Diagnosis and Management of Polycystic Ovary Syndrome During Adolescence: Questions and Controversies

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1 Diagnosis and Management of Polycystic Ovary Syndrome During Adolescence: Questions and Controversies 2017 Illinois-AACE 2017 Annual Meeting October 14, 2017

2 Learning Objectives 1) Understand the challenges in making a definitive diagnosis of polycystic ovary syndrome during the adolescent years. 2) Discuss the long term reproductive and metabolic outcomes associated with polycystic ovary syndrome. 3) Discuss responses to various treatment approaches for polycystic ovary syndrome during adolescence. 4) Understand the evidence for the importance of early origins in the pathogenesis. 2

3 Polycystic Ovary Syndrome (PCOS) Diagnostic Criteria NIH (1990) 3 of 3: ü Chronic anovulation ü Clinical and/or biochemical hyperandrogenism ü Exclusion of other possible etiologies (CAH, androgen secreting neoplasm) Rotterdam (2003) 2 of 3: ü Oligo- and/or anovulation ü Clinical and/or biochemical hyperandrogenism ü Polycystic ovaries AE-PCOS Society (2006) 2 of 2: ü Clinical and/or biochemical hyperandrogenism ü Ovarian dysfunction - oligo-anovulation - polycystic ovaries 3

4 PCOS Phenotypes Diamanti-Kandarakis & Dunaif, Endocrine Reviews

5 Phenotypic Heterogeneity - PCOS POTENTIAL PCOS PHENOTYPES Hyperandrogenism Hyperandrogenemia Oligo-anovulation PCOM NIH Rotterdam AE-PCOS Rotterdam AE-PCOS Rotterdam 5

6 Reproductive Phenotype PCOS GnRH pulse frequency Insulin Androgen LH DHEAS SHBG Free T AMH Testosterone 5αR DHT

7 Metabolic Phenotype Insulin Resistance A. Dunaif et al. J Clin Endocrinol Metab 65: ,

8 Metabolic Phenotype β-cell dysfunction Obese PCOS Lean PCOS A. Dunaif and D. T. Finegood. J Clin Endocrinol Metab 81: ,1996 8

9 Pathophysiology of PCOS Reproductive features: - Altered GnRH pulse generator - LH:FSH - Ovarian hyperandrogenism - Adrenal hyperandrogenism Metabolic features: - Insulin resistance - Obesity - Β-cell dysfunction - Adipose dysfunction 9

10 Hyperandrogenemia and Hyperinsulinemia T, DHEA Altered insulin action skeletal muscle and adipose tissue Increased visceral fat Decreased adiponectin secretion IR Insulin Alterations in gonadotropin secretion increase in LH:FSH Co-gonadotropin to increase LH-induced androgen synthesis in theca cells Decrease in SHBG HA

11 PCOS Diagnosis in Adolescence 11

12 PCOS in Adolescence Transient Oligomenorrhea Legro et al JCEM 85(3),

13 Polycystic Morphology (PCOM) in Adolescence Limitations of transabdominal U/S for evaluation of PCOM Compounded by obesity Multifollicular ovaries are normal in puberty, difficult to distinguish from PCOM Role of AMH as serum marker for PCOM? 13

14 PES Consensus Recommendations 1) Biochemical hyperandrogenemia using sensitive assays (LC-MS) 2) Oligo/anovulation: Menstrual cycles shorter than every 20 days or longer than every 45 days at 2 years post-menarche Repeated menstrual cycles longer than every 90 days within the first year of menarche Lack of menses by age 15 years or 2-3 years post-thelarche 3) No role for ovarian imaging in the diagnostic work up PCOS adolescence Witchel et al, Horm Res Ped 83,

15 Long Term Outcomes PCOS Metabolic Reproductive Psychological Type 2 diabetes Subfertility Depression/Anxiety Obstructive Sleep Apnea Adverse pregnancy outcomes NAFLD Endometrial cancer Cardiovascular disease (??) 15

