Polycystic ovary syndrome in young women - new ideas

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1 Polycystic ovary syndrome in young women - new ideas

2 Disclosures Minor shareholder IVF clinic Grant support MSD, Merck and Ferring Grant support NHMRC

3 Perspective is everything in PCOS

4 Peacock s 2013

5 Polycystic ovary syndrome Unknown aetiology but familial elements Very diverse phenotype presenting to different practitioners Insulin resistance is very common Name implies this is a reproductive condition and medical aspects ignored.

6 Complex clinical syndrome Norman et al Lancet 2007

7 A changing paradigm in PCOS Human Reproduction 27:14-24 (2012)

8 Teede et al MJA 2011, Deeks et al Fertil Steril 2010 Psychological features Anxiety & depression Eating disorders Quality of life Poor body image Psychosexual dysfunction

9 PCOS phenotypes across ethnicity Ethnicity-specific guidelines for appropriate screening, diagnosis, treatment in high risk ethnic groups Europeans: - Relatively mild phenotype East Asian: - High prevalence of metabolic syndrome - Lower BMI - Mild hyperandrogenic phenotype South Asians: - high prevalence of insulin resistance and metabolic syndrome - high risk for type 2 - diabetes mellitus - high central obesity Surinam hindustani: - More insulin resistance Africans: - High BMI levels - More metabolic problems Middle Eastern / Mediterranean: - More hirsutism Hindustani: - More insulin resistance (Louwers et al. JCEM 2014, courtesy Joop Laven)

10 PCOS prevalence LUCINA community prevalence study N=728 women from retrospective cohort study Representative population of all female births at QEH NIH Group AES Group Rotterdam Group 9% 10-12% 12-18% (March 2010; Boyle et al 2012)

11 Different types of PCOS Hyperandrogenism, normal cycles, PCO ultrasound Normal androgens oligo-anovulation, PCO 17% 7% 16% Hyperandrogenism, oligoanovulation, PCO ultrasound (NIH) 61% Hyperandrogenism, oligoanovulation, normal ultrasound (NIH) N= 380 Prevalence of PCO around 20% Prevalence of PCOS 12-17% Prevalence in Indigenous women 21%

12 PCOS and other conditions Hart and Doherty JCEM 2015

13 PCOS and other conditions Hart and Doherty JCEM 2015

14 Over nutrition reduces reproduction Early puberty and menstrual abnormality Anovulation and infertility Increased androgens Miscarriage Gestational diabetes and other pregnancy disorders Reversal with caloric restriction Dependent on fat distribution

15 The prevalence of obesity in PCOS Lim SS, Davies MJ, Norman RJ, Moran LJ. Hum Reprod Update :

16 Type 2 Diabetes Mellitus and PCOS Study or Subgroup Dos Reis 1995 Rajkhowa 1996 Cibula 2000 Yarali 2001 Sir-Petermann 2004 Sawathiparnich 2005 Lo 2006 Alvarez-Blasco 2006 Leibel 2006 Marquez 2008 Shaw 2008 Bhattacharya 2009 Moini 2009 PCOS Control Odds Ratio Odds Ratio Events Total Events Total Weight M-H, Fixed, 95% CI Year M-H, Fixed, 95% CI % 0.2% 0.8% 0.1% 0.2% 0.1% 89.9% 0.6% 0.1% 0.6% 6.6% 0.7% 0.1% 5.15 [0.25, ] 2.80 [0.13, 59.82] 5.46 [2.37, 12.60] 3.10 [0.12, 79.23] 6.16 [0.33, ] [0.51, ] 4.68 [4.28, 5.11] 0.31 [0.02, 6.09] 4.49 [0.22, 91.35] 3.05 [0.72, 12.82] 1.50 [0.92, 2.45] 1.33 [0.26, 6.67] 9.23 [0.49, ] Total (95% CI) % 4.43 [4.06, 4.82] Total events Heterogeneity: Chi² = 26.82, df = 12 (P = 0.008); I² = 55% Test for overall effect: Z = (P < ) Lower risk for PCOS Higher risk for PCOS PCOS greater prevalence of DM2 : OR 4.43 [4.06, 4.82] (Moran 2010)

17 Aetiology unknown Ovary Hypothalamic pituitary Insulin resistance Pregnancy Genetic Lifestyle

18 Serum AMH as a marker for PCOM Australian and New Zealand Journal of Obstetrics and Gynaecology Volume 55, Issue 4, pages , 30 JUL 2015 DOI: /ajo.12366

