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PCOS, dyslipidemia and CVD


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PCOS, dyslipidemia and CVD

  1. 1. PCOS, dyslipidemia and CVD Nelly Pitteloud, MD Reproductive Endocrine Unit Massachusetts General Hospital COI: Repros Consultant
  2. 2. Objectives <ul><li>PCOS </li></ul><ul><ul><li>Definition </li></ul></ul><ul><ul><li>Pathophysiology </li></ul></ul><ul><ul><li>Metabolic features </li></ul></ul>
  3. 3. 22 yo woman with oligomenorrhea <ul><li>22 yo with 9 months oligoamenorrhea </li></ul><ul><li>Menarche age 11 yrs, cycles approx 45 days </li></ul><ul><li>Slightly overweight since elementary school </li></ul><ul><li>Acne with menses </li></ul><ul><li>Waxes upper lip, chin weekly for one year </li></ul><ul><li>Family history of type 2 diabetes </li></ul>
  4. 4. Examination <ul><li>Weight 178, height 5’5”, BMI 29 kg/m2 </li></ul><ul><li>Terminal hair on face </li></ul><ul><li>Acanthosis nigricans </li></ul><ul><li>Work-up: Neg hCG, FSH 5.2 IU/L, Prl 10 ng/ml, TSH 2.0 uU/ml, T 90 ng/dL </li></ul>Diagnosis? Further work-up?
  5. 5. Hypothalamic-Pituitary-Gonadal Axis Hypothalamus LH GnRH FSH Pituitary Ovary E2
  6. 6. POLYCYSTIC OVARIAN SYNDROME Definition 1990 NIH Workshop <ul><li>CHRONIC OLIGO/ANOVULATION </li></ul><ul><li>HYPERANDROGENISM </li></ul>in the absence of other known causes of androgen excess (tumor, CAH, hyperprolactinemia)
  7. 7. POLYCYSTIC OVARIAN SYNDROME 2003 Rotterdam Workshop <ul><li>2 of 3: </li></ul><ul><li>CHRONIC OLIGO/ANOVULATION </li></ul><ul><li>HYPERANDROGENISM </li></ul><ul><li>POLYCYSTIC OVARIAN MORPHOLOGY </li></ul>in the absence of other known causes of androgen excess
  8. 8. Polycystic Ovarian Syndrome <ul><li>Affects 6-10% of women of childbearing age (3.2 to 5.4 million women in the U.S.) </li></ul><ul><li>Chronic anovulation and hyperandrogenism </li></ul><ul><li>Most common cause of female infertility (approximately 50-60%) </li></ul><ul><ul><li>Anovulation </li></ul></ul><ul><ul><li>Early miscarriage </li></ul></ul><ul><li>Most common endocrinopathy in young women </li></ul><ul><li>Insulin resistance is a prominent feature </li></ul>
  9. 9. The Polycystic Ovary
  10. 10. <ul><li>Polycystic ovary (PCO) </li></ul><ul><li>Ovarian vol >10 ml or </li></ul><ul><li>>12 small follicles (2-8 mm) </li></ul><ul><li>Peripheral distribution </li></ul><ul><li>Increased stromal vol </li></ul><ul><ul><ul><ul><ul><li>(Jonard et al, 2003) </li></ul></ul></ul></ul></ul><ul><li>Normal ovary </li></ul><ul><li>Few follicles </li></ul><ul><li>Random distribution </li></ul><ul><li>No increased stroma </li></ul>
  11. 11. Proportion of Anovulatory PCOS Subjects 0 20 40 60 80 100%
  12. 12. POLYCYSTIC OVARY SYNDROME: Clinical concerns <ul><li>Menstrual cycle irregularity/Chronic unopposed estrogen exposure </li></ul><ul><li>Hyperandrogenic symptoms (hirsutism, acne, alopecia) </li></ul><ul><li>Anovulatory infertility (but risk of intermittent ovulation) </li></ul><ul><li>Metabolic risks </li></ul>
  13. 13. Menstrual Irregularity + Hyperandrogenism Pathophysiology of PCOS Insulin Androgens Neuro- endocrine
  14. 14. Hyperandrogenism Pathophysiology of PCOS adrenal morphology ovary 1 o or 2 o
  15. 15. PCOS Normal Taylor et al, 1994 PCOS Normal
  16. 16. Neuroendocrine abnormalities Pathophysiology of PCOS Hypothalamus Pituitary 1 o or 2 o ? LH FSH
