UP WITH REPRODUCTIVE LIFE PLANS TO AND THAT IS TO HAVE REGULAR CYCLES HAVE KIDS EARLY, ET CETERA, SO IN LIGHT OF KURT AND ROGERS TALKS YOU LIKE TO ASK THEM, DO YOU THINK WE ARE INTERVENING TOO MUCH IN TERMS OF GIVING PEOPLE PLANS, YOU KNOW, HAVE TO HAVE A MENSTRUAL CYCLE VERY REGULARLY THEY HAVE TO TRY AND HAVE CHILDREN EARLY BUT THAT--STANDARD THEY MAY NEED TO HAVE CLAMMA FINE WHEN THEY DON'T NEED IT LATER IN LIFE. SO, ARE OUR PLANS BECOMING TOO INTERVENTIONIST AND CAN WE RELAX A LOT MORE AND SAY, BECAUSE CYCLES ARE LIKELY TO GET BETTER LATER IN LIFE, PEOPLE CAN AFFORD TO WEIGHT. BUT THERE'S NOT AN OVERWHELMING INSTANCE OF ENDOMETRIAL CANCER AND IN PARTICULAR IF YOU HAVE 3 OR 4 PERIODS A YEAR IF THEY'RE IRREGULAR THAT MAY BE FINE. >> THAT'S RELATED TO A QUESTION WE HAD HERE, PARTICULARLY ABOUT A YOUNGER PATIENT, ADOLESCENT PATIENT WHO DOESN'T HAVE WANT TO HAVE PERIODS, CAN SHE JUST BE LEFT ALONE, DR. BARNHART? >> I THINK THERE'S 2 QUESTIONS IN THERE, I THINK WE UNDERSTAND THAT THERE'S A KNOWN ASSOCIATION AMENORIA SO I DON'T THINK THE SHORT ANSWER IS YOU DON'T WANT TO HAVE A PERIOD LEAVE ME ALONE. THAT'S A BAD PRACTICE. THERE'S' NUMBER OF WAYS TO DEAL WITH THAT TO ELIMINATE AND NOW WE'RE TALKING ABOUT PILLS AND OTHER WAYS THAT WOULD BE POOR. THE QUESTION ABOUT LIFESTYLE CHANGE SYSTEM A GREAT 1, WHEN I'M LOATHE TO MAKE A VERY BROAD SWEEPING COMMENT ABOUT THE LIFESTYLE CHANGE FOR POPULATIONS OF WOMEN WHAT TRUMPS IT IS THE WOMAN'S PLAN WHEN IS SHE WALKS INTO THE OFFICE, DOES HE WANT TO GET PREGNANT NOW AND IF SO, I SISTER [INDISCERNIBLE] HER TO GET PREGNANT. IT WOULD BE POOR OF US TO SAY, YOU CAN WAIT. HAVING SAID THAT THOUGH, I DO BELIEVE THAT PERHAPS WE COULD BE TOO AGGRESSIVE AND I THINK NOW, GOING INTO CONVERSATION WE HAVEN'T HAD YET ABOUT HOW YOU TREAT A WOMAN WITH PCOS THAT HAS FERTILITY PROBLEMS, CERTAINLY WEB CONNECTED CAN'T BE TOO AGREES WEUF RCYSTIVE REPRODUCTIVE TECHNOLOGIES IN SOME CASES AND MAYBE WE'RE PROGRESSING TOO FAST. SO THERE'S A LOT OF WORK THAT NEEDS TO BE DONE AND WHAT'S THE OPTIMAL TREATMENT, THERE'S GOOD RANDOMIZED TRIALS WITH OVULATION INDUCTIONS THAT HAVE COME OUT AND WE SHOULD PAY ATTENTION TO BUT THAT'S A VERY BIG QUESTION THAT I DON'T THINK CAN BE ANSWERED GLOBALLY ON EPIDEMIOLOGIC TRENDS. >> THE TERM CAME UP, ROGER ON SHOULD WE CALL IT BURNT OUT PCOS. >> [LAUGHTER] >> BURNT OUT. >> NO I DON'T THINK IT'S BURNT OUT BUT LET ME CHIME IN ON WHAT KURT SAID. WE ARE IN AGREEMENT AND I ALSO MAKE THE POINT PARTICULARLY IN YOUNG INDIVIDUALS THAT WE CAN REALLY TALK ABOUT PREVENTION AND IF THERE'S A REASON TO USE AN ORAL CONTRACEPTIVE, THE 2 ASSOCIATIONS OF RISKS THAT WE KNOW ABOUT, ENDOMETRIAL CANCER AND OVARIANCE CANCER HAVE BEEN SHOWN TO BE REDUCE WIDE ORAL CONTRACEPTIVES SO IT'S A GOOD REASON TO SWAY A PATIENT IN THAT DIRECTION. TO ROB'S POINT ABOUT FERTILITY, I ALSO AGREE, IINE WAWE HAVE LOOKED AT, WHAT I SHOWED ARE ASSOCIATIONS ON AN INDIVIDUAL BASIS IT WOULD BE HARD FOR US TO SAY, YOU'RE OKAY FOR ANOTHER 5 YEARS WE SHOULDN'T DO ANYTHING. THAT'S PROBABLY NOT ACCEPTABLE. >> WE TALK A LOT ABOUT METABOLIC LONG-TERM CONSEQUENCES AND KIND OF PEOPLE WHO COME IN THROUGH THE GYNECOLOGY SIDE WE'VE TALKED ABOUT WHAT THIS IS SO CAN YOU TALK MORE ABOUT BOTH KURT AND ROGER ABOUT KIND OF TABULATION INDUCTION AND THE LONG-TERM CONSEQUENCES OF THE INDUCTION AND WE KNOW THE CONSEQUENCES AND HHS, I MEAN THERE'S SOME DATA THAT'S CONCERNING ABOUT LONG-TERM CANCER AND THEY CONTINUE TO KIND OF PLAGUE US. BUT WHAT DO WE KNOW ABOUT THE LONG-TERM CONSEQUENCES OF FERTILITY TREATMENT AND FERTILITY THERAPY AND WHAT ROLE COULD POTENTIALLY LEAD THE I. U. D. IF THE MANAGE AM AND WE EVAPORATE TALKED AT ALL ABOUT THE SURGERY AND WHAT IF THEY HAPPEN TO GET SOME KIND OF EITHER RESECTION OR DRILLING OR SOME OF THE COMMON SURGICAL PROCEDURES WHAT DO WE KNOW ABOUT THE LONG-TERM CONSEQUENCES OF THOSE. MAYBE KURT WOULD WANT TO ADDRESS THE CANCER RISKS BUT THIS HAS BEEN LOOKED AT FOR A LONG TIME AND I DON'T WANT TO STEAL THE THUPBD TPRER THE FERTILITY TALKS WHICH ARE AFTER LUNCH, TO THE BEST OF OUR KNOWLEDGE,ARS PART FROM FEW TODAY STUDIES, MOST HAVE SHOWED NOW RUST SO IT FROM A FERTILITY TREATMENT STANDPOINT FROM WHAT WE DO IN PRACTICE, I TRY TO REASSURE PATIENTS ABOUT THAT. I DON'T KNOW IF RICK'S GOING TO COVER RESECTION? >> NO I'M GOING TO PREVENTIVELY ALLUDE TO IT. BUT THEY HAVE BEEN NOW LONG-TERM SIDES THE ORIGINAL NORWEG AN STUDY OUT 20 YEARS OR MORE, AND A LOT OF THOSE STUDIES THEY HAVE SHOWN THAT THERE IS ACTUALLY A PERSISTENCE OF THE AMELIORATION IN TERMS OF THAT, AND STAY LOW FOR A LONG PERIOD OF TIME SO THOSE PATIENTS CAN HAVE ACTUALLY HAVE A GREATER CHANCE OF EVEN A SECOND PREGNANCY AFTER THEY'VE BEEN TREATED COMPARED TO THOSE WHO HAVE NOT AND THIS CONFERENCE WE THOUGHT IT WAS ON PARWITH USING THE TAUPEINS SO YOU KNOW WORLD WIDE I THINK DONE THE RIGHT WAY IS AN ACCEPTABLE AN APPROACH PARTICULARLY FOR THE HYPER STIMULATE WITH LONG-TERM STUDIES UP TO I SAY ABOUT 20 YEARS IT WOULD LOOK PRETTY REASONABLE AT THIS POINT. >> DR. LEGRO. >> THE FRENCH PRONUNCIATION. >> [LAUGHTER] >> SO THIS IS FOR EVELYN AND OTHERS BUT THE IDEA THAT THE CARDIOVASCULAR METABOLIC PROFILE STABILIZES OR RELATIVE TO A CONTROL POPULATION ACTUALLY IMPROVES AND I THINK THAT'S 1 OF THE THINGS THAT WE SAW ON YOUR DATA THAT FOR INSTANCE LDBLOOD SUGAR CLEVELS INCREASES STABILIZE WHILE THEY GET WORSE IN THE CONTROLS AND WE HAVE A SIMILAR DATA SOMEONE SHOWED BASELINE DATA WE PULLED OUT OF THE SWAN COHORT, THIS IS THE WORK WE DID WITH NANOGET SANTORO AND ALEX POETIC LOT SKI, AND THEY HAVE ELEVATED TESTOSTERONE AND AMEN ORRERIA AT THE BEGINNING OF THE TRIAL. WE PUBLISH TH-D IN ACM. BUT WE HAD THE ADVANTAGE OF FOLLOWING THESE WOMEN THROUGH THE--THROUGH THE COMPLETE TRIAL AND WHAT WE FOUND IS SIMILAR TO ACTUALLY METABOLIC SYNDROME AS THEY WORK THROUGH MENOPAUSE AND THE WOMEN WHO DID NOT, ARE THE 1 WHO HAD WORSENING METABOLIC PROFILE. SO IT'S VERY SIMILAR TO I THINK YOUR FINDING THAT PERHAPS THE METABOLIC PROFILE MAY BURN OUT WITH AGING MENOPAUSE, EXPLAIN THIS LACK OF CARDIOVASCULAR EVENTS. >> YEAH, I WOULD AGREE. THE WOMEN IN PITTSBURGH WE LOOKED AT WERE MUCH WORSE AND SOMETHING HAPPENED AT AGE 44, THEY SORT OF PLATEAU AND QUEEN AND CONTROL WOMAN HIT THE PERO MOAN O PAUSAL TRANSITION, THEY--THEY JUST CAME UP TO THE LEVEL OF THE PCO WOMEN, SO AGAIN I THINK MORE FOLLOW UP, I THINK AN ADDITIONAL FOLLOW UP TO 5 YEARS FOLLOW UP IS CALLED FOR BUT IT DOES APPEAR TO ME TO BE THAT WAY, ALSO. >> DID YOU WANT TO COMMENT? >> YEAH, I WANTED TO COMMENT BACK ON THE INITIAL QUESTION ABOUT FERTILITY. I THINK IT'S SOMETHING THAT'S NOT COMING UP. NOW THE REPRODUCTIVE MEDICINE NETWORK IS DOING A NUMBER OF TRIALS ON OPTIMIZING OVULATION INDUCTION AND THAT'S PRETTY STRAIGHT FORWARD BUT THERE'S FUNDAMENTAL QUESTIONS WE DON'T KNOW ABOUT FCO AND FERTILITY THAT WILL AFFECT A WOMAN'S REPRODUCTION. ONE THEY MENTIONED A LITTLE BIT YESTERDAY, WE HAVE TO PAY ATTENTION TO OVERGRESSIVE CYSTIC REPRODUCTIVE TECHNOLOGIES AND MULTIPLE BIRTHS CANNOT BE UNDERESTMAYED HOW MUCH A PROBLEM THAT IS FOR PEOPLE AS WELL AS HYPER STIMULATION SYNDROME BUT MY POINT IS WE LACK FUNDAMENTAL UNDERSTANDING WHETHER A WOMAN WITH PCO ESPECIALLY GIVEN THE DIFFERENT PHENOTYPES HAS REPRODUCTIVE DISORDERS OR WHETHER IT'S JUST THE TAIL END OF A CURVE. IS THIS RESPONDING TO MEDICATION OR IS THERE SOMETHING FUNDAMENTAL DIFFERENT ABOUT THEIR COMPETENCE, ABILITY TO REPRODUCE AND OUTCOMES AND THOSE ARE QUESTION WHAT'S HAVEN'T BROUGHT UP HERE AND THE PRODUCTION--REROUGH ATOM CONDUCTION IN WOMEN WITH THIS DISORDER NEEDS TO BE ADDRESSED AS WELL. >> YES. >> THANK YOU VERY MUCH, QUESTIONS REALLY FOR ROGER, I THINK, THE METHOD LOGICAL CAPS AND I THINK IT IS THE VALUE LARGER TIME SCALE HERE AND I THINK THAT THAT'S A REAL DEFICIT GLOBALLY AT THE MOMENT IN THIS AREA. AND I THINK THERE'S A REAL NEED TO TRY AND AIRCRAFT DENTIFY AVAILABLE DATA SETS, AND SYNTHETIC DATA SETS. FOR EXAMPLE, WE HAVE THE IF YOU DON'T EPD TO YOUR STUDY, WHERE WE CONSTRUCTED THE BIRTH COHORT, AND NOW PIRRING 40, BUT WE CAN ACTUALLY CREATE AN ENTIRE REFLECTIVE LIFE COURSE AND THIS IS OF SOME INTEREST BECAUSE OF THE ONLY COHORT, THIS WE KNEW TO GENERATE THE PREVALENCE SYSTEM, IT'S ALL CURRENT CRITERIA. THE OTHER THING ABOUT THIS APPROACH IS THAT WE'RE NOT DOING ENOUGH FOR AROUND FAMILY CLUSTERING OF CO-MORBIDITY AS WELL, WHICH IS A COMMENT ON THIS, SO EXTERIOR EXAMPLE, SOMETHING ELSE IS THAT WE FIND A MORE ROBUST HISTORY OF HYPERTENSION AND CARDIOVASCULAR DISEASE, BOTH IN THIS THE MOTHER AND FATHER WHERE FOR EXAMPLE THIS IS 4 TIMES RISK OF DAUGHTERS WHERE THE FATHER HAD A STROKE FOR EXAMPLE, THERE'S THE HIGH RISK PREGNANCY SO WE CAN'T DISENGLAND JOURNAL TANGL THE PATHWAYS--DISENTANGLELE THE PATHWAYS UNTIL WE DO THE STUDY SPECIALIZATION OF SPECIFIC ENDOTHELIAL I'M INTERESTED NUR COMMENTS TO HOW WE CAN GEAR UP AND FIND LARGEST COLLABORATIONS TO GET AT SOME OF THE MORE PUZZLING ETO LOGICAL SO I'M WONDERING HOW WOCAN RESOLVE THIS PARADOX AND I'M WONDER IF YOU HAD THOUGHT ABOUT TEASING [INDISCERNIBLE] TO LOOK AT PHENOTYPES BECAUSE THERE'S A SUBSET OF WOMEN WHO ARE NOW MOVING THROUGH IN A TRANSGENERATIONAL SENSE WHO ARE GOING TO BE ADVANTAGED BOTH THE REPRODUCTIVE CAREERS AND THE LONGEVITY. >> YEAH, OBVIOUSLY I AGREE THIS IS AN AREA THAT WE REALLY NEED TO ESTABLISH THE RIGHT COHORTS AND FOLLOW THEM ALONG AND I DON'T KNOW OF ANY DATA ABOUT LONGEVITY AND PCOS AND IT COULD BE THAT THESE WOMEN UNLESS THEY REALLY DO SUCCUMB TO CARDIOVASCULAR DISEASE WHICH TO DATE THERE IS NO CLEAR EVIDENCE THAT THEY HAVE INCREASED LONGEVITY WE JUST DON'T KNOW ABOUT IT. >> RELATED TO THE OVARY THERE WAS A QUESTION ON WHETHER OR FOCUS ON THE THERE'S DIRECT EFFECT OF METAFORMIN ON THE OVARY AND CELLULAR MOLECULAR MECHANISM, ANY DATA ON THAT? >> THERE IS A DIRECT EFFECTOT OVALID AND RELIABLE SCHETHE ENDOMEET RIIMPEDIMENTS AS WELL AND IT IS AFFECT THE GENESIS AND RESPONSIBLE FOR THE LITTLE MODDIC UMKC OF OBSERVED DECREASE IN ANDROGEN WITH METAFORMIN THERAPY BI AT THE LEVEL OF THE OVARY ITSELF IT HAS A GREATER INTERFOLLICULAR RESPONSE IN TERMS OF REDUCING ANTIGEN ACTION SO YOU KNOW THAT'S 1 OF THE MECH NICHES OF WHY IT HELPS OVULATION IN A SUBSET OF PATIENTS. BUT IT'S BEEN SHOWN THAT IT DOESN'T IMPROVE IF YOU ARE TALKING ABOUT PREGNANCY RATE. >> RIGHT. >> IF IT'S NOT A FERTILITY TREATMENT AND SHOULDN'T BE CONSIDERED. >> WELL IT'S NOT BETTER THAN CLOMINAEZIPURABUT IF YOU CONSIDER PLACEBO IT'S BETTER THAN NOTHING, SORRY. >> I AM ELIZABETH FROM SWEDEN I WILL CHANGE THE TOPIC TO THE MENTAL HEALTH AND I WOULD LIKE TO EMPHASIZE A LITTLE BIT MORE ABOUT NOT JUST THE BIPOLAR DISORDER AND DEPRESSION, I THINK THERE IS RELATIVELY HIGH AMOUNT OF EVIDENCE THAT THESE WOMEN HAVE INCREASED PREVALENCE OF BOTH INTERESTS OF DEPRESSION AND ANXIOUS DISORDER. AND I THINK THERE IS CLEARLY A NEED FOR SCREENING OF THESE WOMEN IN ALL BOTH IN THE CLINICAL AND IN ALL STUDIES ANDOOSE NOT JUST DEPRESSION, BUT THE ANXIOUS DISORDERS IS 1 THAT IS THE HIGHEST AND THIS IS THE QUESTION ABOUT THE EATING DISORDERS. THIS WAS ALSO QUESTION ABOUT AND GIVES ME THE OPPORTUNITY TO SPEAK SO IT'S REALLY HARD TO PUT A LOT OF INFORMATION IN 20 MINUTE TALK THERE ARE MULTIPLE AND MULTIFACETED SO LET'S START WITH AND PREVALENCE OF DEPRESSIVE SYMPTOMS OR OVER ALL PSYCHOLOGICAL DYSPHORIA ASSAY AMONG WOMEN WITH PCOS, WHEN WE STARTED THE STUDY AT UCLA WHEN I WAS DOING THE PCOS DEPRESSION STUDY, WE DID AN INTERNET 1 OF THE FIRST SURVEYSOT INTERNET WE POSTED THE QUESTION AIR WHICH IS THE TOOL FOR THE MONTH PREVALENCE OF DEPRESSION ON A PCOS SITE AND WE GOT 2000 HITS IN FIRST 2 DAYS. THE PREVALENCE OF THAT OF DEPRESSION IN THOSE SELF-REPORTED RESPONDERS WAS ABOUT 80%. SO IT'S LEERILY NOT DEPRESSIVE DISORDER, IT'S DYSFUNCTION, IT'S UPSET, THERE ARE A NUMBER OF OTHER STUDIES AND AFTER THAT LOOKING AT THE SPECTRUM AGAIN OF THE IN WOMEN WHO HAVE PCOS AND THE QUESTION IS TO WHAT EXTENT IT PRESENTS PATHOPHYSIOLOGICAL ABNORMALITY WHICH MAY CO EXIST WITH THE EPD O CRIB ABNORMALITY AND WHETHER TREATING 1 WILL YIELD IMPROVEMENT IN THE OTHER. AND WE ACTUALLY DOING STUDIES LOOKING AT THE THE iPAD GLUTESTUDIES OF MULTIPLE ENDOCRINE IN MET FORMIN ON THIS C& S, BECAUSE THERE'S I CLEAR EFFECT OF THE INSULIN SENSITIZING AGENTS WHICH MAY YEAR-OLD SECONDARY FACT IN THE RESOLUTION AND SUPPRESSION, AND OTHER QUESTION OF LIFESTYLE, I WANT TO ACTUALLY CHIME IN TOXIC EFFECTS ALL THIS DISCUSSION, TALKING ABOUT LIFESTYLE WHICH I WILL UNFORTUNATELY HAVE TO MISS IN THE AFTERNOON SESSION AND ALSO TALKING ABOUT THE COMPLIANCE WITH THE FERTILITY TREATMENTS AND RATES OF MOOD DISORDERS, ANXIETY DISORDERS IN WOMEN WHO HAVE INFERTILITY AND GUTMACHER THROUGH FERTILITY TREATMENTS THOSE ISSUES ARE HUGE, VAST AND VERY POORLY RESEARCHED BUT I TELL YOU A WOMAN WHO HAS PCOS AND SHE NEEDS TO STOP EATING CERTAIN AMOUNT OF FOODS OR CERTAIN TYPES OF FOOD SYSTEM INCREDIBLY DIFFICULT. THE WOMAN WHO IS OVERWEIGHT AND DOESN'T OR OBESE AND DOESN'T WANT TO SHOW UP IN THE GYM, CAN YOU MAYBE SECUES HER WITH SOME TALK OF A STUDY BUT OVERALL TO IMPROVE LIFESTYLE CHANGES IN THEM IS NOT AS SIMPLE TRIVIAL TASK SO I THINK THAT THESE ISSUES ALL REQUIRE SIGNATURES ANYWAY KACCT TININE PATHWAY ATTENTION IN BRINGING MENTAL HEALTH AND MENTAL WELL BEING AS PART OF THE EVALUATION WHICHEVER STUDY IT IS,AT LESSENTS OR AGING WOMEN IT'S MANDATORY. AND ALSO TO FOLLOW THEM, WE DON'T KNOW HOW THE TREATMENT AFFECT THEIR MENTAL HEALTH AND SOME TREATMENT MAY MAKE IT WORSE, ACTUALLY, AND WE DON'T KNOW THAT. >> SO, WE PUBLISHED ABOUT 10 YEARS AGO A CASE WHERE A WOMAN WAS PRIMARY PCOS, TREATMENT NONRESPONDER FOR DEPRESSION, SHE CAME TO US AND I TREATED HER WITH MEASURE FOR DEPRESSION, SEVERE MITRAL ERITY, TREATED HER APPROXIMATE MET FORMIN AND RESULTS WERE ACHIEVE INDEED 6 WEEKS SHE BECAME OVAL ATORY, GOT PREGNANT AND DEVELOPED POST PARTEM DEPRESSION, IN TERMS OF THE--[LAUGHTER] --IN TERMS OF THE EFFECTS, WORSENING WE CLEARLY KNOW THAT WOMEN IF THEY HAVE UNDERLYING ANXIETY OR DEPRESSION AND THEY GO THROUGH FERTILITY TREATMENT WHETHER IT'S A CHROMA SIN OR FSH, WHATEVER IT IS, THEY HAVE SIGNATURES CAN'T WORSENING OF--SIGNIFICANT WORSENING OF MOOD AND ANXIETY WITH THE FERTILITY TREATMENT. >> CAN I MAKE A QUICK COMMENCEMENT, A NUMBER OF YEARS WE LOOKED AT WHAT WAS NOT A DEFINITIVE STUDY BUT WE ELECTRIC AT CORRELATES OF DEPRESSION USING STANDARD VALIDATED MEASURES OF DEPRESSION IN THESE WOMAN IN THE GOING INTO IT THE HYPOTHESIS WAS THAT THE HIGHER THE FREE TESTOSTERONE, THE MORE LIKELY THERE WOULD BE DEPRESSION AND IN FACT, THAT DID NOT TURN OUT TO BE THE CASE AT ALL. THE BEST CORRELATE OF DEPRESSION WAS HEARSEATISM SCORE AND THAT CORRELATED LOW SELF-ESTEEM SO I THINK WE CALL IT, WHEN PEOPLE CALL IT A COSMETIC DISORDER, I THINK, UNDER T UNDER PLAYS THE IMPORTANCE, THAT IT HAS FOR THESE WOMEN AND SO, OBESITY AND HEARSEATISM HAS A MAJOR CONTRIBUTION AT LEAST IN THE POPULATION THAT WE SEE TO SELF-ESTEEM ASK DEPRESSION. >> THERE THAT'S ALSO IS IT COSMET AND I CAN THEY GET DEPRESSED OR IS IT DID DISEASE ASSOCIATED WITH INFLAMMATION IS THAT THE MECHANISM OF THE DEPRESSION? >> WELL WHEN YOU ASK THEM WHAT ARE THE FACTORS THAT ARE MOST IMPORTANT TO YOU, THEY TALK ABOUT THE HAIR GROWTH AND BODY MASS, BODY WEIGHT. >> A SHORT COMMENT, COMPLETELY RIGHT BUT ALSO IN STUDIES IT HAS BEEN ADJUSTED FOR BMI AND ALSO THE [INDISCERNIBLE] AND THEY ARE STILL MORE SEVERE COMPARED TO CONTROLS. SO I THINK THAT IS IMPORTANT TO EMPHASIZE. >> YEAH. >> I DON'T DON'T MEAN THAT IT'S--THOSE ARE IMPORTANT ISSUES TO CONSIDER IN EVALUATING INTERVENTIONS FOR THOSE PATIENTS. >> YES. >> QUESTION FOR DR. OSCO, IN THE SAME CHANNEL THAT WE'RE HERE, I'M DR. ROSS, I'M A GYNECOLOGIST INFERTILITY AND IN YOUR SLIDE PRECEPTATION SHOWED NICELY THAT THE WOMAN WHO WERE TAKING THE BIRTH CONTROL PILLS THEY ACTUALLY HAD LESS CHANCE OF BIPOLAR AND DEPRESSION PROBLEMS. HOW ABOUT THE PREGNANCY AND DELIVERY? DO THEY AFFECT ON THEM OR NOT BECAUSE WE AS GYNECOLOGYST WE OTHER THAN ALL THESE YEARS FOR THE PCOS PATIENTS, IF IT DON'T WANT TO GET PREGNANT TO BE ON THE BIRTH CONTROL PILLS ASK THEY CAN CONTINUE WITH THE LOW DOSE 10 MICROGRAM ESTROGEN WE HAVE THESE DAYS UP TO AGE MENOPAUSE AND THEN WE SEE THAT THE PRESENTATION WHEN THEY GET MENOPAUSE THE SYMPTOMS GO AWAY AND THE CARDIOVASCULAR PROBLEMS AND DIABETIC PROBLEMS GET LESS. THEY DID DO WANT THE TO GET PREGNANT AND WE DO THE INDUCTION AND LET THEM GET PREGNANT. SO I JUST WANT TO ASK YOU, DOES THE PREGINANCE SCHEDELIVERY ALSO HAVE THE EFFECT ON DECREASING LIKE PERSON WHO ARE 2 OR 3 PREGNANCIES HAVE DECREASE EFFECTS OF THE MENTAL PROBLEMS? >> YES, THANK YOU FOR THAT QUESTION. SO, IT'S ACTUALLY KIND OF 2 QUESTIONS, 1 IS ON KOPBT ARE CEPTIVES AND MOOD WE FOUND AND PUBLISH INDEED SEPTORSERATE STUDIES COMLITELY UNRELATED TO THE PCOS WOMEN THAT ORAL CONTRACEPTIVES, WHEN WE WELL KNOWN WE'RE PRESCRIBING THEM FOR FAMILY PLANNING MAY BE ASSOCIATED WITH WORSE MOOD AND SOMETIMES DEPRESSION AND IT'S 1 OF THE MAIN REASONS WHY WOMEN GO OFF CONTRACEPTIVES, AND ORAL CONTRACEPTIVES AND POLAR DEPRESSION, WE SHOW NOW CONSISTENTLY THEY ACTUALLY AMELIORATE THAT OVULATION INDUCED VORCEEBING OF WHATEVER THE MENTAL ILLNESS MIGHT BE WHETHER IT'S DEPRESSION OR ANXIOUS, ET CETERA. SO, THAT'S THE DIFFERENTIAL, IN TERMS OF EFFECTS OF HORMONE AND PREGINANCE SCHEPOSTPARTUM, THERE ARE 2 SETS, 1 IS WE SEE RANGE MEDIATED EFFECTS WHICH ARE CLEARLY PREDISPOSED WOMAN TO THE EFFECTIVE EPISODE, IF THEY HAVE EXISTING VULLENERRABILITY AND THE OTHER IS THAT PRECIPITOUS DECLINE IT PROGESTERONE AND ESTRO DIAL, AND WHY DO KNOW THERE ARE STUDIES, IN FACT, CASEY WIZZENER AT NORTHWESTERN HAS ALMOST DONE THE PLACEBO CONTROLLED ESTROGEN TREATMENT IN POST PARTEM DEPRESSION ON SHOW AN EFFECT ON MOOD WITH ESTROW GEN WE'VE DONE THE STUDIES BUT THERE IS A CYCLICAL ACCUMULATION OF THE RISK TO WORSENING MENTAL HEALTH, TO WORSENING INCREASED FREQUENCY IN SPECIFICALLY BIPOLAR DEPRESSION, MORE MAN UNIPOLAR DEPRESSION WITH A SUBSEQUENT PREGNANCIES. SO THERE IS A CERTAIN ALMOST SENSITIZATION OF THE RECEPTORS SO WOULD EVERY SUBSEQUENT PREGNANCY OR INDUCED PREGNANCY THERE WOULD BE HIGHER RISK FOR DEVELOPING THE START. THAT BRINGS A QUESTION OF THE TYPES OF ORAL CONTRACEPTIVES THAT SHOULD BE USED IN WOMEN AND I WONDER IF MAYBE KURT OR ROGER YOU COULD COMMENT ON THE DIFFERENCE OF PROJECTINS OR ESTROGENS THAT GOT A LOT OF TV COMMERCIAL PRESS. >> I THINK THE SHORT ANSWER IS ALL MODERN ORAL DOSE CONTRACEPTIVE PILLS ARE DOSED TO HAVE SIMILAR POTENCY SO THEY'RE FORCONTRACEPTIVE PURPOSES AND THE NONCONTRACEPTIVE BENEFITS ARE REALLY NOT DIFFERENTIAL. >> ALL ABOUT THE SAME. >> ALL ABOUT THE SAME. >> ROGER THERE WAS A REQUESTY ABOUT POST MENOPAUSAL WOMEN AND HORMONE REPLACEMENT THERAPY AND WOULD YOU DEAL WITH THEM IN ANY DIFFERENT WAY THAN A WOMAN WHO DID NOT HAVE PCOS? >> SO I THEN IS A FAIRLY GOOD CONSENSUS, NOW, THAT YOU KNOW A WOMAN WHOSE HEALTHY AT THE ONSET OF MACHINE O PAUSE AND AS SYMPTOMS SHOULD BE TREATED. I THINK THAT'S PRETTY DEFINITIVE, BUT YOU OBVIOUSLY SCREENED THEM AND I'M TALKING ABOUT, YOU KNOW FAMILY HISTORY, SIDE EFFECTS, CARDIOVASCULAR RISK FACTORS ALL THOSE KINDS OF THINGS AND THE GENERALLY HEALTHY PCOS PATIENT IS PROBABLY A GOOD CANDIDATE FOR THAT JUST BECAUSE IT WOULD POTENTIALLY HELP HER AND SO THAT HE WON'T HAVE AS MUCH OF A PIRCYST ENSEL, AND SO THE BOTTOM LINE IS YES, THEY NORMALLY