19 Role of AMH in Follicle Development Androgens Estrogens FSH a c AMH b Primordial Small Preantral Large Preantral Antral (2-7 mm) Antral (8-12 mm) Preovulatory (Broekmans et al., Trends in Endocrin & Metab,2008)

20 AMH & GnRH neuron exitability (Cimino et al., Nature Communications 2016)

21 Pathophysiology of Anovulation in PCOS Progesterone Hyperandrogenism Anovulation X (Cimino et al., Nature Communications 2016; Blank et al., JCEM 2009)

22 PCOS in twins Heritability index: of PCOS Oligomenorrhea 1 Hirsutism Acne MZT DZT 0 MZT DZT (Vink et al., JCEM, 2006)

23 Genome Wide Association Studies (GWAS) in PCOS GWAS in Han Chinese PCOS women: Discovery set: 744 cases; 895 controls Replication 1: 2840 cases; 5012 controls Replication 2: 498 cases; 780 controls (Chen et al., Nature genetics, 2011)

24 GWAS in European Descent Women with rsid SNP (chr:position) Eff. All. Freq. Nearest Gene Population. rs : THADA# Chinese Han rs : LHCGR Chinese Han rs : FSHR Chinese Han rs : C9orf3* Chinese Han rs : DENND1A Chinese Han rs : YAP1# Chinese Han rs : RAB5B Chinese Han rs : HMGA2 Chinese Han rs : TOX3 Chinese Han rs : INSR Chinese Han rs : SUMO1P1 Chinese Han (Hayes et al., Nature Communications, 2015; Day et al., Nature Communications, 2015) rs : KCNA4 /FSHB# rs : GATA4 /NEIL2 rs : ERRB4 rs : IRF1/RAD50 rs : KRR1 European Ancestry (G.H. et al)* European Ancestry (G.H. et al)* European Ancestry (F.D. et al)# European Ancestry (F.D. et al)# European Ancestry (F.D. et al)#

25 Lifestyle changes

26 Lifestyle intervention and infertility 6 month curriculum: Weekly group meetings Modest dietary/exercise advice, social/psychological support Study 1: n=13 (8 PCOS): 6.2 kg wt loss, 12/13 ovulation, 11/13 pregnancies Study 2: n=67 (53 PCOS): 10.2 kg wt loss, 60/67 ovulation, 52/67 pregnancies Average (kg) weight loss Spontaneous ovulation Number of spontaneous pregnancies Months Start End (Clark Hum Reprod 1995, 1998)

27 Dietary interventions in PCOS 8 weeks of energy restriction, dietary intake/day: 1167 kcal/day Weight (kg) Waist circumference (cm) Weight 5.6 kg Waist circumference 6.1 cm Weight Week Improvement in menstrual * regularity or ovulation for 57% of women Waist circumference * Insulin (mu/l) Free androgen index * Time p < 0.01 Mean±SD Insulin: 2.8 mu/l Free androgen index: Insulin Week Free androgen index * * (Moran AJCN 2006)

28 Lifestyle modification improves fertility Legro et al JCEM 2015

29 Prevention of weight gain Logical, lower cost, more acceptable, small changes Weight loss requires reduction 2-4 Mj ( kcals)/day to achieve 5-10% weight loss over 6 months Weight gain prevention requires 250kj (60kcals) per day less 250ml juice down to 100 ml

30 What fertility options do we have?

31 Scientific question: Which is the most effective treatment option in WHO group II anovulation? Clomiphene Clomiphene + Metformin Tamoxifen Placebo/No treatment WHO Group II anovulation Letrozole Laparoscopic Ovarian Drilling Gonadotropins Metformin

32 Results - Cumulative Rankograms - Clinical pregnancy Overall population 1st CC CC+Met FSH Cumulative Probabilities LOD Let Met Pla Tam th Graphs by Treatment Rank SUrface under Cumulative RAnking(SUCRA)

33 Clustered Ranking Plot Clinical & Multiple pregnancy by SUrface under Cumulative Ranking (SUCRA) LOW risk of multiples Pla Tam CC Met Let CC+Met FSH SUCRA values of higher Clinical Pregnancy HIGH chance of pregnancy

34 Assisted reproduction Use of GnRH antagonist/agonist cycle to reduce OHSS In vitro maturation Single embryo transfer Peacock s 2013

35 Models of care for PCOS healthcare Specialists: Endocrinologist Gynaecologist Dermatologist Midwives Patient central to care and holds management plan Allied Health: Psychologist Dietitian Exercise Physiologist Reputable education sources and consumer support group: Websites, media, health Primary care: Central to ongoing care and co-ordination

36 is integration of best research evidence with clinical expertise and patient values Clinical judgment Patient preference Evidence from research Evidence Based Practice

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