  17. 17. Gonadotropin Abnormalities in PCOS Normalized transiently after ovulatory cycle or progestin PCOS 50 25 100 20 10 LH IU/L FSH IU/L Yen et al, 1970
  18. 18. LH LH Obesity results in decreased serum LH
  19. 19. Hyperinsulinemia Pathophysiology of PCOS signaling  insulin SHBG
  20. 20. <ul><li>Insulin resistance is a very common feature of women with PCOS (60-75%) </li></ul>Insulin Resistance and PCOS <ul><li>Insulin resistance occurs in both obese and non-obese women with PCOS </li></ul><ul><li>Obesity has a synergystic effect on glucose metabolism and IR </li></ul>Palomba S, Endocrine Review, 2009 <ul><li>Anomalies in insulin Receptor mediated transduction </li></ul>
  21. 21. WHO 2006 Criteria to define hyperglycemia 2-h glucose/OGTT      NGT <140 mg/dl (7.8 mmol/liter) IGT >140 mg/dl (7.8 mmol/liter) and < 200 mg/dl (11.1 mmol/L) DM = or > 200 mg (11.1 mmol/liter Fasting glucose Normal FG <110 mg/dl (6.1 mmol/liter) IGT 110 mg/dl (6.1 mmol/liter) to 125 mg/dl (6.9 mmol/L) Diabetes = or > 126 mg/dl (7.0 mmol/liter)
  22. 22. Insulin and Glucose Responses in PCOS INSULIN GLUCOSE MINUTES Dunaif A et al, 1987 OBESE 0 20 40 60 80 100 120 0 50 100 150 200 * * * * NL PCOS 0 20 40 60 80 100 120 0 50 100 150 200 * * * * NL PCOS 0 20 40 60 80 100 120 0 50 100 150 200 NL PCOS 0 20 40 60 80 100 120 0 50 100 150 200 * * * * NL PCOS LEAN
  23. 23. Insulin Sensitivity PCOS Obese PCOS Lean Nl Obese Nl Lean IR is present in both lean and obese PCOS compared to their BMI and age matched counterpart Dunaif A et al, 1987
  24. 24. PCOS and Obesity <ul><li>60% of US women with PCOS are obese </li></ul><ul><li>Distribution of fat: visceral adiposity (Android pattern) </li></ul><ul><ul><li>Known to be metabolically active </li></ul></ul><ul><ul><li>Highly associated with hyperinsulinemia </li></ul></ul><ul><ul><li>Central obesity correlates with  CV risk. </li></ul></ul><ul><li>70% of lean PCOS women have an android pattern of fat distribution. </li></ul><ul><ul><li>Is obesity an intrinsic clinical sign of PCOS or promoting environmental factor? </li></ul></ul><ul><ul><li>Nelson SM, 2007 </li></ul></ul>
  25. 25. Prevalence of Glucose intolerance and Diabetes in PCOS
  26. 26. Prevalence of IGT (by OGTT ) in 254 women with PCOS 14-44 yr old NGT IGT Type II DM 61,3% 31.1% 7.5% Legro et al, JCEM, 1999
  27. 27. Conversion rate to IGT and type II DM <ul><li>Controlled Study </li></ul><ul><li>Baseline OGTT </li></ul><ul><li>71 PCOS and 23 normal </li></ul><ul><li>F/U 2-3 yr </li></ul><ul><li>PCOS: </li></ul><ul><ul><li>37% IGT and 10% DM2 at baseline </li></ul></ul><ul><ul><li>16% conversion/year from NGT to IGT </li></ul></ul><ul><ul><li>2% conversion/year from IGT to DM2 </li></ul></ul><ul><ul><li>The conversion from IGT to frank diabetes is substantially enhanced in women with PCOS </li></ul></ul><ul><ul><ul><li>Legro et al, JCEM, 2005 </li></ul></ul></ul>
  28. 28. Development of Gestational DM <ul><li>Meta-analysis </li></ul><ul><li>720 women with PCOS and 4505 controls </li></ul><ul><li>RR 2.94 (CI 1.70-5.08) of developing GDM than control women </li></ul><ul><li>Besides converting to IGT or type 2 DM, women with PCOS are also at high risk for developing gestational DM </li></ul><ul><ul><ul><li>Boomsma et al, Hum Reprod Update, 2006 </li></ul></ul></ul>
