1. PCOS as a Metabolic syndrome Sang Ho Yoon Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Dongguk University Graduate School of Medicine

2. Diagnostic criteria for Metabolic syndrome : International Diabetes Federation (IDF)

3.  Stein & Leventhal in the 1930s Described the association between PCO morphology, hirsutism, menstrual disturbances and obesity  The most common endocrine disorder in women  3 ~ 10 % of women of reproductive age  25 ~ 30% of infertility patients  Major cause of anovulatory infertility 75% of PCOS: infertility d/t anovulation Polycystic ovary syndrome (PCOS)

4. N Engl J Med, 2005

5. PCOS pathogenesis Jayasena et al., Nat Rev Endocrinol, 2014

6. Clinical problem in PCOS 배란장애에 의한 불규칙한 월경 및 불임 남성호르몬 과다증세 당뇨, 심혈관계 질환 위험도 증가 Katsiki et al, Drugs, 2009

7. Lifelong complications Norman et al., Lancet, 2007

8. Diagnostic criteria for PCOS Jayasena et al., Nat Rev Endocrinol, 2014

9. Polycystic Ovary  Definition TV USG Follicular phase 12 or more follicles measuring 2–9 mm in diameter Increased ovarian volume (>10 mL)  Serum anti-Műllerian hormone (AMH) Secretion : granulosa cells of developing follicles Potential surrogate for USG Correlate : AFC If USG is inappropriate or unavailable

10. Rotterdam Criteria of PCOS Polycystic Ovaries Androgen Excess Anovulation 2 1 3 Area 2 Hyperandrogenism (clinical and/or biochemical) Polycystic ovaries Regular cycles Area 3 Anovulation Polycystic ovaries No evidence of androgen excess Area 1 NIH criteria 1990 Frank S, J Clin Endocrionol Metab, 2006

11. All possible phenotypes Features Hyperandrogenemia Hirsutism Oligoanovulation Polycystic ovaries NIH 1990 criteria Rotterdam 2003 criteria AES 2006 criteria ++++++++ A +++-+++- B +-+++-++ C +-+-+-+- D -+++-+++ E -++--++- F ++-+++-+ G -+-+-+-+ H +--++--+ I --++--++ J ++--++-- K ---+---+ L --+---+- M -+---+-- N +---+--- O -------- P Phenotypes Azzizz et al, J Clin Endocrionol Metab, 2006

12. Hyperandrogenism Nuremberg chronicle – Strange people – Hairy lady, 1493

13. Definition  Clinical signs: hirsutism, acne, alopecia (male-pattern balding) and frank virilization  Biochemical indicators ↑total testosterone & androstenedione, ↑free androgen index However, these markers has proved markedly inconsistent d/t problems with various assays → Reliable detection of this feature is not straightforward The ESHRE/ASRM Rotterdam Consensus Meeting, 2003 Norman et al., Lancet, 2007

14. Clinical sign: Hirsutism  Being present in 65-75% of patients with PCOS defined by the NIH criteria  Rarely present in Asian women  Degrees vary greatly in different ethnic population  Modified FG score might underestimate clinical sign Threshold of abnormality should be measured on a population basis Androgen Excess Society Guideline., JCEM, 2006 Legro et al., JCEM, 2013 Carmina et al., AJOG, 1992 DeUgarte et al., JCEM, 2006

15. Assessment of Hirsutism  95 th percentile as upper normal limit in the white or black: 6-8 modified Ferriman- Gallwey score Ferriman D, Gallwey JD, JCEM. 1961

16. Escobar-Morreale., Hum Reprod Update, 2012

17. Clinical sign: androgenic alopecia Ludwig., Brit J Derm, 1977 In MenIn Women

18. Other clinical signs  Acne Affects 14-25% of PCOS pts. Unclear whether the prevalence of acne is significantly increased than general population  Androgenic alopecia The prevalence in PCOS is unclear Less frequent and presents later  Acne or androgenic alopecia could not be used reliably as clinical sign of hyperandrogenism. Androgen Excess Society Guideline., JCEM, 2006 Norman et al., Lancet, 2007 Legro et al., JCEM, 2013

