Obesity and PCOS. Robert Norman The Robinson Institute for reproductive health and regenerative medicine The University of Adelaide

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1 Obesity and PCOS Robert Norman The Robinson Institute for reproductive health and regenerative medicine The University of Adelaide

2 Disclosures Honoraria and research grants from MSD, Merck Serono, Ferring Travel support from ESHRE Grant funding NHMRC, ARC and other Australian sources

3 Outline of talk Nutrition, obesity and reproduction Obesity and the egg The effect of obesity on PCOS The effect ec of PCOS on obesity Intervention strategies in PCOS and obesity

4 Nutrition and reproduction An appropriate diet and fat stores are essential for healthy reproduction

5 Obesity and reproduction bad synergies Prior to pregnancy Increases length of time to pregnancy, menstrual disorders, more drugs needed Early pregnancy Miscarriage, fetal anomalies During pregnancy Increased gestational diabetes, high blood pressure, PET, DVT, instrumental and operative delivery Postpartum Haemorrhage, infection, DVT After pregnancy Increases diabetes mellitus, high blood pressure, endometrial cancer, cardiovascular disease, musculoskeletal problems

6 Obesity may lead to infertility Abundant evidence for infertility in overweight women on natural cycles regardless of menstrual regularity: Green et al 1988, Zaadstra et al 1993, Rich-Edwards et al 1994, Lake et al 1997, Bolumar et al 2, Hassan and Killick 24, Gessink Law et al 27 Evidence for reduced success of ovulation induction and ART in overweight women: Wang et al 2, Bellver et al 23, Legro et al 27 Evidence for increased success in reproductive outcomes in overweight women with lifestyle intervention: UK (Franks), Italy (Pasquali), Australia (Norman), USA (Hoeger, Legro)

7 Overweight and infertility Extra- gonadal effects eg hyperinsulinaemia, male factor issues Ovarian and oocyte development impairment Uterine endometrial impairment Sexual intercourse impaired by high BMI in woman or partner Intercourse frequency same in RM PPCOS trial Fertility and Sterility 29

8 Effect of uterus vs egg on pregnancy Egg donation program Pregnancy rates 2656 egg donor cycles All donors had normal BMIs Recipients had different BMIs Pregnancy and live birth rates reduced according to BMI of recipient Allows comparison of egg vs uterine contribution BMI Ongoing pregnancy (%) Appears as if there is also an effect of the uterus < >3 35 Bellver et al 27

9 Influence of insulin on obesity effects Diet and exercise programs reducing weight by >5% lead to restoration of menstrual cycles and fertility (Kiddy et al, Clark et al, Moran et al, Pasquali et al) Caloric restriction more important than dietary composition (Moran et al) Insulin sensitisers eg metformin or PPAR agonists restore menstrual cycles and fertility despite weight (Nestler et al, Legro et al, Azziz et al, Norman et al, Zain et al) Associated with improved insulin sensitivity and altered body composition (Robinson et al, Huber-Bucholz et al, Pasquali et al)

10 Follicular fluid analytes CRP (mg/l) P<.1 Gluc cose mm P= BMI BMI 9 Lacta ate mm P=.18 /ml Insulin ng/ P= BMI BMI

11 Obesity and fertility in mice 4 weeks PMSG 44h hcg 13h Mtd Mated High Fat Diet Control Diet GCs COCs COCs g body weight *** # of females ovulation incidence * Control Diet High Fat Diet % fe ertilised 8 fertilization rate 6 * 4 2 Control Diet High Fat Diet ovulated did not ovulate Control Diet High Fat Diet T test. (means+ SEM, n=1) * * * P<.1 * P<.5; Fisher s Exact Test. Robker et al 21

12 Mouse COC lipidlipid localization Mouse COC localization PMSG 44h HIGH FAT DIET PMSG, hcg 13h High Fat Diet 1 8 PMSG 6 PMSG, hcg 13h 4 PMSG 2 Di Distance PMSG 44h Control Diet High Fat Diet 3 Fluorescence Units Control Diet CONTROL DIET Flu uorescence u units (Mean++SEM) PMSG/hCG 13h Xing Yang PMSG/hCG 13h Robker et al 21 PMSG PMSG, hcg 13h

13 Oocyte Mitochondrial Membrane Potential CONTROL DIET HIGH FAT DIET 1 1. Mean Re ed/green fluoresce ence ratio ** PMSG PMSG. Control Diet High Fat Diet.8 n io an Red/Green escence rat Mea fluore * PMSG/hCG PMSG/hCG. Control Diet High Fat Diet Linda Wu Robker et al 21 T test. (means+ SEM, n=3) **P<.1, *P<.5

14 Lipotoxicity in response to high fat diet [Ca 2+ ] Increased dietary fat Fatty Acids Lipid droplet accumulation ER Stress ROS [Ca 2+ ] Unfolded Protein Response (UPR) ATF4, GRP78 Mitochondrial Damage Apoptosis Robker et al 21

15 Effect of obesity in PCOS Does obesity increase the prevalence of PCOS? Does obesity affect treatment of infertility in PCOS? Does obesity increase the prevalence of diabetes? Does obesity increase the prevalence of impaired glucose tolerance? Does obesity increase the prevalence of metabolic syndrome?