  29. 29. PCOS and Type II diabetes <ul><li>Nurses’ Health Study II (NHSII): 101.073 women </li></ul><ul><ul><li>Women followed for 8 years </li></ul></ul><ul><ul><li>Conversion rate to DMII was 2-fold higher in oligo- </li></ul></ul><ul><ul><li>menorrheic women, independent of weight </li></ul></ul><ul><ul><li>By age 30, 30-50% of obese PCOS developed IGT or DM </li></ul></ul><ul><ul><li>3-7x increase as compared to the general population </li></ul></ul><ul><ul><ul><li>Legro et al, JCEM, 1999 </li></ul></ul></ul>
  30. 30. Mechanisms of Predisposition to the development Type II DM in PCOS <ul><li>Women with PCOS are insulin resistant independent of obesity </li></ul><ul><ul><li>Defects in insulin receptor or post-receptor signal transduction </li></ul></ul><ul><ul><li>Altered adipocyte lipolysis </li></ul></ul><ul><ul><li>Decrease GLUT-4 expression in the adipocytes </li></ul></ul><ul><ul><li>Many PCOS women exhibit β- Cell dysfunction </li></ul></ul><ul><li>Ek I et al JCEM 1997 </li></ul><ul><li>Ek I et al, Diabetes 2002 </li></ul><ul><li>Kelsey ES, JCEM 2007 </li></ul>
  31. 31. PCOS and Metabolic Syndrome
  32. 32. > 3 of the following for women: Triglycerides >150 mg/dL HDL Cholesterol (F) < 50 mg/dL Blood Pressure >130/85 mm/Hg Waist > 88 cm Glucose (fasting) > 100 mg/dL Metabolic Syndrome NCEP 2001 ATP III
  33. 33. Prevalence of Metabolic syndrome in PCOS Apridonidze T eta al JCEM 2005 <ul><li>33.4% of obese PCOS </li></ul><ul><li> ( Ehrmann et al, 2006 ) </li></ul><ul><li>24% of PCOS (BMI </li></ul><ul><li>= 31 kg/m2) </li></ul><ul><li>(Welt et al, 2007) </li></ul><ul><li>37% of adolescent </li></ul><ul><li>girls </li></ul><ul><li>(Coviello et al 2006) </li></ul>
  34. 34. Prevalence of Metabolic syndrome in PCOS compared to NHANES women Apridonidze T eta al JCEM 2005 Age Group BMI (kg/m 2 ) <25 25–30 >30 20–29 yr (n = 29)      PCOS (%) 17 58 45      U.S. females (%) 0.8 8.3 27 30–39 yr (n = 49)      PCOS (%) 23 40 62      U.S. females (%) 1 14 43
  35. 35. PCOS and CVD
  36. 36. <ul><li>Surrogate endpoints suggest increased CV risk: </li></ul><ul><ul><li>Hypertension, Obesity,  WHI, Insulin resistanc,  HDL </li></ul></ul><ul><ul><li> TG , Chronic inflammation,  C-reactive protein & PAI-1 </li></ul></ul><ul><ul><li> Likely due to both: </li></ul></ul><ul><ul><li> Hyperandrogenism </li></ul></ul><ul><ul><li> Impaired insulin sensitivity  </li></ul></ul>CV Risk Factor in PCOS
  37. 37. <ul><li>Age (yr) 38.5 39.0 0.40 </li></ul><ul><li>BMI (kg/m 2 ) 31.4 31.2 0.26 </li></ul><ul><li>Waist (cm) 94.75 94.5 0.14 </li></ul><ul><li>Ferriman-Gallwey 16.0 4.0 0.0001 </li></ul><ul><li>Systolic BP (mm Hg) 116 116 0.73 </li></ul><ul><li>Diastolic BP (mm Hg) 74.8 71.5 0.03 </li></ul><ul><li>Smoking status 8.3% 11.4% </li></ul><ul><li>Fasting insulin (µIU/ml) 7.65 6.3 0.11 </li></ul><ul><li>Fasting glucose (mg/dl) 90.5 93.0 0.43 </li></ul><ul><li>IGT 36.1% 23.2% 0.18 </li></ul><ul><li>Cholesterol (mg/dl) 190 174 0.008 </li></ul><ul><li>HDL (mg/dl) 48 48 0.49 </li></ul><ul><li>LDL (mg/dl) 111 99 0.04 </li></ul><ul><li>TG (mg/dl) 125 118 0.33 </li></ul><ul><li>SHBG (nmol/liter 31.7 38.5 0.04 </li></ul><ul><li>Total T (ng/dl) 47.5 34 <0.0001 </li></ul><ul><li>Free T (ng/dl) 0.19 0.12 <0.0001 </li></ul>Distribution of CHD risk factors in premenopausal women PCOS vs. control Variable PCOS (n=36) NL (n=71) Pvalue Christian RC, JCEM, 2003