19. Biochemical hyperandrogenism  Elevated circulating androgen levels In 60-80% of PCOS pts. The vast majority of abnormal value: free testosterone  Low SHBG Excellent diagnostic accuracy for PCOS Surrogate marker of insulin resistance and androgen excess  However, between 20-40% of PCOS will have androgen levels within the normal range Assays for androgens tend to be highly variable and inaccurate Some patients have normal levels of free T Androgen Excess Society Guideline., JCEM, 2006 Jayasena., Nat Rev Endorinol, 2014 Conway et al., Eur J Endocrinol, 2014

20. Biochemical assessment  Single most reliable indices of hyperandrogenism Hirsutism & free T levels  Total testosterone is the first-line recommendation for assessing androgen excess in women RIA to measure free T directly → been criticized for lack of accuracy, so should not be used  FAI (Free androgen index) By measurement serum total T and SHBG (T/SHBG x 100) Practical alternative to the measurement of free T Androstenedione, DHEAS → need in severe hirsutim Jayasena., Nat Rev Endorinol, 2014 Conway et al., Eur J Endocrinol, 2014 Norman et al., Lancet, 2007

21. Excessive ovarian androgen production  PCOS is the underlying factor in as many as 92% of women with hirsutism & 84% with persistent acne  PCOS should primarily be regarded as a disorder of excessive androgen biosynthesis, use or metabolism Adams et al., BMJ, 1986 Homburg., Hum Reprod, 1996 Androgen Excess Society Guideline., JCEM, 2006

22. Hyperandrogenism  PCO Associated with hypersecretion of LH Thickened theca cell layer Theca cells secrete excessive androgens in basal state or in response to LH stimulation  Both insulin and LH, alone and in combination, exacerbate ovarian androgen production Homburg., Best Pract Res Clin Obstet Gynecol, 2008 Jayasena., Nat Rev Endorinol, 2014

23. Insulin resistance

24. Pathophysiology-hyperinsulinemia Speroff 8 th ed., 2011

25. The role of hyperinsulinemia in the pathogenesis of PCOS Homburg., Best Pract Res Clin Obstet Gynecol, 2008

26. Reported IR in PCOS Legro et al., Obstet Gynecol Survey, 2004

27. Assessment of IR  Still several problems… Apparent lack of consensus on “normal” insulin sensitivity Ethnic and genetic variability Other factors contributing to IR such as obesity, stress, and aging Concern about whether simplified models of IR have the precision to predict treatment needs, response, and future morbidity.  Assessment of insulin as a fasting hormone or as a surrogate of IR (HOMA…) is of little value although widely used for research studies. Norman et al., Lancet, 2007 Legro et al., Obstet Gynecol Survey, 2004

28. Consensus  No test of insulin resistance is needed either to make the diagnosis of or to select treatment for PCOS  Recommend the use of 75g OGTT to screen for IGT and T2DM in adolescent and adult women with PCOS The ESHRE/ASRM Rotterdam Consensus Meeting, 2003 Legro et al., JCEM, 2013

29. Hyperinsulinemia  Overall prevalence of IGT among US women with PCOS was 30-35%, and 3-10% had T2DM Non-obese PCOS: 10-15% prevalence of IGT and 1-2% prevalence of T2DM  A diagnosis of PCOS confers a 5-10-fold increased risk of developing T2DM  Key factor in the pathogenesis of anovulation and hyperandrogenism Legro et al., JCEM, 2013

30. Cardiovascular events

31. Cardiovascular events in PCOS  Initial studies did not find an increased prevalence of nonfatal/fatal CVD in women with PCOS (Pierpoint et al., 1998; Wild et al., 2000)  Lifetime risk for CVD in PCOS women is high and mostly preventable, all PCOS women should be screened for CVD risk factors Wild et al., JCEM, 2010

32. Incidence  Glucose intolerance: 30% of adolescents with PCOS  Dyslipidemia: 70 % of reproductive aged PCOS women  Non obese PCOS women: also may have Glucose intolerance Dyslipidemia  Syndrome X

