Outline. Diagnos(c Criteria and PCOS features Diagnos(c Criteria by age Reproduc(ve Care for the woman with PCOS, a focus on fer(lity and pregnancy.

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1 Across the Lifespan: PCOS and Reproduc<ve Care Heather Huddleston, M.D. Associate Professor Director of UCSF Mul<disciplinary Clinic for Women with PCOS University of California, San Francisco Outline Diagnos(c Criteria and PCOS features Diagnos(c Criteria by age Reproduc(ve Care for the woman with PCOS, a focus on fer(lity and pregnancy. 1

2 PCOS Criteria Phenotypes Hyperandrogenism Oligo or Anovula(on Other Features: Insulin Resistance Obesity Metabolic Syndrome Depression Polycys(c Ovaries Diagnos<c Criteria Across the Lifespan Childhood Adolescence Young Adult Mid- Adult Menopause and Beyond Can t be diagnosed Acne, Irregular cycles common Recommend assessing 2 years post menarche Stable: Criteria are reliable Cycles and Androgens may regularize Fer(le window extended Can t be diagnosed. No cycles, decreased androgens 2

PCOS and Insulin Resistance Insulin Resistance (min -1/nmol/ml) 90 80 70 60 50 40 30 20 10 0 Lean Lean PCOS

JCEM 81: 942-947, 1996 Metabolic Syndrome 368 Non- diabe(c PCOS pa(ents (Ages18-41) 80% 60% 40% 20% 0% 33% 80%

3 PCOS and Insulin Resistance Insulin Resistance (min -1/nmol/ml) Lean Lean PCOS Obese Obese PCOS Adapted from Dunaif A, et al. JCEM 81: , 1996 Metabolic Syndrome 368 Non- diabe(c PCOS pa(ents (Ages18-41) 80% 60% 40% 20% 0% 33% 80% 66% 32% 21% 5% No Metabolic syndrome in Women with BMI <27 (n=52) Women with BMI > 30 had 13X chance of Metabolic syndrome Ehrmann et al. J Clin Endocrinol Metab Jan;91(1):

80% Insulin Resistance and PCOS Phenotype B- coeff P 60% 40% 20% 0% P<.

$11 <.001 Moghe\ et al JCEM April 2013 Epub Insulin and the Pathophysiology of PCOS$ Insulin Resistance Hyperglycemia Diabetes Cardiovascular disease Hyperinsulinemia

Insulin Resistance Hyperglycemia Diabetes Cardiovascular disease Hyperinsulinemia

4 80% Insulin Resistance and PCOS Phenotype B- coeff P 60% 40% 20% 0% P<.001 All Classic Ovulatory Normal Androgens Insulin Resistance Metabolic Syndrome Classic Ovulatory Normal Androgens Age Fat Mass <.001 Moghe\ et al JCEM April 2013 Epub Insulin and the Pathophysiology of PCOS Insulin Resistance Hyperglycemia Diabetes Cardiovascular disease Hyperinsulinemia Decreased SHBG ovary IGF RECEPTOR Androgen produc<on Increased Free Androgen Clinical Hyperandrogenism Anovula<on 4

5 IR and DEPRESSION in PCOS Controlling for BMI and age, a one unit increase in HOMA IR increased risk of depressive symptoms by 7% (p =.06) Huddleston, submi3ed Diagnos<c Criteria Across the Lifespan Childhood 5

6 Studies in PCOS daughters BMI Tanner Stage PCOS daughters n= 135 Control daughters n=93 Matched for Tanner Stage AGE Tanner Stage PCOS and Control daughters have similar BMI and age at a given tanner stage PCOS Daughter Control Daughter Sir Peterman JCEM :1923 Ovarian volume Testosterone PCOS P<0.05 Control PCOS Control Tanner Tanner 2 Hour Glucose 2 Hour Insulin Tanner Control 100 PCOS P< Control Tanner Sir Peterman JCEM :1923 6

7 Diagnos<c Criteria Across the Lifespan Adolescence Why make a diagnosis in an adolescent? Pro Con Early diagnosis of metabolic disease Early interven<on in lifestyle changes Early treatment of clinical symptoms causing anxiety Diagnos<c criteria problema<c Puberty mimics several signs of PCOS Risk of overdiagnosis and underdiagnosis 7

