The Impact of Insulin Resistance on Long-Term Health in PCOS

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1 Saturday, April 16 th, 2016 PCOS Challenge & Thomas Jefferson University PCOS Awareness Symposium Philadelphia The Impact of Insulin Resistance on Long-Term Health in PCOS Katherine Sherif, MD Professor & Vice Chair, Department of Medicine Director, Jefferson Women s Primary Care Sidney Kimmel Medical College, Thomas Jefferson University

2 Question #1 Polycystic ovary syndrome is 1. The most common cause of anovulatory infertility 2. Associated with a high rate of miscarriages 3. Associated with a higher incidence of type 2 diabetes 4. Characterized by high androgens 5. All of the above

3 Question #2 PCOS is associated with 1. Endometrial carcinoma 2. Endometriosis 3. Coronary artery disease 4. All of the above

4 Question #3 Initial testing for irregular menses includes 1. Thyroid stimulating hormone 2. Cortisol alpha-hydroxyprogesterone 4. All of the above

5 Question #4 Diagnostic criteria for PCOS include: 1. A history of irregular menstrual intervals 2. Signs of high androgens or elevated levels of androgens 3. Characteristic polycystic ovaries by ultrasound 4. All of the above

6 Polycystic Ovary Syndrome Prevalence is high Essential to diagnose early to prevent metabolic sequelae Earlier: Later: Infertility, acne, hirsutism, alopecia Significant metabolic abnormalities & morbidity Dyslipidemia, IR/IGT/T2D, hypertension, obesity, fatty liver Obstructive sleep apnea Eating disorders Endometrial carcinoma, dysfunctional uterine bleeding Miscarriages, preterm births, stillbirth, gestational diabetes

7 PCOS: a reproductive disorder Oligomenorrhea, amenorrhea Infertility (50 60% of all infertility in the US) Pregnancy loss (30-50%), preterm and stillbirths Polycystic ovaries Endometrial carcinoma? Gestational diabetes (30% GD are PCOS) with hirsutism, acne and weight gain

8 Cardiometabolic Disorder Elevated blood pressure 50% Abnormal glucose metabolism 50-70% insulin resistance, IFG, IGT, diabetes Abnormal lipids 70% High triglycerides, low HDL-C Obesity 40-80% Sleep apnea? Fatty liver? J Intern Med 1996, 239: , J Clin Epidemiol 1998, 51:

9 Obstetric Complications N = 4982 PCOS, N = 119,692 Controls RISK OR 95% CI Gestational DM PIH Preeclampsia Preterm birth C-section NICU admission Qin JZ, Reprod Biol Endocrin 2013

10 PCOS - Economic Cost to Health Care Annual costs = $4.3 billion Initial evaluation: $93 million (2%) Treat hirsutism: $622 million (14%) Infertility costs: $533 million (12%) Treat irregular bleeding: $1.35 billion (31%) T2D in PCOS: $1.77 billion (40%) Conclusion: Screen aggressively, treat aggressively & prevent sequelae Azziz, R. et al., Health Care-Related Economic Burden of the Polycystic Ovary Syndrome during the Reproductive Life Span, JCEM 2005, 90(8):

11 PCOS & Population Health 2566 women 25,660 age-matched controls Gynecological Diagnoses Non-PCOS (25 660) PCOS (2560) P Value HR 95% CI Endometriosis 1121 (4.4) 677 (26.4) < Endometrial hyperplasia a 24 (0.1) 46 (1.8) < Menstrual problems 1269 (4.9) 520 (20.3) < Hysteroscopy 1965 (7.7) 1107 (43.1) < D&C 5695 (22.2) 1641 (64.0) < Endometrial ablation 244 (1.0) 94 (3.7) < Data are shown as number (percentage) with χ 2 test P values, and HRs and their 95% CI values adjusted for birth epochs (<1972, , ). aendometrial adenomatous hyperplasia found in one control and four cases, respectively. - See more at: Hart et al., JCEM 100(3): , 2015

12 PCOS & Population Health 2566 women 25,660 age-matched controls Hysterectomy 649 (2.5) 204 (8.0) < Infertility 1188 (4.6) 1050 (40.9) < Miscarriage 1572 (6.1) 286 (11.1) < Ectopic pregnancy 386 (1.5) 97 (3.8) < Procreative management 668 (2.6) 527 (20.5) < Investigation- 91 (0.4) 93 (3.6) < testing IVF 518 (2.0) 445 (17.2) < Pregnancy 20 wk (62.9) 1786 (69.6) < Hart et al., JCEM 100(3): , 2015

13 PCOS & Population Health 2566 women 25,660 age-matched controls Diagnoses Non-PCOS PCOS P Value HR 95% CI Endocrine Obesity (3.7) 411 (16.0) < Late-onset diabetes 980 (3.8) 321 (12.5) < a Other endo, nutr, 1873 (7.3) 521 (20.3) < metab a Circulatory Hypertension 192 (0.7) 98 (3.8) < a IHD 50 (0.2) 21 (0.8) < a CVA 51 (0.2) 15 (0.6) a Other cardiac 266 (1.0) 44 (1.7) a Arterial/venous dis 1497 (5.8) 275 (10.7) < a Hart et al., JCEM 100(3): , 2015