WOULD BE GOOD CANDIDATE. >> SO YOU WOULD NOT THINK OF THEM DIFFERENTLY THAN A WOMAN THAT DID NOT HAVE-- >> YEAH, SOMEBODY WHO IS SO HIGH RISK FROM A CARDIO CASKULAR STANDPOINT THAT YOU'RE WORRIED TO DO IT BUT THAT'S RARE. >> OKAY. >> CAN I ASK A QUESTION 1 MORE QUESTION TO ROGER? WHAT IS THE PREVALENCE OF MENOPAUSAL SYMPTOMS OR SAY CHIMERIC PRESENTATION ON WOMEN WHEN HAY REACH MENOPAUSE. >> THAT'S AN EASY ANSWER. WE DON'T KNOW. IT HASN'T BEEN LOOKED AT. IT HASN'T BEEN LOOKED AT. YOU KNOW THE ONLY THING CAN YOU RELATE TO THAT IS WOMAN WHO ARE HEAVIER, WORSEN. SO IF THE PCOS AT LEAST IN THIS COUNTRY ARE MORE OBESE YOU THINK THEY HAVE A HIGHER PREVALENCE, WELL WE DON'T KNOW. >> YOU THINK THEY HAVE HIGHER ESTROGEN LEVELS AND WOULD BE LESS DRAMATIC. >> QUESTION IF THE BACK. >> A QUESTION ABOUT MENTAL HEALTH ISSUES AGAIN SO 1 OF THE INTERESTING THINGTHIS FORUM IS THEY--LACK OF CONTINUING PARTICIPATION AND INDEED WHEN YOU ACTUALLY HAVE ACTIVE CONSUMER PARTICIPATION AND THE THOUGHTS OF FORUMS, 1 OF THE PRIORITY SYSTEM ABOUT MENTAL HEALTH AND IT'S NOT JUST HAD FROM THE PARTICIPATION BUT THE DEMORRALLIZATION OF THE LACK OF ABILITY TO LOSE WEIGHT, THERE'S PSYCHOSEXUAL DISFUNCTIONS AND OTHERS IN THAT POPULATION BUT THAT EVIDENCE IS NOT AS STRONG AS ANXIETY AND DEPRESSION. SO THE QUESTION IS REALLY GIVEN WE'VE GOT POOR QUALITY OF LIFE IN THESE WOMEN AND SIGNIFICANT ANXIOUS AND DEPRESSION AND FOR THE WOMEN THEMSELVES IT'S A CRITICAL ISSUE AND IT IMPAIRS THE ABILITY TO ENGAGE WITH FERTILITY TREATMENT AND TO SUSTAIN LIFESTYLE TREATMENT, I POSE MY QUESTION IS SHOULDN'T WE BE DOING THAT UPFRONT AND CENTER AND MAKING IT AN ABSOLUTELY FUNDAMENTAL PART OF MANAGEMENT, OF ALL OF THESE WOMEN, RESPECTIVE OF WHERE THEY'VE BEEN DEALING WITH FERTILITY AND METABOLIC RISKS OR DEALING WITH IT BECAUSE ANY OF OUR TREATS WILL MORE EFFECTIVE IF WE DEAL WITH THOSE ISSUES. >> DOCTOR SHOULD WE ECHICIZE THE PSYCHOSOCIAL A LOT MORE? >> WELL, I WOULD SAY YES. BUT IT'S A AN EASY ANSWER FOR ME, BUT I'M PAID TO SAY THAT, RIGHT. I WOULD SAY, THAT OVER ALL IN MEDICINE WE'RE UNDEREMPHASIZED MENTAL WELL BEING IN GENERAL AND I THINK IT'S A VERY COMMON STATEMENT BUT I BELIEVE THAT IN WOMEN WITH POLYCYSTIC OVARIAN SYNDROME, IT'S MORE IMPORTANT THAN OTHERS JUST BECAUSE THEY HAVE SUCH A CONSTELLATION OF SUCH BOTH BIOCHEMICAL GENETIC FAMILIESIAL AND AND PHENOTYPICAL CHALLENGES AND I THINK THAT JUST INCORPORATING THE CERTAIN TYPE OF QUESTION AIR WHICH WOULD ASCERTAIN THE BASELINE PSYCHOLOGICAL STATUS AMONG THESE WOMEN WOULD BE HELPFUL BECAUSE IT WILL HELP FOR THE MANAGEMENT WITH REGARD TO WHETHER THEY NEED MORE HANDS ON ASSESSMENT OR WE CAN JUST DEAL WITH THEM IN THE REGULAR PROFILE. NSHOULD IS QUICK YES OR NO DOES PCOS AFFECT LESBIAN BEHAVIOR. >> I DON'T KNOW. >> ALL RIGHT. >> THIS QUESTION IS FOR EVELYN. WE KNOW IN YOUNG PCOS PATIENTS THERE'S A 10 FOLD HIGHER PREVALENCE OF TYPE 2 DIABETES. WE ALSO KNOW THAT 80% OF DIABETIC PATIENTS DIE OF CARDIOVASCULAR DEATH. SO GIVEN THAT 1 WOULD BE SURPRISED, NOT DESEE A HIGHER INCIDENCE OF CARDIOVASCULAR EVENTS IN PCOS WOMEN FROM THE EPIDEMIOLOGIC STUDIES DO WE KNOW WHAT THE RATE IS IN THAT SUBSET OF PC Os FOR WOMEN WHO HAVE DIABETES? SO AYE REPEAT THE QUESTION, IT IS--I'LL REPEAT THE QUESTION IF YOU LOOK AT ALL WOMEN WHO HAVE PCOS AND YOU TAKE OUT THE DIABETIC POPULATION CAN YOU PREDICT WHAT THE CARDIOVASCULAR EVENT RATE WILL BE? IN THE DIABETIC PCOS? >> RIGHT BUT WHEY WANT TO KNOW IS IT THE SAME AS NONPCOS, ANOTHER DIDN'TIC WHO DOES NOT HAVE--DIABETIC WHO DOES NOT HAVE PC OS? >> ARE WE TALKING TYPE 2. >> DO IENT KNOW. >> FIRST OF ALL I DON'T THINK THAT'S' GOOD QUESTION BECAUSE YOU WOULD INFER AS YOU SAID THAT KNOWING THAT WE KNOW ABOUT DIABETES AND KNOWING WHAT WE KNOW ABOUT THE OUTCOME OF DIABETES OVER TIME, AND THE INSULT OF OF DIABETES, IT WOULD NOT BE GOOD. RIGHT? IT WOULD BE AN INCREASED RISK. I DON'T THINK THAT STUDY'S NOBODY'S EVER LOOKED AND THAT'S PROBABLY WORTH LOOKING AT. >> ANYTHING I CAN RELATE TO THAT, JOHN WHICH YOU KNOW TAORBGS THE NATIONAL HEALTH SERVICE STUDIES THEY SHOW NO CHANGE IN MORTALITY EXCEPT FOR THE DIABETIC AND IN THE DIABETIC THERE WAS INCREASE AND SARAH WILD, WHICH WAS THE SUBGROUP OF PEER POINT, THEY SHOWED INCREASED DEATH FROM DIABETES SO I WOULD SAY THAT'S CORRECT. >> THIS SOPHISTICATED ME IS SUCH AN INTERESTING QUESTION BECAUSE IT BRINGS UP THE DISCIPLINARY MORPHIC RESPONSE OF MEN AND WOMEN AND THERE'S SO MUCH--INCREASING DATA THAT TESTOSTERONE IS A GOOD THING FOR MEN AND THEN MEN THAT HAVE LOW TESTOSTERONE HAVE INCREASE RISK OF DEVELOPING DIABETES AND INCREASED RISK OF DEVELOPING HEART DISEASE AND YET HERE WE'RE SAYING THE OPPOSITE. YOUR QUESTION REFERS TO YOU KNOW IF YOU TAKE 2 PEOPLE WITH DIABETES, 1 HAS HIGH TESTOSTERONE, 2 WOMEN AND THE OTHER DOESN'T IS HAVING THE HIGH TESTOSTERONE AND INTRINSIC RISK FOR THE DEVELOPMENT OF CARDIOVASCULAR DISEASE AND THERE IS SOME DATA AS SHE CAME AND I HAVE DAT FROM MESA TO SAY THAT HIGH TESTOSTERONE IS AN INDEPENDENT RISK FACTOR FOR HEART DISEASE BUT THIS WHOLE THING, IN WOMEN, IN WOMEN, EXACTLY. >> I JUST WANT TO COMMENT. >> SO I THINK NOW IT APPEARS THAT HALF OF THESE WOMEN ALSO HAVE SLEEP APPLICATIONSNIA, WE NEED TO CONSIDER THAT AS PART OF THE EQUATION FOR CAUSAL INCIDENT. YOU KNOW FOR DEATH, SUDDEN DEATH IN PARTICULAR. AND THAT SHOULD BE FACTORED IN. >> SEVERAL QUESTIONS ABOUT SCREENING FOR OBLIGATIONS INSTRUCTIVE SLEEP APNEA DO YOU THINK IT SHOULD BE PART OF THE BASELINE EXAM IN WOMEN WITH WITH PCOS OR ONLY WITH OTHER OBESITY OR CRITERIA? >> THERE ARE SURVEY TOOLS THAT CAN BE USED TO STRATIFY RISK AND BY HISTORY, AND SOME PHYSICAL EXAM FINDINGS THAT ALSO INCREASE THE LIKELIHOOD OF FINDING SLEEP APNEA, RIGHT NOW, THE GOLD STANDARD IS TO DO AN IN-HOUSE IN-HOSPITAL POLYSOMNIO GRAM AND THERE ARE SOME THAT ARE LESS EXPENSIVE AND THERE CAN BE AT HOME SCREENING. IT'S NOT IDEAL BUT IT'S ALTERNATIVE MAYBE LESS EXPENSIVE METHOD. SO IF THE PREVALENCE IS TRULY 50%, IF YOU SEE AN O'BEES OPERATING GLOBALLIULATION WITH PCOS, I WOULD SAY THAT IT'S SOMETHING TO CONSIDER VERY HIGHLY AS PART OF THE SCREENING, JUST LIKE INCORPORATED GLUCOSE TOLERANCE TESTING. >> OKAY I'LL CLOSE WITH 1 FINAL QUESTION WHICH IS THE 21 YEAR-OLD COMES IN FOR ROUTINE GOS AND EXAM, HAS PCOS DEFINED BY IRREGULAR MENSEIS, AND NORMAL AC1 C AND WOULD 1 START MET FORMIN IN THAT SCENARIO? >> WE'LL GO AROUND AND MY ANSWER TO THAT IS NO, I WOULD NOT. I THINK THAT I WOULD JUST DO AGGRESSIVE LIFESTYLE AND THEN TREAT THE INDIVIDUAL FACTORS SUCH AS ORAL CANT RACEPTIVE PERIODS AND THE EXCESS TESTOSTERONE ANYONE ELSE HAVE A COMMENT? NCS STUDY I WOULD NOT. >> I WOULD DO THE SAME. >> I WOULD NOT TREAT. >> I WOULD TREAT ALTHOUGH I DON'T TREAT THEM BUT I WOULD RECOMMEND THE MET FORMIN. >> DAVE? >> I WOULDN'T IN NECESSARILY GO TO MET FORMIN AS FIRST LINE THERAPY EITHER. >> I WOULD ASK THEM WHAT IS THEIR COMPLETE. IT APPEARS OR THE HAIR AND AND HIGH RISK DUE TO FAMILIAR NATURE OF DIABETES AND THIS METABOLIC SYNDROME AND I WOULD GIVE HER THE TRIAL. SO IT ALL DEPENDS ON WHAT HER WISHES ARE. >> OKAY SO DIFFERENT QUESTIONS AND DIFFERENT ANSWERS SO I WANT TO THANK EVERYONE VERY MUCH AND WE WILL START AGAIN AT 1:30. [ APPLAUSE ] >> THANK YOU. >> EAR GOING TO FOCUS ON THE METABOLIC CONSEQUENCES IN SESSION FOUR. WE HAVE FIVE PRESENTATIONS THEN WE'LL TAKE ABOUT AN HOUR QUESTION AN ANSWER LAKE WE HAD BEFORE FOR -- LIKE WE HAD BEFORE FOR THOSE TALKS THAT ENAT 4. BETWEEN 4 AND 5 WE'LL HAVE THE MODERATORS UP HERE, JUST TO FIELD GENERAL QUESTIONS, A PRE-WRAP UP AND THEN DR. DATALO AND PARIS WILL BE UP HERE AT 5:00 O'CLOCK THE WRAP THINGS UP. SO WE TROY OUR BEST TO STAY ON TIME. YOU KNOW STEVE FRANKS, PROFESSOR IMPERIAL COLLEGE IN LONDON, STRATEGIES FOR MANAGEMENT OF METABOLIC PHENOTYPES. >> GOOD AFTERNOON, EVERYONE. AND THANKS FIRST TO ORGANIZERS FOR INVITING ME TAKE PART IN THIS VERY INTERESTING MEETING. STRATEGIES FOR MANAGEMENT OF METABOLIC PHENOTYPE. THESE ARE THE QUESTIONS I'M POSING. WHAT ARE METABOLIC PHENOTYPE? DONE NEED TOO MUCH TIME ON THAT, WE HEARD ABOUT THAT AND A BIT ABOUT LONG TERM CONSEQUENCES. HOW CAN ADVERSE OUTCOMES BE PREVENTED OR ATTENUATED. THAT'S WHAT WE IMMEDIATE TO KNOW. HOW THEY CAN BE MANAGED AND SOMETHING WHICH I THINK IS PRETTY CONTENTIOUS, THAT'S BEEN EVIDENT FROM THE DISCUSSIONS THAT WE HAVE HAD SO FAR. WHAT'S THE ROLE OF SCREENING AND WHAT TESTS SHOULD BE DONE AND HOW OFTEN. ET CETERA. WHAT ARE METABOLIC PHENOTYPES IN PRETTY WELL, GLUCOSE, INSULIN HOMEOSTASIS WHICH IS CENTRAL METABOLIC ABNORMALITY, DISLIPIDEMIA AND NON-ALCOHOLIC FATTY LIVER DISEASE WE HEARD TODAY AND NOT TALKING METABOLIC SYNDROME AS DISTINCT ENTITY BUT WILL COVER THE EVIDENCE OF THAT. OF COURSE ALL OF THESE FEATURES ARE EXACERBATED BY OVERWEIGHT AND OBESITY AND INDEED THERE'S STILL SOME CONTROVERSY ABOUT WHAT FEATURES ARE SPECIFIC TO PCOSND THOSE RELATED TO OBESITY. I THINK THERE'S NOW THE WEIGHT OF STUDIES SUGGEST THAT THERE IS A MILD DISTHE LIPIDEMIA SPECIFIC TO PCOS AFTER YOU ADJUST FOR BMI. THIS GOES BACK TO WHAT ADRIENNE SHOWED EARLIER, JUST TO POINT OUT THAT FROM STUDIES FIRST BY ANDROGEN -- IF YOU TAKE LEAN WOMEN WITH POLYCYSTIC OVARY SYNDROME, WHITE MATCH PAIRS OF SUBJECTS YOU CAN SEE A REDUCTION IN INSULIN SENSITIVITY IN THIS OCCASION MEASURED BY SHORT INLYNN TOLERANCE TEST. AND -- INSULIN IT WILL ANSWER TEST. IMPORTANTLY THE SEPARATION BETWEEN NORMAL AND P POLYCYSTIC OVARIES INCREASES AS YOU GAIN BMI. SO FOR ANY GIVEN BMI OR WEIGHT CIRCUM FRIEND YOU'RE RELATIVELY MORE INSULIN RESISTANT IF YOU HAVE POLYCYSTIC OVARY SYNDROME. THAT HAS IMPACT ON REPRODUCTIVE SYMPTOMS AS WE SEE HERE FROM COHORT OF OVER 600 WOMEN PRESENTING WITH WHAT WE MIGHT CALL ROTTERDAM CRY TIERIA, THEY HAD -- CRITERIA, THEY HAD -- YOU SEE OVER WEIGHT AND OBESE WOMEN HAVE HIGHER PREVALENCE OF MENSTRUAL DISTURBANCEN HIGHER PRE-LENS O HERSTISM. SO WHAT WE'RE FOCUSING ON IS LONG TERM CONSEQUENCES OF METABOLIC DISTURBANCES. DIABETES, PREGNANCY, TYPE 2 DIABETES AN CARDIO CARDIOVASCULAR DISEASE. TY INCLUDED RETENTION IN THAT. WHAT ARE THE AIM? IN CONSIDERING THESE LONG TERM COMPLICATIONS? WELL WE'LL HEAR MORE ABOUT HOW YOU IMPROVE REPRODUCTIVE FUNCTION, CURTAINIUS MANIFESTATIONS OF POLYCYSTIC OVARY SYNDROME FROM REGULAR GROWTH SHORTLY. WE'RE TRYING TO REDUCE RISK OF DEVELOPING TYPE 2 DIABETES AND ALSO REDUCE PERCEIVED RISK OF HEART AND VASCULAR DISEASE. HOW CAN WE MANAGE THESE MANIFESTATIONS OF METABOLIC FEATURES? BUT HER ABOUT IT IN ALREADY IN CONTEXT OF TYPE 2 DIABETES, INSULIN, I WON'T SAY MUCH ABOUT THAT, AND BARIATRIC SURGERY WHICH IS BEGINNING TO BE USED MORE AND MORE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. HERE ARE STUDIES, THOSE THE EVIDENCE LOOKS PROMISING WE DON'T HAVE ENOUGH LARGE SCALE STUDIES AN PRECIOUS LITTLE DATA IN WOMEN WITH POLYCYSTIC OVARY SYNDROME REGARDING PREVENTION OR EFFECTIVE TREATMENT OF LONG TERM SEQUELLA. THAT'S THE CONUNDRUM OF THE MOMENT. BACK TO STUDIES OF THE EARLY 1990s FOLLOWED BY A PLETHORA OF EXCELLENT STUDIES FROM THE ADELAIDE GROUP, WE'VE PROOF OF PRINCIPLE IF YOU LIKE WE CAN SEE A MODEST REDUCTION IN WEIGHT MADE A BIG DIFFERENCE IN GLUCOSE STIMULATED INSULIN AN ENDOCRINE FEATURES INCLUDING FREE TESTOSTERONE LEVELS SO IT WORKED AND IMPORTANTLY, IT WAS ASSOCIATED WITH IMPROVED OVULATION RATE AND FERTILITY, WE'LL HEAR MORE ABOUT THAT IN DUE COURSE. DOES TYPE OF DIET MATTER? PROBABLY NOT VERY MUCH BUT HERE IS A LOW GI DIET COMPARED WITH STANDARD CALORIE MATCHED DIET. ONE OR TWO THINGS ARE DIFFERENCE, THIS SEEMS BETTER IN TERMS OF GROWTH, THAT SEEMS BETTER IN TERMS OF EMOTIONAL IMPACT BUT THERE'S NOT A LOT OF DIFFERENCE IN TYPE OF DIET, CALORIE RESTRICTION WHICH IS THE MOST IMPORTANT THING THIS REMAINS A CONTENTIOUS AREA, YES SNOOKERED BY THE FACT WE ONLY HAVE A SMALL NUMBER OF PROPERLY CONDUCTED CLINICAL TRIALS. ONE OF THE PIONEERS RICHARD FLEMING SHOWS IN CONTROLLED STUDY THERE WAS SIGNIFICANT BUT MODEST INCREASE IN OVULATION RATE. AND YOU SEE HERE THAT CHANGE IN OVULATION RATE DOESN'T MAKE IT A FERTILITY DRUG. QUESTIONABLE EFFECTS ON UNWANTED BODY HAIR. AND IN THE STUDY THAT ADAM BALEN COORDINATED MULTI-CENTER CONTROLLED STUDY, THERE WAS AN EFFECT IN OVULATION BUT THEY COULDN'T SHOW THAT IT WAS INDEPENDENT OF WEIGHT LOSS, AT THIS STAGE EFFICACY AND INDICATIONS FOR TREATMENT WERE UP CLEAR. THAT LED TO LARGE CLINICAL TRIALS YOU'LL HEAR RICKLY GROVE ESTORIL FROM HORSES MOUSE, BUT THE CONCLUSION FROM THIS META ANALYSIS IS THE USE OF METAPHORMAN IS OVERESTIMATED. NICE WORD. HOW CAN WE SUM UP METAPHORMAN IN NOT VERY USEFUL TREATMENT IN FERTILITY OR MEN STALL DISTURB BANS. NOT VERY EFFECTIVE FOR TREATMENT OF HERSTISM BUT CHEERILY HAS A PLACE IN MANAGEMENT OF WOMEN AT HIGH RISK OF DEVELOPING DIABETES Z HERE ARE SOME PERSPECTIVE DATA FROM RICK LEGRO IN WOMEN WITH POLYCYSTIC OVARY SYNDROME, OVER 2, 3 YEARS IN THIS PARTICULAR COHORT THE PREVALENCE OF IMPAIRED GLUCOSE TOLERANCE GOES UP FROM OVER 35% TO ABOUT 45% AND THERE IS A SIMILAR INCREASE IN THE PREVALENCE OF FRANK DIABETES. SO THIS IS WHAT'S IN STORE FOR WOMEN WITH POLYCYSTIC OVARY SYNDROME IF ALREADY OVERWEIGH AND IMPAIRED GLUCOSE TOLERANCE. WE KNOW DIABETES THE PROGRAM RESEARCH GROUP AND LIFESTYLE, EFFECTIVE IN TERMS OF REDUCING CONVERSION FROM IMPAIRED GLUCOSE INTOLERANCE, NOT AS GOOD AS LIFESTYLE. INTERESTINGLY THE FOLLOW-UP STUDY I THINK IN THIS STUDY FROM THAT PROGRAM, IT'S VERY INTERESTING TO SEE OF COURSE BY TEN YEARS MOST OF THOSE SUBJECTS ON DIET AND LIFESTYLE REGAINED THEIR WEIGHT. BUT YOU STILL PRESERVE THE REDUCED RISK OF DEVELOPING DIABETES. EVEN THOUGH THEY HAVE GONE BECOME THE THEIR NORMAL WEIGHT. SO DIET AND LIFESTYLE UNDOUBTEDLY THE FIRST CHOICE. WHAT ABOUT (INDISCERNIBLE)? UNDOUBTEDLY AGAIN IMPROVEMENT IN INSULIN SENSITIVITY YOU CAN SHOW ANDROGENS GOING DOWN, YOU CAN SEE IMPROVING THE LARGE SCALE TRIAL SHOWED THIS NICELY BUT IT HAS TO BE WITHDRAWN. THEY SEEMED TO BE BETTER THAN METAPHORMAN IN REDUCING INSULIN BUT NO SIGNIFICANT EFFECT ON BLOOD GLUE CO-. AND NOT MUCH CHANGE IN LIPIDS AND IF NEVER, WEIGHT GOES UP. THERE IS CONCERN ABOUT SAFETY, PARTICULARLY WOMEN OF REPRODUCTIVE AGE THOUGH RECENT DATA ARE MORE REASSURING. WE'RE JUST BEGINNING TO LEARN NOW ABOUT GLP-1 AGONISTS IN POLYCYSTIC OVARY SYNDROME, VERY SMALL SCALE STUDY SO FAR. AND WHAT WE DON'T HAVE OF COURSE IS THE IMPACT OF THESE MEDICATIONS LONGITUDINAL STUDIES IN TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. THESE ARE DATA FROM (INDISCERNIBLE) SHOWING THAT BEFORE BIG CHANGES AFTER BARIATRIC SURGERY IN FASTING INSULIN IN ANDROGEN LEVELS SO IT'S CERTAINLY BETTER AND THEY GET BETTER IN MENSTRUAL DYSFUNCTION BUT LACK LONG TERM METAPHOR MINUTE P PROMISING HIGH BMI. NOT ALL PATIENTS ARE OBESE. THIS IS A COHORT OF 600 WOMEN RECRUITED FOR GENETIC STUDIES. I SUPPOSE THE RECRUITMENT YOU SEE THE MEDIAN BMI IS 25 SO IN THAT COHORT MANY HA WERE LEAN AND HAD POLYCYSTIC OVARY SYNDROME AS THEY WERE OVERWEIGH OR OBESE. HOW DO WE MANAGE LEAN WOMEN WITH POLYCYSTIC OVARY SYNDROME WHETHER HAVE EVIDENCE OF MET BOLL PIC DYSFUNCTION? THIS IT;$ ONE STUDY FROM THE ADELAIDE GROUP SHOWING THIS CHANGE IN TERMS OF INSULIN SENSE ACTIVITY, GLUCOSE INFUSION RATES HERE AND TRIGLYCERIDES IN WOMEN WITH POLYCYSTIC OVARY SYNDROME OR CONTROLS, PCOS IN SOLID LINE HERE, AND SHOWING REALLY THAT IN THE BROKEN LINE, PCOS GROUP YOU SEE SOME IMPROVEMENT IN TRIGLYCERIDES AN INCREASE IN INSULIN SENSITIVITY. IN THIS GROUP YEAR WEIGH OR OBESE WOMEN WITH WITH NO SIGNIFICANT WEIGHT LOSS DURING THAT PROGRAM. SO THAT'S IN OVER WEIGH AND OBESE SUBJECTS. AND YOU ALSO SEW THIS THAT STUDY REDUCTION IN VISCERAL FAT, THAT'S GOOD. INCREASE IN SUBCUTANEOUS FAT. BUT IF YOU LOOK AT THIS STUDY FROM THOMPSON ET AL, THEY CONCLUDE THAT EXERCISE TRAINING PROVIDED NO ADDITIONAL BENEFIT TO FOLLOWING HIGH PROTEIN DIET IN TERMS OF ENDOTHELIAL FUNCTION IN OVER WEIGHT OR OBESE WOMEN. SO WE DON'T KNOW HOW USEFUL EXERTIZE IS AND IMPORTANTLY BECAUSE YOU THINK THIS IS A GROUP IT MIGHT BE EFFECTIVE IF YOU HAVE INSULIN RESISTANT WOMEN WHO ARE LEAN NO SUBSTANTIAL EXERCISE WITH POLYCYSTIC OVARY SYNDROME SO WE BADLY NEED STUDIES TO SEE WHETHER THAT'S GOING TO HELP THEIR PRERE PRODUCTIVE BUOY CHEMICAL FUNCTION. WHAT ABOUT SCREEN SOMETHING BACK TO ROTTERDAM CONSENSUS MEETING IN 2003 AND THIS WAS THE CONFLATION ABOUT SCREENING FOR METABOLIC DISORDERS, DON'T NEED TO TEST INSULIN RESISTANCE, YOU SHALL HAVE A GLUCOSE TOLERANCE TEST, REALLY WHAT YOU NEED TO DO RATHER THIS THAN FASTING GLUCOSE. AND LIPID PROFILE IS INTERESTING. DOING A LIPID PROFILE? PROBABLY YES. WE DOPE HAVE DATA ABOUT LONG TERM EFFECTS IN THESE WOMEN AND YOU COULD ARGUE TO DO A BASELINE TEST IS QUITE GOOD BECAUSE AT LEAST YOU EXCLUDE FAMILIAL HYPERCHOLESTEROLE MIA THERE. BUT YOU PUT ON STATINS, HOW OFTEN WOULD YOU DO THE TEST? SOMEHOW IT WILL WE KNOW WHAT THE CONSEQUENCES ARE, IT SEEMS LIPID PROFILE IS QUESTIONABLE IMPORTANCE IN TERMS OF SCREENING. WE'RE CONCERNED ABOUT UTILITY IN NON-OBESE WOMEN WITH POLYCYSTIC OVARY SYNDROME. SO I DON'T THINK WE CAN APES THOSE QUESTIONS AT THE MOMENT. WHO WHAT, WHERE AND WHEN AN HOW OFTEN. ESTIMATES OF RISK GROUPS WE'RE TALKING ABOUT IF YOU LOOK AT EPIDEMIOLOGICAL DATA WE EXPECT IF YOU HAVE PCOS YOU HAVE A TWOFOLD INCREASE IN RISK. THAT'S AMPLIFIED BY OBESITY, 3 TO 4 FOLD. IF NOT MORE. FAMILY HISTORY OF DIABETES SHOWED BEAUTIFULLY MAKE AS BIG DIFFERENCE AND IF YOU HAVE A PERSONAL HISTORY OF IMPAIREDDED GLUCOSE TOLERANCE THEN YOU'RE AT A DIFFERENT STRATA OF RISK. WHO WAS AT RISK, BACK TO DIAGNOSTIC SUP GROUP, WE ALREADY -- SUBGROUP, I OWN SPEND A LOT OF TIME ON IT, PHONE TYPE AFFECT RISK AND WHAT ARE IMPLICATIONS TO FAMILY MEMBERS, DAUGHTER, SISTERS AND BROTHERS. SO HERE ARE THE ROTTERDAM CRITERIA, TWO OUT OF THREE NEEDED AN THESE DATA WHICH YOU HAVE SEEN BRIEFLY FROM TOM BARBER BRIEF YOULY SIMILAR DATA FROM (INAUDIBLE) SHOWING THE SAME THING. HERE IS NIH CRITERIA FOR DIAGNOSIS INCREASED INSULIN RESISTANCE COMPARED WITH CONTROL GROUP. THIS IS A GROUP NEARLY 4 HUNCH WOMEN. HERE IS OUR GROUP WITH HYPERANDROGENISM REGULAR CYCLES SHOWED SOME TIME AGO WERE LESS LIKELY INSULIN RESISTANCE AN THIS IS THE OTHER GROUP WITHOUT EVIDENCE OF SUCCESS, THEY TOO SEEM TO HAVE NORMAL INSULIN SENSITIVITY, THIS IS THE AT RISK GROUP PARTICULARLY. THAT IS CONSENSUS BUT THEN THIS RAISES THE QUESTION ABOUT WHETHER THAT'S ALWAYS THE CASE, AND IT MAY VARY FROM POPULATION TO POPULATION. WE'RE LOOKING AT THAT TIME FINISHED DUBOSE RISK SCORE AND YOU SEE THAT OVERALL IT'S PCOS IS HIGHER RISK BUT THERE'S NOT MUCH DIFFERENCE BETWEEN NIHQh AND NON-NIH DEFINITION HERE. AND THERE IS BOUND TO BE SOME OVERLAP BETWEEN THE COHORTS. WHAT WE'RE SAYING IS THOSE WHO HAVE FULL BLOWN SYNDROME HAVE BOTH HYPERANDROGENISM AND ANOVULATION TO THOSE AT RISK OF DEVELOPING DIABETES. AS FAMILIES RICH LEGRO SHOWED TEN YEARS AGO NOW THAT THERE IS SIMILARITY IN FASTING INSULIN LEVELS BETWEEN WOMEN WITH POLYCYSTIC OVARY SYNDROME APPROXIMATE AFFECTED SISTERS. THIS PARTICULAR STUDY SIMPLY ON THE BASIS OF ULTRASOUND SCANS, SO THE SYMPTOM PROFILE IS DIFFERENT BUT THEY HAVE EQUALLY HIGHER INSULIN FASTING INSULIN LEVELS THAN UNAFFECTED SISTERS OR CONTROLS SO SISTERS ARE AT RISK AND ACTUAL HI AS THE GROUP HAS SHOWN SO ARE BROTHERS. SO LET'S THEN LOOK AT RESULTS OF THIS MEETING. WHICH DESPOT NOT BEING P NIH MEETINGS ACTUALLY BASED ON EVIDENCE SO WHAT WERE THE CONCLUSIONS, WHAT WERE -- LEVEL OF