16 Long Term Outcomes PCOS Association with Type 2 diabetes well-established Early IGT: 30% prevalence of IGT in PCOS reported in both adult and adolescent cohorts Hyperglycemia mainly post-prandial in early dysglycemia: A1C & fasting blood glucose not sensitive Danish National Register, cohort >70,000* Hazard Ratio T2D: 4.0 ( , p<0.0001) Age of onset for T2D was younger in PCOS compared with population (31 v. 35 years) *K. Hass Rubin et al. J Clin Endocrinol Metab 2017, Epub ahead of print 16

17 Long Term Outcomes PCOS - CVD Anderson, et al. Int J Cardiology 176: ,

18 Long Term Outcomes PCOS Endometrial Carcinoma Increased risk largely related to chronic anovulation and unopposed estrogen Obesity a significant contributing risk factor Haoula Z, et al. Human Reproduction, 127: 5,

Improve biochemical HA +/- improvement in hirsutism and acne Mechanism Androgen receptor

19 Treatment of PCOS Reproductive Features Mechanism Progestin suppresses LH levels - ovarian HA Estrogen increases SHBG - bioavailable androgen Effects Restore regular menstrual cycles Improve biochemical HA +/- improvement in hirsutism and acne Mechanism Androgen receptor blockade Inhibition of 17- hydroxylase and 17,20-desmolase Effects Improvement in hirsutism and acne 19

20 Treatment of PCOS Metabolic Features Mechanism Decreased hepatic glucose output Some effects on insulin sensitivity Mechanism Improvement in insulin resistance Effects Reduction in central obesity +/- weight loss? More modest improvement in HA, anovulation Modest risk reduction in T2DM Effects Greater impact risk reduction T2DM Can normalize HA in subset of morbidly obese PCOS 20

21 Treatment of PCOS - Choice of OCP EE dose: 20 mcg, 30 mcg, 35 mcg, 50 mcg Monophasic vs. triphasic Continuous vs. Intermittent therapy Progestin Progestin Androgenic Activity Thrombosis OR (95%CI) Norethindrone ( ) Levonorgestrel ( ) Norgestimate ( ) Desogestrel ( ) Drospirenone ( ) Vlieg, et al, BMJ

22 Treatment of PCOS Impact of Weight Loss In bariatric surgery populations, weight loss can result in resolution of metabolic and reproductive features of PCOS Weight loss resulting from hypocaloric diet + metformin has resulted in improvement in insulin sensitivity, androgen concentrations, hirsutism scores, menstrual cyclicity Pre-conception weight loss improves ovulation rates in women undergoing ovulation induction 22

23 Treatment of PCOS in Adolescence Metformin N=6 Placebo N=10 OCP N=10 Lifestyle N=8 Pre Post Pre Post Pre Post Pre Post BMI * Total T ** FAI ** * FG score Fasting insulin *p<0.05 **p< Hoeger K et al JCEM (11):

24 Early Origins PCOS Premature Pubarche Birth size (LGA/SGA) Peripubertal Obesity PCOS Genetic Risk Intrauterine factors 24

25 Premature Pubarche & PCOS Ibanez et al: 16 of 35 girls with PP followed for > 2.5 years after menarche developed oligomenorrhea, hirsutism, ovarian hyperandrogenism Ibanez L et al. JCEM :

26 Premature Pubarche & PCOS Post-pubertal ovarian hyperandrogenism correlated with prepubertal androgen levels Figure: Rosenfield RL JCEM : Data: Ibanez L et al. JCEM :

27 PCOS: Preventative Interventions? Ibanez et al JCEM 89(9)

28 Early Origins PCOS Premature Pubarche Birth size (LGA/SGA) Peripubertal Obesity PCOS Genetic Risk Intrauterine factors 28

29 Birth Weight and PCOS Ibanez L, et al. JCEM :

30 Birth Weight and PCOS Mumm et al. Fertility & Sterility 99(3):

31 Early Origins PCOS Premature Pubarche Birth size (LGA/SGA) Peripubertal Obesity PCOS Genetic Risk Intrauterine factors 31

32 Intrauterine Factors Prenatal androgen exposure in primates results in phenocopies of PCOS in the offspring. Ovarian/adrenal hyperandrogenism Oligomenorrhea Polyfollicular ovaries LH Abdominal obesity Insulin resistance Impaired glucose tolerance Dyslipidemia Abbott & Dumesic