8 Challenges PCOS diagnosis in adolescents: #1 Ovulatory Dysfunc(on Immature HPO axis leads to ovulatory irregularity for several years following #2 Hyperandrogenism Normative data for adolescents does not exist for androgen assays Many physiologic pubertal changes overlap with PCOS findings. #3 Ultrasound Transvaginal ultrasound undesirable Transabdominal suboptimal Polycystic ovaries may be very common in this age group Natural History of Oligomenorrhea Van Hooff: nested case control of adolescents at 3 years (mean) post menarche and three years later Cycles at 15 Cycles at 18 Regular Cycles Regular 87% Irregular 13% Oligomenorrhea 2% Irregular (24-41 day) Regular 48% Irregular 39% Oligomenorrhea 11% Oligomenorrhea Regular 22 % Irregular 27% Oligomenorrhea 51% Van Hooff et al Human Reprod 2004; 19:

Natural History of Oligomenorrhea Hazard Ratio for Oligomenorrhea at 18 yo amongst those with Oligomenorrhea at 15 yo Predictor Hazard Ra(o BMI 5.1 (1.7, 15) Testosterone 2.5 (1.0, 6.0) LH 1.6 (0.

9 Natural History of Oligomenorrhea Hazard Ratio for Oligomenorrhea at 18 yo amongst those with Oligomenorrhea at 15 yo Predictor Hazard Ra(o BMI 5.1 (1.7, 15) Testosterone 2.5 (1.0, 6.0) LH 1.6 (0.6, 3.6) Androstenedione 2.8 (1.2, 6.6) Polycys(c ovaries 2.1 (0.7, 6.7) Insulin 0.3 (0.7, 1.3) Van Hooff et al Human Reprod 2004; 19: Adolescent PCOS Characteris(cs Acne Hirsutism High Total T High Trig High Free TT High LDL Type II Diabetes High Fast Insulin Gluc/insul <4.5 Bekx et al; J Pediatr Adolesc Gynecol

Testosterone 80% 60% 40% 20% 0% Percent Metabolic Syndrome 0% Quar<le 1 20% Quar<le 2 Quar<le 3 Testosterone 55% 70% Quar<le 4 3.

10 Prevalence of Metabolic Syndrome by BMI Percent with Metabolic syndrome 100% 80% 60% 40% 20% 0% 37% 5% 11% 0% 0% 0% 63% 32% 4.5 fold increased risk of metabolic syndrome, adjusting for BMI PCOS Coviello et al 2006 JCEM 91: Metabolic Syndrome and Testosterone 80% 60% 40% 20% 0% Percent Metabolic Syndrome 0% Quar<le 1 20% Quar<le 2 Quar<le 3 Testosterone 55% 70% Quar<le fold increase in metabolic syndrome for each quartile of T Adjusted for BMI and insulin resistance Coviello et al 2006 JCEM 91:

11 Take Home Message: PCOS in Adolescent Diagnosis should be approached gingerly with op<on to re- assess over <me encouraged o Menstrual paeerns fairly well established 2-3 years post menarche o Acne is common in adolescents o Hirsu<sm and biochemical more specific o High prevalence of metabolic risk Diagnos<c Criteria Across the Lifespan Childhood Adolescence Young Adult Mid- Adult Menopause and Beyond 11

12 Before Pregnancy: Preconcep<on Rou<ne pre- natal labs Discussion of implica<ons of BMI for pregnancy Discussion of poten<al lifestyle changes before pregnancy Counseling about risks in pregnancy Screening - Hyperglycemia with OGTT - Hypertension - Dyslipidemia Risk of Pregnancy Complica<ons Meta- analysis of 2544 pa<ents with PCOS compared with 89,848 pa<ents without PCOS. Gesta(onal diabetes mellitus (OR 2.82; 95% CI: ), Pregnancy- induced hypertension 4.07 ( ) Preeclampsia 4.23 ( ) Preterm delivery 2.20 ( ) Small- for- gesta(onal age 2.62 ( ) Kjerulff. Pregnancy outcomes and polycyscc Am J of OBGYN

13 Ovula(on Induc(on: Mechanism Follicle S<mula<ng Hormone Hypothalmamus Pituitary Gland Clomid Estradiol Letrozole Insulin Resistance Megormin Weight Loss Decreased hyperinsulinemia Lifestyle Change : Exercise vs. Diet 40 women with PCOS/anovulatory infer(lity Patient Choice Structured Exercise 3 sessions per week 24 weeks Hypocaloric Diet High Protein 800 kcal deficit Palomba et al Human Reproduction