EVIDENCE WERE CONCLUSIONS BASED AND DO THEY HAVE CLEAR ANSWER? THE ANSWER I CAN IT WILL TELL YOU IS NOT REALLY. SO I VISE FOR THIS LONG LIST BUT THERE ARE IN TERMS OF IMPACT ON IMPAIRED GLUCOSE TOLERANCE AN TYPE 2 DIABETES, WE CAN SAY WE HAVE A MAJOR RISK FACTOR MADE WORSE BY OBESITY, LIKELY TO GET WORSE, BECAUSE OF INCREASING PREVALENCE OF PCOS BUT YOU SEE DIET AND LIFESTYLE IS FIRST CHOICE, METFORMIN OBVIOUSLY USEFUL FOR IMPAIRED GLUCOSE INTOLERANCE TYPE 2 LEVEL A BUT WHAT ABOUT OTHER AGENTS? WE DON'T KNOW YET. SO KNOWLEDGE GAPS IDENTIFIED REALLY I THINK THE MOST IMPORTANT I THINK IS THE FOR COLLECTION OF GOOD LONGITUDINAL DATA AND PROGRESSION FROM IDG TO TYPE 2 DIABETES. AND THE NEED TO GATHER DATA ON EFFICACY AN SAFETY OF NEW DRUGS. THE MOST IMPORTANT THING REALLY IS SURROGATE MARKERS UNDOUBTEDLY HIGHER BUT AS YOU HEARD FROM EVELYN ASSOCIATION WITH CARDIO VAS COW ALREADY EVENTS REMAINS UNCOLOR AND WILL BE UNTIL WE HAVE FURTHER STUDIES. ALSO PCOS PER SE IN INCREASED CARDIOVASCULAR MORTALITY, A LOT OF THINGS ARE NEEDED. WE COME TO THIS, LONGITUDINAL STUDIES NEED TO ASSOCIATE CARDIOVASCULAR RISK MODELS WITH VASCULAR EVENTS. I DON'T NEED TO DWELL BECAUSE IT'S DISCUSSED IN GREAT DETAIL. A CAUTIONARY WORD ABOUT BASED ON GENERAL PRACTICE THEY DID THIS SCREENING, BLOOD GLUCOSE, THESE WERE THOSE WHO DIDN'T HAVE IMPAIRED GLUCOSE TOLERANCE BUT THOUGHT TO BE AT SLIGHTLY INCREASED RISK ON THE BEST OF THAT ARE FINISH RISK DIABETES RISK SCORE. THE MEAN AGE OF POPULATION, 58, AS I SAID BOTH MEN AND WOMEN. BUT HERE WE SEE THAT CLEARLY IF YOU HAVE DIABETES, YOU HAVE DIABETES, THIS WAS AN INTERESTING GROUP, 5 BROADBAND 5 TO 11. YOU SEW THEY GO THROUGH HERE IF FASTING BLOOD GLUE CO-WAS OKAY, THEN ALL RIGHT BUT NOT A BAD STEP WISE WAY OF DOING THINGS SO THEY DID THE SCREENING AN FOLLOWED UP TEN YEARS AND THIS IS THE CUMULATIVE INCIDENCE OF DEATH SCREENED AND NON-SCREENED. SUBJECTS, YOU SEE IT MAKES NO DIFFERENCE TO DEATH RATES. SO YOU HAVE TO ASK YOURSELF THIS IS AN EXTREME EXAMPLE BUT YOU HAVE TO ASK YOURSELF WHAT WE'RE DOING BY SCREENING, HOW WELL ARE WE DOING IN TERMS OF SCREENING. LET'S GO BACK TO CONCLUSIONS TO DRAW HERE. MAKES SENSE TO MAKE EARLY DIAGNOSIS. WHAT MIGHT BE IMPORTANT INTERVENTION THERE MAYBE PLASTICITY IN MANAGEMENT HERE AND YOU MAYBE ABLE TO PREVENT DEVELOPMENT OF FULL BLOWN SYNDROME IF YOU CAN INTERVENE IN ADOLESCENCE. THIS IS IMPORTANT, LEAN WOMEN WITH PCOS SHOULDN'T GET FAT. EASIER SAID THAN DONE. LOSE WEIGHT, IMPROVE YOUR EXERCISE BUT WE ALL KNOW LONG TERM COMPLIANCE. THOUGH AN EPISODE OF LOSING WEIGHT AND INCREASING EXERCISE FOR A WHILE HELPS. WE'RE LEFT WITH QUESTIONS, HOW OFTEN, WHEN AND HOW TO INTERVENE. WE DONE REALLY KNOW HOW OFTEN WOULD SHOULD WE DO ORAL FLEW COATS TOLERANCE TESTS. THIS IS REALLY THE CRUCIAL THING, WE STILL AWAIT LARGE RANDOMIZED CONTROL TRIALS OF INTERVENTIONS AND WE NEED LONGITUDINAL STUDIES. THANK YOU. >> RICK LEGRO, PROFUSE OF OBGYN AT PENN STATE. SO I WOULD LIKE TO THANK THE ORGANIZERS FOR THE OPPORTUNITY. I APOLOGIZE FOR MY LONG CONFLICT OF INTEREST HE WASTRYING TO BE TRANSPARENT BUT I HAVE NO SIGNIFICANT CONFLICT OF INTEREST WITH ANY OF THE MATERIAL I'M GOING TO PRESENT AS STEVE ALLUDED TO I'LL CONCENTRATE ON THE REPRODUCTIVE ASPECTS HERE. SO INFERTILITY, HERSTISM AND UP FRONT THERE ARE FEW TRIALS TO TREAT ANDROGEN ALOPECIA WHICH IS A PROBLEM IN THESE WOMEN AND THERE'S DEBATE ABOUT WHETHER ACNE WITHIN PCOS IS DIFFERENT ACNE OUTSIDE OF PCOS. AND ALSO TALK ABOUT CONTROL OF DYSFUNCTIONAL BLEEDING. THIS IS A DOWNWARD, MOST EVIDENCE I HAVE FROM GOOD CLINICAL TRIALS IN THE TREATMENT OF INFERTILITY. THERE ARE MULTIPLE WAYS TO INDUCE OVULATION APPROXIMATE TREAT INFERTILITY IN PCOS. AS WE'LL SEE WITH HERSTISM WHEN WE DON'T REALLY HAVE A GOOD TREATMENT WE EVOLVE MULTIPLE TREATMENTS. MOST SAY THE GOAL STANDARD IS CHROMESINE TO DRAW ANDREA'S ANALOGY, IT'S CHEAPER TO TREAT UPSTAIRS HYPERTHAT WILL MIC PITUITARY ACCESS THAN DOWNSTAIRS. AND MORE COSTS AND COMPLICATIONS WITH SURGERY OR USE INJECTABLE GONADOTROPIN. I WON'T FOCUS A LOT, WON'T STEAL ROB'S THUNDER TO TALK ABOUT WEIGHT LOSS AND EXERCISE TODAY BUT THESE ARE CERTAINLY OTHER THERAPIES THAT CAN IMPACT ON HYPERTHAT WILL MIC PITUITARY ACCESS. ONE THING WE HAVE TO REALIZE THAT'S ALLUDED TO THESE WOMEN ARE LIKELY INCREASED RISK FOR COMPLICATIONS OF OVULATION INDUCTION COMPARED TO OTHER GROUPS OF INFER UNTIL WOMEN. DUE TO LARGER FOLLICLE POOL THEY'RE INCREASED FOR OVARIAN HYPERSTIMULATION SYNDROME AND ALSO GOING TO BE AT INCREASE RISK FOR MULTIPLE PREGNANCY. FURTHER, AS BART AND THOSE ALLUDED TO OBESITY IS A CONFOUNDER THAT MAKES IT DIFFICULT TO HIT THE TARGET AND OFTEN PREDICTS FAILURE OF OUR INFERTILITY THERAPY. ONE CONSENSUS ALLUDED TO OFTEN MADE THIS EXPERT BASED OPINION. WE START WITH CHROME SEEN WHEREAS OBESE WOMAN SHOULD FIRST BE COUNCIL DUE TO UNDERGO LIFE STYLE THERAPY AND WEIGHT LOTS PRIOR TO PROCEEDING WITH THERAPY. WE NOTED THE MAJOR FACTORS THAT PREDICT PREGNANCY INCLUDE THE OBVIOUS ONE, AGE, DEGREE OF HIRSUTISM THAT'S THE BOTTOM X AXIS THERE. HISTISM AND B MI AND ANDROGEN ACCESS AND OBESITY ARE TWO FACTORS YOU COULD IMPACT PRIOR TO PROCEEDING WITH OVULATION INDUNK. ASK INDUCTION THE. TYPE 1 IS FAILURE UPSTAIRS, TYPE 3 IS FAIL YOUR DOWNSTAIRS. EVERYTHING ELSEWHERE THERE'S EVIDENCE OF HYPERTHALAMIC P PI THANK YOUTY FUNCTION GETS LUMPED INTO TYPE 2 AND MOST ANALYSES I'M GOING TO TALK ABOUT INCLUDE MANY OVULATORY DYSFUNCTION PATIENT WHOSE ARE NOT CLASSIC PCOS. CERTAINLY THE STUDIES THAT LOOKED AT CHROMEASENE DIDN'T DIFFERENTIATE DUE TO PCOS AND WAS DUE TO OTHER CAUSES BUT PLACEBO CONTROLLED STUDIES ESTABLISH CLOMATHENE AS FIRST CHOICE OVULATION INDUCTION IN THESE WOMEN. THEY HAVE ALSO SHOWN A DOSE RESPONSE IMPROVEMENT IN OVULATION RATES. SO MANY OF YOU ARE ARGUING WHAT IS THE IMPORTANCE OF PCOS TO PATIENTS? THE FACT THAT MOST TRIALS HAVE BEEN DONE FOR INFERTILITY THE FACT THAT THE CLASSIC ARTICLE BY GOLD THE NUMBER ONE COMPLAINT IS INFERTILITY, THE FACT I'M A REPRODUCTIVE ENDOCRINOLOGIST AND VERY INTERESTED IN THIS FIELD. BUT LARGE SCALE TRIALS HAVE LOOKED AT INFERTILITY. IF YOU LOOK ALSO AT OUR FEW SELECT EXAMPLES OF WHERE INDUSTRY HAS GOTTEN INTERESTED IN PCOS, MOST RECENT TRIALS WOULD INCLUDE THE PARK DAVID (INDISCERNIBLE) AND THE RECENT SERONO TRIAL OF ENASTRASOL ARECOMMENDTASE INHIBITOR LOOKING AT OVULATION AS PRIMARY END POINT SO FERTILITY WAS THE END GOAL OF THESE DRUGS THAT WERE BEING DEVELOPED BY INDUSTRY. ALL THREE WHICH FAILED INDUSTRY DRUGS. SO IN THESE TRIALS ONE ARE THESE ARE MULTI-CENTERED TRIALS, TWO, TRIAL VERSUS A CONSISTENCY WHICH YOU'LL SEE SYNTHESIZED IN MULTIPLE META ANALYSIS. AND 3, THEY FOCUSED ON LIVE BIRTH. THE INITIAL TRIAL OUT OUT OF ITALY, SHOWS METAPHOR MAN WAS SUPERIOR IN TERMS OF LOVEBITE BUT EVERYTHING APPEARED SINCE OF DUTCH MULTI-CENTER TRIALS, THE TRIAL IS A NIH SPONSORED REPRODUCTIVE NETWORK MULTI-CENTER TRIAL. THE (INAUDIBLE) IS A MA LAY SHAN TRIAL THAT ROB NORMAN WAS INVOLVED WITH AND MOST RECENTLY THERE WAS A SCANDINAVIAN TRIAL. BASICALLY NONE SHOW THAT METFORMIN IS GOOD TO ACHIEVE LOVEBITE. THERE IS A QUESTION I'LL BUSINESS -- LIVE BIRTH, AND WHETHER USING IT AS ADJUVANT AGENT. THIS IS RESULT FROM THE REPRODUCTIVE MEDICINE NETWORK. THIS IS CHROMEASINE, THIS IS THE KAPLAN MEYER CURVE OF LIVE BIRTH, THERE IS PERHAPS A SLIGHT BENEFIT TO THE ADDITION OF METFORMIN, TO PROVE THIS YOU NEED TO RANDOMIZE OVER 2400 SUBJECT SO TYPE OF TRIAL WE DIDN'T FEEL WORTH PURSUING WHETHER IT'S BETTER METFORMIN, HERE IS METFORMIN ALONE, THIRD AS EFFECTIVE AS CHROMEATHENE. YOU SEE STEP DOWN IN PREGNANCY, THESE ARE PREGNANCIES REGARDLESS HOW CONCEIVED. AS PATIENT GETS MORE OBESE SHE'S LESS LIKELY TO RESPOND TO THE THERAPY. THIS IS THE RECENT TRIAL SCANDINAVIAN MULTI-CENTER TRIAL OVER 300 SUBJECTS WERE RANDOMIZED. THIS IS MORE OF A PRAGMATIC TRIAL SO THE WAY THIS TRIAL WORKED IS THAT FOR THE FIRST T 0 DAYS -- 90 DAYS PATIENTS RECEIVED METFORMIN OR MRS. BOW AND AFTERWARDS THE CLINICIAN CHOOSES THE INDIVIDUAL THERAPY FOR THAT COUPLE SO THAT COULD BE ANYTHING FROM CHROMEATHINE TO GONADOTROPIN TO IVF. AFTER THE ADJUVANT THERAPY WAS INTRODUCED IN THE PRAGMATIC PHASE OF THE TRIAL YOU SEE A SEPARATION, THE CAP PLAN MIRE CURVE OF PREGNANCY RATE AND THIS WAS FOUND IN THE OBESE SUBGROUP AS OPPOSED TO THE NON-OBESE SUBGROUP. ADAM BERLIN IS INVOLVED IN DOING THE COCHRAN SYSTEMATIC REVIEW. THIS IS THE GOLD STANDARD COCHRAN SYSTEMATIC REROW FOR PCOS. EVERY OTHER SYSTEM MA IT CAN REVIEW I'LL SHOW YOU SAY THERE'S A PAUCITY OF TRIALS TO FORM ANY CONCLUSION ON THE EFFICACY AND RISK BENEFIT RATIO OF TREATMENTS. BASICALLY NO EVIDENCE METFORMIN ALONE OR COMBINATION IMPROVES LIVE BIRTHRATE. THERE'S A SUGGESTION AND I THINK THAT IS INCREASED BY THE SCANDINAVIAN TRIAL ALLUDED TO ADDING METFORMIN MOST LIKELY IN OBESE GROUPS MIGHT HAVE A IMPACT ON LIVE BIRTHRATE. POSITIVE IMPACT. I WANT TO BRING UP ADJUVANT THERAPY BUZZ THERE'S A LOT WE DONE KNOW ABOUT IT. SO OUR RMN TRIAL, WE ONE OF THE UNWRITTEN RULES IN INDUCING OVULATION IS THAT YOU SHALL HAVE A WITHDRAWAL BLEED PRIOR TO CHALLENGING A PATIENT OVULATION AGENT. THE IDEA TO START WITH A FRESH ENDOMETRIUM AN OVULATION INDUCTION CYCLE. WE TOOK A LOOK RETROSPECTIVELY BECAUSE WE ALLOWED INDIVIDUAL PRACTITIONERS TO GO RIGHT AHEAD AND CHALLENGE THE PATIENT WITH HIGHER DOSE CHROME THI NEXTE WITHOUT WITHDRAWAL BLEED OR CHOOSE A WITHDRAWAL BLOOD. SO THAT WAS A PRAGMATIC PART OF THE TRIAL. THE PATIENTS DID BEST AGAINST A COMMON PRACTICE WERE ONES WHO DID NOT RECEIVE A PROJESTIN PRIOR TO OVULATION INDUCTION I.E. OVULATED ON UNCHALLENGED ENDOMETRIUM OR ALSO IF IT HAD A SPONTANEOUS MENSES AFTER OVULATION PATIENTS ANOVULATORY PRIOR TO OVULATION DID BETTER. SO THE REASON FOR THIS IS UP CERTAIN, WE NEED TO TEST IT IN A PROSPECTIVE TRIAL. IT RACES A QUESTION OF THESE POTENTIAL ADDITIONAL HARM OR BENEFIT FROM IT. TO LOOK AT THINGS THAT ARE RECOMMENDED, I TALKED ABOUT METFORMIN ALREADY. THERE'S TWO TRIALS WITH DEX METH ZONE THAT SHOW ADDITION OF IT TO CHROMETHENE INCREASES OVULATION RATES. META ANALYSIS ON THAT. NO EVIDENCE PRE-TREATMENT H TO TRIGGER OVULATION OR SUPPLEMENTS IMPROVES THE PREGNANCY RATES. LET'S TALK ABOUT AROMATASE INHIBITORS BECAUSE THESE HAVE BECOME DE NOVO TYPE THING. ONE ADVANTAGE OF AROMATASE INHIBITORS IS THEY MAY HAVE MORE FAVORABLE ENDMETRIAL EFFECTS SO IT'S AN ANTI-ESTROGEN RESULTS ON ULTRASOUND IN A THIN ENDOMETRIUM. THAT'S LESS CON DUE SHY TO PREGNANCY IMPLANTING. WE ALSO HAVE A COMPLEX METABOLISM, A LONG HALF LIFE THAT CONTINUES INTO EARLY PREGNANCY. SO IF THERE ARE POTENTIAL FETALt7 EFFECTS, WE WOULD BE BETTER OFF WITH A DRUG WITH SHORT HALF LIFE SUCH AS AROMATASE INHIBITORS HAVE. SO THIS IS FROM ONE OF THE PHASE 2 TRIALS CONDUCTED WITH ANASTROZOL. COMPARED TO CHROMEATHEN OVULATED MUCH LESS, THEY FAILED TO NOTICE A DOSE RESPONSE INCREASE IN OVULATION AND OVERALL PREGNANCY RATES WERE RELATIVELY LOW, HALF, A THIRD TO THAT OF CHROMEATHENE. ONE INTERESTING THING OUT OF THIS TRIAL THAT'S BURIED IN THERE, IS THAT IN TERMS OF EFFICIENCY AND I BELIEVE THAT'S MY NEXT SLIDE, SO IN TERMS OF EFFICIENCY AN ASTROZOL WAS SUPERIOR TO CHROME ATHENE. IN THE POLYCYSTIC OVARY STUDY ALL OVULATIONS ARE NOT ALIKE. YOU'RE MORE LIKELY TO CONCEIVE, THIS IS NORMALIZED TO EITHER OVULATION SO ALL OVULATION NO, MA'AM NAYTOR OR ANY PATIENT WHO OVULATED. YOU'RE MUCH MORE LIKELY TO CONCEIVE IF YOU HAVE CHROMEATHINE ON BOARD AS OPPOSED TO METFORMIN ALONE ROUGHLY TWICE TO THREE TIME IT IS CHANCE. SIMILARLY THAT WAS NOT OVERALL EFFECTIVE INDUCING OVULATION, WHINNIED DATE IT WAS MORE EFFICIENT PRODUCING A PREGNANCY. THAN CHROMEAFINE. THIS IS FROM ROB NORMAN'S SYSTEMATIC REVIEW. AND IF YOU'RE INTO BIBLIOMETRICS, METFORMIN IS THE MOST STUDIED DRUG IN PCOS AND YOU HEARD ABOUT EPIDEMIC OF PCOS ARTICLES IN THE 20 YEARS. FOR EVERY TWO ORIGINAL CLINICAL TRIALS OF MET FOR MINUTE IN PCOS THERE IS A REVIEW ARTICLE SYSTEM MA IT CAN REVIEW OR META ANALYSIS. YOU CAN PICK WHAT YOU WANT THAT SUPPORTS YOUR VIEW OF THE DRUG. SO ROB, IN AGREEMENT WITH YOU, THERE'S NO EVIDENCE THAT LOOKETROZOL IS BETTER THAN PALACE BEOR CLOMAFE NEXTE. THE REPRODUCTIVE NETWORK COMPLETED A DOUBLE RAN DOCUMENTIZED MASS BOW CONTROL TRIAL, WE'RE WAITING FOR THE LAST PREGNANCIES TO FINISH AND WE SHOULD HAVE OUR RESULTS PRESENTED AND HOPEFULLY IMPRESSEDDED -- IN PRESS BY 2013, SO STAY TUNED. WHAT ELSE CAN WE USE FIRST LINE THERAPY SAFE AND EFFECTIVE? GRATEFUL TO PROFESSOR HAMBURG, ONE THING THAT HUMBLES US WHEN WE DO CLINICAL TRIALS IS FINE OUT HOW MUCH HYPOTHESIS IS WRONG AND HE ALWAYS MAINTAINED THAT STARTING WITH THE LOW DOSE FSH THERAPY WOULD BE MUCH MORE EFFECTIVE THAN CHROMEATHINE CITRATE AND DID RANDOMIZED TRIAL WHICH SHOWED NO CHROMEAFINE AN FSH ARE EQUAL IN TERMS OF PREGNANCY RATE. THAT'S AN IMPORTANT FINDING BECAUSE CHROMEAFINE WAS CHEAPER, EASIER TO USE. AND ULTIMATELY SAFER IN TERMS OF FOLLICULAR RECRUITMENT AND OHHS AND MULTIPLE PREGNANCY. SO I DO WANT TO MENTION METFORMIN CERTAINLY HAS A ROLE TREATING METABOLIC CONSEQUENCES, AS STEVE ALLUDED TO BUT ALSO FOR REPRODUCTION. THERE'S A NUMBER OF TRIALS THAT SHOW METFORMIN IN THE CONTEXT OF IVF AND OVULATION INDUCTION WITH GONADOTROPINS LOWERS THE RISK FOR OHHS. SO THIS MAYBE AN INDICATION FOR ONE ANOTHER REPRODUCTIVE USES OF METFORMIN. SO CONCLUSIONS. TOME OF INFERTILITY PCOS. CHROMEAFINE IS FIRST LINE AGENT, AROMATASE INHIBITORS QUESTIONABLE BENEFIT UNTIL WE RECEIVE FURTHER TRIALS. DURING GONADOTROPIN OVULATION INDUCTION AND MAY ALSO HAVE USES IN ADJUVANT THERAPY, IN OBESE WOMEN. I THINK GONADOTROPIN ARE IVF ARE SECONDARY THERAPIES OF UNCERTAIN RANK. THERE IS A -- I KNOW SOMEONE IN THE AUDIENCE INTERESTED IN OVARIAN SURGERY, THERE'S PROBABLY ONLY ONE TRIAL OUT OF NEW ZEALAND THAT RANDOMIZED WOMEN RESISTANT TO GONADOTROPIN THERAPY OR OVARIAN SURGERY AND FOUND IT HAD SIMILAR PREGNANCY RATES. SO AT LEAST IN TERMS OF SECOND OR THIRD LINE THERAPY, THEY APPEAR EQUAL THREE IN TERMS OF SUCCESS. SO I ONLY TALKED 5 OR 6 TREATMENTS FOR OVULATION INDUCTION. YOU CAN SEE WHAT WE'RE UP AGAINST WITH THE TREATMENT OF HIRSUTISM. SO NEVER HAS THIS BEEN SO MANY TREATMENTS WITH SO LITTLE EVIDENCE ANY TREATMENT IS EFFECTIVE OR ANY TREATMENT IS SUPERIOR TO ANOTHER. SOME OF THE PRINCIPLES WE USE WHEN TALKING MEDICAL TREATMENT OF HIRSUTISM IS THAT WE DON'T HAVE CURES, WE'RE LOOKING AT AMEAL YOUR RAYTIVE THERAPY. WE HAVE TO REALIZE THAT DUE TO THE LONG SHELF LIFE OF A SEBACEOUS UNIT ONCE A HAIR IS DIFFERENTIATED FROM A TERMINAL HAIR, THAT HAIR DOES NOT FADE FROM THE FACE STILL THE SEBACEOUS UNIT DIES OUT SO THE TREATMENT IS TO PREVENT THE DEVELOPMENT OF OTHER TERMINAL HAIRS. WE JUST AS IN INFERTILITY WE'RE INDEBTED TO BREAST CANCER BECAUSE IF YOU LOOK AT THE DRUGS WE USE AROMATASE INHER HUBTORS SERUM WERE DEVELOPED TO TREAT BREAST CANCER, WE ARE INDEBTED TO PROSTATE CANCER FOR OUR ADJUVANT THERAPIES WE USED ARE DEVELOPED TO TREAT PROSTATE CANCER IN MEN. THE CONCERNS WITH APT ANDROGENS IS THAT WE DONE LIKE TO GIVE THEM ALONE. BECAUSE P CERTAINLY DRUGS ANN RECEPTOR ANTAGONIST REDUCTASE INHIBITORS ARE ASSOCIATED WITH HIGH RISK FOR CONGENITAL ABNORMALITIES AND AMBIGUOUS GENITALIA DUE TO ROLE OF TESTOSTERONE AND DHT AN FORMATION OF MALE GENITALIA SO WE RECOMMEND COMBINING WITH ORP. BECAUSE WE DONE HAVE GOOD INDIVIDUAL TREATMENT WE ALSO HAVE POLYPHARMACY, ALSO COMBINED WITH POLYTHERAPY, SO WE RECOMMEND MEDICAL THERAPY AS WELL AS A MECHANICAL THERAPY TO REMOVE HAIR WITH LASER BEING CURRENT MECHANICAL THERAPY OF CHOICE. I'M GOING TO DRAW ENDOCRINE SOCIETY HIRSUTISM GUIDELINES, I AGREE WITH THEM BUT ALSO THEY HAVE ADOPTED A GRADE THING, PART OF THE ISSUE IS THAT THE LEVEL OF EVIDENCE FOR ALL THESE THERAPIES IS RELATIVELY LOW. ORAL CONTRACEPTIVES FIRST LINE THERAPY FOR MAJORITY OF WOMEN BECAUSE OF POTENTIAL AVOID ANTI-ANDROGEN MONOTHERAPY. FOR THOSE WHO WANT MECHANICAL HAIR THERAPY LASER IS THE CHOICE. AND THERE'S ALSO A DRUG CALLED (INDISCERNIBLE) WHICH MAY BE USEFUL AS ADJUVANT AGENT FOR TREATING HIRSUTISM. I WANT TO ADDRESS THE ISSUE THAT WAS BROUGHT UP ABOUT IS THERE A BEST PILL FOR WOMEN WITH WITH PCOS WHO HAVE HIRSUTISM AND HYPERANDROGENNIC FEATURE, THE ANSWER IS NO. THIS TRIAL IS PROBABLY THE LARGEST AND LONG ESTRIOL SO THIS IS A 12 MONTH TRIAL CONDUCTED IN INDIA THAT RANDOMIZED OVER 200 WOMEN TO 3 TIMES OF PILL, THE PILL THAT WAS SUPERIOR ONE NOT AVAILABLE THAT CONTAINS (INDISCERNIBLE) ACETATE. BUT IF YOU LOOK AT THE DIFFERENCE IN SCORES THEY IMPROVES IN ALL THREE PILLS SO I DON'T THINK WE CAN SAY IT'S PEER YOUR TO (INDISCERNIBLE) THESE ARE ALL THREE TYPES OF PROJEST TINS IN ORAL CONTRACEPTIVE PILLS. SO IT TENDS IT CAN THE DRUG WE USE, PART IS THAT IT HAS THE SAFEST PROFILE FROM AN ANTI-ANDROGENIC STANDPOINT THOUGH IT COULD CAUSE BIRTH DEFECTS IN MALE FETUS, NOT A LOT OF CASE REPORTS TO SUPPORT THAT. IT'S USUALLY FAIRLY WELL TOLERATED AND THE SPEAKERNAL LACK TONE IS A CORTICOID ANTAGONIST AND A DIE RIC AND CONTRACTS REACTS WITH THE ANDROGEN RECEPTOR. SO THERE'S ONE FDA APPROVED DRUG TO TREAT FEMALE HIRSUTISM. AND THAT IS EFRONATHINE, THIS IS A CELL CYCLE INHIBITOR SO DOESN'T HAVE MECHANISMS OF ACTION THAT WE USED FOR OTHER INCASES WITHIN PCOS. AND IT DOES APPEAR EFFECTIVE IN A BROAD RANGE OF PATIENTS FROM PREMENOPAUSAL TO POST MENOPAUSEAL WOMEN. NO EVIDENCE LYNN SENSITIZERS IMPROVE HIRSUTISM, THAT'S ALREADY BEEN ALLUDED TO. SO PHARMACOLOGIC TENDS TO BE OCP WITH AND WITHOUT CERTAINAL LACTONE. NO EVIDENCE ONE PILL IS( SUPERIOR TO ANOTHER. LASER IS THE MECHANICAL HAIR THERAPY, ADJUVANT MAKES SENSE WHETHER MEDICAL OR MECHANICAL TO USE A SIMPLE CREAM THAT IS SAFE AND AFFECTIVE. HERE IS THE AREA WITH THE LEAST AMOUNT OF TIME WHICH IS TREATMENT OF OLIGOAMENRRHEA AND DYSFUNCTIONAL BLEEDING. WE HAVE OCP AND SURGICAL THERAPIES. I'LL GO THROUGH IT QUICKLY BECAUSE WE DON'T HAVE EVIDENCE WHAT'S BEST. I THINK WHAT WE CAN SAY IN THIS BIG DEBATE OF METFORMIN VERSUS OCP IS THAT OCP IS BETTER AT REGULATING MENSES, MET FOR FOR MINUTE IS BETTER AT LOWERING INSULIN BUT OCP IS BETTER AT LOWERING SERUM ANDROGEN LEVELS. SO I WILL STOP RIGHT NOW AND JUST TALK ABOUT ONE ISSUE ABOUT THE OCP THAT I THINK WE STILL NEED TO KNOW. THESE OTHER ISSUES WERE ADDRESSED. WHICH IS HOW WE SHOULD GIVE OCT. SO REMEMBER THAT OCP WAS DEVELOPED TO HAVE A WITHDRAW BLEED SO PATIENT AND PHYSICIAN IS CONFIDENT THE WOMAN WAS NOT PREGNANT. BUT NOW WE SEE EXTENDED USE OF IT AND RATIONALE FOR EXTENDED NOT HAVING A THREE, FOUR OR 7 DAY PILL FREE INTERVAL IS THIS ALLOWS TIME FOR OVARIAN REBOUND. SO IF YOU TREAT A CHRONIC PROBLEM LIKE HIRSUTISM FROM A THEORETICAL POINT OF VIEW YOU WILL BE BETTER OBTAINING CONTINUE P WAS SUPPRESSION EXTENDED CYCLE PILL ALLOWING FOR ENDOGENOUS REBOUND, ESTRA DIAL AND PROGESTERONE LEVELS DURING PILL FREE INTERVAL AS OPPOSED TO CONTINUOUSLY SUPPRESSING THESE IN WOMEN. THIS IS AN ISSUE WE NEED TO ADDRESS. I APPRECIATE THIS OPPORTUNITY. I WANT THE ACKNOWLEDGE THE WORK I RECEIVED WITH REGARD TO THIS, RECORD TO THAT, THESE PEOPLE DID EVERYTHING AND COLLABORATORS DID THIS. IT WOULDN'T BE POSSIBLE WITHOUT SUPPORT OF THE NIH TO ANSWER THESE QUESTIONS. THANK YOU. [APPLAUSE] >> SO WE HAVE OOH LITTLE SWITCH IN THE PROGRAM, THE NEXT TWO SPEAKERS WILL CHANGE THEIR SLOTS SO WE'RE GOING TO HAVE ROB NORMAN FIRST. HE'S AT UNIVERSITY AD LATE AUSTRALIA, HE'S COME A LONG WAY, THAT'S WHY WE HAVE GOT TO GET HIM GOING HERE. >> APPARENTLY CHANGING THE