  38. 38. PCOS AND CARDIOVASCULAR DISEASE <ul><li>Retrospective study of Swedish women who had ovarian </li></ul><ul><li>wedge resection in 1950s’: </li></ul><ul><li>RR for MI of 7.4 </li></ul><ul><li>Acta Obstet Gynecol Scand, 1992;71;599 </li></ul><ul><li>Death certificates from women with PCOS in the UK showed no </li></ul><ul><li>Increase in MI above expected number </li></ul><ul><li>J. Clin. Epidemiol 1998; 51;581 </li></ul>
  39. 39. PCOS AND CARDIOVASCULAR DISEASE <ul><li>Nurse Health Study: 82.439 women followed for 14 years. </li></ul><ul><li>In women with very irregular menses: </li></ul><ul><li>RR for CHD was 1.5 (CI 1.3-1.9) </li></ul><ul><li>RR for fatal MI was 1.9 (CI 1.3-2.7) </li></ul><ul><li>JCEM, 2002; 87;2013 </li></ul>Prospective controlled studies on CVD morbidity and mortality in PCOS are LACKING
  40. 40. Evaluation of metabolic anomalies In PCOS patients
  41. 41. Evaluation of Women with PCOS: Metabolic issues <ul><li>Check for : </li></ul><ul><ul><li>Glucose intolerance (OGTT) </li></ul></ul><ul><ul><li>Position of the Androgen Excess Society (2008) </li></ul></ul><ul><ul><li>Women with PCOS regardless of their weight should be </li></ul></ul><ul><ul><li>Screened for IGT and DMII by an OGTT at presentation </li></ul></ul><ul><ul><li>And every 2 yrs. </li></ul></ul><ul><ul><li>HTA </li></ul></ul><ul><ul><li>Dyslipidemia </li></ul></ul><ul><ul><li>Risk factors for heart disease </li></ul></ul>
  42. 42. Traditional and novel therapy for PCOS patients
  43. 43. Traditional and Novel Goals of Therapy in PCOS <ul><ul><li>Improve reproductive function/fertility </li></ul></ul><ul><ul><li>Decrease risk of endometrial cancer </li></ul></ul><ul><ul><li>Treatment of acne and hirsutism </li></ul></ul><ul><ul><li>Ameliorate complications putatively due to insulin resistance </li></ul></ul><ul><ul><ul><li>Prevent IGT and DM </li></ul></ul></ul><ul><ul><ul><li>Prevent ATS and acute cardiac events </li></ul></ul></ul>
  44. 44. PCOS: Management <ul><li>Menstrual cycle irregularity/Chronic unopposed estrogen exposure: </li></ul><ul><li>Oral contraceptives (avoid levonorgestrel) </li></ul><ul><li>Cyclic progestin therapy </li></ul><ul><li>medroxyprogesterone acetate 10mg x10d every other month </li></ul><ul><li>Natural progesterone 200mg x 12d every month </li></ul><ul><li>Metformin? (need for monitoring) </li></ul>
  45. 45. PCOS: Management <ul><li>Hirsutism </li></ul><ul><li>Oral contraceptives </li></ul><ul><li>Oral contraceptives + antiandrogen (spironolactone) </li></ul><ul><li>Insulin lowering agents ineffective </li></ul><ul><li>Direct hair removal (laser and electrolysis) </li></ul><ul><li>Topical agents (eflornithine) </li></ul><ul><li>Martin et al. JCEM 2008 </li></ul>
  46. 46. PCOS: Management <ul><li>Infertility </li></ul><ul><li>Weight loss! </li></ul><ul><li>Ovulation induction (metformin vs clomiphene) </li></ul>
  47. 47. PCOS: Management Prevention of IGT and Type II diabetes
  48. 48. Prevention of type II DM in non-PCOS Population <ul><li>Diabetes Prevention Program Research Group 2002 (DPP) </li></ul><ul><ul><li>Large placebo controlled RCT on 3234 subjects in the US with high risk of developing DM </li></ul></ul><ul><ul><ul><li>Gestational DM </li></ul></ul></ul><ul><ul><ul><li>Presence of IGT </li></ul></ul></ul><ul><ul><ul><li>First degree relative with DM </li></ul></ul></ul><ul><ul><li>Subjects were randomized to </li></ul></ul><ul><ul><ul><li>Standard management </li></ul></ul></ul><ul><ul><ul><li>Intensive life style intervention </li></ul></ul></ul><ul><ul><ul><li>Metformin </li></ul></ul></ul><ul><ul><ul><li>Troglitazone (discontinued after 18 M– hepatic dysfct) </li></ul></ul></ul><ul><ul><ul><li> DPP Group, NEJM, 2002 </li></ul></ul></ul>