14 Lifestyle: Exercise vs. Diet Palomba et al. Exercise Diet p Age NS BMI NS Dropout 15% 35% 0.14 % Ovulatory 65% 25% 0.01 Pregnancy 35% 10% 0.06 Palomba et al Hum Reprod Nov;25(11): Lifestyle vs. Standard Treatments 344 overweight women with PCOS Randomized to clomiphene, metformin, both or lifestyle Lifestyle included advice on diet and exercise Followed up after six months Clomid Megormin Clomid and Megormin n Lifestyle Age Infer<lity BMI kg/m Waist (cm) Karminzadeh Fertil and Steril 2010; 94:

15 Lifestyle vs. Standard Treatments 20% 20% 15% 12% 14% 14% 10% P=NS 5% 0% CC CC/MET MET Lifestyle Clinical Pregnancy Rate Karminzadeh Fer<l and Steril 2010; 94: Physical ac<vity in PCOS 326 women with PCOS included 56% of PCOS pa<ents met DHHS guidelines for exercise Of these, 83% did so through vigorous ac<vity criteria while 17% did so by moderate ac<vity. ` No Yes Moderate Vigorous Huddleston, unpublished data 15

Results: Univariate Logis<c Regression Odds Ra(o (95%CI) for Metabolic Syndrome Vigorous (60 min) 0.82 (0.7, 0.798) Moderate (60 min) 1.02 (0.98, 1.07) Total METs (500) 0.96 (0.88, 1.

16 Results: Univariate Logis<c Regression Odds Ra(o (95%CI) for Metabolic Syndrome Vigorous (60 min) 0.82 (0.7, 0.798) Moderate (60 min) 1.02 (0.98, 1.07) Total METs (500) 0.96 (0.88, 1.05) Vigorous, but not moderate or total METS, is associated with a reduced odds of metabolic syndrome Huddleston, unpublished Results: Mul<variate Logis<c Regression Vigorous (60 min) Adjusted Odds Ra(o (95% CI) for Metabolic Syndrome 0.78 (0.62, 0.98) Total METs 1.12 (0.99, 1.20) Age 1.10 (1.04, 1.18) BMI 1.15 (1.09, 1.21) 1 60 minutes of vigorous exercise per week decreases odds of Metabolic Syndrome by 22%, controlling for age, BMI and total volume of exercise 16

Lifestyle for Overweight and Obese PCOS Lifestyle interven<ons may increase ovula<ons and chance of pregnancy Weight reduc<on may reduce pregnancy complica<ons Weight loss is helpful for lifelong

17 Lifestyle for Overweight and Obese PCOS Lifestyle interven<ons may increase ovula<ons and chance of pregnancy Weight reduc<on may reduce pregnancy complica<ons Weight loss is helpful for lifelong health Lifestyle interven(ons should be considered first line Clomiphene Citrate (Clomid) Synthe<c An<- estrogen Convenient Inexpensive Long- standing first choice for ovula<on induc<on in women with PCOS 17

18 How Many Women Will Ovulate With Clomid? About ¾ of women with PCOS will ovulated with clomid Imani, B. et al. J Clin Endocrinol Metab 1998;83: Clomid: Chances for conception? 160 pa(ents Normogonadotropic anovula(on Successful response to clomid Normal SA BMI >18.5 Imani, B. et al. J Clin Endocrinol Metab 1999;84:

19 Memormin For Ovula<on Biguanide Insulin Sensi<zer Category B Not FDA approved Palomba: Met vs. Clomid Randomized, double blind, double dummy Inclusion: NIH-defined PCOS with primary infertility Exclusion: BMI>30, prior fertility treatment, evidence of glucose intolerance Megormin Clomid Age BMI Dura<on of infer<lity MFG FAI% HOMA Palomba et al JCEM 2005; 90:

20 Reproduc(ve Medicine Network Mul(center Double blind 626 women with PCOS Randomized Megormin Clomiphene Both Legro et al. NEJM 2007; 35: Results of RMN PPCOS Trial P<.001 P<.001 Legro et al. NEJM 2007; 35:

21 Live Birth Prediction Chart Rausch M E et al. JCEM 2009;94: Predictors of success: Low hirsu<sm score Lower BMI Younger age Shorter dura<on of infer<lity The Withdrawal Bleed Could Be a Hindrance Secondary analysis of RMN PCOS trial Use of withdrawal bleed prior to cycle start was up to discretion of site investigators 30% 20% 10% * 0% Preg/cycle Preg/Ov LB/cycle LB/Ov Spont menses 3% 5% 2% 3% Withdraw 2% 7% 2% 5% No Withdraw 8% 27% 5% 20% * * * P<.001 * Diamond et al Obset Gyncol :

22 Aromatase Inhibitors Letrozole versus Clomiphene for Infer<lity RCT of 750 women comparing letrozole of cloniphene for five treatments Cumula<ve Ovula<on Rate higher in Letrozole (61.7% vs. 48.3%) No differences in pregnancy loss rate or twin pregnancy rate. 30% 25% 20% 15% 10% 5% 0% Live Birth Rate 28% Letrozole 19% Clomid Legro et al NEJM

23 Why Memormin Doesn t Want To Die Are there subgroups of pa<ents who respond? Have we studied appropriate dosing? The recommended second line is expensive and entails risk Memormin has some benefits: Ø - Requires less monitoring Ø - Has lower rate of mul<ple gesta<on PCOSMIC: Met/Clomid in BMI <32 and >32 Johnson et al: Randomized double blind trial in New Zealand o BMI >32 (n=65): placebo vs.metformin o BMI < 32 (n=106) CC vs. Met vs. CC/MET o Six month treatment period 50% 40% 30% 20% 10% 0% Live Birth Rates 43% 36% 29% 16% 6% Placebo Memormin Clomid Memormin Clomid + Met BMI >32 BMI <32 Johnson et al 2010 Hum. Reprod. 25 (7):

24 Memormin Pretreatment Morin-Papunen et al Mul<center randomized double blind placebo controlled study 321 with PCOs and anovulatory infer<lity randomized to memormin or placebo for three months, Aser three months, another appropriate infer<lity treatment was combined if necessary. Mean age 28 Mean BMI is 27 Morin-Papunen JCEM Megormin as Pre- Treatment: Results Pregnancy rate: Memormin 52.6% Placebo: 40.4% Effect more pronounced in obese women Obese Non-Obese Morin-Papunen L et al. JCEM 2012;97:

25 Diagnos<c Criteria Across the Lifespan Childhood Adolescence Young Adult Mid- Adult Menopause and Beyond PCOS with Reproduc<ve Aging N p-trend Total N PCOS % 76% 52% 0.05 PCO % 93% 75% 0.46 AFC Ovarian volume (mm 3) Oligo-ovulation % 79% 72% 0.18 Clinical hyperandrogenism % 71% 69% 0.38 Biochemical hyperandrogenism % 47% 24% < Elevated total T % 29% 5% Elevated free T % 25% 5% Elevated DHEA-S % 16% 9% 0.18 MFG (mean) Acne % 58% 48% 0.03 Androgenic alopecia 189 7% 18% 26%

26 PCOS with Reproduc<ve Aging N p- trend N BMI (kg/m2) Waist circumference (inches) Diastolic blood pressure (mm Hg) LDL choleterol (mg/dl) Fas(ng glucose (mg/dl) Fas(ng insulin (miu/ml) HOMA- IR h OGTT Number of metabolic syndrome elements Johnstone et al Gynecol Endo 2012 PCOS and Reproduc<ve Aging Summary Increasing menstrual regularity Decreasing biochemical hyperandrogenemia Cardiac risk factors may increase Currently no clear evidence suppor<ng increased cardiac events 26

27 Summary and Key Points PCOS diagnos(c criteria all for a high degree of heterogeneity PCOS diagnos(c criteria have limita(ons in adolescent, peri- menopause and menopausal pa(ents. Summary and Key Points Lifestyle interven(ons should be considered first line as high BMI decreases chance of pregnancy, increases rates of miscarriage and pregnancy complica(ons Letrozole first choice in pharmacologic therapy Role of megormin remains unclear, though poten(al uses in leaner women without (me pressure to conceive remains possibility 27

28 Thank you 28

Polycystic Ovary Syndrome HEATHER BURKS, MD OU PHYSICIANS REPRODUCTIVE MEDICINE SEPTEMBER 21, 2018

Polycystic Ovary Syndrome HEATHER BURKS, MD OU PHYSICIANS REPRODUCTIVE MEDICINE SEPTEMBER 21, 2018 Learning Objectives At the conclusion of this lecture, learners should: 1) Know the various diagnostic