BATTERIES IN THE MICROPHONE SO MIGHT TAKE A FEW SECONDS. I WOULD LIKE TO JUST START BY EMPHASIZING THAT PROFESSOR (INDISCERNIBLE) IN THE AUDIENCE IS EQUAL AND GREATER CO-AUTHOR THAN ME ON THIS PAPER. SHE HAS NO DISCLOSURES TO MAKE. BUT THIS WAS A TEAM EFFORT. ALSO IN THE AUDIENCE IS MICHAEL DAVIES WHO CONTRIBUTED TO SOME OF THIS PAPER. THE OUTLINE OBJECTIVES OF MY TALK TODAY FIRSTLY TO REMIND OURSELVES PCOS IS A LIFE COURSE CONDITION. AND NEEDS INTERVENTIONS AND PREVENTION AT ALL STAGES. I WANT US TO LOOK AT WHERE THE LIFESTYLE INTERVENTIONS ARE EFFECTIVE, STUDY WHAT ARE OPTIMAL COMPONENTS OF LIFESTYLE AND INTERVENTIONS. EXERCISE, DIET? WHAT IS IT? HOW CAN WE INTEGRATE THIS INTO HEALTHCARE? WHAT IS THE BEST WAY TO DO THAT? FINALLY, HIGHLIGHT RESEARCH GAPS. WHAT I WANT TO EMPHASIZE FROM MY TALK, THIS IS GOING TO BE VERY MUCH A BALCONY VIEW. NOT GOING TO LOOK AT INDIVIDUAL STUDIES JUST GOING TO LOOK AT AN EVIDENCE BASED OVERVIEW OF THESE AREAS. LET'S START OFF AS PCOS AS PART OF LIFE COURSE HEALTHCARE. SURE WE'RE USED TO THIS CONCEPT IN WOMEN'S HEALTH. GOING FROM PREGNANCY RIGHT THROUGH TO (INAUDIBLE) SO THERE ARE SPECIFIC INTERVENTIONS AND PROBLEMS THAT HAVE TO BE ADDRESSED WHETHER NEWBORN BLOOD SCREAMING, PRE-CONDITION ACCEPT ACTUAL CARE, WHETHER TREATMENT OF MENOPAUSE. IF WE ADD INTO THIS WHAT WE HAVE DONE OVER 50 YEARS IN PCOS, WE HAVE SAID THAT FROM PRE-PUBERTY TO MENOPAUSE IS THE CRITICAL TIME HOWEVER GOING WAY BECOME TO CONCEPTION AND PRE-CONCEPTION IS ALSO PART OF OUR INTEREST IN PCOS. AND THEN BEYOND MENOPAUSE AN INDEED STARTING IN TEENAGE YEARS WE HAVE THE, SOMEHOW OF CHRONIC DISEASE SCREENING. WHICHEVER WAY WE LOCK WHETHER INTERESTED IN HAIR FELONYCLE OR OVARY OR INSULIN MOLECULE, WE HAVE TO BE INTERESTED IN THE LIFE COURSE. SO WHY LOCK MORE AT PREVENTION? FIRST IT'S PREVALENCE O OBESITY IN PCOS. AND I THINK IT'S VERY CLEAR NOW THAT IF YOU MATCH FOR AGE, RACE AND EVERYTHING, THAT PCOS ARE MORE OBESE. THIS IS A ME ANALYSIS THAT WE PUBLISHED THIS YEAR. IT WAS BASED ON 10,000 PAPERS THAT WE WENT THROUGH ON PCOS. WHERE WE PULLED OUT ADEQUATE PCOS VERSUS CONTROLS. AND YOU'LL SEE THAT SIGNIFICANTLY INCREASED PREVALENCE OF OVER WEIGHT AND OBESITY, THAT FIGURE COMES TO 2.96. SO THERE IS NO DOUBT THAT OBESITY IS INCREASED IN PCOS WHEN YOU CONTROL FOR ALL OTHER VARIABLES. THEN THERE'S THE AREA OF WHETHER OBESITY IMPACTS ON PCOS. I THINK THROUGH DATA THAT BUT GIVEN FROM TURKEY, AND FROM THIS DATA THAT HELENA T GENERATED WE CAN SAY INCREASED OBESITY LEADS TO INCREASING PCOS THIS IS AN AUSTRALIAN COMMUNITY BASED STUDY OF MORE THAN 8,000 WOMEN SELF-REPORTED PCOS STUDIED CONTINUOUSLY FOR TEN YEARS. THE PREVALENCE GOES UP DRAMATICALLY AS BMI GOES UP. PCOS HAD HIGHER CHILDHOOD WEIGHT AN INCREASED WEIGHT GAIN, FEATURES THAT PREDICT THOSE PROBLEMS COMING. WE NEED TO REMIND OUTSIDES PCOS HAS IMPERATIVES IN SIGNIFICANCE WE NEED TO LOOK AT. IT IS EXTREMELY FRUSTRATING FOR WOMEN AND CLINICS PARTICULARLY PRIMARY CARE PHYSICIANS, IT HAS A SIGNIFICANT HEALTH ECONOMIC BURDEN, QUANTITATED IN U.S. SOME YEARS BACK. IN AUSTRALIA, UP TO 70% WOMEN WHO HAVE PCOS ARE NOT DIAGNOSED AND THERE'S A HUGE AMOUNT OF PEOPLE IN THE MOBTY WHO HAS THIS CONDITION. WE HAVEN'T SAID MUST HAVE ABOUT EMOTIONAL WELL BEING BUT IT'S CHEERILY IMPAIRED. METABOLIC RISKS ARE BEING APPRECIATED BUT PROBABLY NOT AT THE RIGHT LEVEL. WHEN WEAPON ASKN'T WHAT THEY WANT TO KNOW -- WHEN WE ASK ABOUT WHAT THEY WANT TO KNOW THAT'S DEMAND FOR EDUCATION IN THIS AREA. THERE'S ALMOST NO EVIDENCE BASED GUIDELINES TO FIND ANYWHERE. AND WHEN WE DO HAVE THE EVIDENCE WE'RE NOT ABLE TO TRANSLATE IT INTO PRACTICE. SO PREVENTION AND LIFESTYLE IS POOR. BUT VERY SMALL COHORT STUDIES AND SMALLER RCTs, I COULD HAVE SPENT 20 MINUTES GOING THROUGH SMALL STUDIES. WE ALSO PAY A LOT OF ATTENTION TO LIP SERVICE TO LIFESTYLE. BUT NO EVIDENCE WE EXECUTE THIS ANYWHERE. OVERWHELMINGLY WE TALK MEDICAL THERAPY AND METFORMIN RA HER THAN LIFESTYLE AND PREVENTION BECAUSE WE DONE THINK THAT WE CAN PUT THIS TO PRACTICE. SO I WANT A STORY ABOUT WHAT WE HAVE DONE IN AUSTRALIA AND HELL HENA AND I GOT TOGETHER A GROUP OF PEOPLE WHO FORMED PCOS AUSTRALIAN ALLIANCE. THIS CONSISTED OF CONSUMERS, PCOS SUPPORT GROUP, SPECIALIST, GENERAL PRACTICE, FAMILY PHYSICIANS, PSYCHOLOGISTS, HEALTH ECONOMIC PEOPLE, EPIDEMIOLOGISTS. AND WE CETERA NOT JUST TAKING THE LITERATURE BUT USING CLINICAL JUDGMENT WHERE LITERATURE ISN'T ABLE TO INFORM US AND ASK PATIENTS THEIR PREFERENCE, PARTICULARLY THE CONDITIONS WE LOOKED AT, THE QUESTIONS WE LOOKED AT CAME FROM THE CONSUMERS. THESE WERE THE ONES THEY WANTED ANSWERED. SO JUST LITTLE BIT ABOUT METHODOLOGY. THIS WAS A MAJOR NATIONAL COLLABORATION ACROSS UNIVERSITIES AND HOSPITALS AND WE NEEDED MONEY. FOR 12 MONTHS WE LOBBIED THE GOVERNMENT. THIS IS WHERE CONSUMERS CAME INTO PLAY, EVERY TIME THERE WAS A POLITICAL MEETING WITH MINISTER OF HEALTH THERE WERE PEOPLE IN THE AUDIENCE SAYING WHY NOT LOOKING AT PCOS? EVERY MEETING SHE WEPT TO SHE WAS ADDRESSED ABOUT PCOS. AND ULTIMATELY SHE HANDED OVER 1.2 MILLION AUSTRALIAN DOLLARS WHICH IS SAME AS U.S. DOLLARS. WE HAD LARGE NATIONAL WORKSHOP TO DEVISE QUESTIONS AN PRIORITIZE THEM. AND MADE THE FUNDAMENTAL DECISION TO USE ROTTERDAM. MANY ENDOCRINOLOGISTS DIDN'T LIKE THAT BUT WE AGREED THAT WAS OUR DIAGNOSTIC CRITERIA. WE LOOKED AT 38,000 ARTICLES AN SCREENED THEM. WE PUBLISHED OR WILL PUBLIC 22 SYSTEMATIC REVIEWS. AND WE GENERATED ONLINE AND PUBLISHED LARGE NUMBER OF DOCUMENTS RAILROADING OUR FINDINGS. THIS IS AVAILABLE TO ANYBODY. WE WERE STRICT ABOUT CONFLICT OF INTEREST BUT WE HAD TO DECLARE ANY CONFLICT OF INTEREST AND ALL PAPERS THAT WE PUBLISHED THESE HAVE BEEN DECLARED. WE HAD FOUR DISCIPLINARY GUIDELINE GROUP WHO MED REGULARLY. A CONSUMER, A GENERAL PRACTITIONER OR FAMILY PHYSICIAN, WE HAD SCIENTISTS, AND WE HAD SPECIALISTS. SO WE COVERED THE WHOLE REALM OF INTEREST. WE LOOKED AT ALL LEVELS OF AUSTRALIAN HEALTHCARE SYSTEM FROM FAMILY PHYSICIANS AND FROM ALLIED HEALTH THROUGH TO SUPER SPECIALISTS. AS I HAVE EMPHASIZED WE ENGAGE CONSUMERS AT EVERY ENGAGEMENT. AND THEN ONE WE GOT TO WHERE WE WANTED, WE WENT OUT AN ADVERTISED IF THE NEWSPAPER THAT OUR GUIDELINES ARE AVAILABLE FOR CONSULTATION. WE WENT TO ALL THE SPECIALISTS, LOOKED AT DIFFERENT ETHNIC AND INDIGENOUS GROUPS AND WE HAD A PERIOD OF CONSULTATION WHERE PEOPLE WRITE BACK TO USER SPEAK TO US ABOUT WHAT WE WERE DOING BEFORE WE FINALIZED IT. WE THEN FORMULATED THE RECOMMENDATION AND TOOK IT TO OUR TOP BODY T NATIONAL AUSTRALIA AND MEDICAL RESEARCH COUNCIL, THE SAME AS THE NIH EQUIVALENT, AND AFTER EXTERNAL REVIEW, THEY PASSED US SO IT'S AN OFFICIAL GOVERNMENT APPROVED GUIDELINE. WE HAVE PUBLISHED IT. THE LEVELS ARE WELL KNOWN TO YOU, A IS A LEVEL THAT CAN BE TRUSTED TO GUIDE PRACTICE AND D IS PRETTY WEAK. WE HAVE ALSO GOT SOMETHING WE CALL CLINICAL CONSENSUS RECOMMENDATION. THERE'S NO EVIDENCE, WE ISED EXPERTS WHAT THEY THOUGHT WAS REASONABLE. AND THEN WE ALSO RAISED PRACTICE POINTS, THINGS WE THOUGHT WERE INCREDIBLY IMPORTANT ABOUT DISCUSSION. WE IDENTIFIED AREAS OF RESEARCH. SO I'M GOING TO PRESENT A NUMBER OF AREAS ABOUT LIFESTYLE AND PREVENTION AND GOING TO USE THIS WAY OF DOING IT. FIRST OF ALL TO GIVE YOU THE EVIDENCE BASED RECOMMENDATION AND AGAIN THESE ARE HIGH LEVEL ONES, TO GIVE YOU THE EVIDENCE LEVEL AND NUMBER OF TRIALS THAT THAT WAS BASED ON. CLINICAL RECOMMENDATIONS AND WHAT IT MEANS FOR PRACTICE AN FUNDING AND RESEARCH RECOMMENDATIONS. WHAT SHOULD BE RESEARCH. I'M GOING TO TAKE A NUMBER OF QUESTIONS AND JUST GO THROUGH THOSE. WE HAVE PUBLISHED THIS IN TWO AREAS EASILY ACCESSIBLE, ONE IS WEBSITE, OTHER IS MEDICAL JOURNAL OF AUSTRALIA ARTICLE THAT I MENTIONED HERE YOU CAN GET FULL TEXT. SO THESE ARE THE IMPORTANT TO LOOK AT. DIETARY INTERVENTION, EXERCISE AND BEHAVIORAL INTERVENTION. SO THE FIRST QUESTION WE LOOKED AT IS ARE LIFESTYLE INTERVENTIONS EFFECTIVE IN PCOS. THIS WAS LEVEL B EVIDENCE, RELATIVELY SMALL NUMBER OF TRIALS. THE LEVEL OF EVIDENCE IS GOING TO REFER TO WEIGHT LOSS AND NOT JUST WEIGHT PREVENTION BECAUSE IT'S MUCH LESS DATA SO LIFESTYLE MANAGEMENT FOR WEIGHT LOSS PREVENTION OF WEIGHT GAIN OR GENERAL HEALTH BENEFIT SHOULD BE RECOMMENDED FOR ALL WOMEN WITH PCOS. REASONABLE EVIDENCE. IT HAS IMPLICATIONS FOR PRACTICE AND FUNDING IF WE BELIEVE IN THIS IT WILL TAKE TIME AND WILL TAKE MONEY TO EXECUTE. AND RESEARCH RECOMMENDS ARE THERE WERE LOTS OF OTHER AREAS WE HAD TO INVESTIGATE. WITH EXPANDED CLINICAL OUTCOMES, HIGH RISK GROUPS, HOW TO EBB GAUGE WITH PEOPLE -- ENGAGE WITH PEOPLE BETTER AND ALSO ASK THE QUESTION WHAT IT MEANS FOR PEEP NOT OVERWEIGHT. THE SECOND QUESTION, WHAT ARE OPTIMAL DIETARY INTERVENTIONS, THERE'S NUMEROUS DIETS AVAILABLE. OBVIOUSLY A LOW GI DIET IS POPULAR AT THE MOMENT. WE WANT TO SEE ANY EVIDENCE FOR ONE DIET OR THE OTHER. SO EVIDENCE BASE RECOMMENDATIONS WAS FOR WEIGHT LOSS WE SHOULD TARGET ALL WOMEN WITH PCOS AND BMI OVER 25. BY REDUCINGCAL IS ARE -- CALORIES IN SETTING OF FOOD CHOICES IRRESPECTIVE OF DIET COMPOSITION, AS MENTIONED WITH NO EVIDENCE THAT ONE DIET IS BETTER OVER ANOTHER. BUT THERE IS EVIDENCE THAT CALORIC RESTRICTION IS EFFECTIVE. IN TERMS OF WEIGHT GAIN IT WAS MUCH LESS EVIDENCE. BUT AGAIN IT WAS -- WE SHOULD TRY AND PREVENT WEIGHT GAIN THROUGH CALORIC INTAKE MONITORING, AGAIN IN THE SETTING OF HEALTHY FOOD CHOICES. SO AGAIN, THE CLINICAL IMPLICATIONS OF THESE EVIDENCE BASED GUIDELINES ARE ENORMOUS. BECAUSE IT MEANS THAT WEIGHT LOSS AND PREVENTION OF WEIGHT GAIN IS IMPORTANT NOT JUST FOR PATIENT BUT ALSO THE DOCTOR. PARTNERING WITH THE PATIENT. AND IT ALSO MEANS -- SORRY, THAT'S MY TIMER, IT MEANS REFERRAL TO DIETITIAN MAYBE IMPLICATED. FOR RESERGE IS NEEDED ON VARIOUS DIETS PARTICULARLY LOW GI DIET. THIRD, WHAT IS EFFECTIVENESS OF DIET VERSUS EXERCISE? CAN YOU SEPARATE OUT ONE FROM THE OTHER THIS IS LEVEL C, NOT STRONG. BUT LIFESTYLE INTERVENTIONS INCLUDE DIET AND EXERCISE AND BE FIRST LINE THERAPY. IN TERMS OF CLINICAL IMPLICATION S, VERY IMPORTANT IF WE PUT THIS INTO PRACTICE, WE MAY NEED TO FUND EXERCISE PHYSIOLOGISTS WE NEED A RANGE OF ALLIED INTERVENTION, RESEARCH RECOMMENDATIONS WE NEED LOTS MORE DIET MORE TRIALS LOOKING AT DIET VERSUS EXERCISE. WE NEED TO LOOK AT LONG TERM EFFECT OF DIET AND PARTICULARLY WE NEED TO WORK OUT HOW TO ENGAGE WITH PATIENTS SO WE GET COMPLIANCE. I JUST REFER YOU TO, THIS IS A MATTER -- A SYSTEMATIC REVIEW ON EXERCISE. FOURTHLY, HOW TO DELIVER LIFESTYLE, BEST WAY OF DOING IT? RELATIVELY POOR EVIDENT BUT FACE TO FACE DIETARY ADVICE INCLUDING EDUCATION, BEHAVIORAL MODIFICATION, ONGOING SUPPORT RESPOND PROVIDED. -- SHOULD BE PROVIDED. IT'S THE JOINT RESPONSIBILITY OF THE DOCTOR AND HEALTH SERVICES TOGETHER. THIS AGAIN HAS ENORMOUS IMPLICATIONS IF WE BELIEVE AND PRACTICE IN IT. WE PROBABLY NEED TO BE TRAINING PEOPLE IN MOTIVATIONAL CHANGE TECHNIQUES. WE NEED THE USE OF METHOD METERS, SELF-MONITORING AND WORK OUT WHETHER INTERVENTIONS ARE BEST DONE AS AN INDIVIDUAL GROUP OR MIXED. AND THE RESEARCH RECOMMENDATIONS MINIMAL TRIAL ON DELIVERY METHODS OF LIFESTYLE TECHNIQUES. ARE THEY EFFECTIVE? IT BASICALLY COMES BACK TO DIABETES RECOMMENDATIONS OF AT LEAST TWO AND A HALF HOURS A WEEK. OF WHICH 90 MINUTES AEROBIC ACTIVITY. SIGNIFICANT CLINICAL INDICATIONS. PEOPLE MAY NEED ASSISTANCE IN GETTING THE RIGHT EXERCISE PATTERN. RESEARCH RECOMMENDATION WE NEED TO KNOW MORE ABOUT TYPE, INTENSITY AND DELIVERY METHS OF EXERCISE. WHAT ABOUT -- METHODS OF EXERCISE. WHAT ABOUT DIFFERENT ETHNIC GROUP? IN TERMS OF EVIDENCE BASED RECOMMENDATIONS WE COULD FIND FEW TRIALS BUT WE'RE WELL AWARE THAT INDIGENOUS IMMIGRANT WORKS HAVE WORSE OBESITY IN MANY AREAS WE HAVE DIFFERENT PATTERNS OF OBESITY AND METABOLISM AND ACCESS TO HEALTHCARE IS MUCH WORSE. SO WE NEED TO HAVE PROGRAMS THAT DEAL WITH ETHNIC AND MIGRANT GROUPS AT RISK. FOR RESEARCH RECOMMENDATIONS, WE NEED TO LOOK PARTICULARLY ETHNIC AND MIGRANT GROUPS IN OUR COMMUNITY. FINALLY, WHAT ARE OPTIMUM MODELS OF CARE FOR PCOS? WE RECOMMENDED THAT YOU NEEDED INTERDISCIPLINARY MODELS OF CARE. AND THIS INVOLVES A LOT OF REORGANIZATION OF AUSTRALIAN HEALTH CARE SYSTEM. WHERE WE'RE NOT VERY WELL EQUIPPED TO COVER CHRONIC DISEASE. THE CONCEPT IS PATIENT IS CENTRAL TO CARE AN HOLDS THE MANAGEMENT PLAN. THERE'S A ROLE FOR PRIMARY CARE PHYSICIAN WHO WOULD WORK WITH THE PATIENT. OUTSTANDING EDUCATIONAL SOURCES, SUPPORT GROUPS THAT MEET TOGETHER. WE NEED TO INVOLVE SPECIALISTS AS AND WHEN IS NEEDED AND NEED GOOD ALLIED HEALTH PERSONNEL. SO THERE'S A CLINIC THAT HELENA RUNS IN MELBOURNE THAT HAS ALL THESE TOGETHER IN ONE ROOF AND PATIENTS ARE THEN REFERRED BACK TO GENERAL PRACTITIONER. FINALLY WE PUT A LOT OF TIME INTO TRANSLATION. AND HERE WE'RE JUST SHOWING YOU SOME WEBSITES BUT THERE ARE LOTS OF BOOKLETS, WE HAVE GONE OUT TO GENERAL PRACTICES, WE HAVE GREAT PATIENTS SUPPORT BOOKS WE HAVE A VERY GOOD WEBSITE. AND CONSTANTLY HAVE A MEDIA PRESENCE ABOUT PCOS. SO THIS IS NOT JUST COMING UP WITH EVIDENCE BUT TRANSLATING INTO THE HEALTHCARE SYSTEM. AND THEN FINALLY INTO TRANSLATION. SO I JUST WANT TO END UP AND ACKNOWLEDGE ALL THE PEOPLE THAT TOOK PART IN THIS EXERCISE GENE HAIL CENTER IS WOMEN'S HEALTH CENTER VERY WELL KNOWN IN MELBOURNE AND MINISTER OF HEALTH IN OUR FEDERAL DEPARTMENT WAS VERY MUCH INVOLVED IN THAT. THERE ARE BOOKS THAT ARE PRINTED THAT YOU CAN GET, THIS IS ONLINE. AND ALTHOUGH HELENA AND I HAVE TO DISAPPEAR VERY QUICKLY AFTERWARD WE'RE AVAILABLE TO TALK TO YOU ON LINE, EMAIL OR TELEPHONE SOMETIME ABOUT THIS EXERCISE. THANK YOU VERY MUCH. [APPLAUSE] >> SO NEXT WOULD LIKE TO INTRODOES ADAM BALEN FROM UNIVERSITY OF LEADS WHO WILL TALK PREGNANCY AND ITS OUTCOMES. THANK YOU VERY MUCH, GOOD AFTERNOON, I WOULD LIKE TO EXTEND THANKS TO THE ORGANIZERS FOR INVITING ME TO PARTICIPATE IN THIS IMPORTANT MEETING. MY BRIEF IS TO TALK ABOUT PREGNANCY AND OUTCOMES IN POLYCYSTIC OVARY SYNDROME. WE HAVE TO OF COURSE THINK ABOUT OUTCOMES FOR THE MOTHER, OUTCOMES FOR THE BABY. WHICH MAYBE RELATED TO THE PRESENCE OF POLYCYSTIC OVARY SYNDROME OR MANY OF THE ASSOCIATED WE HAVE BEEN HEARING ABOUT DURING THE COURSE OF THIS MEETING. AND CONSIDER WHETHER PREGNANCY IS CONCEIVED NATURALLY OR WITH SOME FORM OF ASSISTANCE. SO WOMEN WITH POLYCYSTIC OVARY SYNDROME AS WE HEARD FROM RICK LEGRO RELATES TO ANOVULATION BUT EFFECTS OF OBESITY AND ASSOCIATED MET BOLL PIC ENDOCRINE AND INFLAMMATORY ABNORMALITIES WHICH NOT ONLY IMPACT UPON THE REGULARITY OF OVULATION BUT POTENTIALLY ALSO THE QUALITY OF OVULATION. WE ALSO HEARD YET IN DETAIL EFFECTS POTENTIALLY ON FETAL DEVELOPMENT. WE HAVEN'T HEARD FROM EGGS. THE NEUROCYTES FROM POLYCYSTIC OVARY HAS BEEN STUDIED BY OUR GROW AND OTHERS AND THERE'S NO DOUBT THERE ARE PACK FORS -- FACTORS DURING FOLLICULAR GENESIS THAT MAYBE DIFFERENCE IN WOMEN WITH POLYCYSTIC OVARY AFFECTING THE INTRAFOLLICULAR ENVIRONMENT WHICH MAY HAVE AN EFFECT ON OOCYTE DEVELOPMENT. ITS ABILITY TO MATURE NORMALLY, COMPLETE MYOSIS, ITS ABILITY TO FERTILIZE NORMALLY AND PRODUCE A NORMAL EMBRYO. OBVIOUSLY TIME DOESEN ALLOW ME TO EXPLORE BASIC SCIENCE IN ANY DETAIL. BUT WE AND OTHERS HAVE LOOKED AT OOCYTE METABOLISM FROM OOCYTE OBTAINED USUALLY FROM STIMULATED POLYCYSTIC OVARIES COMPARED WITH NORMAL OVARY IN THE CONTEXT OF IVF BUT ALSO UNSTIMULATED OVARIES IN CONTEXT OF OUR IN VITRO MATURATION STUDIES. WE FOUND METABOLIC IN MARCH HYPERANDROGENEMIA KEY GENE ASSOCIATED WITH NORMAL CHROMOSOMEAL DEVELOPMENT AND OUR GROUP OF -- HAVE SHOWN CHROMOSOMEAL PRE-DIVISION IN OOCYTE FROM WOMEN WITH POLYCYSTIC OVARY SYNDROME. SO WE HAVE TO BARE THIS IN MIND WHEN WE LOOK AT THE OUTCOMES NOT ONLY THE CHANCE OF GETTING PREGNANT BUT THE CHANCE OF CONCEIVING A NORMAL HEALTHY EMBRYO AND SUBSEQUENTLY HEALTHY BABY. WHICH BRINGS ME ON TO THE SUBSTANCE OF THE TALK, THE PREGNANCY OUTCOMES WOMEN WITH POLYCYSTIC OVARY SYNDROME. FOR MANY YEARS IT'S THOUGHT THERE MIGHT BE AN INCREASE RISK OF MISCARRIAGE IN WOMEN WHO CONCEIVE POLYCYSTIC OVARY SYNDROME. SECONDARY TO ENDOCRINE FEATURES IN MARCH FOR MANY YEARS IT WAS CONSIDERED HYPERSECRETION OF LH OR HYPERANDROGENISM MAY HAVE EFFECT ON MISCARRIAGE. THE METABOLIC FACTORS AND OOCYTE FACTORS OR EVEN FACTORS AT LEVEL OF ENDOMETRIUM. WE HAVE TO CONSIDER THE DEFERENCE BETWEEN NATURAL CONCEPTION AND CONCEPTION AFTER OVULATION INDUCTION. INCREASE RISK OF MISCARRIAGE IN WOMEN WHO HAVE HYPERINSULINEMIA WHICH MAY HAVE AN EFFECT ON FIBRIN ISIS AND SMALL STUDIES IN PATIENTS GROUPS WITH POLYCYSTIC OVARY SYNDROME SUGGESTING INCREASE RISK OF THROMBOPHILIA, ELEVATED ACTIVATED INHIBITOR AND PROTEIN C DEFICIENCY, ALL OF WHICH MAY HAVE AN IMPACT ON BLAH SENNATION AN MAYBE ASSOCIATED WITH INCREASE RISK OF MISCARRIAGE AND OTHER PREGNANCY RELATED PROBLEMS SUCH AS PREECLAMPSIA I'LL REFER TO IN A MINUTE. BUT THESE ARE SMALL STUDIES AND I THINK IT'S FAIR TO SAY THE LITERATURE IS REALLY STILL@ RATHER SCANT IN THIS REGARD. WHEN WE LOOK AT MISCARRIAGE AFTER ASSISTED CONCEPTION, THE NUMBER OF GROUPS OF ATTEMPTED TO LOOK AT WOMEN WITH POLYCYSTIC OVARY SYNDROME, ROB NOR MAP'S GROUP IN AD LATE HAVE PUBLISHED WIDELY AND THIS IS A STUDY LOOKING AT MISCARRIAGE AFTER IVF. OVER A THOUSAND PATIENTS WHOM JUST UNDER 40% HAD POLYCYSTIC OVARY SYNDROME, AND THEY HAVE A SIGNIFICANTLY HIGHER RISK FOR MISCARRIAGE BUT WITH LO GIST HEALTHCARE REGRESSION ANALYSIS IT WAS SHOWN THAT IT WAS OBESITY RATHER THAN PRESENCE OF POLYCYSTIC OVARY SYNDROME THAT WAS THE KEY FACTOR. THIS IS BEEN FOUND IN OTHER STUDIES AS WELL. RATE OF MISCARRIAGE IN WOMEN WHO CONCEIVE NATURALLY, THE BEST STUDY IS FINISHED BIRTH COHORT LOOKING AT OVER 5 1/2 THOUSAND WOMEN BORN IN 19 # 6 STUDIED AT AGE 31 A QUARTER HAD SYMPTOMS SUGGESTING THEY HAD POLYCYSTIC OVARY SYNDROME. AND THOSE WITH POLYCYSTIC OVARY SYNDROME PERHAPS NOT SURPRISING LY HAVE INCREASED WASTE CIRCUMFERENCE AN THOSE WITH HYPERANDROGENISM HAD LOWER FECUNDITY COMBINED WITH MENSTRUAL CYCLE DISTURBANCE BUT NO INCREASED RISK FOR MISCARRIAGE IN THESE INDIVIDUALS IRRESPECTIVE OF THEIR BODY WEIGHT. SUGGESTING NO INCREASE RISK OF MISCARRIAGE IN NATURALLY CONCEIVED PREGNANCIES WITH POLYCYSTIC OVARY SYNDROME. SMALL LITERATURE AND THERE'S NO EVIDENCE THAT POLYCYSTIC OVARY SYNDROME IS ASSOCIATED IN INCREASE RISK FOR RECURRENT MISCARRIAGE ONCE WE EXCLUDE OBESITY. WHICH APPEAR IT IS PRINCIPLE FACTOR THAT IS ASSOCIATED WITH MISCARRIAGE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. ONGOING PREGNANCY THERE'S A NUMBER OF STUDIES META ANALYSES AND POPULATION STUDIES WHICH SUGGEST WOMEN WITH POLYCYSTIC OVARY SYNDROME HAVE SIGNIFICANTLY INCREASE RISK OF PREGNANCY RELATED PROBLEMS IN PARTICULAR GESTATIONAL DIABETES, PREGNANCY INDUCED HYPERTENSION, PREECLAMPSIA AND NEONATAL MORBIDITY, INCREASE ADMISSION TO NEONATAL INTENSIVE CARE UNITS. INCREASED RISK OF SMALL AND LARGE AGE FANTASTICS. SMALL FOR GESTATIONAL AGE USUALLY ASSOCIATED WITH PREMATURE DELIVERY AND PARTICULARLY IN MULTIPLE PREGNANCIES AN LARGE FOR AGE ASSOCIATED NOT ONLY WITH GESTATIONAL DIABETES BUT OBESITY AND METABOLIC PROBLEMS IN THOSE WHO DON'T HAVE GESTATIONAL DIABETES. SO I HAVE LISTED HERE SOME OF THE REFERENCES, SOME OF THE RECENT ME THE ANALYSES. AND THEN THE PAPER FROM SWEDEN, THE LARGEST POPULATION BASED STUDY, 4,000 WOMEN WITH POLYCYSTIC OVARY SYNDROME WITH A MILLION CONTROLS IN NEIGHBORNAL DATABASE, SHOWING THOSE WITH WITH POLYCYSTIC OVARY SYNDROME HAVE INCREASED RISK IN PREGNANCY. THE DATA I'M GOING TO SHARE WITH YOU IS FROM THE LARGEST MOST RECENT META ANALYSIS PUBLISHED JUST OVER A YEAR AGO IN THE AMERICAN JOURNAL. A META ANALYSIS OF 23 STUDIES OF JUST OVER 2 1/2 THOUSAND WOMEN WITH POLYCYSTIC OVARY SYNDROME VERSUS 90,000 CONTROLS SHOWING SIGNIFICANT ODDS RATIO FOR GESTATIONAL DIABETES, THESE ARE THE 95 PERCENT CONFIDENCE INTERVALS. PREGNANCY INDUCED HYPERTENSION OVER 4. PREECLAMPSIA, PRE-TERM DELIVERY, HARM FOR GESTATIONAL AGE. SO WOMEN WITH POLYCYSTIC OVARY SYNDROME APPEAR TO HAVE SIGNIFICANT RISKS DURING PREGNANCY BUT ONE PROBLEM THESE STUDIES THEY RARELY MAKE REFERENCE TO BASELINE CHARACTERISTICS IN THOSE WITH POLYCYSTIC OVARY P SYNDROME COMPARED TO CONTROL PATIENTS. IN PARTICULAR BODY WEIGHT WASTE CIRCUMFERENCE AN ENDOCRINE ABNORMALITIES AT BASELINE. SO THAT'S!