  49. 49. Prevention of DMII in non-PCOS Population (DPP) DPP Group, NEJM, 2002 Mean F/U of 2.8 yr <ul><li>Intensive life style intervention  incidence of new type II DM by 58% </li></ul><ul><li>Metformin  incidence of new type II DM by 31% </li></ul>Improvement in insulin sensitivity either through intensive life Style modification ++ or metformin reduces the risk of developing DM in High risk population
  50. 50. Metformin and Prevention of IGT in PCOS Sharma et al End. Pract, 2007 <ul><li>Limited data on the long-term beneficial effect of Metformin on the </li></ul><ul><li>risk for type II DM in women with PCOS. </li></ul><ul><li>One retrospective study of PCOS women treated with metformin for an </li></ul><ul><li>average of 43 M </li></ul><ul><li>At baseline: 78% had NGT & 22% had IGT </li></ul><ul><li>At F/U: No woman developed DM </li></ul><ul><li>IGT group: 45% continued IGT </li></ul><ul><li>55% revert to NGT </li></ul><ul><li> NGT group: 5% converted to IGT </li></ul><ul><li>95% continued NGT </li></ul><ul><li> 11-fold decrease in the annual conversion rate from NGT to IGT </li></ul><ul><li>with 55% of IGT patients reverting to NGT </li></ul>
  51. 51. Metformin and Prevention of IGT in PCOS Sharma et al End. Pract, 2007 <ul><li>Meta-analysis (Salpeter et al, Am J Med. 2008) </li></ul><ul><li>Goals: To assess the effect of metformin on metabolic risk in patients at </li></ul><ul><li>high risk for DM </li></ul><ul><li>Inclusions: 31 clinical trials (n= 4570) including 620 PCOS subjects </li></ul><ul><li>F/U : Average 2 yrs </li></ul><ul><li>Results: Fasting glucose Reduction - 4.5 mg/dL; 95% CI -6 to -3 </li></ul><ul><li>Fasting insulin Reduction - 14.4 IU/L 95% CI -19 to -9 </li></ul><ul><li>PCOS vs non-PCOS & obese vs nonobese -- p value NS </li></ul><ul><li>New onset DM 40% decrease p< 0.01 </li></ul><ul><li>Absolute risk of DM 6% decrease 95% CI 4 to 8 </li></ul><ul><li>No data on subgroups. </li></ul>
  52. 52. PCOS: Management <ul><ul><li>INTENSIVE LIFE STYLE CHANGES </li></ul></ul><ul><ul><ul><li>Diet low in CH </li></ul></ul></ul><ul><ul><ul><li>Exercise </li></ul></ul></ul><ul><ul><ul><li>? Surgery for morbid obesity </li></ul></ul></ul><ul><ul><li>Medication to enhance insulin sensitivity </li></ul></ul><ul><ul><ul><li>Metformin </li></ul></ul></ul><ul><ul><ul><li>Thiazolidinedione (rosiglitazone, pioglitazone) </li></ul></ul></ul>Metabolic Abnormalities
  53. 53. Insulin Sensitizing Drug in PCOS <ul><ul><li>Insulin sensitizing drug in PCOS </li></ul></ul><ul><ul><ul><li>Improves insulin sensitivity </li></ul></ul></ul><ul><ul><ul><li>Improve glucose tolerance </li></ul></ul></ul><ul><ul><ul><li>May reduce serum TG </li></ul></ul></ul><ul><ul><ul><li>Reduce plasma PAI-1 & CRP </li></ul></ul></ul><ul><ul><li>Insulin sensitizing drug in IGT or GDM </li></ul></ul><ul><ul><ul><li>Prevent progression to DM2 </li></ul></ul></ul><ul><ul><ul><li>May decrease CV disease </li></ul></ul></ul>
  54. 54. Summary <ul><ul><li>PCOS is a GENERAL HEALTH ISSUE </li></ul></ul><ul><ul><ul><li>Evaluation should include screen for : </li></ul></ul></ul><ul><ul><ul><li>IGT </li></ul></ul></ul><ul><ul><ul><li>Dyslipidemia </li></ul></ul></ul><ul><ul><ul><li>HTA </li></ul></ul></ul><ul><ul><ul><li>CV risk factors </li></ul></ul></ul><ul><ul><li>Novel Goals of Therapy </li></ul></ul><ul><ul><ul><li> Decrease risk for type II DM </li></ul></ul></ul><ul><ul><ul><li> Decrease risk for early CV disease </li></ul></ul></ul><ul><ul><ul><li> Life style modification </li></ul></ul></ul><ul><ul><ul><li>Insuline sensitizing agents </li></ul></ul></ul>