16 Prevalence of obesity in PCOS Prevalence of overweight (BMI ) Prevalence of obesity (BMI >3) 4 8 n=4 or greater 35 n= n=1 or less 6 % Prevalence, % Prevalence, n=4 or greater n= n=1 or less Oceania Americas Europe Asia Oceania Americas Europe Asia Africa Siew Lim unpublished

17 Obesity and PCOS Prevalence of PCOS 86 Australian women followed longitudinally Prevalence of PCOS Aboriginal women in Australia 2 Prevalence e of PCOS (%) < >3 Category of Average BMI Teede et al 21 Boyle et al 21

18 Effect of obesity on treatment of PCOS Less spontaneous ovulation Less response to clomiphene Less response to gonadotrophins Greater danger with laparoscopic ovarian drilling Less pregnancies with ih IVF Worse outcomes of pregnancies Greater risk for long-term health of babies born

19 Prevalence of impaired glucose tolerance (BMI matched) Study or Subgroup Rajkhowa 1996 Yarali 21 Dunaif 21 Phy 24 Faloia 24 Sawathiparnich 25 Diamanti-Kandarakis 25 Alvarez-Blasco 26 Attuoua 28 PCOS Control Odds Ratio Odds Ratio Events Total Events Total Weight M-H, Fixed, 95% CI Year M-H, Fixed, 95% CI % 2.9% 2.5% 6.13 [.75, 49.8] 3.1 [.12, 79.23] 7.61 [.35, ] % 1.67 [1.31, 86.93] % 1.21 [.12, 12.4] %.8 [., 1.96] % 2.37 [.9, 6.96] % 1.14 [.32, 4.11] % 3.84 [1.37, 1.79] 28 Total (95% CI) 347 Total events 44 2 Heterogeneity: Chi² = 9.97, df = 8 (P =.27); I² = 2% Test for overall effect: Z = 3.22 (P =.1) % 2.54 [1.44, 4.47] Lower risk for PCOS Higher risk for PCOS Moran et al 21

20 Prevalence of diabetes mellitus in PCOS (BMI matched) Study or Subgroup Rajkhowa 1996 Cibula 2 Yarali 21 Sawathiparnich 25 Alvarez-Blasco 26 Moini 29 PCOS Control Odds Ratio Odds Ratio Events Total Events Total Weight M-H, Fixed, 95% CI Year M-H, Fixed, 95% CI % 42.3% 6.9% 36% 3.6% 31.1% 7.1% 2.8 [.13, 59.82] 5.46 [2.37, 12.6] 3.1 [.12, 79.23] 13. [.51, 33.48].31 [.2, 6.9] 9.23 [.49, ] Total (95% CI) Total events Heterogeneity: Chi² = 4.27, df = 5 (P =.51); I² = % Test for overall effect: Z = 3.84 (P =.1) 1.% 4. [1.97, 8.1] Lower risk for PCOS Higher risk for PCOS Moran et al 21

21 Prevalence of metabolic syndrome in PCOS (BMI matched) Study or Subgroup Faloia 24 Alvarez-Blasco 26 Shroff 27b Attuoua 28 Gulcelik 28 PCOS Control Odds Ratio Odds Ratio Events Total Events Total Weight M-H, Fixed, 95% CI Year M-H, Fixed, 95% CI % 37.6% 12.9% 14.9% 2.% 1.42 [.35, 5.8].93 [.36, 2.42] 1.67 [.4, 6.87] 4.53 [1.47, 13.98] 3.79 [1.46, 9.82] Total (95% CI) Total events Heterogeneity: Chi² = 6.47, df = 4 (P =.17); I² = 38% Test for overall effect: Z = 3.23 (P =.1) 1.% 2.2 [1.36, 3.56] Lower risk for PCOS Higher risk for PCOS Moran et al 21

22 Metabolic syndrome related to obesity BMI and androgens TT mmol/l BMI and metabolic syndrome kg/m2 Median BMI No Yes No Yes No Yes No Yes No Yes BP* component HDL-C* component TG* component FG* component WC* component All metabolic features of PCOS were explained by increased BMI and central adiposity rather than PCOS itself SHBG mmol/l * 25-34* normal overw eight obese FT pmol/l * 1 Boyle et al * 25-34* 35-44* obese overw eight normal 25-34* normal overw eight obese *p<.5 between normal BMI and obese BMI category

23 Effect of PCOS on obesity Abnormal appetite regulation (Moran et al 27) Impaired quality of life and greater depression Added problem of insulin resistance Increased androgens and hirsutism s Increased risk of menstrual disorders and cancer Increased risk of infertility

24 Intervention strategies Lifestyle management better than drugs Few randomised trials Dropouts major problem Almost impossible to maintain May change oocyte lipid Metformin addition has little value on weight Bariatric surgery may be required in some people

25 Intervention strategies Weight Weight change % Insulin with GTT Moran et al Cochrane 21

26 Acknowledgements Lisa Moran for systematic reviews, Cochrane reviews Siew Lim for systematic reviews on obesity Gill Homan for reviews on interventions Becky Robker for lipid id and egg data National Health and Medical Research Council for funding

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Polycystic ovary syndrome in young women - new ideas Disclosures Minor shareholder IVF clinic Grant support MSD, Merck and Ferring Grant support NHMRC Perspective is everything in PCOS Peacock s 2013 Polycystic