Outline Across the Lifespan with PCOS and Reproductive Care: - PowerPoint PPT Presentation

10/20/2017 Outline Across the Lifespan with PCOS and Reproductive Care: • Diagnostic Criteria and PCOS features A focus on adolescents, fertility and aging • Diagnostic Criteria by age • Care for the woman with PCOS, with a focus on: – Adolescence Heather Huddleston, M.D. – Fertility and pregnancy Associate Professor Director of UCSF Multidisciplinary Clinic for Women – Post Reproductive with PCOS University of California, San Francisco PCOS Criteria Phenotypes PCOS and Insulin Resistance Hyperandrogenism 90 Oligo or 80 Anovulation 70 Insulin Resistance (min -1/nmol/ml) 60 50 Other Features: Polycystic 40 30 Ovaries 20 • Insulin Resistance 10 • Obesity 0 Lean Lean PCOS Obese Obese PCOS • Metabolic Syndrome • Depression Adapted from Dunaif A, et al. JCEM 81: 942-947, 1996 1

10/20/2017 Metabolic Syndrome Insulin and the Pathophysiology of PCOS 368 Non-diabetic PCOS patients (Ages 18-41) Cardiovascular Insulin disease Hyperglycemia Resistance Diabetes • 80% No Metabolic syndrome 80% 66% in Women with BMI <27 Hyperinsulinemia (n=52) 60% 33% 32% 40% • Women with BMI > 30 21% 20% had 13X chance of Decreased SHBG 5% Metabolic syndrome 0% ovary IGF RECEPTOR Increased Free Androgen Androgen Clinical Hyperandrogenism production Anovulation Ehrmann et al. J Clin Endocrinol Metab. 2006 Jan;91(1):48-53. PCOS Across the Lifespan Diagnostic Criteria Across the Lifespan Can’t be diagnosed Childhood Childhood Acne, Irregular cycles common Adolescence Adolescence Recommend assessing 2 years post menarche Young Adult Young Adult Criteria are most appropriate for reproductive aged women 18-35 18-35 Stable: Criteria are reliable Cycles and Androgens may Mid-Adult Mid-Adult regularize 35-50 35-50 Fertile window extended Menopause Menopause Can’t be diagnosed. and Beyond and Beyond No cycles, decreased androgens 2

10/20/2017 Studies in PCOS daughters Diagnostic Criteria Across the Lifespan • PCOS daughters n= 135 • Control daughters n=93 Childhood • Matched for Tanner Stage AGE BMI 14 25 12 20 10 8 15 6 10 PCOS 4 Daughter 5 2 Control 0 0 Daughter 1 2 3 4 5 1 2 3 4 5 Tanner Stage Tanner Stage PCOS and Control daughters have similar BMI and age at a given tanner stage Sir Peterman JCEM 2009 94:1923 Ovarian volume Testosterone Diagnostic Criteria Across the Lifespan 12 80 PCOS PCOS 60 8 40 P<0.05 4 Control Control 20 Adolescence 0 0 1 2 3 4 5 1 2 3 4 5 Tanner Tanner 2 Hour Glucose 2 Hour Insulin 110 100 PCOS 100 80 P<.05 90 60 Control 80 40 Control 20 70 1 2 3 4 5 1 2 3 4 5 Tanner Tanner Sir Peterman JCEM 2009 94:1923 3

10/20/2017 Challenges PCOS diagnosis in adolescents: Why make a diagnosis in an adolescent? #2 Hyperandrogenism #3 Ultrasound #1 Ovulatory Dysfunction Pro Con Normative data for Transvaginal Immature HPO axis leads adolescents does not ultrasound • Early diagnosis of • Diagnostic criteria to ovulatory irregularity exist for androgen undesirable for several years following metabolic disease problematic assays • Puberty mimics Transabdominal • Early intervention in Many physiologic suboptimal several signs of PCOS lifestyle changes pubertal changes • Risk of overdiagnosis overlap with PCOS Polycystic ovaries • Early treatment of findings may be very and underdiagnosis clinical symptoms . common in this age group causing anxiety Natural History of Oligomenorrhea Natural History of Oligomenorrhea Van Hooff: nested case control of adolescents at 3 years (mean) Hazard Ratio for Oligomenorrhea at 18 yo post menarche and three years later amongst those with Oligomenorrhea at 15 yo Cycles at 15 Cycles at 18 Predictor Hazard Ratio Regular Cycles Regular 87% BMI 5.1 (1.7, 15) Irregular 13% Oligomenorrhea 2% Testosterone 2.5 (1.0, 6.0) LH 1.6 (0.6, 3.6) Irregular (24-41 day) Regular 48% Irregular 39% Androstenedione 2.8 (1.2, 6.6) Oligomenorrhea 11% Polycystic ovaries 2.1 (0.7, 6.7) Oligomenorrhea Regular 22 % Insulin 0.3 (0.7, 1.3) Irregular 27% Oligomenorrhea 51% Van Hooff et al Human Reprod 2004; 19: 383-392 Van Hooff et al Human Reprod 2004; 19: 383-392 4