  55. 55. Return to patient <ul><li>Irregular menses </li></ul><ul><li>Hyperandrogenism (acne and hirsutism, high serum T) </li></ul><ul><li>Nl Prolactin, not pregnant </li></ul><ul><li>= PCOS </li></ul><ul><li>High BMI, acanthosis nigricans, FH of type II diabetes </li></ul><ul><li>BP normal, Waist 89 cm </li></ul><ul><li>Fasting glucose : normal </li></ul><ul><li>OGTT: 2h glucose was 190 mg/dL </li></ul><ul><li>Lipid profile: Cholesterol 210, HDL 53, TG 160, LDL 126 </li></ul>
  56. 58. IRS1/2 mediation of PI3 kinase  glucose transport & carbohydrate metabolism MAP kinase  mitogenesis Insulin Signaling Pathways in PCOS – Differential Effects
  57. 59. POLYCYSTIC OVARIAN SYNDROME 2000 NIH Workshop Irregular cycles Hyperandrogenism PCOS PCOS PCO Morphology Idiopathic Hirsutism Hypothalamic Amenorrhea
  58. 60. Implications of Rotterdam Criteria <ul><li>Ovulatory vs anovulatory bleeding </li></ul><ul><li>PCOS vs hypothalamic amenorrhea </li></ul><ul><ul><li>Estrogen status </li></ul></ul><ul><ul><li>LH/FSH ratio </li></ul></ul><ul><li>Is insulin resistance present in all patients? </li></ul><ul><ul><li>Risk for diabetes </li></ul></ul><ul><ul><li>OGTT </li></ul></ul><ul><li>What are the cardiovascular implications? </li></ul><ul><ul><li>Lipids, hypertension </li></ul></ul>
  59. 61. POLYCYSTIC OVARIAN SYNDROME 2003 Rotterdam Workshop Less obese Less hyperandrogenic No increase in LH No IR Less obese Increased LH Mild IR (1 of 3 studies) No hyperandrogenism PCO Morphology Irregular cycles Idiopathic Hirsutism PCOS PCOS PCOS Hypothalamic Amenorrhea
  60. 62. WHAT IS THE ROLE OF GENETICS IN PCOS? <ul><li>familial clustering of PCOS </li></ul><ul><li>not every obese woman develops PCOS, not all women with PCO morphology develop PCOS </li></ul><ul><li>in vitro </li></ul><ul><ul><li>theca cells from PCOS ovaries are more efficient at synthesizing androgens from precursors </li></ul></ul><ul><ul><li>insulin stimulates androgen production by ovaries of PCOS women, but not by ovaries of normal women </li></ul></ul><ul><li>complex multigenic disorder </li></ul><ul><ul><ul><li>candidate genes - </li></ul></ul></ul><ul><ul><ul><ul><li>steroid pathways – CYP11  (P450scc) (Waterworth et al, 1997) ; HSD17B5 SNP-71G (Qin et al 2006) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>~D19S884 (chromosome 19p13.2) (Urbanek et al 2005) </li></ul></ul></ul></ul>
  61. 63. <ul><li>association studies </li></ul><ul><ul><li>marker ~D19S884 (chromosome 19p13.2) near the insulin receptor </li></ul></ul><ul><ul><ul><li>Tucci S, JCEM 2001 p=0.006, corrected p=0.042 </li></ul></ul></ul><ul><ul><ul><li>Urbanek M, JCEM 2005, 2006 </li></ul></ul></ul><ul><ul><ul><ul><li>linkage and association now confirmed in 3 independent data sets </li></ul></ul></ul></ul><ul><ul><ul><ul><li>fine mapping of insulin receptor region, including an intragenic marker: no other positive associations </li></ul></ul></ul></ul><ul><ul><ul><ul><li>marker is within fibrillin 3 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>evidence of regulatory regions near D19S884 </li></ul></ul></ul></ul>What is the Role of Genetics in PCOS?