+– STARTED COMPARED WITH CONTROL PATIENTS AND THERE ARE FEW IF ANY PUBLISHED LONGITUDINAL STUDIES AT WOMEN WHO CONCEIVE WITH POLYCYSTIC OVARY SYNDROME BART FACER HAS A STUDY BEING COMPLETED AND HE TELLS ME WILL BE PUBLISHED NEXT YEAR AT ABOUT 300 WOMEN WHO HAVE BEEN STUDIED FROM CONCEPTION THROUGH PREGNANCY. THIS STUDY FROM STENO PALUBA TRIED TO TEASE OUT DIFFERENT PHENOTYPES OF WOMEN WITH POLYCYSTIC OVARY SYNDROME. IT IS A SMALL STUDY, 97 WOMEN WITH PCOS VERSUS 73 CONTROLS, THESE ARE NATURAL CONCEPTIONS, THE PATIENTS HAVEN'T RECEIVED FERTILITY TREATMENT. THEY DIDN'T HAVE METFORMIN THROUGH PREGNANCY. THERE'S A NUMBER OF OUTCOMES INCLUDING GESTATIONAL DIABETES, PREECLAMPSIA AND PRE-TERM DELIVERY. HYPERANDROGENISM OLIGOMENRRHEA AND OVULATORY PATIENTS WITH POLYCYSTIC OVARY SYNDROME. YOU SEE IT'S THOSE WITH THE FULL BLOWN HYPERANDROGENEMIC INCREASED RISK OF PROBLEMS DUG PREGNANCY, THIS IS A SMALL STUDY AND DIFFICULT TO TEASE OUT SPECIFIC PROBLEMS AN LARGER STUDIES ARE REQUIRED TO LOOK AT DIFFERENT PHENOTYPES AND OUTCOMES AND MAYBE BART'S STUDY WILL ADDRESS THIS ALSO. THIS IS KOREAN STUDY OVER A YEAR AGO. WE ARE LOOKING AT JUST OVER 300 WOMEN WITH PCOS VERSUS 1,000 CONTROLS WHO UNDERWENT IVF, THEY SEPARATED OBESE WOMEN AGAINST OBESE CONTROLS AND TRIED TO MATCH THE TWO, AND THERE WAS NO DIFFERENCE IN THE CLINICAL PREGNANCY RATE OR LIVE BIRTHRATE OR PREGNANCY RELATEDDED COMPLICATIONS IN THOSE WITH PCOS COMPARED WITH CONTROLS. THOSE WITH INCREASED RISK OF INFANTS SMALL FOR GESTATIONAL AGE LARGELY DUE TO PREMATURITY. AS FAR AS GESTATIONAL DIABETES THIS WAS ONLY SEEN IN THE OBESE WOMEN WITH POLYCYSTIC OVARY SYNDROME. SO THIS IS ONE FEW STUDY TRYING TO MATCH OBESITY WHICH IS A KEY COMPONENT WHEN CONSIDERING PREGNANCY OUTCOME. THE OTHER KEY ISSUE, HOW CAN YOU PREDICT PROBLEMS SUCH AS YES, SIRRATIONAL DIABETES. AND I REFER YOU TO A STUDY FROM BART FACER'S GROUP LOOKING AT I THINK APPROXIMATELY 50 WOMEN WHO WERE STUDIED THROUGH PREGNANCY OF WHOM 42% DEVELOPED GESTATIONAL DIABETES WHICH IS IN KEEPING WITH OTHER STUDIES LOOKING AT INCIDENCE OF GESTATIONAL DIABETES IN WOMEN WITH PCOS. TRYING TO TEASE OUT PREDICTORS BY STEP WISE LOGISTIC REGRESSION IT WAS A LOW SH BG THAT WAS THE MOST SIGNIFICANT PREDICTOR THOUGH BECAUSE OF RELATIVELY SMALL NUMBERS THEY WERE UNABLE TO GIVE A CUT OFF BUT SHBG WAS BETTER PREDICTOR THAN WASTE CIRCUMFERENCE, BODY MASS INDEX, BLOOD PRESSURE, PLASMA GLUCOSE OR HOMEA IR BEFORE CONCEPTION. INTERESTING INFORMATION SUGGESTING WE SHOULD BE LOOKING AT SHBG CONCENTRATIONS IN THOSE WOMEN WHO CONCEIVE AND SCREENING THEM FOR GESTATIONAL DIABETES. WE HAVE TO REMEMBER AS ALLUDED TO IN ONE OR TWO OF THE TALKS DURING THIS MEETING BUT PERHAPS NOT SUFFICIENTLY, THERE ARE BIG ETHNIC VARIATIONS IN WOMEN WITH PCOS NOT ONLY IN EXPRESSION OF CONDITION BUT ALSO IN REPRODUCTIVE OUTCOMES. AND THIS IS AN AREA OF INTEREST FOR LARGE NUMBER OF YEARS WITH (INAUDIBLE) WHO DID HAVE HER Ph.D. WITH US A FEW YEARSING A AN NOW PROFESSOR OF REPRODUCTIVE ENDOCRINOLOGY IN SRI LANKA WHICH WE CONTINUE TO COLLABORATE AND HAVE SHOWN IN A NUMBER OF STUDIES IN THE SOUTH ASIAN POPULATION, NOT ONLY DO THEY HAVE A WORSE PHENOTYPE AND METABOLIC PROBLEMS THE DIFFERENCE IS IN FOE AT A TIME METABOLISM THAT MAY IMPACT NOT ONLY ON CARDIO CARDIOVASCULAR RISK BUT REPRODUCTIVE RISK. AND WE FOUND THAT PATIENTS FROM THE SOFT ASIAN COMMUNITY THAT WE HAVE STUDIED HAVE LOWER FERTILIZATION OF THEIR OOCYTES AND LOWER PREGNANCY RATES UNDERGOING ASSISTED CONCH SECTION SO THERE'S A WEALTH OF INFORMATION HERE. MORE RESEARCH REQUIRED FOR TEASING OUT OUTCOMES WITH DIFFERENT ETHNIC GROUPS WITH PCOS. RICKLY GREW ALOUDED THE METALLY GREW METFORMIN ALONE OR COMBINED WITH DRUGS TO INDUCE OVULATION DOES NOT APPEAR TO HAVE A SIGNIFICANT BENEFIT OFFICIAL LIVE BIRTHRATE TRYING TO INDUCE OVULATION BUT THERE'S NUMBER OF STUDIES THAT HAVE LOOKED AT ITS EFFECT DURING PREGNANCY. I WILL REFER YOU TO THE TWO LARGER STUDIES. THEIR FIRST STUDY LOOKED AT 40 PCOS, 18 PRESCRIBED METAPHOR MIGHT BE, APPROXIMATELY TEN WEEKS GESTATION THROUGH DELIVERY COMPARED WITH 22 GIVEN PLACEBO. AND THERE WAS NO DIFFERENCE IN KEY OUTCOMES, PREVALENCE OF PREECLAMPSIA, GESTATIONAL TIE BEE TEASE AGE OR BIRTH WEIGHT. THE WOMEN IN THE PLACEBO GROUP HAD MORE PRE-TERM DELIVERY BUT THIS WAS A SMALL STUDY AND THREE OF FIVE PRE-TERM DELIVERIES RELATED TO INCOMPETENCE. THIS LED THEM TO PERFORM A MUCH LARGER STUDY PUBLISHED A COUPLE OF YEARS AGO NOW, THIS IS A MULTI-CENTER STUDY LOOKING AT 274 PREGNANCIES AND 57 WITH PCOS. 136 WERE GIVEN METFORMIN AROUND TEN WEEKS GESTATION. THAT'S A DOSE OF TWO GRAMS A DAY. VERSUS 138 PRESCRIBED MRS. BOW. IN THIS STUDY THERE WAS NO DIFFERENCE IN THE PREVENIENCE OF PREECLAMPSIA PRE-TERM DELIVERY OR BIRTH WAY. THOSE GIVEN METFORMIN GAINED LESS WEIGHT BUT KEY CLINICAL OUTCOMES THE USE OF METFORMIN THROUGH PREGNANCY DIDN'T APPEAR TO BE BENEFICIAL. SINCE THIS YEAR PERFORMED EPIANALYSIS OF THESE TWO STUDIES THAT COMBINE THEM TOGETHER SUGGESTING WHEN YOU PULL THE DATA FROM THESE 313 PREGNANCIES WOMEN IN THE PLACEBO GROUP HAD MORE SECOND TRIMESTER MISCARRIAGE AND MORE LIKELY TO DELIVER UNDER 37 WEEKS. THIS REACHED SIGNIFICANCE SO THIS IS LED TO SUGGEST THAT EVEN LARGER STUDIES MAY NOW BE REQUIRED. I WOULD SUGGEST LARGE RCT WHICH FAILED TO SHOW STATISTICCAL DIFFERENCE IS LESS IMPORTANT. WHEN YOU THINK ASSISTED CONCEPTION YOU HAVE TO THINK ABOUT THE DRUGS THAT WE USE AND RISKS RELATING TO MULTIPLE PREGNANCY TIME DOESN'T ALLOW ME THE TALK ABOUT MULTIPLE PREGNANCY. WE'RE ALL FAMILIAR WITH INCREASE MORBIDITY WITH MULTIPLE PREGNANCY WHICH PROBABLY HAS GREATEST HEALTH BURDEN THINKING REPRODUCTIVE OUTCOMES IN PATIENTS UNDERGOING CONCEPTION. CONGENITAL ANOMALIES, THAT'S A LIT FROM A CHU BACK TO 19 # 0s SUGGESTING INCREASED RISK OF NEURAL TUBE DEPECKS AND POSSIBLY CARDIAC DEFECTS. THE LARGE STUDY IS FROM THE NORTH AMERICAN NATIONAL BIRTH DEFECTS PREVENTION STUDY PUBLISHED OVER A YEAR AGO. LOOKING AT 19,000 WOMEN WHO WERE AFFECTED BY ONE BIRTH DEFECT. UNDER #% USE CHROMEAFINE COMPARED TO 6 AND A HALF THOUSAND CONTROLS, COMPARED TO THE CHROMEAFINE. THE KEY INFORMATION HERE, THESE ARE THE CONGENITAL ANOMALY, IN BLUE HIGHLIGHTED THOSE WHICH RELATED TO MULTIPLE PREGNANCIES BUT ESSENTIALLY THE USE OF CHROMEAFINE DOES APPEAR INCREASE RISK FOR CENTRAL NERVOUS SYSTEM AND CARDIAC ANOMALIES. THE PROBLEMS THOUGH, IT'S DIFFICULT TO DETERMINE THE REASON FOR USE OF CHROMEAFINE, DIFFICULT TO SEE WHICH PATIENTS ACTUALLY HAVE POLYCYSTIC OVARY SYNDROME, NO INFORMATION ON OBESITY DIET FOLIC ACID SUPPLEMENTATION, KEY ASPECTS TO THE RISK OF DEVELOPMENT OF CONGENITAL ABNORMALITIES. FROM RICK LEGRO IT HAS A LONG HALF LIFE COMPARED TO AROMATASE INHIBITERS TO WHICH HAVE SHORTER HALF LIFE THIS IS WHY THEY MAYBE MORE ATTRACTIVE BECAUSE THEY'RE ELIMINATED BEFORE IMPLANTATION AND THEREFORE LESS LIKELY TO HAVE TERATOGENIC RISK. BE AS A RESULT OF ABOUT TRACT IN THE 2005 ASRM MEETING, THERE WERE CONCERNS ABOUT ABNORMALITIES LOCKED AT OVER 500 BABIES BORN AS A RESULT OF (INDISCERNIBLE) TREATMENT, 400 BABIES FROM CHROMEAFINE REASSURING WITH RESPECT TO AROMATASE INHIBITORS AN THOSE TREATED WITH CHROMEAFICNE HAVE INCREASE RISK OF CARDIAC ANOMALIES SO LOOK FORWARD THE RICK AND COLLEAGUES ON THAT YOU ARE AROMATASE INHIBITOR STUDY NEXT YEAR WHICH WILL BE REASSURING ONCE AGAIN. SO THE OTHER ISSUE RELATING TO AROMATASE IS A LOWER OVERALL RISK FOR MULTIPLE PREGNANCY. MULTIIT WILL PREGNANCY THAT ACTUALLY RESULTS IN HUGE HEALTH BURDEN WITH RESPECT TO NEONATAL MORTALITY AND MORBIDITY YOU SHOULD BE FAMILIAR WITH THIS AND TIME DOESN'T ALLOW ME TO EXPAND BUT RESPONSIBILITY AS FERTILITY IS OBVIOUSLY TO REDUCE THE RISK OF MULTIPLE PREGNANCY AND WHICHEVER WAY WE CAN. TO CONCLUDE, WHEN WE THINK OF THE OUTCOMES PREGNANCY POLYCYSTIC OVARY SYNDROME IT'S IMPORTANT TO TEASE OUT THE DIFFERENCE BETWEEN NATURAL VERSUS ASSISTED CONCEPTION, THE POTENTIAL RISK OF DRUGS IN PARTICULAR CITRATE WHICH MAYBE ASSOCIATED WITH INCREASED RISK OF CONGENITAL ANOMALIES. RISKS TO MULTIPLE PREGNANCY, WHEN WE THINK ABOUT IT TO PCS THERE MAYBE EFFECTS ON OOCYTE DEVELOPMENT, THE EPIGENETIC EFFECTS THAT WE HEARD ABOUT YESTERDAY RELATING TO NEUTRAL ENVIRONMENT. AND THE RISKS TO MOTHER AND ALSO RISK TO BABY ASSOCIATED WITH GESTATIONAL DIABETES AN PREECLAMPSIA. BUT THERE WAS STILL A NUMBER OF UNANSWERED QUESTIONS. AND IT'S VERY IMPORTANT I THINK TO STRATIFY THE EFFECTS OF ETHNICITY, OBESITY WHICH IS INADEQUATELY REPORTED IN THE OUTCOME STUDIES, AND OTHER FERTILITY FACTORS IN PARTICULAR DIET AND USE OF FOLIC ACID WHICH HAS BEARING ON CONGENITAL ANOMALY RISK. METFORMIN THROUGH PREGNANCY WHICH HAS BEEN STUDIED BUT MANY OUTCOME PUBLICATIONS THAT'S NO MENTION WHETHER METFORMIN IS TAKEN THROUGH PREGNANCY. IMPORTANT TO CONSIDER THE DIFFERENT PHENOTYPES OF PCOS AND BEARING THEY HAVE ON REPRODUCTIVE OUTCOME. ONE QUESTION STILL UNANSWERED IS WHETHER OR NOT MORE SCREENING IS NECESSARY DURING PREGNANCIES OF WOMEN WITH PCOS, INFORMATION FROM THE FOLLOW-UP STUDIES SUGGEST SHOULD BE SCREENING THESE PATIENTS IN MORE DETAIL BUT NO CLEAR GUIDANCE ON. THIS WE HAVE TO THINK LONG TERM SCREENING OF OFFSPRING AND ALSO CONSIDERING WHAT ARE LONG TERM OUTCOMES FROM WOMEN WITH PCOS WHO DEVELOP PROBLEMS DURING PREGNANCY, MAYBE ATRYK FOR LONGER -- RISK FOR METABOLIC AND CARDIOVASCULAR PROBLEMS. THANK YOU. [APPLAUSE] >> SO NOW OUR FINAL SPEAKER FOR THIS PROGRAM THEN WE'LL TAKE QUESTIONS. OKAN YILDIZ WILL TALK ABOUT FAMILY SCREENING. >> I WOULD LIKE TO THANK THE ORGANIZERS FOR THE I WERE VISITATION TO PARTICIPATE IN THIS WORKSHOP. I TRULY APPRECIATE BEING HERE. TODAY I'M GOING TO DISCUSS THE ROLE OF FAMILY SCREENING IF WILL IS ANY ROLE, IN PCOS. SO I WANT TO START WITH THE DEFINITION OR SUGGESTION THE U.S. PREVENTIVE SERVICES TASK FORCE IS USING WHEN IT COMES TO SCREENING A DISORDER. ANY SCREENING PROGRAM MUST BE BASED ON BENEFITS OF EARLY DETECTION AND TREATMENT BEYOND THE HEALTH IMPROVEMENT SEEN IF DIAGNOSIS AN TREATMENT OCCURRED DURING USUAL PROCESS OF CARE. FOR FAMILY SCREENING OF PCOS IN THE FIRST DEGREE RELATIVE IT IS OF THESE WOMEN, BY DEFINITION THAT SHOULDN'T BE ANY SIGNS OR SYMPTOMS AND IF WE SCREEN THOSE INDIVIDUALS, THEN BIG QUESTION COMES WHETHER WE SHOULD BE COUNSELING THEM. ON WHAT WE FIND. AND ANY PREVENTIVE MEASURES BASED ON AVAILABLE EVIDENCE WE CAN USE IN THESE INDIVIDUALS. AND WHAT ARE BENEFITS AND HARMS OF THIS KIND OF SCREENING BECAUSE THERE COULD BE BENEFIT BUT THERE COULD ALSO BE HARM AS WELL. SO AS OF TODAY, EVEN THOUGH WE HAVE THIS TITLE I WOULD LIKE TO REMIND NO OFFICIAL RECOMMENDATIONS OR GUIDELINES FROM ANY SOCIETY. FOR CONCEPT OF OPTIONAL MANAGEMENT, THERE ARE NO OFFICIAL RECOMMENDATIONS FOR SCREENING. SO WHAT WILL BE THE RATIONALE IF WE WOULD LIKE TO DO THAT? AS STEVE FRANCE SET THE STAGE WELL, WE WILL DO THAT, WHY ARE WE GOING TO DO THIS? WHAT ARE WE GOING TO MEASURE AND HOW WE WILL DO THIS. WE CAN ALSO ADD WHEN AS WELL. WHAT ARE GAPS IN METHODOLOGY THAT WE HAVE FROM THE FAMILY STUDIES OF PCOS. SO TO ANSWER THE QUESTION WE COME UP WITH TWO IMPORTANT RESEARCH QUESTIONS. NUMBER ONE BEING IS PCOS MORE COMMON IN FIRST DEGREE RELATIVES IN WOMAN THOUGH THERE ARE STUDIES SHOWING SOME FEATURES ARE MORE COMMON IN THE RELATIVES OF THOSE WOMAN. THIS ISSUE IS NOT SYSTEMATICALLY REVIEWED. IS CARDIO METABOLIC RISK INCREASED IN FIRST DEGREE RELATIVES WOMAN WITH PCOS AND IN THAT REGARD WE CAN TAKE GLUCOSE HOMEOSTASIS, GLUCOSE INTOLERANCE, HYPERTENSION DISLIPIDEMIA AND OTHER SURROGATE MARKERS. SO BECAUSE THE FIRST WORKSHOP OF THIS KIND WAS IN 1990, WE SEARCH THE NATIONAL LIBRARY OF MEDICINE STARTING FROM JANUARY 1990 TO NOVEMBER 20 12789 AND WE LOOKED AT THE ARTICLES PUBLISHED IN ENGLISH. KEY WORDS WAS PCOS, FIRST DEGREE RELATIVE, MOTHER FATHER SISTER BROTHER AND ALL THESE SURROGATE MARKERS YOU CAN THINK OF ANY RISK OR DISORDER THAT WOULD BE ASSOCIATED WITH PCOS. WE USE SELECTION CRITERIA. STUDIES USING ANY SETS OF DIAGNOSTIC CRITERIA, NIH, ANDROGEN SOCIETY AND ROTTERDAM. ALL STUDIES WITH CONTROL GROUPS WERE INCLUDED BUT WHEN IT COMES TO THE PREVALENCE OF PCOS WE HAVE INCLUDED STUDIES WITHOUT CONTROL GROUPS. WHY WOULD ADULT FIRST DEGREE RELATIVES, MOTHERS FATHERS SISTER AND BROTHERS ARE INCLUDED THOSE IN INFANCY CHILDHOOD I WON'T GET INTO ANY INFORMATION FOR THOSE INDIVIDUALS, IT WAS ELEGANTLY COVERED BY DR. PETER MAN. STUDIES WITH NO OBJECTIVE DATA OR WITH HISTORICAL DATA ONLY REGARDING DIAGNOSIS OF PCOS OR OTHER YOU COMES OF INTEREST. SO WE EXACTED THE GENERAL STUDY PARAMETERS AND DEMOGRAPHIC CHARACTERISTICS OF THE STUDY POPULATION. STUDY LOCATION, HBMI, ETHNICITY AND NUMBER OF PARTICIPANTS. THE CRITERIA FOR DIAGNOSIS AND NUMBER OF INDIVIDUALS AND OTHER DISORDERS ASSOCIATED WITH THE SYNDROME. BARRIERS FOR SURROGATE MARKERS INCLUDING FASTING INLYNN, TWO HOUR INULINS, LIPID LEVELS. THEN OUTCOME OF INTEREST WE CHOSE WAS PRIME RATE PREVALENCE OR INCIDENCE OF PCOS TYPE 2 DIABETES, IGT HYPERTENSION AND DISLIPIDEMIA, WE HAVE SURROGATE MARKERS OF INSULIN RHESUS TAN, BLOOD PRESSURE AND LIPO PROTEIN LEVELS. FOR STATISTICAL ANALYSIS WE USE (INAUDIBLE) AND WE CALCULATED THE STANDARDIZED MEAN DIFFERENCE UNDER THE FIXED EPIC MODEL AND WE ALSO TAKE INTO ACCOUNT HETEROGENEITY EFFECT FOR THE VARIATION BETWEEN STUDIES AN DEPENDING ON THOSE VARIATION WE USE FIXED OR RANDOM FX MODEL. AND PROPORTIONS FOR PREVALENCE OF PCOS IN MOTHERS AN SISTERS. SO IN THIS SYSTEMATIC REVIEW ANALYSIS THERE WERE 23 STUDIES AN MORE THAN 30 WERE EXCLUDED IF THAT REGARD SO IF YOU LOOK AT THE BIBLIOGRAPHY PROVIDED BY NATIONAL LIBRARY OF MEDICINE 65 PAPERS COULD BE RELATED TO THE TOPIC OF THE SPECIFIC TOPIC. THIS SLIDE ILLUSTRATES HOW MANY STUDIES ARE EVALUATING PARAMETERS, AS YOU CAN SEE FOR EXAMPLE WHEN IT COMES TO THE PREVALENCE OF PCOS STUDIES ASSESS SISTERS AN P MOTHERS, WHETHERREN YOU SEPARATE DIABETES AND IGT YOU SEE NUMBER OF STUDIES HERE DIFFERENT STUDIES ARE USING DIFFERENT PARAMETERS, DIFFERENT SURROGATE MARKERS FOR INSULIN RESISTANCE FOR HYPERTENSION AND FOR LIPID LEVELS. MORE IMPORTANT ISSUE BECAUSE OF THESE DIFFERENCES IN THE MEASUREMENTS OF DIFFERENT PARAMETERS, WE CAN METABOLIZE ONLY STUDIES FOR WHICH PARAMETERS MORE THAN TWO STUDIES SO I WOULD LIKE TO EMPHASIZE THERE ARE SINGLE STUDIES WE COULDN'T INCLUDE IN THIS ANALYSIS. WHEN WE LOOK AT PREVALENCE OF PCOS, THE PREVALENCE RANGE FROM 8 TO 35% AND BILL ESTIMATED PREVALENCE WAS 20% BUT ONE THING TO EMPHASIZE HERE IS AGAIN DEFINITION OF PHENOTYPE THE DIAGNOSIS BECAUSE THERE ARE PRE-MENOPAUSAL AND POST MENOPAUSAL MOTHERS, WHEN I COMES TO SISTERS THERE ARE WOMAN WHO HAVE USED HORMONEAL CONTRACEPTIVES WHICH UNDERESTIMATE PREVALENCE RATE AS WELL. WHEN YOU LOOK AT PREVALENCE OF DIABETES WHAT WE SEE HERE IS EVEN THOUGH THE ODD RATIO IS 1 PONTIUS PILATE 5 IT'S NOT STATISTICALLY SIGNIFICANT BUT IGT YOU SEE IT IS SIGNIFICANT THOUGH THE NUMBER WE HAVE HERE ARE QUITE SMALL. WHEN IT COMES TO SURROGATE MARKERS INCLUDING FASTING AND HOHO IR, THEY ARE SIGNIFICANT WHEN YOU USE THIS, IF YOU COME UP WITH A NUMBER OF .2, IT'S A SMALL EFFECT, IF YOU COME UP WITH A NUMBER .5 IT'S MEDIUM EFFECT. IF IT IS BIGGER THAN .8, THEN IT'S LARGE EFFECT. AS YOU CAN SEE, MOTHERS SEEM TO HAVE INSULIN RESISTANCE. LOOKING AT HYPERTENSION, THE RISK IS CRANEsED. 1.6 IS THE NUMBER FOR THE ODDS RARE YES, MA'AM FOR DISLIPIDEMIA WE COULDN'T FIND ANYTHING SIGNIFICANT. FOR SYSTOLICDFROM PRESSURE IT WAS INCREASED IN MOTHERS. ESPECIALLY TOTAL CHOLESTEROL AN TRIGLYCERIDES SEEM TO BE INCREASED IN MOTHER BUT HDL LEVELS ARE SIMILAR BETWEEN MOTHERS AND CONTROLS. WHEN WE COME TO SISTER IT IS PREVALENCE RANGES FROM 13 TO 76% BUT HUGE INFLUENCE OF HORMONEAL VIEWS AND AGE OF THE SISTERS BUT THE POOL PREVALENCE IS 27% FOR THIS GROUP OF WOMAN. WHEN WE LOOK AT FASTING INSULIN AND HOMOIR LEVELS STUDIES TELL US THERE'S INSULIN RESISTANCE IN FEMALE FIRST DEGREE RELATIVES BUT BECAUSE IN MOST OF THE STUDIES THOSE INDIVIDUALS ARE YOUNG SISTERS WE DON'T SEE THE OUTCOME DIABETES OR IMPAIRED GLUCOSE TOLERANCE. FOR SYSTOLIC AND DIASTOLIC BLOOD PRESSURE WE DIDN'T DETECT DIFFERENCE BUT CHOLESTEROL LEVELS SISTER OF PCOS SEEM TO HAVE HIGHER CHOLESTEROL LEVELS COMPARED TO H AND BMI MATCH CONTROLS. THOUGH PREVALENCE FOR DIABETES AN IGT TENDS TO INCREASE WHEN YOU ADD UP ALL THESE STUDIES TOGETHER, THERE IS NO STATISTICAL SIGNIFICANCE FOR ANY AND I CAN GO INTO DETAILS OF THAT. BUT WHEN YOU MEASURE FASTING INLYNN OR SURROGATE MARKERS YOU CAN SEE FATHERS ARE MORE INSULIN RHESUS TAN COMPARED TO CONTROLS. FOR HYPERTENSION AND DISLIPIDEMIA, WE DON'T SEE STATISTICALLY SIGNIFICANT INCREASE RISK. THEY HAVE SIMILAR LEVELS FOR CONTROLS BUT DIASTOLIC BLOOD PRESSURE HAVE INCREASED LEVEL. WHEN IT COMES TO CHOLESTEROL THEY HAVE HIGHER CHOLESTEROL LEVELS COMPARED TO CONTROLS OF SIMILAR H AND BMI. THOUGH THE RISK SEEMS INCREASED IT DOESN'T REACH STATISTICAL SIGNIFICANCE BUT THE HOMO IR ARE INCREASED IN BROTHERS OF WOMEN WITH PCOS AND ALSO HAVE INCREASED PREVALENCE OF METABOLIC SYNDROME, THERE ARE SOME STUDIES ASSESSING PRE-LENS OF METABOLIC SYNDROME, SOME TRYING THE ASSESS INDIVIDUAL COMPONENTS OF THE METABOLIC SYNDROME AND BOTH. FOR SYSTOLIC AND DIASTOLIC PRESSURE, THERE'S INCREASED SYSTOLIC IN BROTHERS. FOR TOTAL LDL CHOLESTEROL THESE BROTHERS HAVE HIGHER LDL CHOLESTEROL COMPARED TO MATCH CONTROLS. SO WHEN I TRIED TO SUMMARIZE FINDINGS WE SCREEN THE FIRST DEGREE RELATIVES OF WOMAN WITH PCOS, MOTHERS AN SISTERS INCREASE PREVALENCE OF PCOS AND THE AVERAGE RANGES ARE BETWEEN 20 TO 27%. THOUGH INDIVIDUAL STUDIES SHOW INCREASE PREVALENCE RATES WHEN YOU PUT THEM TOGETHER THE DATA AT THIS POINT DOES NOT REACH TO ANY STATISTICAL SIGNIFICANCE BUT MOTHERS OF POS HAVE HIGHER IGT. THE MOTHERS OF PCOS HAVE HIGHER PREVALENCE OF HYPERTENSION, WE DONE HAVE ANY DATA FOR SISTERS AN BROTHERS YET, AGAIN, THESE ARE YOUNG INDIVIDUALS IS MEASUREMENTS OF BLOOD PRESSURE SHOW INCREASED LEVELS BUT PREVALENCE OF HYPERTENSION WE DON'T HAVE ANY DATA FOR THAT. FOR LIPIDS IN BOTH MOTHERS SISTERS FATHERS AND BROTHERS OF WOMAN WITH PCOS THE LIPID LEVELS SEEM TO BE INCREASED. SO BASED ON THIS, WHAT KIND OF INFORMATION WE HAVE AND WHAT KIND OF INFORMATION WE NEED, FIRST THERE ARE VERY FEW STUDIES LIMITS RESEARCH ADDRESSING THE ROLE OF FAMILY SCREENING IN PCOS. MOST OF THESE DATA COME FROM THE PHENOTYPE AND GENOTYPE ASSOCIATION AND HERITABILITY MODEL SO MOST OF THESE STUDIES DO NOT HAVE THE HYPOTHESIS TO TEST WHETHER DISORDER IS INCREASED IN FIRST DEGREE RELATIVES OF WOMAN WITH PCOS. ALL THE STUDIES AVAILABLE ARE PROFESSIONAL SO WE DON'T HAVE ANY FOLLOW-UPS STUDIES THOUGH WE TRIED TO SCREEN ANY PARAMETER WE DON'T KNOW WHETHER IT WOULD CONNECT TO OUTCOME IN THOSE INDIVIDUALS. AND AT THIS POINT WE DON'T HAVE SUFFICIENT EVIDENCE TO PROJECT IMPACT OR BENEFIT OF SCREENING IN FIRST DEGREE RELATIVES. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] (OFF MIC) >> I GUESS ROB HAS GONE BUT ADAM AND RICK AND STEVE FRANKS -- IF I CAN HAVE ALL OF YOU COME UP, WE'LL DO SOME GENERAL QUESTIONS AN ANSWERS FOR ABOUT AN HOUR OF THIS SESSION. I THINK THAT'S ABOUT IT. PROBLEM PROBABLY HAD TO LEAVE. >> GREAT. >> ANY GENERAL QUESTIONS FROM THE PANEL MEMBERS >> RICK, YOU TALKED A LITTLE BIT ABOUT SURGICAL APPROACHES, THIS SEEMS TO BE A GENERAL TREEN TOWARDS MORE DRILLING AND LESS -- CAN YOU TALK ABOUT WHAT'S GOING ON IN THE FEEL OF SURGICAL APPROACHES TO PCO AN RESEARCH QUESTIONS, WHAT ARE IMPORTANT ISSUES WE'RE FACING? >> AS SURGERIES BECOME INCREASINGLY LAPAROSCOPIC OR ROBOTIC, DOES EVERYBODY HEAR ME? WE PROCEEDED TO WHERE YOU DRILL HOLES WITH ELECTRIC LASER, ADAM DISTUDIES SHOWING THAT DESTROYING TISSUE IS AS EFFECTIVE AS DESTROYING TISSUE ON BOTH OVARIES. WE HAVE SEEN IN PRIMARILY CHINESE HAVE BEEN DOING THIS TRANSVAGINAL THROUGH OOCYTE RETRIEVAL AND DESTROYING TISSUE THAT WAY. SO THESE THINGS ALL LOOK PROMISING FROM STANDPOINT OF U.S., ONE OF THE REASONS I THINK THAT WE SEE A LOT LOWER UTILIZATION OF SURGERY IS THAT IN STATES THAT DON'T COVER INFERTILITY INSURERS TEND TO BE EXCLUDED FROM INSURANCE COVERAGE. ALSO WHEN YOU LOOK AT ONE OF THE RESEARCH QUESTIONS, WOULD YOU DO BETTER LONG TERM FROM OVARIAN PROCEDURE TO DESTROY TISSUE OR ONE OR TWO CYCLES OF IVF? AND BASICALLY A SURGERY WOULD BE ABOUT THE COST OF TWO CYCLES OF IVF SO A LOT OF PEOPLE WHEN THEY GET TO THE POINT THEY DON'T RESPOND TO OVULATION INDUCTION MEDICINE, IN THE PAST WERE PART IRF THE TO SURGERY WE SKIP THE SURGICAL STEP. >> ONE IMPORTANT RESEARCH QUESTION, COMPARE SUBPOENA ON INITIAL SURGICAL THERAPY VERSUS (INDISCERNIBLE), WHAT QUESTIONS IN HOW CLINICS APPROACH PATIENT WHO COMES IN THE OFFICE AND SAYS I THINK I HAVE POLYCYSTIC OVARY AND I WANT TO GET PREGNANT NEXT MONTH? >> THE BIG ISSUE IS WHAT SECOND LYNN THERAPY IS FOR SOMEBODY THAT FAILS AN ORAL AYEN BECAUSE THEY OVULATE AND DO NOT CONCEIVE OR DO NOT RESPOND AND OVULATE. THAT NEXT LEVEL IS WHERE INFERTILITY TRIALS SHOULD HEAD. SO IS THERE A -- IN THE THREE FORMS WE LOOK AT THIS MONTH IVF VERSUS SURGERY VERSUS INJECTABLE GONADOTROPINS TO ESTABLISH RISK BENEFIT AS WELL AS RELATIVE COST EFFECTIVENESS OF THESE THREE THERAPIES. WOULD BE VERY IMPORTANT TRIAL. >> IF IF I MAY ADD TO THIS, I AGREE, WITH EVERYTHING THAT RICK SAID. ONE ADVANTAGE IS IT'S ASSOCIATED WITH MINIMAL RISK FOR MULTIPLE PREGNANCY AND YOU DON'T PROVIDE THE MONITORING NECESSARY FOR OVULATION INDUCTION WITH GONADOTROPIN AN CERTAINLY FOR IVF THERAPY. SO THOSE PATIENT WHOSE FIND IT DIFFICULT REGULAR MONITORING THAT'S A BENCH THE LARGEST IS THE MILLION CENTER STUDY PUBLISHED IN BMJ FROM NETHERLANDS WHICH TOOK A PRAGMATIC APPROACH, RAN TOMMIZED RECEIVE OVARIAN DIATHERMY OR GONADOTROPIN THERAPY, THEY ACTUALLY CONCEIVED MORE QUICKLY BUT THE 12 MONTH CUMULATIVE CONCEPTION RATE WAS THE SAME AND BENEFIT FOR OVARIAN (INAUDIBLE) WAS LOW MULTIPLE PREGNANCY RATE SO IT HAS A ROLE. BUT THOSE PATIENTS WHO HAVE ACCESS TO CAREFULLY MONITORED OVULATION INDUCTION WITH GONADOTROPIN PROBABLY CONCEIVE MORE QUICKLY. BUT THE KEY THING IS KEEPING THE PREGNANCY RATE DOWN. >> REMEMBER (INAUDIBLE) ABOUT THIS. YOU'RE POINTING OUT THAT INCREASED NUMBER OF FOLLICLES MAYBE INCREASE FECAL CELLS AND TESTOSTERONE PRODUCTION. YOU POINTED OUT YOU HAVE DECREASED NUMBER OF FOLLICLES, PRESUMABLY DECREASED MASSIVE FETAL CELLS FROM DOUSING WHATEVER YOU'RE DOING. ONE OF Y'ALL SUGGESTED THIS MAY ALTER THE AMH TO THE THE PERIMENOPAUSE AREA. SO THIS IS NATURAL HISTORY DISEASE SO YOU GET TO PRIMARY OVARY VERSUS -- IF YOU LOOK AT GLUCOSE TOLERANCE AND OTHER THINGS THE LAST COUPLE OF DAYS BY DECREASING THE NUMBER OF FOLLICLES DOES H THAT CHANGE THE -- ARE YOU AT A DIFFERENT LEVEL BECAUSE YOU'RE DOWN BY THIS NUMBER OF FOLLICLES? >> THERE'S NUMBER OF STUDIES IN ENDOCRINE AND REPRODUCTIVE AND METABOLIC PARAMETERS AFTER OVARIAN SURGICAL PRO PROCEDURE AND IMMEDIATE DROP IN TESTOSTERONE. I HAVEN'T SEEN THIS STUDY WITH, AMH BUT AS YOU SUGGESTED IT WOULD GO DOWN BUT METABOLIC FACT TOES DO NOT CHANGE AS A RESULT OF LOSS OF OVARY. >> OVER 10, 15, 20 YEARS WHAT HAPPENS TO AMH? Q. THE OUTCOME IS LONGITUDINAL STUDIES. WITHIN QUESTION IS AS A WOMAN PROGRESSES SHE HAS INCREASE INDENSE OF DIABETES, CARDIOVASCULAR, MAYBE, MEMBER NOT SO THE CRUX DO YOU HAVE THOSE OUTCOMES COMPARED TO STANDARD THERAPY SOME OTHER FORM? >> THE ISSUE HERE IS A HUGE CHANGE IN THE TECHNIQUE. THE NEXT 30, 30 YEARS PERFORM WHICH THEY REMOVE UP TO 50% SOMETIMES 75% OVARY. THOSE PATIENTS ARE STUDIED LONGITUDINALLY IN THE CARDIOVASCULAR OUTCOME STUDY THAT'S BEEN REFERRED TO. WHEN WE DO OVARIAN DI -- WE'RE NOT TRYING TO DESTROY OR REMOVE ANY PART OF THE OVARY OR FOLLICLE POOL, YOU JUST NEED A LITTLE BUZZ AND I THINK IT INDUCES RELEASE OF GROWTH FACTOR THAT SENSITIZE FOLLICLE TO ENDOGENOUS CIRCULATING GONADOTROPIN SO WHAT WE DO WITH VARYIAN (INAUDIBLE) IT'S MINUTE MALL SURGERY COMPARED WITH THE OLDER PRACTICE OF (INAUDIBLE). >> THERE WAS NO LONG TERM CHANGE IN WHATEVER -- >> AS RICARDO ALLUDED TO, LEVINTHAL HAD ONLY SEEN 75 PATIENTS IN A LIFETIME, THERE ARE LONG TERM DATA FROM NETHERLANDS WHICH THE WOMEN THAT UNDERWHEN OVARIAN SURGERY BY THE TIME THEY REACHED MENOPAUSE HAD THE SAME THAN FOR FERTILITY AND SAME HEALTH PROFILE AS CONTROLS WHO HADN'T. IF YOU ASK DOES IT IMPACT LONGER TERM HEALTH? I DON'T THINK SO. HAD INCREASED RISK OF DIABETES.01„ >> THE ACUTE STUDY DID NOT CHANGE INSULIN RHESUS TAN AT ALL. SO THEY DIDN'T DO IT SHORT TERM, IT WAS LONG TERM. >> I WANT TO THROW OUT THE OTHER MECHANISM THROWN AROUND WHY WEDGE RESECTION WORKS AND THE PCS OVARY IS NOT CHOCK FULL OF FOLLICLES, IT'S ALSO RELATIVELY STEMAL DENSE AND FIBROTIC SOME THEORIZE THE LOSS OF TISSUE CREATES A GAP WHICH A FOLLICLE CAN EXPAND. OTHERWISE THERE'S NO PLACE FOR IT TO GO. >> THANK YOU VERY MUCH. IT'S A COMMENT FOR ADAM AND PERHAPS THE QUESTION ALSO FOR RICK. I APPRECIATE THE CIRCUMSPECT WAY, (INAUDIBLE) HALF LIFE. I BELIEVE CATEGORY X DRUG HERE WHICH IS NOT TO BE USED IN PREGNANCY. HAND HAS A HALF LIFE AROUND FIVE DAYS. THE (INAUDIBLE) INDICATES TERATOGENIC TO EMBRYO DESCENDING THE FLOWIAN TUBE. AND WHEN -- FALLOPIAN TUBE, IT'S EASY FOR THE FETUS TO SEE IT. SO I THINK THE FOLLOWING THAT UP, I FIND THE PAPER EXTREMELY INTERESTING FROM 2011. ONE LIMITATION OF THE STUDY, ALSO REGISTRY BASE CASE CONTROL STUDY. SO SUBJECT TO SOME RECALL BIAS. BUT INDICATE WE ALSO FOUND THE SAME EFFECT. IN OUR NEW ENGLAND JOURNAL OF MEDICINE PAPER PUBLISHED IN MAY CONCEPTION, 320,000 POPULATION CONTROLS. INTERESTINGLY ONE IMPORTANT POINT IS IS IT A PATIENT OR TREATMENT AFFECT. WE FOUND OVULATION I WERE DUCTD IF A CLINIC IN A STRICT CONTROLLED CIRCUMSTANCE WASN'T ASSOCIATED WITH INCREASE RISK OF BIRTH DEFECTS IN SMALL SUBSET OF PEOPLE WHO WERE GIVEN A SCRIPT OF CLONOPIN AND TOLD TO GO HOME AN POSSIBLY WITH REPEAT SCRIPTS AS WELL, OMMON PRACTICE IN OUR COUNTRY, THERE'S A PREVALENCE IN THOSE DEFECS OF 18% ODDS RATIO OF 3. THE TALK IS TIMELY AND PEOPLE GOING USING CLONOPIN TO RELIEVE THEMSELVES OF HANDICAP OF INFERTILITY, THE LAST THING WE WAN IS TO ADD TO BURDEN OF CATASTROPHIC ADVERSE EVENT, HOWEVER RARE THEY MAY BE. >> THANK YOU. ANOTHER RESEARCH QUESTION RELATED TO USE OF FOLIC ACID AN ADVISE TO GIVE TO OUR PATIENTS, DIET AND TO LATE METABOLISM IS KEY. WE ADVICE IN THE UK NOT SURE THE GUIDANCE HERE TO TAKE 400 MICROGRAMS OF TO LATE. THOSE OBESE AND WITH DIABETES TAKE FIVE MILLIGRAMS THOSE WITH EPILEPSY HAS TO HAVE HIGH DOSE. WHILE THERE'S NO DATA MAYBE THOSE WITH POLYCYSTIC OVARY SYNDROME METABOLIC PROBLEMS MAY BENEFIT FROM INCREASED FOLIC ACID, JUST A THOUGHT. BUT MAY HAVE A BEARING ON CONGENITAL ANOMALY RISK AS WELL. >> IF I CAN COMMENT GENERALLY INFERTILITY TRIALS RARELY DO THEY REPORT ANYTHING BEYOND CLINICAL PREGNANCY AND EVEN LIVE BIRTH IS REPORTED FETAL COMPLICATIONS ARE REPORTED. SO AS PART OF THE REPRODUCTIVE MEDICINE NETWORK WE'RE DOING TWO -- WE COMPLETED RANDOMZATION OF OVER 1600 WOMEN OF WHICH WE'RE GOING TO HAVE 5, # HUNDRED PREGNANCIES AND THOSE THAT PHOTO TERM AS PART OF THE FDA IND WE HAVE TO HAVE INFANT EXAMINED BY A DEVELOPMENTAL PEDIATRICIAN OR GENETICIST TO SCREEN ANOMALIES. WHEN WE PUT THE RESULTS OF TWO TRIALS ONE INFERTILITY, YOU NEED A CERTAIN END TO DO THAT, AS YOU KNOW FROM YOUR OWN STUDY. BUT FIVE OR 600 LIVE BIRTHS WILL BE A GOOD START. >> I HAD A SMALL COMMENT. PREVALENCE OF BIRTH E DEFECTS DEPENDS GREATLY ON FOLLOW-UP, AND THAT WE FOUND WE CAN -- WE DID SENSITIVITY ANALYSIS AND (INAUDIBLE) HALF THE DEFECTS BECAUSE WE FOLLOWED UP TO FIVE YEARS (INAUDIBLE) AND IF WE GO OUT TO ONE YEAR, HALF. SO POSSIBLY IT'S A CAVEAT, SOME DEFECTS WON'T BE REPLICATED IN A STUDY WITH SHORE TERxh$ FOLLOW-UP CARDIOVASCULAR -- >> THE NEXT QUESTION YOU DIDN'T TALK ABOUT IT BUT THERE'S A QUESTION ABOUT ARE YOUR THOUGHTS ON PROGRESSION TO DIABETES WITH STATIN TREATMENT? >> NO DATA, NO THOUGHTS REALLY. >> YOU -- >> I DIP MENTION STAFF, >> BECAUSE YOU DON'T BELIEVE IN IT? >> LOOK AT THE DATES WE HAVE, SUGGEST MAKEUP PROVEN IN TERMS OF -- MAYBE IMPROVEMENT IN PRODUCTION OF -- BUT NO CHANGE IN METABOLIC PROFILE OTHER THAN OF COURSE DEALING WITH ASSOCIATED LIPID -- HYPERLIPIDEMIA. >> IT RELATES TO THE FACT THERE ARE DATA THAT STATINS INCREASE THE RISK OF DEVELOPING DIABETES. SO THAT'S IN THIS HIGHER RISK GROUP. >> IT'S NOT SOMETHING ONE USE READILY IN WOMEN OF REPRODUCTIVE AGE. >> QUESTION FOR WITHDRAWAL BLEEDING, WOULD YOU PREFER TO USE ORAL CONTRACEPTIVE PILLS OR PERIODIC PROGESTERONE, CONCERNS WITH OCT AND DOES IT MAKE DIFFERENCE IN YOUR SPECIMEN? >> THERE ARE TWO INSTANCES FOR DRAW BLEED. TO PREVENT END DOEMETRIAL CANCER SO FOR THAT I USE THE ORAL CONTRACEPTIVE PILL FOR BENEFITS BUT I ALSO GOT -- THIS TIME I TALK A LITTLE BIT BUT THERE'S EVIDENCE THAT THE ORAL COP TRAY CEPTIVE PILL DOES NOT EXACERBATE EITHER TYPE 2 DIABETES RISK OR MET BOLL PIC PROFILE WITH PCOS SO THAT'S A MUTE CLINICAL ISSUE. SO I WOULD PREFER THE ORAL CONTRA ACCEPT PILL. FOR THE SECOND ISSUE OF THE WITHDRAW BLEED FOR PRIOR OR DURING INFERTILITY TREATMENT CYCLE I'M GOING WITH MY HUNCH AND I TEND NOT TO USE IT AND GO STRAIGHT TO NEXT LINE OF DRUG OR NEXT DOSE OF DRUG TO INDUCE OVULATION BUT WE NEED A TRIAL TO ANSWER THAT ISSUE IS A WITHDRAW BLEED DURING INFERTILITY TESTING POTENTIALLY HARMFUL. >> SO I WOULD LIKE TO CONGRATULATE YOU FOR DOING A STUDY BECAUSE SOMETHING HAS TO -- BUT YOUR CONCLUSION, I WASN'T CLEAR. SHOULD WE SCREEN OR NOT SCREEN? BASED UPON YOUR STUDY? >> IF I THINK IT WAS SHORTER ON THE PANEL. BASED ON AVAILABLE EVIDENCE WHEN IT COMES TO SCREENING FOR ANYTHING, IT SHOULD BE RELATED TO THE OUTCOME. SO FOR ANY FIRST DEGREE RELATIVE I DON'T THINK WE HAVE ENOUGH EVIDENCE TO SCREEN ANY DISORDER AT THIS POINT SO BEING A RELATIVE OF A WOMAN WITH PCOS I DON'T THINK ADDS MUCH TO RISK OF ANY CARDIO METABOLIC DISORDER AT THIS POINT. >> SO QUESTION HERE ABOUT THE TREATMENT OF PCOS WITH METFORMIN AND (INDISCERNIBLE) IF SHE GETS WHAT DATA EXISTS TO SUPPORT FOR CONTINUING OR DISCONTINUING, SO SHE GETS PREGNANT, SHOULD YOU CONTINUE THE METFORMIN OR NOT? ANYBODY, ADAM WANT TO TAKE THAT? >> ON THE BASIS OF THE PUBLISHED EVIDENCE, NO. >> YOUR CONCLUSION WAS THAT THERE REALLY IS NO INCREASE RISK OF MISCARRIAGE IN PCOS? >> THAT'S RIGHT. >> >> I SAW YOUR DATA BUT IT'S OBESE PATIENTS, THE OTHER STUDY EVEN WITH OBESITY DIDN'T SEEM THE MAKE A DIFFERENCE. GENERALLY WE USED USED TO QUOTE IT IN THE OLD DAYS BUT NO LONGER. >> THOSE STUDIES ARE FROM INDUCTION OF OVULATION MAINLY, OBVIOUSLY. AND WITH ASSOCIATED PROBLEMS MENTIONED, MULTIPLE PREGNANCY WHICH CONFOUND THE OUTCOME IN TERMS OF MISCARRIAGE RATES. >> SO THIS QUESTION CAME IN. ANY COMMENTS ON INCREASE RISK OF VENOUS THROMBOSIS FROM PCOS? EXPLANATION FOR INCREASE RISK FOR (INDISCERNIBLE). >> LET ME ANSWER, I WAS ON THE FDA ADVISORY PANEL, SO WAS DR. HOAGER THAT REVIEWED THAT EVIDENCE. FIRST TO WOMEN INCREASE OR DECREASE YES BECAUSE THEY HAVE MULTIPLE RISK FACTORS THAT INCREASE RISK FOR IT. BUT THERE'S LITTLE DATA TO SAY WOMEN WITH PCOS HAVE INCREASED NUMBER OF EVENTS ON THE PILL. THE ONLY STUDY I COULD QUOTE APPEAR MISDEMEANOR THE AMERICAN JOURNAL OF OBSTETRICS AN GYNECOLOGY, SIMILAR TO THE MORGAN STUDY THAT DR. TO BEES SHOWN REVEALED ICD-9 BILLING CODES FROM OUTPATIENT AND IN PATIENT VISITS. WITH PCOS ON THE PILLOWER CHANCE OF BLOOD CLOTTING THAN WOMEN WITH PCOS OFF THE PILL. I ATTRIBUTE THAT TO SELECTION PROPER SELECTION ON BASIS OF PHYSICIAN NOT TO GIVE WOMEN WITH RISK FACTORS THE BIRTH CONTROL PILL AN SELECTION BIAS IS YOU WERE PROTECTED FROM PCOS BY BEING ON THE PILL WHICH IS >> ADVISORY ON CONTAINING OCP SAYING THAT'S LIKELY INCREASED RISK SOMEWHERE IN THE RANGE OF 50 TO 100 PERCENT OF CLOT COMPARED TO FIRST GENERATION PROJESTIN. >> ONE MORE QUESTION, FOR YOU, RICK, WOULD ANYONE -- ANYONE CAN CHIME IN. TREATMENT FOR ANDROGENIC ALOPECIA. >> I THINK YOU SHOULD ANSWER THAT. >> YOU HAVE AS MUCH EXPERIENCE AS ANYONE. IT DOESN'T WORK WELL. MANY MATTER WHAT YOU DO. ONE MISSTALK I SEE IS THAT THEY THINK IT'S LIKE MEN. AND THEY USE (INDISCERNIBLE), IT DOESN'T WORK WITH WHEN FOR REASONS WE DON'T UN, ALPHA REDUCTASE AND SO FORTH, SO WE TEND TO USE AN ANTI-ANTIGEN, WITH IN CONJUNCTION WITH ORAL CONTRACEPTIVE. AMELIORATION RATE WAS VERY LOW. BOB. >> LET ME JUMP INTO IT. FURTHER COMMENT GLAXOSMITHKLINE SO HE TOOK THEIR (INDISCERNIBLE), WHICH IS A TYPE TWO AND POST MENOPAUSAL WOMEN WITH ANDROGENIC ALOPECIA. POST MENOPAUSAL BECAUSE OF REPRODUCTIVE IMPLICATIONS. AND IT WAS COMPLETELY INHE CANTIVE SO DIDN'T DO ANYTHING POST MENOPAUSAL STATE. THAT'S THE ONLY ADEQUATELY POWERED DESIGN TRIAL INTEREST ALLO GENIC ALOPECIA. FOR REASONS WE DON'T UNDERSTAND THEY DON'T WORK IN WOMEN. I WOULD LIKE TO ASK DR. YILDIZ A QUESTION. IT WAS A GREAT META ANALYSIS, WILL THAT BE PUBLISHED? >> NO, IN PREPARATION. >> BUT MAIN QUESTION I HAVE, I'M -- REALLY SURPRISED DIABETES DIDN'T SHOW IN PATHERS. IN OUR STUDY, THREE QUARTERS OF THE FATHERS HAD DIABETES. ONLY HALF THE FATHERS HATD DIABETES HISTORY TO DETECT IT. WHAT ABOUT THE OTHER STUDY? WHAT BROUGHT IT DOWN IN THE OTHER STUDY? HISTORY OR DID THEY DO GLUCOSE TOLERANCE TEST SOMETHING >> VERY GOOD POINT. THANK YOU FOR QUESTION THE QUESTION. THE DATA WE HAVE OVER 200 INDIVIDUALINGS MORE THAN 50% FATHERS HAVING BOTH DIABETES AND IDT, THERE'S ANOTHER STUDY FROM TURKEY, SHOWING THE SAME THING. THE STUDY FROM AUSTRALIA, THEY HAVE A COHORT AND THEY PUBLISH RECENTLY LAST YEAR. OVER 700 INDIVIDUALS THE HISTORY OF DIABETES IN THAT COHORT SEEMS QUITE LOW COMPARED TO ONES WE ASSESS. THEY DON'T HAVE THE OGG DATA, INTERGENERATIONAL 700 INDIVIDUALS, MORE THAN 700 INDIVIDUALS SO WHEN YOU ADD UP THE STUDIES IT DOESN'T COME UP STATISTICALLY SIGNIFICANT INCREASE RISK BUT WE HAVE THE EXPERIENCE WITH FATHERS, MORE THAN 50% WHEN YOU DO THE OGT, IN FACT IF YOU DONE DO THE OGT SIMILAR TO THE PATIENTS WE HAVE, THEY HAVE NORMAL FASTING BLOOD GLUCOSE LEVEL SO WE DETECTED DIABETES BY OGTT IN FATHERS, ANDREA HAS SIMILAR DATA. BUT THERE IS A LARGE STUDY, WE WOULD LIKE TO COMMENTEN THAT. >> JUST TO CLARIFY, WE SAW INCREASED RISK OF (INAUDIBLE) ODD RATIO OF 1.25, 1.26 BUT IT WAS UNDERPOWERED FOR THAT OUTCOME BECAUSE -- >> 12% VERSUS 9.6. >> I CAN'T QUITE REMEMBER BUT WE WEREN'T POWERED FOR THAT OUTCOME. BY CONTRAST, THE EFFECT SIZE REALLY JUMPED OFF THE CHART ENTIRELY CONSISTENT WITH YOUR REVIEW, THERE WAS EXCESS OF HYPERTENSION AND CVD IN THE MOTHER BUT CVD AND STROKE IN THE FATHER. PARTICULARLY THE STRONGEST WAS ODDS RARE YES OF 4 FOR PATERNAL STROKE. THAT WAS ONE QUESTION FOR YOU IS WHAT'S THE MECHANISM HERE. SO IT IS AN STRIGGING STORY. THE OTHER -- INTRIGUING STORY. THE OTHER WAS PREECLAMPSIA. >> SEEMS TO ME THAT YOU COULD MAKE A MORES FORFUL RECOMMENDATION THAT CERTAIN -- AT THE LEAST CERTAINLY MORE RESEARCH IS NEEDED ON THIS RELATIONSHIP RATHER THAN SAYING THERE'S NO INDICATION FOR SCREENING. IT WAS VERY GOOD PRESENTATION. >> I CAN ADD TO THE MALE FIRST DEGREE RELATIVE. WE DID IT IN FAIRLY LARGE COHORT OF BROTHERS AND FATHERS PREVALENCE OF METABOLIC SYNDROME, WE DIDN'T HAVE IT ON MANY SUBJECTS BUT YES THE PREVALENCE INCREASED COMPARED TO NHAYNES NATIONAL PRE-LENS BUT WHEN YOU CONTROL FOR OBESITY IT WAS ENTIRELY ACCOUNTED FOR BY OBESITY. SO THE MALE PHENOTYPE IS INSULIN RHESUS TAN, BETA CELL DYSFUNCTION AND THEY TEND TO BE OVERWEIGHT. AND THE -- THERESA PETERMAN IN THE OVERWEIGH STARTS IN THE BOYS VERY, VERY YOUNG. SO IT DOES, THERE IS A BIT OF A SEX DIFFERENCE IN PHENOTYPE BETWEEN FEMALE AND MALE RELATIVE. I DON'T KNOW IF YOU REALIZE IN THE STUDIES RICK AND I DID THAT YOU USED THAT THERE'S A LOT OF OVERLAP IN THOSE SUBJECTS. SO NOT COMPLETELY INDEPENDENT COHORTS. >> I WANT TO ASK YOU ABOUT WHEN YOU OBSERVE ONE OTHER THING. IN OUR STUDY ANDREA MENTIONED METABOLIC SYNDROME REMINDED ME IN OUR STUDY ALL THE GIRLS WITH POLYCYSTIC OVARY SYNDROME WHO HAD A POLYCYSTIC OVARY HAD A MOTHER WHO HAD PCOS OR HAD A IFTHER WITH ME BOLLIC SYNDROME, IT WAS QUITE STRIKING. DO YOU HAVE -- WHAT IS YOUR EXPERIENCE HAVE TO SAY ABOUT THAT? DEFINING PCOS IN MOTHERS AND BECAUSE OF THE AGE -- >> THIS IS PRE-MENOPAUSAL. OURS WERE PRE-MENOPAUSAL MOTHERS. >> IN OUR STUDY FOR THE PREMENOPAUSAL MOTHERS, PREVALENCE OF PCOS WAS 16%. IT GOES TO POST MENOPAUSE IT WAS 18%. >> THE RELATIONSHIP OF THE GIRLS POLYCYSTIC OVARY TO THE FATHER'S METABOLIC SYNDROME THAT WAS REALLY STRUCK US, WE THOUGHT THIS WAS INDICATION OF FUNDAMENTAL RELATIONSHIP OF INSULIN RESISTANCE AND DIABETES TO THE POLYCYSTIC OVARY IN OFFSPRING. >> THERE IS MORE RESEARCH NEEDED WHEN I COMES THE SCREEN OR NOT TO SCREEN AT THIS POINT, NOT SURE. >> IN THE INTEREST OF TIME WE'LL TAKE ONE MORE QUESTION, THIS IS A COMMENT. I GUESS I'LL ADDRESS IT TO THE ADAM BECAUSE IT INVOLVES SURGERY, 50% OF WOMEN WITH PCOS HAVE ENDOMETRIOSIS. IS THERE A VALUE DOING LAP PROSSCOPY TO DETECT IT AND DIAGNOSE KNOW ENDOMETRIOSIS. >> INTERESTING QUESTION I HAVE NOT HEARD THAT ASSOCIATION BEFORE. ENDOMETRIOSIS IS COMMON, COMMON THINGS THAT CO-EXIST. BUT I'M NOT AWARE OF LITERATURE TO SUGGEST A STRONG ASSOCIATION BETWEEN ENDOMETRIOSIS. THE INTERESTING QUESTION POTENTIALLY IS IF YOU HAVE A WOMAN WITH ANOVULATORY INFERTILITY AND ALGORITHM FOR MANAGEMENT WHAT STAGE YOU TEST PATENCY BY WHICH MEANS. IN THE UK WE TAKE THE APPROACH WOMEN WITH WITH NO GYNECOLOGICAL HISTORY, WE DO X-RAY IN OUR PATIENT WHOSE ARE UNDERGOING OVULATION INDUCTION RATHER THAN STRAIGHT FOR LAP PROSSCOPY WHICH WE DO HIGH RISK PATIENTS BUT SOME ARGUED IF YOU HAVE A WOMAN WITH PCOS WHY NOT CHECK PATENCY BY DOING LAP PROSSCOPY IN BOTH OVARIES AT THE SAME TIME. THAT'S NOT THE APPROACH WE TAKE, IT'S SOMETHING WE DEBADED. LAPOSCOPY BECAUSE OF INHERENT RISK AND NATURE SHOULD BE RESERVED AS SECOND LINE APPROACH. RICK DO YOU WANT TO COMMENT ON THAT? >> I AGREE WITH ADAM. AT LEAST ACCORDING TO OUR SAM SON THEORY OF RETRO GRADE MENSTRUATION AN ACKNOWLEDGEMENT THAT UNINTERRUPTED OVULATION MENSTRUATION IS A RISK FACTOR FOR ENDOMETRIOSIS, I EXPECT WOMEN WITH PCOS TO BE RELATIVELY PROTECTED AGAINST ENDOMETRIOSIS. ANOTHER INTERESTING AREA I THINK RELATIVELY PROTECTED AGAINST, WE'LL HAVE DATA WHEN WE FINISH THE TRIALS WE'RE