14 PCOS & Population Health 2566 women 25,660 age-matched controls Diagnoses Non-PCOS PCOS P Value HR 95% CI Musculoskeletal 4167 (16.2) 661 (25.8) < a Mental disorders Stress/anxiety Depression Drug use-related Other disorder 1525 (5.9) 358 (14.0) < (4.3) 252 (9.8) < (4.5) 227 (8.8) < (6.6) 353 (13.8) < Hart et al., JCEM 100(3): , 2015

15 PCOS & Population Health 2566 women 25,660 age-matched controls Diagnosis Non-PCOS PCOS n P Valu e HR 95% CI Cervical cancer 970 (3.8) 67 (2.6) Endometrial cancer 4 (<0.01) 9 (0.4) < Breast cancer 88 (0.3) 8 (0.3) Skin cancer 169 (0.7) 14 (0.5) Other cancers* 165 (0.6) 24 (0.9) Hart et al., JCEM 100(3): , 2015

16 PCOS & Population Health 2566 women 25,660 age-matched controls Diagnoses Non-PCOS PCOS P Value HR 95% CI External causes Adverse outcome of medical treatment 1936 (7.5) 486 (18.9) < Self-harm 750 (2.9) 185 (7.2) < Land transport accident 982 (3.8) 134 (5.2) victim Respiratory Asthma 1160 (4.5) 271 (10.6) < Other respiratory 3635 (14.2) 585 (22.8) <

17 Weight gain and/or androgens cause adiopose tissue hypertrophy, followed by release of adipokines and inflammatory mediators that cause insulin resistance, weight gain and androgen excess Poli Mara Spritzer et al. Reproduction 2015;149:R219-R Society for Reproduction and Fertility

18 IRS-1 is in muscle cells and adipocytes Pathophysiology Weight gain Larger adipocytes Hyperinsulinemia Insulin resistance in muscle Insulin Receptor Substrate-1 gene mutation (G972R)

19 Pathophysiology: Reproduction Weight gain Hyperinsulinemia Insulin resistance IRS-1 mutation Testosterone Irregular menses Infertility

20 Pathophysiology: Metabolic Weight gain Hyperinsulinemia Insulin resistance IRS-1 mutation Blood pressure Triglycerides, HDL β cell dysfunction Coagulation Obesity Acanthosis nigricans

21 Traditional treatment does not address cardiometabolic issues ovary ovary endothelium testosterone hyperinsulinemia endothelial dysfunction cysts acne, hirsutism, alopecia anovulation dyslipidemia diabetes infertility Overweight Acanthosis nigricans hypertension Sherif 2006

22 Figure 1 Natural history of PCOS. PCOS has a multifactorial aetiology that includes intrauterine, genetic and environmental factors which might or might not be interrelated. Anderson Sanches de Melo et al. Reproduction 2015;150:R11-R24

23 I can t be insulin resistant, my sugar is fine. After years of being insulin resistant. Beta cells in the pancreas die Now the pancreas cannot produce enough insulin to metabolize nutrients and get them into the cells The blood sugar is high (because the sugar is in the blood, not in the cells of the body as fuel) You are told you are diabetic..

24 How do we prevent becoming diabetic? Keep the pancreatic beta cells happy Become insulin sensitive so the beta cells don t have to work as hard How do you become insulin sensitive?

25 Key: improve insulin sensitivity Nutrition Decrease both calories & simple carbohydrates Increase physical activity and muscle mass Sleep 8 hours per night treat sleep apnea Insulin-sensitizing medications Insulin-sensitizing supplements

26 Key: improve insulin resistance Nutrition Decrease both calories & simple carbohydrates Increase physical activity and muscle mass Sleep 8 hours per night Insulin-sensitizing medications Insulin-sensitizing supplements

27 Metformin Benefits: Weight loss (minimal) Improved lipid profile Improved acne, hirsutism and alopecia Normalization of transaminases Ovulation & pregnancy Cochrane meta-analysis: first-line agent for anovulation Side effects Gastrointestinal: diarrhea, nausea Decreased B-12 absorption and homocysteine Lord, BMJ, 2003

28 Insulin sensitizers improve metabolic & reproductive problems ovary ovary endothelium testosterone hyperinsulinemia endothelial dysfunction cysts acne, hirsutism, alopecia anovulation dyslipidemia diabetes infertility Overweight Acanthosis nigricans hypertension Sherif 2006

29 Supplements with insulin-sensitizing properties Cinnamon Vitamin D Chromium 250mg TID N-acetyl cysteine 500mg Alpha lipoic acid Resveratrol D - chiro inositol & myo-inositol

30 Summary of Management 1. Nutrition counseling & increase physical activity 2. Metformin for metabolic abnormalities 3. Consider supplements 4. Hormonal contraception for dermatologic problems 5. Screen early for Type 2 diabetes A1c Fatty Liver - transaminases Hypothyroidism TSH, free T4 Sleep apnea STOP BANG Depression

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