33 Early Origins PCOS Premature Pubarche Birth size (LGA/SGA) Peripubertal Obesity PCOS Genetic Risk Intrauterine factors 33

34 Peripubertal Obesity & PCOS McCartney CR et al JCEM 92, 2007,

35 Early Origins PCOS Premature Pubarche Birth size (LGA/SGA) Peripubertal Obesity PCOS Genetic Risk Intrauterine factors 35

36 Elevated T Levels ~40% Sisters Affected - Bimodal 36

37 Genetic Studies in PCOS GWAS Hayes, et al. Nat Commun. 2015; (6) 37

38 PCOS First-Degree Relatives (FDRs)

39 Previous Findings: PCOS FDRs Infancy Childhood (Prepubertal) Early Puberty leptin (cord blood) androstenedione & estradiol (cord blood) Post-stimulated insulin AMH DHEAS leptin (cord blood) AMH BMI

40 FDRs At-Risk DI AIRg (µ IU/ml) Increased Risk T2D Control Girls Sensitivity Index (min -1 /[mu/ml]) FDRs FDRs with dysglycemia

41 β-cell Dysfunction FDRs 6 S e n s it iv it y In d e x (m in - 1 / [m U / m l]) 4 2 p = F D R C o n t ro l n = 1 1 n = 9

42 Steroid Hormone Metabolites Increased 5α-Reductase Activity & Increased Glucocorticoid Metabolites PCOS Women Cholesterol 5-PD Preg 5-PT 17-OHPreg Prog DOC Corticosterone 18OH- Corticosterone PD THDOC THA, 5aTHA 5aTHDOC THB, 5aTHB Aldosterone 17-OHP 11-Deoxycortisol Cortisol DHEA 16OH-DHEA PT 17HP THS THF, 5aTHF, β-cortols, α-cortols Cortisone DHEA Δ 4 A Testosterone Androsterone Etiocholanolone DHT THE β-cortololones, α-cortololones

43 Increased 5α-Reductase Activity PCOS Daughters 6 *p = a T H F /T H F P C O S - d, n = 2 1 C o n t r o l, n = 3 6

44 Are there distinctions in the hyperandrogenemia observed in PCOS daughters and obese girls? 44

45 Differing Genetic Risk PCOS PCOS-d v. OB-g ~ 40% PCOS daughters 7-10% Obese girls

46 Similar Increase in Free T PCOS daughters & Obese girls F r e e T n g /d l L - g P C O S - d O B - g n = 1 8 n = 3 7 n = 2 3

47 Decreased AMH Obese girls < A M H n g /m L 2 0 L - g P C O S - d O B - g n = 1 8 n = 3 8 n = 2 3

Timeline for Reproductive Function & Findings in PCOS FDRs Ovarian sex steroid production Fetal life Mini Puberty Puberty Increased T Increased

48 Timeline for Reproductive Function & Findings in PCOS FDRs Ovarian sex steroid production Fetal life Mini Puberty Puberty Increased T Increased AMH Reproduction Adrenal androgen production PCOS FDRs? Childhood 5αR activity Decreased Δ 4 A Increased DHEAS Adrenarche Birth 1 y 6-8y 10-16y 52y

49 Conclusions PCOS is a common endocrine disorder affecting 7-10% of reproductive aged women Significant reproductive and metabolic consequences: subfertility and increased diabetes risk, impact on CVD risk unclear Treatment with combination OCPs first line for improvement if symptoms associated with hyperandrogenemia, mitigation of endometrial CA risk PCOS likely has developmental and/or genetic origins: High heritability Milder features of the disorder seen in FDRs Phenocopies in androgen-exposed animal models 49

50 Acknowlegements Andrea Dunaif, MD Genetics mentors: Margrit Urbanek, PhD M Geoffrey Hayes, PhD Funding: R01 DK (Dunaif) K12 HD (Torchen) K23 HD (Torchen) 50

Phenotypes in Male & Female First Degree Relatives of Women with PCOS. Andrea Dunaif, MD

Phenotypes in Male & Female First Degree Relatives of Women with PCOS Andrea Dunaif, MD 1 ~7% Prevalence Anovulatory PCOS Leading Cause Hormonally-Related Infertility 4-Fold Increased Risk Type 2 Diabetes