DOING IS A MYOMAS WE SEE LESS COMMONLY IN WOMEN WITH PCOS THAN OTHER WOMEN. SO SOME OF THE BENEFITS OF PCOS WHICH WE MIGHT NOT WANT TO GET INTO OR WHICH MIGHT ALSO ON OUR VISIT IS CHRONIC PAIN IS A RELATIVELY INFREQUENT PRESENTING COMPLAINT TO WOMEN WITH PCOS AND THEY'RE PROTECTED AGAINST DYSMENORRHEA AN MULTIPLE COMPLAINTS HA RESULT FROM UNINTERRUPTED OVULATION MENSTRUATION. YOU SPEAKING REMINDED ME A QUESTION I WANTED TO ASK YOU RELATING TO PRESCRIBING CHROMEAFENE IN ABSENCE OF WITHDRAWAL BLOOD. I CAN UNDERSTAND THE PHYSIOLOGICAL RATIONALE BUT WHAT IF YOU HAVE SOMEBODY WHO IS PREGNANT? WHO HAS UNDIAGNOSED PREGNANCY WITH CONGENITAL ANOMALY. >> IT'S VERY INTERESTING, THE WAY WE WOULD DO IT IS WE MONITOR MID GLIDEIAL SO THIS IS STUDY AND CLINICAL PRACTICE, WE MONITOR THE OVULATION AND PROGESTERONE AS NEEDED HCG SCREEN TRIALS WE SEND HCG SCREEN EVERY VISIT IS FEW WHERE SEE SOMEBODY WITHOUT A FOLLICLE CORPUS LUDIEM WE WOULD IMMEDIATELY CHALLENGE THAT DAY WITH THE NEXT DOSE KNOWING THERE'S NO FOLLICLE IN DEVELOPMENT. SO IT REQUIRES COORDINATED USE OF SERUM LABS AN ULTRASOUND AND INTERPRETING WHAT YOU SEE ON THE OVARY. THESE ARE WOMEN WHO DON'T HAVE NORMAL FOLLICULAR DEVELOPMENT, THEY'RE CONTROLCLES ARE LESS THAN TEN MILLIMETERS SO YOU CAN JUDGE BY ABSENCE OF DEVELOPING FOLLICLE IN BLOOD WORK WHETHER TO GO AHEAD. THIS IS A NAME, THERE'S THAT PROTOCOL, THERE'S A PAPER ON THIS WHERE YOU ACCELERATE AND WHAT THEY DO SHOW AND YOU CAN ADVANCE MUCH SHORER PERIOD OF TIME TO THE HIGHEST DOSE AND DETERMINE IF THERE IS CHROMEAFENE RESISTANCE OR FAILURE AND MOVE ON TO THE NEXT FORM OF THERAPY. WE KNOW CLINICALLY THIS DRAGS ON AND ON AND ON MULTIPLE CYCLES AND NOT REALLY MONITORING FOR OVULATION. AND WE HAVE ALL SEEN PATIENTS TAKING IT FOR YEARS WITH NO BENEFIT OR WELL BEYOND THE INDICATION >> SO THERE'S A SMATTERING OF SMALL CLINICAL QUESTIONS THAT I THINK AT THIS TIME YOU CAN COME UP TO THE INDIVIDUAL PEOPLE. IN THE INTEREST OF TIME IF WE JUST STOP THE PANEL NOW AND THEN MOVE ON TO THE FINAL SESSION. THANK YOU VERY MUCH. [APPLAUSE]l >> WHOLE SESSION LEADS ARE GETTING SET UP I WANT TO SAY THIS IS AN OPPORTUNITY FOR FINAL THOUGHTS, THE PANEL MAY HAVE, SPEAKERS MAY HAVE AND AUDIENCE. WE HAVE OUR SESSION LEAD, FEEL FREE TO ASK QUESTIONS, MAKE COMMENTS. >> I WOULD LIKE TO TAKE THIS OPPORTUNITY THIS OPPORTUNITY AND TO ASK EACH OF YOU TO HELP US AS THE PANEL WRITE OUR REPORT. I GUESS THERE'S AN ADVANTAGE, DEPARTMENT CHAIRMAN FOR 20 YEARS, YOU KNOW HOW TO FINE JOBS. I GUESS MY QUESTION FOR EACH OF YOU IS HAVING SAT THROUGH WONDERFUL TWO DAYS, WHAT IS TAKE HOME MESSAGE? WHAT ARE THE PRIORITIES THAT YOU THINK WE SHALL FOCUS ON WHAT THINGS SHIFT THE PARADIGM THE WAY WE THINK ABOUT PCO AS HAPPENED BEFORE AT MEETINGS LIKE THIS. >> I CAN GIVE GENERAL CONCEPT THOUGH THERE'S SPOKES IN THE WHEEL. I THINK THAT YOU HAVE SEEN WHERE WE HAVE COME AND YOU HAVE SEEN SOME OF THE FRUSTRATION AND SOME OF THE OBSTACLES THAT WE HAVE ENCOUNTERED ALONG THE WAY THAT IS SOMEWHAT DELAYED ADVANCEMENT OF THE KNOWLEDGE OF THE SYNDROME. IF YOU CAN DISSECT IN PART SOME AREAS THAT NEED MORE KNOWLEDGE SO THAT WE CAN MAKE THE NEXT STEP FORWARD, AND THEN FOCUS ON WHERE SUPPORT WOULD BE NEEDED TO GET THESE KIND OF STUDIES DONE. THAT I THINK FOR ME OVER THE LAST COUPLE OF DAYS IS QUITE APPARENT WHEN WE GO UP AGAINST CERTAIN TOPICS AND QUESTIONS WEAR TRYING TO ANSWER, GET TO A CERTAIN POINT THEN WE'RE STUCK. YOU SEE IN DETHE SUBSCRIPTION OF STUDIES AVAILABLE YOU SEE WHERE WE'RE NOW IMPEDED. AND I THINK SOME OF THE NECESSARY INFORMATION BECOMES SOMEWHAT OBVIOUS, WE STRUGGLE AND TRY TO POINT OUT WHAT WE NEED TO DO BUT I WOULD LIKE TO HAVE YOUR IMPRESSION FROM IMPARTIAL VIEW AND PERHAPS INTRODUCTION TO THIS MYSTERIOUS DISORDER WHERE SHOULD WE PLACE THE FOCUS AND EMPHASIS? >> APPROACHING THIS ONE TRIES TO EMPHASIZE THE PATIENT. WHAT ARE THE NEEDS THERE. SO THAT STARTS OUT ON A BASIC UNDERSTANDING WHAT'S THE PHYSIOLOGY WHICH IS STILL NOT KNOWN RAREIOUS ASPECTS THAT CAN BE DISECTED AND SEPARATED OUT. ALL THE WAY TO DIAGNOSING CONTINUING TO TRY TO OBTAIN SOME CONSISTENCY AN DEFINITIONS SO THAT WE'RE BETTER ABLE TO STUDY THIS FROM A EPIDEMIOLOGICAL POINT OF VIEW TO ISSUES OF TREATMENT, TREATMENT OF VARIOUS MAJOR DISORDERS THAT A PATIENT MIGHT HAVE AT VARIOUS TIMES OF THEIR LIFE. FOR PANEL AS OUTSIDERS WE VALUE WHAT YOU'RE GOING TO SAY. AND WHAT YOU THINK ARE MAJOR PROBLEMS, HOPEFULLY IN SOME DOCUMENT TO THINK IN TERMS OF BEST FUNDING MECHANISMS AND WHETHER OR NOT WE WOULD BE ABLE TO GET OTHER SOCIETIES INVOLVED. FEDERAL AGENCIES INVOLVED. SUPPORT GROUPS INVOLVED TO FIGURE OUT A MORE DETAILED RESEARCH AGENDA THAT WOULD BE NEEDED. I THINK THE PROBLEMS ARE THE PROBLEMS OF PATIENT CONCERNED WITH METABOLIC ABNORMALITY, LONG TERM CLINICAL OUTCOMES. AND THE OTHER BIG CHUNK IS ISSUE OF REPRODUCTIVE ABILITY AND PHYSIOLOGY. SO I SEE THOSE ARE TWO MAIN AREAS, ISSUES OF% HIRSUTISM, OTHER HYPERANDROGENISM IS VERY DIFFICULT. AND IF WE BETTER UNDERSTANDING OF THE PHYSIOLOGY WE'LL GO FORWARD WITH THAT BUT I THINK THE MAJOR CONCERNS THAT PATIENTS HAVE MET BOLL PIC ABNORMALITIES AND WHAT THAT MEANS LONG TERM AND REPRODUCTIVE ABNORMALITIES AND WHAT IT MEANS SHORT TERM. >> I GO BACK TO OUR THREE STATED GOALS. BENEFITS ANDREW BACK OF USING ROTTERDAM DIAGNOSTIC PIECE CONDITIONS CAUSES PREDICTIVE LONG TERM CONSEQUENCES AN OPTIMUM PREVENTION AND TREATMENT. SO THINK INCLUDING OVARY AS PART OF DIAGNOSIS IN ROTTERDAM IS WORLDWIDE ACCEPTED AT THIS POINT. I'M NOT ASKING TO RECREATE THE WHEEL. THEY DID A MAJOR SURVEY IN AUSTRALIA, PEOPLE WANTED TO CHANGE THE NAME NOBODY COME UP WITH ANYTHING ELSE. ALONG THOSE LINES WE ALL SUGGEST WITH NEW KNOWLEDGE AND UNDERSTANDING THAT COMPONENT OF IT. WITH THAT CAVEAT IF WE ARE GOING TO USE ROTTERDAM WITH ENHANCED AWARENESS, IT MAKES -- NEEDS TO BE MADE CLEAR THAT IT IS SUCH A HETEROGENEOUS SYNDROME, PCOS IS NOT PCOS. IT IS CLEAR AND WE HEARD SEVERAL TIMES YOU HAVE THE CLASSIC PATIENT, THAT IS THE WOMAN PRIMARILY THAT HAS METABOLIC CARDIOVASCULAR, THE OTHERS DO NO, MA'AM. AND IS MORE REPRODUCTIVE PHENOTYPE. YOU NEED TO NOT TREAT EVERYBODY THE SAME WAY. TO ME THAT'S A VERY IMPORTANT MESSAGE. THIS IS WHAT WE CALL IT NOW BUT IT IS HETEROGENEOUS AND WHAT WE NEED REALLY ARE LONG TERM STUDIES. THROUGHOUT THESE PHENOTYPES TO UNTANGLE WIDOW, WIDOW. AND SHOULDN'T CONSIDER THAT, THEY'RE SO MILD THEY DON'T DEVELOP ANYTHING. SO THAT'S WHAT I WOULD SAY. >> SO I WOULD HAVE A BIT OF A DIFFERENCE WITH WHAT ROGER SAID, I THINK THE ISSUE THAT WE HAVE IS THAT THIS DISEASE OR SYNDROME IS NOT RECOGNIZED IN GENERAL PRACTICE, AUSTRALIA DATA, 70% UNDIAGNOSED, THERE HAVE BEEN SURVEYS BY SUPPORT GROUP HERE ON AVERAGE WOMEN SEE FOUR DOCTORS BEFORE THEY GET DIAGNOSIS. THEY FREQUENTLY SELF-DIAGNOSE SO IN THE INTERNAL MEDICINE COMMUNITY, IN THE ENDOCRINE COMMUNITY AND GENERAL PRACTICE COMMUNITY, THERE'S VERY LITTLE AWAREN, THEY GLAZE OVER WHEN THEY HEAR OVARY AND ALL THESE PULSES SO WE NEED A SIMPLE MESSAGE TO THAT IMMUNITY ABOUT IDE -- COMMUNITY IDENTIFYING HIGH RISK PATIENTS THAT'S STRAIGHT FORWARD. IRREGULAR MENSES MOST HAVE SIX OR FEWER FROM THE FAMILY STUDIES AND THERE'S A LOT OF DATA THAT I THINK THERE'S A SUFFICIENT BODY OF EVIDENCE THAT'S THE HIGH RISK GROUP. SO I THINK ONE THING THAT'S AN OUTCOME TO CONSIDER IS WHAT'S A SUBSET THAT COULD BE DEFINED THAT YOU DON'T NEED OVARIAN ULTRASOUND, THESE THE OTHER THING THAT PUTS THE NON-REPRODUCTIVE ENDOCRINE COMMUNITY, VERY DAUNTING TO THEM. THAT FOR KNOWING THE METABOLIC ISSUES YOU DON'T NEED ULTRASOUND, YOU JUST NEED HYPERANDROGENISM AND CHRONIC OVULATION, EXCLUDING OTHER DIAGNOSES. THE OTHER DIAGNOSIS WE EXCLUDE ARE SO UNCOMMON, IT'S PROBABLY NOT COST EFFECTIVE TO DO THAT. THAT IS SOMETHING REALLY DIAGNOSTIC ALGORITHM IS RESEARCH ISSUE. THEN I THINK FOR RESEARCH ROTTERDAM IS GREAT WHERE PEOPLE HAVE RECOGNIZED IT AND COMPARED THE PHENOTYPE, BUT IT'S ALSO LED TO MUCH MORE HETEROGENEOUS PATIENTS INCLUDED IN STUDIES AND I THINK MASKING A LOT OF THE OUTCOMES THAT THERE MAYBE, IN THIS MORE SEVERE PHENOTYPE, SO I THINK A RECOMMENDATION TO RESEARCH COMMUNITY AND TO JOURNAL EDITORS THAT YOU HAVE TO DEFINE THE PHENOTYPES WHEN YOU DO RESEARCH STUDIES. WE DON'T KNOW WHAT THE IMPLICATIONS, IF IT'S A VARIABLE EXPRESSION, THE SAME THING, BUT AT LEAST IN THE RESEARCH STUDIES THAT THE PHENOTYPE SHOULD BE DEFINED AND YOU CAN'T HAVE THIS LUMPING OF PHENOTYPES. THINK ANOTHER RESEARCH RECOMMENDATION IS FOR POOLING OF COHORTS. I THINK YOU PROBABLY SAW HOW SMALL ALL THESE STUDIES ARE. AND THERE'S NO LARGE SCALE STUDIES BECAUSE INSTITUTES THAT DO LARGE SCALE EPIDEMIOLOGIC STUDIES SUCH AS NHLBI SUPPORTED TWO PCOS STUDIES, I THINK HE'S IN THE ME IS A COHORT TO OTHERWISE THEY DON'T SUPPORT MAYBE A LITTLE BIT OF SLEEP APNEA RESEARCH BUT IT'S NOT A CONDITION THAT'S SUPPORTED BY NHLBI. NIDDK, VERY LITTLE SUPPORT FOR PCOS RESEARCH SO IT FALLS ON NICHD WHO REALLY THOUGH LOVE TO BE INTO THE LONG TERM HEALTH OUTCOMES OF WOMEN, THAT'S NOT THEIR MAIN AREA. NCI SHOULD BE LOOKING INTO THIS. SO I THINK WE HAVE TO GET THIS MUCH MORE GENERALIZED AND HAVE LARGER COHORT STUDIES AND THEN ENCOURAGING FOR THE GENETICS AS WE HAVE SEEN IN TYPE 2 DIABETES THE LARGE POOLING OF BIG COHORTS TO REALLY START POOL COHORTS WITH SUBPHENOTYPES SHOWN FROM MAGIC DATA THAT YOU CAN START TO SEE WHICH FEATURES HAVE THE STRONGER GENETIC BASIS AND GET INSIGHTS. THE COMMENT THAT DIDN'T COME UP IN GENETICS TALK BUT VERY IMPORTANT SO WE HAVE LARGE ENOUGH SAMPLE SIZE FROM CHINESE TO SAY WE DONE FIND GENES IN TYPE 2 DIABETES. THESE ARE DIFFERENT SETS OF GENES SO WHATEVER THESE FINAL COMMON PATH ON METABOLIC PATHWAY S, FRINGE OTHER PHENOTYPES OF TYPE 2 DIABETES. THERE'S TREMENDOUS AMOUNT TO LEARN BUT IF WE LUMP IT AND IT DOES -- STAYS THE WAY IT SAYS AS REPRODUCTIVE ENDOCRINE FOCUS DISORDER WE'RE GOING TO BE STUCK. SO HYPOTHETICAL. SAY WE WOULD AGROW THE CRITERIA SPECIFIC PHENOTYPE DESCRIPTION IS CRITICAL IN THE RESEARCH ARENA AND WE RECOMMEND JOURNAL EDITORS AND MAJOR SOCIETIES, PEOPLE INVOLVED IN RESEARCH REALLY SURE PEOPLE CLARIFY WHAT PHENOTYPES ARE SO THREE, FOUR YEARS WE CAN IDENTIFY WHETHER OR NOT THE POLYCYSTIC MORPHOLOGY IS WORTH KEEPING OR -- I MEAN AS I LOOK AT ROTTERDAM DOCUMENTS, IT'S COLOR THAT THAT WAS THOUGHT TO BE A CLASSIFICATION THAT WOULD BE CHANGED DOWN THE ROAD LIKE ANY OTHER CODING PEOPLE THAT WE USE. -- POLYCYSTIC OVARY SYNDROME MY POSIT IS WE HAVE TO ENGAGE A BROADER COMMUNITY TO THE RESEARCH COMMUNITY. MAKE SURE MEDICAL STUDENTS UNDERSTAND THE ROT THE TEAR DAM CRITERIA AND WHAT THEY ARE. CLINICIANS THAT PRACTICE PRIMARY CARE PHYSICIANS GENERAL OBGYN, YOU TALK ABOUT REPRODUCTIVE -- MEDICAL ENDOCRINOLOGISTS GLAZING OVER TALKING OVARIES DOING ULTRASOUND BUT I CAN TELL YOU'RE PEOPLE DELAY IS OVER WHEN PEOPLE TUCK ABOUT MEASURING TESTOSTERONE. SO TWO SIDES OF THE MIRROR. MY QUESTION TO YOU IS HOW CAN WE ENGAGE IN A BROADER DISCUSSION BECAUSE IF WE WANT TO MAKE THIS DISEASE SYNDROME, TO A BROADER COMMUNITY INCLUDES MEDICAL SCHOOL RESIDENTS WE NEED TO REENGAGE THAT GROUP SO WE HAVE GROUP OF CLINICIANS WHO WHEN THEY SEE PATIENTS IN PRACTICE RECORD THE PATIENT HAS POLYCYSTIC OVARY SYNDROME ON THE BASIS OF THE VAGINAL ULTRASOUND AND ALSO THE FACT THEE CEASE ANOVULATORY AND HIRSUTISM. THAT'S HOW WE CHANGE THE PRACTICE. HOW DO WE DO THAT? HOW TO WE GAUGE THE BROADER CLINICAL COMMUNITY? I THINK YOU SUGGESTED IT HAS TO DO WITH THE PATIENT. CONSUMERS AN THOUGH THINGS ARE THINGS THAT WE CAN THINK ABOUT. BUT MY QUESTION IS HOW DO WE GET THE MESSAGE THAT CAME OUT OF O THIS MEETING TO A BROADER MEDICAL (INAUDIBLE) IN THE UNITED STATES? >> I THINK THE BROADER MEDICAL COMMUNITY NEEDS TO KNOW THAT DETECTION OF PCOS AND WE HAVE A SUBSET, HAS AN IMPACT. TO UNDERSTAND, WE HAVE IN DATA NOW, TO SAY THAT THESE WOMEN ARE AT RISK FROM PRE-DIABETES AND DIABETES. THOUGH WE CAN BE NIGH LISTIC AND SAY IT DOESN'T MATTER DETECTING THAT BUT MOST OF US WOULD SAY IT PROBABLY DOES MATTER TO KNOW PEOPLE HAVE PRE-DIABETES. THERE IS A GREAT PEDIATRIC ARTICLE SAYING MENSES ARE A VITAL SIGN. IF YOU TAKE A MENSTRUAL HISTORY, SIX OR WHATEVER PER YEAR WHATEVER YOU WANT THE DO IT, YOU'RE IDENTIFYING WOMEN T HIGH RISK, MOST ARE PCOS BUT THEIR ANOVULATORY, RISK FOR LOW BONE DENSITY SO EDUCATION CAMPAIGN, THERE'S SOME REASON TO DETECT THESE WOMEN TO DIAGNOSE WOMEN THAT IT'S SIMPLE TO DO, INTERNIST AND CARDIOLOGIST COMMUNITY, THAT'S WHY IT CAN'T BE OVARIAN ULTRASOUND, THEY DON'T NEED TO WORRY ABOUT THAT. AND THAT'S WHY I THINK THE NAME FOR SUBGROUP WITHOUT OVARY IN IT, WOULD BE HELPFUL. PEOPLE THROWING AROUND NAME LIKE MET BOLL UK REPRODUCTIVE SYNDROME, METABOLIC SYNDROME, THERE'S CERTAINLY CONTROVERSY WHETHER THE THAT'S SOME HAVING SYNDROME IS WORSE THAN ANY INDIVIDUAL PARTS. THAT IS A MODEL OF SYMPTOMS WHOSE TIME HAS COMET AND PEOPLE HAVE TAKEN THAT AS DIAGNOSIS AND FIND IT HELPFUL THOUGH LIFESTYLE IS PROBABLY BEST INTERVENTION FOR THAT. I THINK THIS IS PUBLIC AWARENESS CAMPAIGN AN MAYBE ANOTHER STEP TO TAKE FORWARD IS HOW DO YOU START TO PUBLICIZE SOMETHING REALLY DOES HAVE LONG TERM HEALTH RISKS? >> IT'S NOT CLEAR TO ME THAT PURPOSE OF TRYING TO ESTABLISH THE DIFFERENCE PHENOTYPES ARE THE SAME. IT'S A FRUSTRATION OF TRYING TO GO UP AGAINST A PERCEPTION OVARY IS NOT IMPORTANT BY THE NIH AND REVIEWERS. THE FUNDING FOR THIS DISORDER FALLS WOEFULLY SHORT FOR THE AMOUNT OF COMPLAINT AND MYSTERY WE SEE IN OUR PATIENTS. ONE ASPECT. SECOND ASPECT NOT SHOWER WE CAN IMPOSE ON THE PUBLIC EXTREME LAWYERS IN THE COMMUNITY THAT SWITCH TOTALLY EMBRACE IN TOTAL CONFUSION. IT MIGHT TAKE A CONCERTED EFFORT FROM US APPROXIMATE OTHERS TO DEMONSTRATE WHAT THE DIFFERENT PHENOTYPES REALLY ARE. I THINK THEY HAVE ALREADY BECOME ENGRAINED WITH THIS. SO WE JUST CAN'T AUTOMATICALLY CHANGE IT AND EXPECT THEM TO ACCEPT IT. BUT RATHER HAS TO BE A GRADUAL PROCESS OF EDUCATING THEM WHAT THE DIFFERENCE IS. THEN TAKE IT TO THE NEXT STEP. THIS IS NOT SOMETHING THAT HAPPENS OVER NIGHT. IT'S TOO ENGAGED RIGHT NOW. WE CAN MAKE THE EFFORT TO TRY TO SHOW DITCHESES ANDRYK POOLS THAT EXIST. >> THE DIFFERENCES AN RISK POOLS THAT EXIST. >> I DONE MEAN TO BE CYNICAL BUT IT'S AS IF CHOLESTEROL WASN'T DISCUSSED UNTIL THERE WAS A STATIN AVAILABLE AND DEPRESSION DOESN'T P DISCUSSED UNTIL THERE WAS ANTIDEPRESSANTS ON MARKET AND INDUSTRY FOR GOOD OR BAD BEEN INVOLVED IN PUBLICIZEING A DISEASE STATE BECAUSE TREATMENT IS AVAILABLE. THAT'S NOT THE CASE HERE. IN SOME SITUATION IT'S ABSOLUTELY ORAL CONTRACEPTIVE PILLS. IN OTHER SITUATIONS THERE'S ABSOLUTELY NONE. SO WE DON'T HAVE AN INDUSTRY PARTNER THAT MIGHT PROVIDE PUBLICITY AND ABILITY TO HAVE A DRUG TREATMENT. THAT IS A FRUSTRATION. I AGROW THAT MENSTRUAL CYCLE IS A VITAL SIGN, WE HAVE THIS PUREED ATTITUDE IN THE UNITED STATES I'M NOT DISCUSSING SEX OR MENSTRUAL CYCLES, IT'S SO OFTEN IGNORED BY AN INTERNIST AND PRIMARY CAKE DOCTORS WHO WANT TO TAKE CARE OF PATIENTS. THAT WOULD LEAD AT LEAST TO THE DISCUSSION. BUT I THINK THAT THE EMPHASIS THAT I THINK IT SHOULD BE IS THAT ON LONG TERM METABOLIC COMPLICATIONS. I THINK PEOPLE UNDERSTAND THAT, PEOPLE UNHEART DISEASE AND IF WE CAN GET A HANDLE ON THAT MORE TO BE ABLE TO SAY TO HEALTHCARE PROVIDERS THAT THIS IS AN IMPORTANT QUESTION, BECAUSE IT IS ASSOCIATED WITH LONG TERM CARDIAC OUTPUT -- CARDIAC OUTCOMES SO THAT'S THE THING I THINK WOULD GRAM PEOPLE. REPRODUCTION UNFORTUNATELY IS DELL GRATED TO GYN, SPECIAL GYN, NOT SOMETHING PRIMARY CARE DOCTORS THINK ABOUT AND RECALL PRIMARY CARE DOCTORS ARE YOUR MASS OF PHYSICIANS WITHIN THE UNITED STATES. >> WE'RE TALKING TR CAMPAIGN OF SORTS. I THINK THE WORST THING WE COULD DO IS PUT OUT SOMETHING THAT'S CONFUSING. THE EXPERTS CANNOT AGREE. SO WE HAVE NOTHING. WE HAVE NO MESSAGE TO GET OUT. EVERYBODY DISAGREES, EVERYBODY TREATS IT DIFFERENTLY, EVERYBODY DIAGNOSES DIFFERENTLY AND GOING EVERY OTHER DIRECTION. I THINK FOR BETTER, WORSE, THE EXPERTS COULD AGREE, THIS IS WHAT IT IS, THIS IS WHAT WE CALL IT BUT IT IS DIVERSE, IT HAS RAMIFICATIONS AND THERE ARE TREMENDOUSLY IMPORTANT DOWNSTREAM THINGS THAT YOU HAVE TO BE AWARE OF THREE IN SOME OF THE PATIENTS, JUST THAT MESSAGE IF IT COULD GET OUT IT WOULD BE PHENOMENAL. THERE WAS AN OPPORTUNITY -- PUBLIC INTEREST IS UP AND DOWN, I HAVE BEEN IN MAGAZINES A ALL OF US HAVE. IT'S A TREMENDOUS BLIP. WOMEN ARE RUNNING TO THE DOCTORS ASKING IF THEY'RE PCOS. I HAVEN'T SEEN THAT FOR A WHILE. THERE USED TO BE A PCOS ASSOCIATION, LAY GROUP, A HUGE ACTIVE CHAT ROOM AND STUFF LIKE THAT. I DON'T KNOW IF THAT'S TIFFANY MORE. BUT SOMETHING LIKE THAT. IT'S GOT THE START FROM US. IT HAS TO START FROM THE MEDICAL COMMUNITY. WE HAVE DONE THIS RECENTLY AROUND THE MENOPAUSAL, THAT'S THE WHOLE DIFFERENT ISSUE, WHOLE DIFFERENT SET OF PROBLEMS WITH INTENSE THE EXPERTS AGREE, OF COURSE IT WAS SOMEWHAT WATERED DOWN AND DOESN'T BUT IF THERE IS A UNIFICATION, A VOICE AND MESSAGE AROUND SOMETHING, IT WILL HAVE TRACTION OR SHOULD HAVE TRACTION. >> I THINK THERE ARE MODELS FROM OTHER CONSENSUS CONFERENCES AT NIH WHERE DISEASES HAVE BEEN STRATIFIED NEW NAMES OR OR ADDITIONAL NAMES OR TYPE ONE, TYPE 2 BOB CERTAINLY KNOWS FROM DIABETES LITERATURE, WE HAVE TRANSFORMED FROM ADULT ONSET OR NIDDN NOW TO TYPE 2 DIABETES. SO I THINK YOU CAN REFINE, IT CAN BE ADOPTED, IT'S NOT NECESSARILY DAUNTING, AND THERE ARE MODELS TO DO IT. AND PROS AN COBS OBVIOUSLY. WHICH TO A LARGE EXTENT WAS MEDICAL ENDOCRINOLOGISTS, GAIN COLOGIC ENDOCRINOLOGISTS KIND OF HAVING DISCUSSION AROUND THIS ISSUE. IT WAS A VERY INTERESTING DISCUSSION. IF I WERE TO COME BACK TO THE GENERALS IN MY DEPARTMENT AND FAMILY PHYSICIANS IN MY MEDICAL SCHOOL AND THE NURSE MIDWIFE THAT I WORK WITH, ALL THE PEOPLE WHO SEE MOST OF THESE PATIENTS IN THEIR PRACTICE AND TRY TO SUMMARIZE THE ARGUMENTS BEING THROWN AT EACH OTHER FROM THE TOP OF EVERYTHING'S SILO YESTERDAY, IT'S A DIFFICULT MESSAGE TO GET ACROSS, HOPEFULLY WE CAN HELP WITH THAT. THIS IS NOT MY FEEL. IT'S BEEN GREAT BEING HERE BUT I HAVE BEEN STRUCK BY THE FACT THAT THERE IS SO MUCH DISCUSSION ABOUT ISSUES OF DEFINITIONS APPROXIMATE P THOSE KIND OF THINGS. IT IS DIFFICULT TO TRANSLATE BECAUSE OF THE WAY IT'S SILOED. DEPENDING ON FIVE WAYS PEOPLE LOOK AT ELEPHANT DEPENDING ON WHAT THEY TOUCH. OBVIOUSLY THE MEDICAL ENDOCRINOLOGISTS DONE HAVE PATIENTS TO SEE THEM SAYING I WANT TO PREGNANT AND KIND OF GYNECOLOGISTS DON'T HAVE 13-YEAR-OLD COMING AND SAYING I'M HAVING THESE KINDS OF PROBLEMS. BROAD CONSTITUENCY IN ENGAGING PROFESSIONAL SOCIETIES >> IN TERMS OF HOW WE TRAIN MEDICAL STUDENTS AND RESIDENTS ACROSS SPECIALTIES. HOW DO WE MAKE THE ENTITY OPEN TO A BROAD GROUP OF NOT ONLY MEDICAL GENERALISTS AND PRACTITIONERS BUT ALSO ENGAGING. I THINK THAT'S THE KEY, HOW DO WE GAUGE THE NIH TO REALIZE THIS IS AN IMPORTANT TOPIC AND THERE ARE LOTS OF DOCTORS. IF YOU HAD HUNDRED AND HUNDREDS OF GENERAL PRACTITIONERS AROUND THE COUNTRY SAYING I'M OVERLOWED WITH PATIENTS WITH DISEASE I NEED HELP FROM THE NIH TO DO IT, THAT MIGHT BE THE STRONGEST CASE YOU CAN HAVE. I'M STRUGGLING, I THINK MEDICAL SCHOOL IS MY WAY TO DO THIS, PROFESSIONAL SOCIETIES, I KNOW THAT BEFORE THIS MEETING IF THERE HAD BEEN A SESSION OF PCO AT THE ACOG ANNUAL MEETING I WOULD AVOIDED IT. I ALWAYS COME AWAY CONFUSED GOING TO A MEETING ABOUT PCO. COME TOGETHER BE INFORMATIVE PEOPLE IN PRIVATE PRACTICE SO I THINK PROFESSIONAL SOCIETIES ARE ANOTHER WAY TO DO IT. I