  63. 65. Effect of Metformin on Lean PCOS Nestler, JCEM, 1997 <ul><li>Improvement in: </li></ul><ul><li>menstrual pattern </li></ul><ul><li>fertility +/- clomid </li></ul>0 Fast. Insulin pmol/L Free T pmol/L SHBG nmol/L 20 40 60 80 100 120 140 Before After
  64. 66. MENSTRUAL CYCLE IRREGULARITY/ ENDOMETRIAL PROTECTION WEIGHT LOSS WITHDRAWAL BLEEDING IF CYCLES > 60 DAYS cyclic medroxyprogesterone 5 to 10 mg/day x 10-14 days cyclic micronized progesterone 200 mg/day x 10-14 days oral contraceptives
  65. 67. HYPERANDROGENIC SYMPTOMS <ul><li>Cosmetic Approaches </li></ul><ul><li>- electrolysis, laser </li></ul><ul><li>Oral Contraceptives </li></ul><ul><li>Anti-androgens </li></ul><ul><li>Insulin Sensitizing Agents </li></ul><ul><li>Inhibitors of Steroidogenesis </li></ul><ul><li>Direct inhibitors of hair growth </li></ul><ul><li>Glucocorticoids </li></ul><ul><li>GnRH Analogs </li></ul>No primary treatment established Combination treatments better than single-agent approaches
  66. 68. ORAL CONTRACEPTIVES: Androgenic Potential <ul><li>Levonorgestrol Nordette, Triphasil </li></ul><ul><li>Ethynodiol Diacetate Demulen </li></ul><ul><li>Norethindrone Brevicon, Modicon </li></ul><ul><li>Desogestrel Desogen, Ortho-Cept </li></ul><ul><li>Norgestimate Ortho-Cyclen, Ortho Tri-Cyclen </li></ul><ul><li>Drospirenone Yasmin </li></ul>Androgenic Potential
  67. 69. ANTIANDROGENS <ul><li>spironolactone (off label use) </li></ul><ul><li>aldosterone antagonist, competitive inhibitor of DHT, 5-  reductase inhibitor, inhibits p450 enzymes, decreases androgens </li></ul><ul><li>cyproterone acetate </li></ul><ul><li>competitive inhibitor of DHT, 5-  reductase inhibitor, decreased LH </li></ul><ul><li>flutamide (off label use) </li></ul><ul><li>non-steroidal anti-androgen, competitive inhibitor of DHT, inhibits p450 enzymes </li></ul>
  68. 70. TREATMENT OF HIRSUTISM <ul><li>Vaniqa </li></ul><ul><li>anhydrous eflornithine hydrochloride </li></ul><ul><li>irreversibly inhibits ornithine decarboxalase activity in the skin  inhibits cell division and synthetic functions  decreases hair growth </li></ul><ul><li>apply bid, improvement expected in 4 to 6 weeks </li></ul><ul><li>can use in conjunction with other hair removal techniques </li></ul>
  70. 72. INFERTILITY WEIGHT LOSS obesity - infertility and obstetrical risks OVULATION INDUCTION clomiphine +/- metformin controversial aromatase inhibitors – more data needed low dose gonadotropins PCOM – generally responds like PCOS WEDGE RESECTION / LASER SURGERY 8-34% incidence of pelvic adhesions ovulatory status - 60% ovulatory, 30% oligo/ovulatory ASSISTED REPRODUCTIVE TECHNOLOGIES high # of follicles and oocytes retrieved fertilization, cleavage rate low risk of ovarian hyperstimulation
  71. 73. Legro RS 1999; Dahlgren E 1992; Dunaif A1995;Ehrmann DA, 1995. 35 to 50% of obese women with PCOS develop either impaired glucose tolerance or type 2 diabetes by the age of 30! METABOLIC RISK PCOS women are at risk for IGT and DM II at all weights detection is markedly improved by the use of post-challenge glucose values