10/20/2017 Prevalence of Metabolic Syndrome by Adolescent PCOS Characteristics BMI Acne 100% Percent with Metabolic syndrome Hirsutism 80% 63% 60% High Free TT 37% 32% High Total T 40% 4.5 fold increased risk 5% 11% of metabolic High LDL 20% 0% 0% 0% syndrome, adjusting High Trig 0% for BMI Type II Diabetes High Fast Insulin Gluc/insul <4.5 PCOS Coviello et al 2006 JCEM 91: 492-497 Bekx et al; J Pediatr Adolesc Gynecol 2010 Take Home Message: PCOS in Adolescent PCOS Across the Lifespan • Diagnosis should be approached gingerly with option Childhood to re-assess over time encouraged Adolescence Young Adult Criteria are most appropriate for o Menstrual patterns fairly well established 2-3 reproductive aged women 18-35 years post menarche o Acne is common in adolescents Mid-Adult 35-50 o Hirsutism and biochemical more specific Menopause o High prevalence of metabolic risk and Beyond 5

10/20/2017 Risk of Pregnancy Complications Before Pregnancy: Preconception • Routine pre-natal labs Meta-analysis of 2544 patients with PCOS compared with 89,848 patients without PCOS. • Discussion of implications of BMI for pregnancy • Discussion of potential lifestyle changes before • Gestational diabetes mellitus (OR 2.82; 95% CI: 1.93–4.10), pregnancy • Pregnancy-induced hypertension 4.07 (2.75–6.02) • Counseling about risks in pregnancy • Screening • Preeclampsia 4.23 (2.77–6.46) - Hyperglycemia with OGTT • Preterm delivery 2.20 (1.59–3.04) - Hypertension - Dyslipidemia • Small-for-gestational age 2.62 (1.35–5.10) Kjerulff. Pregnancy outcomes and polycystic Am J of OBGYN 2010 Ovulation Induction: Mechanism Lifestyle Change : Exercise vs. Diet 40 women with PCOS/anovulatory Hypothalmamus Clomid Follicle infertility Stimulating Pituitary Gland Hormone Estradiol Patient Choice Letrozole Structured Exercise Hypocaloric Diet • 3 sessions per Insulin 24 weeks week • High Protein Resistance • 800 kcal deficit Metformin Decreased Weight Loss hyperinsulinemia Palomba et al Human Reproduction 2008 6

10/20/2017 Lifestyle: Exercise vs. Diet Lifestyle vs. Standard Treatments • 344 overweight women with PCOS Palomba et al . • Randomized to clomiphene, metformin, both or lifestyle Exercise Diet p • Lifestyle included advice on diet and exercise Age 26.8 25.8 NS • Followed up after six months BMI 33.1 33.2 NS Clomid Metformin Clomid and Lifestyle Metformin Dropout 15% 35% 0.14 n 90 88 90 75 % Ovulatory 65% 25% 0.01 Age 27.5 27.3 27.3 27.5 Infertility 4.1 3.0 4.55 3.9 Pregnancy 35% 10% 0.06 BMI kg/m 2 27.2 27.2 28 27.9 Waist (cm) 102 102 97 98 Karminzadeh Fertil and Steril 2010; 94: 216-220 Palomba et al Hum Reprod. 2010 Nov;25(11):2783-91 Lifestyle vs. Standard Treatments Lifestyle for Overweight and Obese PCOS • Lifestyle interventions may increase ovulations and chance of pregnancy • Weight reduction may reduce pregnancy P=NS complications • Weight loss is helpful for lifelong health • Lifestyle interventions should be considered first line Karminzadeh Fertil and Steril 2010; 94: 216-220 7

10/20/2017 Clomiphene Citrate (Clomid) How Many Women Will Ovulate With Clomid? • Synthetic Anti-estrogen About ¾ of • Convenient women with • Inexpensive PCOS will ovulated with • Long-standing first choice for clomid ovulation induction in women with PCOS Imani, B. et al. J Clin Endocrinol Metab 1998;83:2361-2365 Clomid: Chances for conception? Results of RMN PPCOS Trial P<.001  160 patients  Normogonadotropic P<.001 anovulation  Successful response to clomid  Normal SA  BMI >18.5 Legro et al. NEJM 2007; 35:551-66 Imani, B. et al. J Clin Endocrinol Metab 1999;84:1617-1622 8

10/20/2017 Metformin as Pre-Treatment: Results Aromatase Inhibitors Pregnancy rate: Metformin 52.6% Placebo: 40.4% Obese Non-Obese Effect more pronounced in obese women Morin-Papunen L et al. JCEM 2012;97:1492-1500 Letrozole has superior live birth to Clomiphene • 750 women with PCOS by modified Rotterdam assigned to receive letrozole or clomiphene for up to five treatment cycles • 18-40, had one patent fallopian tube and a normal uterine cavity, normal sperm concentration. • Primary outcome was live birth 9

10/20/2017 Letrozole has superior live birth to Clomiphene Factors that Predict Live Birth in PCOS Hum Reprod. 2015;30(9):2222-2233. doi:10.1093/humrep/dev182 PCOS and Fertility PCOS and Aging • Lifestyle change/weight loss should be Childhood encouraged prior to pregnancy Adolescence Young Adult • Letrozole is now the first line treatment for 18-35 PCOS Mid-Adult 35-50 Menopause and Beyond 10