DON'T KNOW ANYTHING ABOUT YOUR ANDROGEN EXCESS SOCIETY WHICH NOW IN ADDS PCOS THE THEIR NAME. I THINK THOSE GROUPS MAYBE USEFUL IN GETTING THIS MESSAGE OUT AND YOU HAVE TO GO BOTH WAYS. YOU HAVE TO GO RESEARCH SUPPORTERS LIKE NIH TOKENS VINCE IT'S AN IMPORTANT TOPIC BUT YOU'LL HAVE MORE TRACTION IF YOU HAVE PEOPLE OUT THERE SO I'M IN THE BOMBARDED IN MY OFFICE WITH PATIENTS WITH PCO IF THE PREVALENCE IS LIKE WE HER TOOL TODAY AND LACK OF RECOGNITION, IF WE GET DOCTORS SCREENING ABOUT IDENTIFYING AND SO FORTH THEN I THINK THERE WILL BE SOME TRACTION BUT IT'S HARD TO THINK ABOUT WHAT IS THIS -- IT'S A PR CAMPAIGN BUT ALSO AN EDUCATIONAL CAMPAIGN. >> IT STARTS WITH EDUCATION I WOULD THINK. THE EARLIER INITIATIVE TOOK SEVERAL YEARS, NONE OF US CAN BE OVER NIGHT. BUT I GUESS I'M HEARTENED BY THE IMPRESSION WE MAY HAVE GIVEN YOU IF IF I HEARD YOU RIGHT THE REPRODUCTIVE ENDOCRINOLOGISTS AND PEDIATRIC WERE ARGUING NOT OBJECT SAME PAGE, I THINK BY AND LARGE WE ARE ON THE SAME PAGE. WE ALL WORK TOGETHER AND WE ALL SEE THE SAME PATIENTS. I DON'T USE GONADOTROPIN FOR EVERY PCOS PATIENT I SEE. I TREAT IT WELL AS DOES JEFF AND I'M SURE THERE ARE A FEW MEDICAL ENDOCRINOLOGIST WHOSE DO MEDICAL FERTILITY TREATMENT AND WORK SO FOR THOSE OF US REALLY IN THE FIELD, WE WORK CLOSELY TOGETHER, I DON'T THINK WE HAVE MUCH IT IS DISAGREEMENT EXCEPT MAYBE WHAT TO CALL IT >> WE HAVE A LOT OF PEOPLE STANDING BACK THERE. DO WE HAVE GROUND RULES ON THIS? >> KNOWLEDGE IS STANDING THE ENTIRE DISCUSSION. >> I GUESS FIRST I SHOULD THANK YOU FOR GETTING US ALL TOGETHER BUT MY CONCERNS ARE A BIT DIFFERENT. SO THIS IS A SIDE STEP FOR A MOMENT. MY CONCERNS ARE THE PANEL HASN'T BEEN EXPOSED TO ONE PART OF HETEROGENEITY OF THE SYNDROME. THAT IS WHILE WE HAVE BEEN DISCUSSING WHERE POLYCYSTIC OVARY AND ARE THE TEAR DAM VERSUS THE NIH CRITERIA FIT HERE, WE VICE PRESIDENT TAKEN INACCOUNT THE BIOCHEMICAL HETEROGENEITY IN THE SYNDROME, WHICH IS -- AND I THINK UNTIL WE UNDERSTAND THE BIOCHEMISTRY OF THE OVARY, WE'RE NOT GOING TO KNOW WHAT TO MAKE OF SOME OF THE GENETIC FINDINGS WE'RE GOING TO GET AND NOT REALLY GOING TO UNDERSTAND HOW POLYCYSTIC OVARY FITS INTO THIS PICTURE, IT REMIND ME WHEN I WAS STARTING IN PEDIATRICS A LONG TIME AGO WHEN WE USED TO HAVE ARGUMENTS ABOUT DOWNS SYNDROME. DO YOU NEED A SEMIINCREASE, NEED BRUSH FIELD SPOTS, DO YOU NEED HIPPOCAMPAL FOLDS, SO FORTH. THERE WERE PEOPLE THAT SAID YOU COULDN'T MAKE THE DIAGNOSE DIAGNOSIS WITHOUT THIS OR THAT. IT TURNS OUT SIMILAR SIMPLIFIED BECAUSE THERE WAS A LABORATORY FINDING. TRISOMY 21. ON THE OTHER HAND, AS ENDOCRINOLOGISTS, PEDIATRIC -- ANY SORT OF MEDICAL ENDOCRINOLOGIST YOU THINK ABOUT DOING BIOCHEMICAL TESTS. AND WE NEED TO I THINK EDUCATE THE -- THERE MAYBE MORE TO IT THAN JUST THIS SIMPLE CLINICAL PHENOTYPE THAT'S DONE. IT'S LIKE LOOKING FOR THE CAUSE FOR CURBING SYNDROME, YOU CAN ACCEPT THEY'RE ALL SAME. THERE ARE A NUMBER OF CAUSES. USING BIOCHEMICAL OVARIAN FUNCTION TESTING, WE CAN IDENTIFY THREE DIFFERENT PHENOTYPES, IRRESPECTIVE OF THE -- WELL SOMEWHAT INDEPENDENT OF THE THINGS THAT WE HAVE BEEN DISCUSSING. THERE'S -- THERE ARE THOSE THAT HAVE OVARIAN DYSFUNCTION CHARACTERIZED BY HIGH 17 HYDROXY PROGESTERONE OUTPUT IN RESPONSE TO GNRH AGONIST, THOSE TURN OUT TO HAVE A SEVERE PHENOTYPE, THEY HAVE POLYCYSTIC OVARIES, HIGH MH AND SO FORTH, DIABETES OR ABNORMAL GLUCOSE TOLERANCE AND A MILDER PHENOTYPE THAT HAS OVARIAN HYPERANDROGENISM AND NO RESPONSE BUT ANOTHER GROUP DOESN'T HAVE ANY OVARIAN DYSFUNCTION AT ALL AND WE THINK THAT'S OBESITY MIMICKING PCOS. YET WHEN THEY'RE ALL LUMPED UNDER BOTH PHENOTYPE, BROAD ROTTERDAM OR NIH AND IT WILL BE HARD FIGURE OUT WHETHER TO MACK OF GWAS STUDIES IF YOU DON'T KNOW HOW TO RELATE IT TO THE BIOCHEMISTRY. SO WE NEED TO EDUCATE RESEARCH COMMUNITY AS WELL. TO BE INVESTIGATING BIOCHEMICAL BIOLOGICAL BASIS IS OF THESE PHENOTYPES. >> I WANTED TO MAKE A SYMBOL, AS I LISTEN TO PEOPLE THINK ABOUT PRIORITIES IN TERMS OF PATIENT CONCERNS BECAUSE I THINK THE PATIENT IS IMPORTANT. HOW DO YOU EDUCATE PHYSICIANS AN DEVELOP A RESEARCH STRATEGY. YOU THINK ABOUT GETTING TO ADOLESCENCE OR PEOPLE IN THEIR 20s, WHERE THE FACT THEY MYOMIGHT DEVELOP DIABETES 34 YEARS LATER IS SO FAR OFF THEIR RADAR F. YOU THINK PCOS AS SORT OF THREE POTENTIAL COMPONENTS, IT MIGHT BE YOU EDUCATE PUBLIC AND PHYSICIANS IN EACH AREA AND THE RESEARCH AREAS THAT COVER THAT. THE ACUTE FINDINGS THAT BRING A PATIENT INTO YOUR OFFICE, HYPERANDROGENNIC SYMPTOMS THOSE ARE PEOPLE THAT PEOPLE COME IN TO THE OFFICE MAYBE OBESITY DEPENDING ON PATIENT POPULATION. THOSE ARE ALL THINGS THAT THE PATIENT COMES IN TO OUR OFFICE WE NEED TO HAVE A WAY T ADDRESS, WE NEED TO THEN UNDERSTAND THE BIOLOGIC PHYSIOLOGY, TALK TO PRIMARY CARE PHYSICIAN HOW TO DIAGNOSE THAT, IT MIGHT BE PCOS AND ADDRESS THE SYMPTOMS. LIFE STYLE, WEIGHT, ET CETERA AND THEN THERE'S INTERMEDIATE OUTCOMES WHICH ARE THE REPRODUCTIVE ONES AND MAYBE THE 16-YEAR-OLD NOT READY TO GET PREGNANT, SHE'S HER -- THAT'S RELEVANT TO A TEEN, SOMETHING RELEVANT TO SOMEBODY IN 20s, 30s, WHY DONE THESE PEOPLE OVULATE FROM A SCIENTIFIC STANDPOINT? WHAT TEASE SAFEST WAY TO OVULATE FROM A CLINICAL STANDPOINT? REPRODUCTIVELY WHAT ARE THE RISKS, WHAT ARE THE PATERNAL OUTCOMES. THEN LONG TERM RISK IN TERMS OF ENDMETRIAL CANCER, SO MAYBE I NEED TO BE AWARE OF THAT TO PROTECT THEIR UTERUS AND THEN THE MET BOLL UK ISSUE TO NHLBI AND NIDDK, NOW WE'RE TALKING DIABETES AND HEART DISEASE AND THE INTERNIST MIGHT BE MORE INTERESTED IN THAT, THAT'S THEIR -- SO IF YOU THINK ABOUT IT IN TERMS OF ACUTE ISSUES THAT BRING THE PATIENT IN MIDTERM ISSUE IT IS THE PATIENT NEEDS TO BE AWARE OF OR THINK ABOUT AND LONG TERM ISSUES, IT'S IN DIGESTIBLE WAY THAT YOU CAN EDUCATE THE PUBLIC, YOU CAN EDUCATE THE PARTICULAR PRIMARY CARE PROVIDER AND START TO BUILD RESEARCH PORTFOLIO THAT GETS OUTSIDE OF NICHD. MAYBE THAT'S SIMPLISTIC. >> IT'S REASONABLE AND IT DOES MEAN SUBDIVIDING, SOMEONE WAS TALKING ABOUT CONGENITAL HYPERPLASIA. WE'RE ABLE TO DIVIDE THAT NICELY. ATTENUATED FORMS OR TYPE 1 RAND 2 AND I HEARD JEFF SAY SOMETHING ABOUT SHOULD WE MAKE TYPE 1 RAND 2 PCOS AND IF YOU WANT TO COMMENT FURTHER ON THAT? >> IT WAS YOUR A FLASH IDEA. IF YOU WERE TO INCLUDE ANDROGEN ACCESS OVULATION IN POLYCYSTIC OVARY TYPE 1 AND REST ARE TYPE 2. EXCEPT THE POLYCYSTIC BY ITSELF WOULDN'T BE PART OF THAT. IN FACT THE CLASSICAL DESCRIPTION WOULD BE TYPE 1. AND OTHERS WOULD BE TYPE 2. IT WAS JUST A THOUGHT. >> I THINK IT'S AN INTERESTING THOUGHT. I PART OF ME WANTS TO EXCLUDE ALL TOGETHER. BECAUSE IT'S MANIFESTATION OF THE HYPERANDROGENISM AND HOW WE IMPROVE TECHNOLOGY OF ULTRA SOUNDS AND OVARY MORPHOLOGY WITH THINGS AS BEING WIDER RANGE OF NORMAL. BUT THERE'S AN INTERESTING APPROACH SO I THINK DR. PETER MEN HAS BEEN AT THE MIKE FOR A BIT. >> THEY MAY PROGRESS THAT PCOS IS NOT A FEMALE DISEASE. IT'S A FAMILY DISEASE. AND THE MEN ALSO INVOLVED THE FATHERS ARE INVOLVED, BROTHERS ARE INVOLVED, SONS ARE INVOLVED. AND YOU ALWAYS DISCUSS ABOUT IT PHENOTYPES THEY CHANGE WITH PREGNANCY, THEY CHANGE WHEN WE GOT -- WE LOSE WEIGHT OR YOU ARE MORE OBESE, PHENOTYPE CHANGE WITH AGE. THE PROBLEM IS NOT THE PHENOTYPE, THE PROBLEM IS THEY -- THIS IS A FAMILY DISEASE. I THINK WHEN THE PEOPLE UNDERSTAND IT IS A FAMILY DISEASE, I REMEMBER -- A MEMBER OF THE FAMILY IS IMPLICATED, I THINK THE APPRECIATION WILL CHANGE FROM THE PEOPLE, FROM THE PHYSICIANS. >> ONE OF THE MOST PERSUASIVE POINTS IS THE PREVALENCE OF THE SYNDROME. ESPECIALLY IN THIS COUNTRY, B I DON'T KNOW HOW MANY MILLIONS HAVE THIS SYNDROME BUT IT MUST BE ONE OF THE MOST PERSUASIVE POINTS WHEN TALKING ABOUT THE EXTENT OF THE SYNDROME AND THE PROBLEMS THAT IT CAUSES. THAT OF COURSE IS IF YOU DIAGNOSE IT RIGHT USING THE ROTTERDAM CRITERIA. THE OTHER POINT REALLY IS ALSO INFERTILITY PROBLEMS IS TO REMIND ANDREA AND OTHERS THIS IS NOT JUST A METABOLIC PROBLEM, 75% OF ALL THE OVULATORY DISORDERS WE SEE ARE CAUSED BY PCOS. PLEASE DON'T FORGET THIS AS WELL. ALSO I PLEAD WITH YOU NOT TO WASTE TIME IN DIVIDING IT UP INTO TYPE 1, TYPE 2, TYPE 22 A AND B. THIS IS A COMPLETE WASTE OF TIME. I AGREE THERESA WAS TALKING ABOUT THE SAME SYNDROME. >> MY NAME IS JENNIFER FIE, I'M A REPRODUCTIVE ENDOCRINOLOGIST FROM TEXAS TECH. TO ADDRESS THE QUESTIONS ABOUT TEACHING MEDICAL STUDENTS RESIDENTS AND MID LEVEL PROVIDERS, I HAVE THAT OPPORTUNITY ON A DAILY BASIS. IT IS MY RESPONSIBILITY TO TEACH THE MEDICAL STUDENTS AND RESIDENTS. I WILL TELL YOU, THIS IS THE NUMBER ONE QUESTION FROM EVERYONE EVEN PRACTICING PHYSICIANS, IS THERE CONFUSION WITH THE POLYCYSTIC OVARY SYNDROME DIAGNOSIS? AND I DO PRESENT THE I DON'T KNOW HOW MUCH TEAM MEDICAL STUDENTS. THEY DON'T HAVE TEXTBOOKS ANY MORE OR A PEN, THEY HAVE COMPUTERS, THEY DON'T LOOK AT YOU, I DON'T KNOW IF THEY'RE ALMOSTING TO ME. BUT THEY -- THEY ARE. AND WHEN I SAT AT THE BACK OF THE HECKTURE HALL I NOTICED THAT. BUT THEY DO HAVE MY EMAIL ADDRESS AND THEY HAVE IMMEDIATE ACCESS TO ME ON A DAILY BASIS AND THIS IS THE NUMBER ONE QUESTION. HOW DO I DIAGNOSE PCOS? I KNOW HOW TO DIAGNOSE NICU AL BRIGHT. CURBINGS SYNDROME, YOU WILL THESE THINGS THAT ARE UNLIKELY TO EVER SEE IN THEIR WHOLE LIFE BUT PCOS THEY HAVE A ONE IN TEN CHANCE OF SEEING IT IF THEY TALK CARE OF WOMEN. I STRUGGLE ON A DAK. I GREW -- DAILY BASIS. I GREW UP WITH THE NIH CRITERIA. I'M LOYAL TO AMERICA. I LOVE THE U.S. AND I FEEL GUILTY PRESENTING ROTTERDAM. I'M NOW SAYING PLEASE, PLEASE ALLOW US TO INCLUDE THE POLYCYSTIC OVARY AS CRITERIA. YOUNG PEOPLE DON'T UNDERSTAND WHY POLYCYSTIC OVARY SYNDROME DOESN'T INCLUDE POLYCYSTIC OVARY IN ITS CRITERIA AND HAVING TO ALSO BE I HAVE A GRANT ON PCOS STUDY I'M PASSIONATE ABOUT, I'M 100% CLINIC, I'M IN THE TRENCHES SEEING PATIENTS EVERY DAY AND BEGGING TO BE ABLE TO GET AN ULTRASOUND FOR THESE PATIENTS. WE HAVE TO PRE-AUTHORIZE EVERYTHING. PLEASE, I BEG YOU IF WE AT LEAST HAVE THE ULTRASOUND AS POTENTIAL CRITERIA, I RECENTLY TOOK CARE OF A 26-YEAR-OLD PATIENT SINGLE NEVER MARRIED WITH INVASIVE ENDMETRIAL CANCER BECAUSE SHE NEVER HAD AN ULTRASOUND. AND I'M NEVER GOING TO MISS THAT PATIENT IN MY CLINIC. NEVER GOING TO MISTHAT CASE. ANY STUDENTS I TRY AND I TRAIN 100 A YEAR, 12 RESIDENCE AS YEAR, FOUR NURSE PRACTITIONERS, I NEVER WANT THEM TO MISTHAT. THAT'S THE END OF MY TALK, BUT PLEASE, PLEASE ALLOW US TO INCLUDE THE ULTRASOUND. I APPLAUD THE ROTTERDAM CRITERIA THAT'S WHAT OUR MEDICAL STUDENTS WANT TO USE, THEY DR. DR. FYI IS IT OKAY TO USE ROTTERDAM CRITERIA? I DON'T QUESTION ANYONE IN THIS ROOM COULD DIAGNOSE PCOS. YOU'RE NOT GOING TO UNDER OR OVER DIAGNOSE BIT'S NOT THE PEOPLE IN THIS ROOM THAT -- BUT CONSENSUS THEY'LL GOOGLE THE CONSENSUS AN EVERY AMERICAN MEDICAL STUDENT GRADUATE WANT TO USE IT, THIS IS HUGE OPPORTUNITY AND I FEEL PRIVILEGED TO BE HERE WITH YOU DISTINGUISHED SPEAKER. I'M VERY THANKFUL AND THAT'S ALL. [APPLAUSE] >> I WOULD LIKE TO POINT OUT ONE THING, MOST PLACES, I PRACTICE IN NUMBER OF INSTITUTIONS ABOUT GET MANY, MANY REFERRALS. IF YOU ARE NOT A REPRODUCTIVE ENDOCRINOLOGIST WHO DOES YOUR OWN ULTRASOUND, THE LIKELIHOOD MAKE -- HAVE EVEN OPERATOR GIVE YOU INTERPRETATION OF POLYCYSTIC OVARIES, RESEARCH STUDY BUT VERY LOW. OUTSIDE OF ULTRASOUNDS DONE PERSONALLY BY REPRODUCTIVE END COUNTRYNOLOGISTS ARE HIGHLY SKILLED OBSTETRICAL STENOGRAPHERS WHO KNOW THIS, IF YOU GET A CLINICAL ULTRASOUND IN RADIOLOGY DEPARTMENT YOU DONE GET IT INTERPRETED AS POLYCYSTIC OVARY SYNDROME BECAUSE THEY DONE KNOW ABOUT IT. THAT'S IMPORTANT TO KEEP IN CONSIDERATION. >> THANK YOU FOR ORGANIZING THIS. THIS WAS INCREDIBLE. I WANT TO STATE THE OBVIOUS. MANY YEARS AGO WE REACHED OUT TO THE ELECTROLYSIS WORLDWIDE AND DID STUDIES JUST ON WHAT WOULD HAPPEN IF THE ELECTROLYSIS ASK SIMPLE QUESTIONS, TAKE A BLOOD PRESSURE, DO A B MECHANICI CALCULATION, ASK ABOUT OVULATORY CYCLES AND THE A QUICK (INDISCERNIBLE) WHEN THEY START WHATEVER THEY DO. WE FOUND REALLY LOOKING AT I THINK 7, 8 CLINICS THROUGHOUT THE WORLD THE VAST MAJORITY OF WOMEN INTO ELECTROLYSIS HAVE NO IDEA WHAT'S GOINGEN WITH THEIR PERIODS, HALF DON'T HAVE A DOCTOR AND WE REALIZED THERE'S A HUGE NUMBER OF PEOPLE OUT THERE WHO REALLY EITHER DON'T HAVE ACCESS OR HAVEN'T ACCESSED CARE TO FIGURE OUT WHAT'S GOING ON. SO AT UCLA WHEN I STARTED IN 2010 WE REBUILT THE WEBSITES. I WORK WITH WEB MASTERS TO MAKE SURE CODING OF THE WORDS WERE CORRECT, WE DID THEM ALL IN MICROSOFT WORD SO THE SEARCH ENGINES HILT. WEB MASTERS KNOW HOW PEOPLE SEARCH, IF THEY SEARCH BY TWO WORDS THEY TAKE AN ACTION. SEARCH BY ONE WORD THEY WILL NOT AND WE KEPT REVISING, REVISING REVISING EVERY MONTH. WHERE PEOPLE ARE MOVING WITHIN PRACTICE BELIEVE IT OR NOT. I THINK THE INTEREST AND SAME THING OBVIOUSLY BUT THE POINT IS, I THINK COMPONENT TO EDUCATION TOWARD THE LAY PUBLIC IS REALLY IMPORTANT BECAUSE THERE'S A TREMENDOUS NUMBER OF PEOPLE OUT THERE WHO REALLY HAVE NO IDEA WHAT'S GOING ON. BUT GIVEN SUFFICIENT INFORMATION WOULD PROBABLY WANT TO FINE OUT WHAT'S HAPPENING. AND ONCE AGAIN, THANKS, EVERYBODY. >> NEXT AT THE MICROPHONE IS THE FAMOUS DR. ZAVODSKI WHO DID THE FIRST CRITERIA SEPTEMBER OUT THE QUESTIONNAIRE, I HAVEN'T SEEN HER SINCE THAT CONFERENCE. >> GOOD TO SHOW UP EVERY 23 YEARS. WHEN I LISTEN TO THIS CONVERSATION I THINK ABOUT THE DATA THAT I HAVEN'T HEARD AND ONE -- AND I THINK ABOUT AAL. FIRST THING THAT COMES TO MINE IS 30 YEARS AGO WE DID NOT THINK OF TYPE 2 DIABETES AS A DISEASE OF CHILDREN. I HAPPEN TO HAVE WORKED WITH THE P UMA INDIANS AND I DID SEE THEM IN CHILDREN. I DIP REALIZE IT WAS GOING TO BE SUCH IMPORTANT PART OF DISCUSSION TODAY AMONG GENERAL POPULATION. I DIDN'T REALIZE OBESITY WAS GOING TO INCREASE SO FAST JUST IN THE TIME, IN THE JUST MY PERM OBESITY BUT OBESITY IN GENERAL. IN TERMS OF AFFECTING DISEASE STATE. ONE THING THAT I HAVEN'T HEARD HERE IN TERMS OF SPECIFIC DATA, IS PREVALENCE OF PCOS AS SYNDROME INCREASING? DO WE KNOW THAT? IS THAT IMPORTANT? ARE WE SEEING IN YOUNGER CHILDREN THAT WE DIDN'T SEE IT BEFORE? IS IT BEING AFFECTED IN THE SAME WAY OBESITY AFFECTS TYPE 2 DIABETES? AS WE SEE, THERE'S TREMENDOUS SIMILARITY BETWEEN SYNDROMES. THOSE WHO STUDY TYPE 2 DIABETES KNOW WELL IT'S NOT A PURE DISEASE, IT'S ONE TYPE OF DEEP 2 DIABETES DOESN'T DESCRIBE EVERYBODY WITH THAT PARTICULAR DISEASE. THAT'S A LOT OF VARIATION. IF WE LOOK AT PEOPLE FROM ASIA, IT'S A LITTLE DIFFERENT TYPE OF DISEASE, IF WE LOOK AT PEOPLE AMONG AMERICAN INDIANS OR BLACKS OR HISPANICS IN TYPE 2 DIABETES IT'S SIMPLIFIED BECAUSE THERE'S A GLUCOSE NUMBER WE GO BY WHICH CHANGE OVER TIME. EVERY FEW YEARS IT CHANGES AND WE CHANGE MAKING THE DIAGNOSIS RADIOTHER THAN GLUCOSE -- RATHER THAN GLUCOSE NUMBER BUT THAT CONFUSES THE ISSUE. WHAT'S IMPORTANT TO THINK ABOUT IS WHAT ARE IMPORTANT MED BOLLIC SEQUELLA TO WORRY ABOUT IN INDIVIDUAL PATIENTS? IN TERMS OF MARKETING THIS DISEASE BE IT TO THE GENERAL POPULATION OR BE IT TO MEDICAL STUDENTS OR TO PHYSICIANS, USING THE NAME THAT'S ALWAYS USED MAKES SENSE BUT YOU HAVE TO BE HONEST ABOUT IT AND COME UP WITH DISCLAIMERS RIGHT UP FRONT. YES IT'S POLYCYSTIC OVARY SYNDROME. IT CAN BE A CONFUSING NAME. BECAUSE IT HAS THESE AND THESE FINDINGS BUT IT MIGHT NOT HAVE POLYCYSTIC OVARY INCLUDED IN DIAGNOSIS, THAT'S NOT WHAT'S IMPORTANT. WHAT'S IMPORTANT WHEN WE TAKE CARE OF PATIENTS IS HOW TO HELP SOMEBODY STAY BETTER, STAY HEALTHIER OR PREVENT DISEASE. THAT'S WHERE THE FOCUS HAS TO BE. WITH DATA, I HAVEN'T HEARD WHAT HEART HOW MUCH INCREASE IN HEART DISEASE THERE IS IN THIS SYNDROME. WE'RE DISCUSSING WHAT WE SHALL USE WHAT'S IMPORTANT THE A PERSON WITH A DISEASE. >> I WANT TO START BY THANKING THE ORGANIZERS FOR A WONDERFUL TWO DAYS AND FOLLOW-UP ON DR. JOHNSON'S QUESTION ABOUT EDUCATION FOR THE MEDICAL COMMUNITY. I'M INVOLVED WITH THE (INAUDIBLE) COURSE THAT YOU DONE ALWAYS WANT THE ATTEND THE COURSE BUT OVER LAST FOUR YEARS WE HAD PRIORITY TO INCLUDE PCOS AS A SESSION AT ACOG FOR THE GENERAL OBGYN COMMUNITY. AT ESRN IT'S A PRIORITY FOR SEVERAL YEARS TO INCLUDE PCOS EVERY YEAR AS A TOPIC FOR EDUCATION TO THE REPRODUCTIVE ENDOCRINOLOGIST. SO MY SUGGESTION WOULD BE COMING FROM THE RECOMMENDATIONS FROM THIS MEETING IF WE CAN APPROACH SIMILAR SOCIETIES FOR FAMILY PRACTICE IMMUNITIES, RAID IDEAL GIST SO THEY THEN KNOW HOW TO INCLUDE CRITERIA, ENDOCRINOLOGIST, PEDIATRICIANS AND MAKE THIS A PRIORITY IN THEIR EDUCATION, ANNUALLY CONSTANTLY HAVING SESSIONS, MINI SYMPOSIA COURSES LIKE WE DO IN OBGYN, IS THAT A WAY TO GET THE MESSAGE OUT TO THE MEDICAL COMMUNITY? >> WITH REGARD TO PCOS AND -- >> CAN YOU SPEAK LOUDER? >> QUICK ON THE PREFERENCES INCREASING IN RECENT YEARS, I MENTION THE NUTRITION HYPOTHESIS WHICH THERE'S QUITE GOOD INDICATING THAT MATERNAL BODY WEIGH PRE-CONCEPTION INFLUENCES TRAJECTORTRY OF FETUS AND METABOLIC DISEASE COMING FROM A COUPLE OF COORS NOW. WE MODEL IN A PROSPECTIVE MATERNAL BODY COMPOSITION PRE-PREGNANCY AND (INAUDIBLE) DURING PREGNANCY, ONE OF THE BEST PREDICTORS OF OBESITY AT AGE 9 HOWEVER BODILY VIEW THAT IS, ONE OF THE BEST IS PRE-PREGNANCY BMI. SO REALLY SETS US UP FOR POTENTIAL FOR TRANSGENERATIONAL APPLICATION OBESITY WHICH IS GOING TO INCREASE ASSOCIATION, THE PREVALENCE OF PCOS. BUT ALSO THE PHENOTYPE WE SEE IN A SEPARATE COHORT, DIFFERENT PHENOTYPIC PRESENTATIONS RELATED TO (INAUDIBLE). THAT'S PCOS AT AGE 35. 52, 53. >> SO I AM GETTING SIGNALS FROM PARIS WRAPPING UP WOULD THE PANEL HAVE ANY MORE QUESTIONS OR COMMENTS OR THINGS IN THE NEXT MINUTE OR TWO? >> I THINK WE WOULD LIKE TO THANK THE PANEL. >> WE'RE GOING THE COME DOWN. >> NO, YOU'RE GOING TO STAY RIGHT THERE. LET HIM STAY THERE. THEY WERE GOING TO CLOSE WITHOUT -- COME ON. ANYWAY, THIS WAS A VERY INTERESTING, AND I THINK ULTIMATELY PRODUCTIVE TWO DAYS. THERE WAS SOMEONE HERE ACTUALLY FROM THE CDC, CENTERS FOR DISEASE CONTROL, THERE YOU ARE, YOU'RE STILL HERE? AND CAME TO ME AND WANTED TO WORK WITH ME AND NIH. SO HOW DO WE GET IT, HOW DO WE GET IT OUT THERE? CERTAINLY THE CDC IS EXTREMELY IMPORTANT IN GETTING THESE KINDS OF THINGS THROUGH THE -- TO THE PUBLIC AND MAKING THEM AWARE OF THAT. WE CAN MAKE PEOPLE AWARE OF THAT HERE AT THE NIH BUT THERE'S ALWAYS A RESEARCH AGENDA THAT WE GET THEM OUT THIS BUT THAT WOULD BE SO WONDERFUL AND I'M -- AND WITHOUT THIS MEETING THAT PROBABLY WOULDN'T HAPPEN. SO ANYWAY, I JUST WANT TO WRAP IT UP BY SAYING THANKS TO ONCE AGAIN THE OFFICE OF DISEASE PREVENTION, THE STEERING COMMITTEE PARTICULARLY THE CO-CHAIRS HERE AND SESSION LEADERS WHO DID A WONDERFUL JOB. AND THE SPEAKERS. THE ATTENDEES, PARTICIPANTS HERE AND VIA WEBCAST. AND NOW MOST IMPORTANTLY, THE PANEL. WHO IS -- HOPEFULLY WILL GET -- YOU'RE BEING THANKED ALREADY WITHOUT EVEN DOING -- RIGHT. BUT THE THING IS, IS THAT THE REPORT THEY GENERATE WILL BE POSTED TOMORROW AT APPROXIMATELY 9:00 A.M. BUT -- IS IT FRIDAY AT 9? NOT TOMORROW. FRIDAY AT 9:00 A.M. YOU GOT AN EXTRA DAY. SHOULD I GIVE HEM THE WEBSITE? IT'S ON HERE. RIGHT? ONE OF THESE SLIDES HAS THE WEBSITE BUT IT'S PREVENTION.NIH.GOV/WORKSHOPS -- JUST PREVENTION.NIH.GOV? >> YEAH. JUST GO TO ODP AND GET THE WEBSITE. FROM SO ONCE AGAIN, THANKS, AND I DON'T KNOW WHEN WE'LL DO THIS AGAIN BUT I I'M SURE THERE WILL BE ANOTHER MEETING SOMEWHERE, SOMEWHERE IN THIS WORLD VERY SHORTLY ABOUT PCOS BUT I'M HOPING THAT WHAT COMES OUT OF THIS WILL HELP DRIVE THE FIELD BOTH ON THE RESEARCH ENAND CLINICAL PRACTICE END FOR YEARS TO COME. THANK YOU. [APPLAUSE]