33. Metabolic abnormalities : 외국 data 저자국가 PCOS 대조군 제 2 형 당뇨 Ehrmann et al., 1999USA10% (13.5-40 years) 2.5% (NHANES II, 20-44 years) 이상지혈증 Legro et al., 2001USA70% 고혈압 Lo et al., 2006USA12%4.9% 대사증후군 Apridonidze et al., 2005 USA43% * * Nearly 2-fold higher than age-matched general population

34. Metabolic abnormalities : 국내 data Chae et al., 2008 (SNUH) Other Korean reports 제 2 형 당뇨 2.0%1.0% (Lee et al., 2009) 이상지혈증 28.6% (14.1% in controls) 고혈압 (≥140/90mmHg) 13.6% (2.6% in controls) 대사증후군 23.3% (1.4% in controls) 14.5% (Park et al., 2007) 비만 (BMI≥25kg/m 2 ) 25.2%28.4% (Lee et al., 2009) Chae et al, Hum Reprod, 2008

35. Age-related changes in the PCOS phenotype throughout lifespan Reproductive abnormalities Clinical hyperandrogenism Overweight/obesity Metabolic abnormalities (type 2 diabetes) Postmenopausal hyperandrogenism (?) CVD (?) Adolescence Adult fertile age Menopause Postmenopause Pasquali et al., Ann N Y Acad Sci, 2006

36. Therapeutic goals in pt. with PCOS  Restore menses and reduce the signs of hyperandrogenism.  Prevention of endometrial cancer  Achieve successful pregnancy.  Avoidance of the long-term complication that are associated with obesity, insulin resistance, glucose intolerance, and type 2 DM. The Amsterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, Hum Reprod 2012

37. Korean data

38. Prevalence of the PCOS subgroups EthnicsIM+HA+PCOIM+HAIM+PCOHA+PCO Welt et al (2006-12) USA, Iceland 298 (71.3%)7 (1.7%)36 (8.6%)77 (18.4%) Dewailly et al (2006-10)France246 (60.6%)27 (6.7%)66 (16.3%)67 (16.5%) Hsu et al (2007)Taiwan88 (51.7%)15 (8.8%)31 (18.2%)36 (21.1%) Pehlivanov et al (2007)Bulgaria41 (58.6%)8 (11.4%)7 (10.0%)14 (20.0%) Diamanti-Kandarakis (2007)Greece284 (46.4%)251 (39.6%)43 (6.8%)46 (7.2%) SNUH (2008)Korea87 (52.4%)23 (13.9%)52 (31.3%)4 (2.4%) IM: Irregular menstruation (oligo-anovulation) HA: Hyperandrogenism, PCO: Polycystic Ovary

39. No significant difference in the prevalence of metabolic syndrome between women with O+P and control subjects, even in obese women Shroff et al., Fertil Steril, 2007

40. PCOS phenotype in Korean cohort Kim et al, Fertil Steril, 2014

41. PCOS phenotype in Korean cohort Kim et al, Fertil Steril, 2014

42. PCOS phenotype in Korean cohort Kim et al, Fertil Steril, 2014

43. Summary  PCOS is the most common cause of hyperandrogenic chronic anovulation and infertility  Overproduction of androgens is at the heart of PCOS, often exacerbated by associated hyperinsulinemia  Obesity is common feature of PCOS but not a prerequisite for its development  Increased risk of developing type 2 diabetes and cardiovascular disease

44. Summary  PCOS without HA are common in Korea and are less likely to have metabolic dysfunction, insulin resistance and elevated BP  PCOS without HA may be a mild phenotype of PCOS  PCOS in Korea could have a reduced likelihood of having metabolic syndrome compared with other ethnicities

45. Needs Research… Norman et al., Lancet, 2007 Shroff et al., Fertil Steril, 2007 Homburg., Best Pract Res Clin Obstet Gynecol, 2008 Risk of metabolic syndrome may vary among the phenotypes → Individualization of treatment according to phenotype