  72. 74. <ul><li>HEART DISEASE </li></ul><ul><li>no prospective studies have documented an increased risk </li></ul><ul><li>increased prevalence of subclinical atherosclerosis </li></ul><ul><li>surrogate endpoints suggest increased risk </li></ul><ul><ul><li>hypertension, obesity, increased WHR, insulin resistance, lipids (~70%) </li></ul></ul><ul><li>METABOLIC SYNDROME </li></ul><ul><li>33.4% of adults with PCOS ( Ehrmann et al, 2006 ) </li></ul><ul><ul><li>waist circ 80%, HDL 66%, TG 32%, BP 21%, FBS 5% </li></ul></ul><ul><li>37% of adolescent girls (Coviello et al 2006) </li></ul>METABOLIC RISK
  74. 76. Therapeutic Options <ul><li>weight loss </li></ul><ul><li>diet </li></ul><ul><li>surgery </li></ul><ul><li>diet modification </li></ul><ul><li>exercise </li></ul><ul><li>medication to enhance insulin sensitivity </li></ul><ul><li>metformin </li></ul>DPP: importance of lifestyle interventions and metformin in preventing DM in IGT insufficient data to warrant prophylactic use of metformin in all women with PCOS
  75. 77. Metformin: Meta-analysis of RTC in PCOS (n=13) Lord, Flight, Norman BMJ 2003 <ul><li>Ovulation </li></ul><ul><ul><li>metformin alone vs placebo OR 3.88 </li></ul></ul><ul><ul><li>metformin + clomid vs clomid OR 4.41 </li></ul></ul><ul><ul><li>endometrial surveillance if used alone </li></ul></ul><ul><li>Pregnancy* </li></ul><ul><ul><li>metformin + clomid OR 4.41 </li></ul></ul><ul><li>* no teratogenecity in in vitro models, no teratogenecity when administered during pregnancy - limited data; may decrease miscarriage </li></ul><ul><li>Metabolic Syndrome </li></ul><ul><ul><li>positive effect on fasting insulin, BP, LDL </li></ul></ul><ul><ul><li>no effect on weight loss </li></ul></ul>
  76. 78. Effect of 1000 Kcal diet for 7 months in 13 women with PCOS (< 5 % weight loss, mean 12%) Improvement in - menstrual pattern 11/13 - 5 conceived - hirsutism (40%) Kiddy, Clin Endo, 1992 10 15 20 Baseline After 0.6 0.8 1.0 Baseline After * * * = P <0.05 Free T SHBG Ug/dL pg/mL 0
  77. 79. Therapeutic Options – Metabolic Risk <ul><li>weight loss </li></ul><ul><li>diet </li></ul><ul><li>surgery </li></ul><ul><li>diet modification </li></ul><ul><li>exercise </li></ul><ul><li>medication to enhance insulin sensitivity </li></ul><ul><li>metformin </li></ul>DPP: importance of lifestyle interventions and metformin in preventing DM in IGT insufficient data to warrant prophylactic use of metformin in all women with PCOS
  78. 80. <ul><li>Defined as presence of terminal (coarse) hair in male pattern </li></ul><ul><li>Interaction between circulating androgens and sensitivity of the hair follicle </li></ul><ul><li>Majority of women with hirsutism have underlying endocrine disorder </li></ul><ul><li>-- 75-80% have PCOS (Azziz,Carmina) </li></ul><ul><li>--Nonclassic CYP21A2 deficiency </li></ul><ul><li>--Androgen-secreting tumors </li></ul>Hirsutism
  79. 81. Theca Cell Granulosa Cell Androstenedione Testosterone Estrone Estradiol aromatase FSH LH Cholestrol Androstenedione Testosterone   Insulin IGF