BY Mohammad A. Emam Prof. OB GYN Mansoura Faculty of Medicine Mansoura integrated fertility center MIFC EGYP

1. BY Mohammad A. Emam Prof. OB& GYN Mansoura Faculty of Medicine Mansoura integrated fertility center (MIFC) EGYPT www.ivfmifc.com

2. History Stein and Leventhal Polycystic Ovarian disease. Polycystic ovarian syndrome Syndrome O ( Metabolic)

3. Prevalence About 20% of reproductive age women demonstrate the ultrasound picture of polycystic ovaries. About 5- 10 % have clinical or biochemical signs of Anovulation and androgen excess (dunaif 1995 , Norman etal 2002)

4. Rationale Knowledge base for PCOS is rapidly revived and revised Not end story

5. Objective To highlight the progress in PCOS regarding : Definition. Etiology Path physiology. Diagnosis Heterogeneity of clinical presentations Management. Health risks.

6. From recent publications in the relevant subjects of endocrinology, reproductive medicine, and gynaecology. Medline search from 1994 till 2005 for English language articles related to PCOS and "metabolic syndrome in women."

8. Definition of PCOS Europe view:- Ultrasound profile. USA view (NIH ): - Endocrine Profile. Rotterdam definition PCOS (2003).

9. PCOS could be defined when at least two of the following three features are present, after exclusion of other etiologies : (i) Oligomenorrhea and or Anovulation (ii) Hyperandrogenism and/or hyperandrogenemia. (iii) Polycystic ovaries (sonar).

10. Hyperandrogenism is the clinical manifestation of hyperandrogenemia. Hyperandrogenism can exist in absence of hyperandrogenemia e.g. enhanced tissue sensitivity to androgens in many premenopausal women

11. Ultrasonic Criteria of PCO At least one of the following: 12 or more follicles measuring 2�9 mm in diameter, increased ovarian volume (>10 cm3). If there is a follicle >10 mm in diameter, the scan should be repeated at a time of ovarian quiescence in order to calculate volume and area. The presence of a single PCO is sufficient to provide the diagnosis. The distribution of follicles and a description of the stroma are not required for diagnosis.

12. Significant intra-observer and inter-observer variability . What are The Pitfalls Of Ultrasonic Criteria ?

13. What are Trials To Standardize Ultrasonic Criteria PCO? Ratio between ovarian stromal area and total area of ovarian section ( S/A)..with cut �off 0.34 for PCO diagnosis (Belasi etal 2004). The use of high resolution 3D.

14. Polycystic ovaries (PCO), observed on ultrasound are a sign of PCOS and not by themselves diagnostic of the syndrome. PCO & PCOS

15. PCO VS. Multicystic Ovaries Polycystic ovaries Bilateral Multiple cysts Cyst diam 2-<10 mm Stroma increased

16. Emerging & Created Phenotypes &????? Regarding Roterdam 2003 Definition

17. Phenotypes (Rotterdam)

18. What is The significance of polycystic-appearing ovaries versus normal appearing ovaries in patients with PCOS?? The presence of polycystic-appearing ovaries usually correlates with the presence of insulin resistance (Richard J 2002).

19. Late onset congenital adrenal hyperplasia DHEAS > 18mmol/l 17 OH Prog > 6 mmol/l Ovarian + adrenal androgen secreting tumours V. high teslosterone > 6mmol/l Cushings Syndrome - Dexamethsone suppression test - 24 hours urinary cortisol - DHEAS > 13 mmol/l

20. Iatrogenic and illegal androgen ingestion Hypothyroidisms Hyperprolactinemia. Anovulation & Hyperandrogenism What is DD?

21. Is Fertility Normal in patients With Ovulatory PCOS? These patients should be regarded as fertile but many studies have shown that women with ovulatory PCOS have luteal phase defect (Joseph H etal 2002).

22. Asymptomatic PCO (Ovulatory + Normoandrogenic ) There is significantly lower levels of progesterone in the early Luteal phase. This may contribute to the delay in conception in these patients. May be the starting cascade of Pcos!!!!!!!!!

23. Pitfalls Rotterdam Definition doubts still exist regarding borderline groups of patients ,such as hirsute ovulatory Normoandrogenic women with PCO???. Neglect role of IR

24. Etiology Speculation: Complex interaction of genetic ,epigenetic and environmental factors. Recently ,PCOS is mediated by ghrelin ( gastric peptide which is orexigenic and adipogenic)

25. Pathogenesis Three major hypothesis (culprits ) may all interact: Insulin resistance ( central player). Hyperandrogenism & (altered Gonadotropins) Recently (target genes) : Genes encoding Inflammatory cytokines. INSR genes.

26. IR ( Metabolic or Syndrome x) What is? Insulin acts like a key which can open a door on the cell's surface. cells do not have enough insulin receptor sites and cannot effectively burn glucose . this excess glucose is then sent to the liver where it is converted to fat.

27. PCOS, starts in adolescence.But  Unfortunately, not always diagnosed at that age.

28. The Central Player ( Insulin Resistance )

29. The high ovarian response to insulin. Opposed by the whole body resistance. IR : The central paradox

31. How IR Can Be Assessed ?? OGTT ( the best ). Fasting insulin (mu/ L) to fasting glucose (mmol/L) ( Hyperinsulinemic � euglycemic).

32. Emerging & Created PHENOTYPES &????????????? Regarding Pathogenesis

33. PCOS + IR ( 50-70 % ). PCOS without IR. Phenotypes According to IR

34. 1) IR Phenotype of PCOS: What are the characteristics ? Obese ( may be lean) Acanthosis Nigerians. Hirsutism. Resistance to CC,

35. 2) PCOS Without IR:What are characteristics? Lean. Euinsulinemic/ Euglycemic Enhanced Ovarian Sensitivity to insulin (although no Hyperinsulinemia).

36. Diagnosis In the past (before 2003) Necessary Lab Tests or sonar Recently ( after 2003)�clinically.

37. What is needed after clinical diagnosis PCOS? BMI: >31 = Obesity Lipid profile: Triglycerides: <200 mg/dl LDL <100 mg/dL HDL >45 mg/dL Cholesterol <200 mg/dL 2 hour fasting blood glucose: 140-200 mg/dL = impaired glucose tolerance Fasting insulin >15 uU/ml Main reason to diagnose insulin resistance is go further on to look for type 2 diabetes Blood pressure: Normal systolic <130 mm Hg Normal diastolic <85 mm Hg Medications: Birth control methods Insulin-sensitizing agents Weight control drugs Hypertensive drugs Fertility drugs BMI: >31 = Obesity Lipid profile: Triglycerides: <200 mg/dl LDL <100 mg/dL HDL >45 mg/dL Cholesterol <200 mg/dL 2 hour fasting blood glucose: 140-200 mg/dL = impaired glucose tolerance Fasting insulin >15 uU/ml Main reason to diagnose insulin resistance is go further on to look for type 2 diabetes Blood pressure: Normal systolic <130 mm Hg Normal diastolic <85 mm Hg Medications: Birth control methods Insulin-sensitizing agents Weight control drugs Hypertensive drugs Fertility drugs

38. CREATED PHENOTYPES & ????????? REGARDING CL/P

39. 1) Symptomatic PCOS : What is the most important parameter ? Any or all of these symptoms may be present: Irregular menstrual cycles. Weight gain. Abnormal hair growth on the face or the body. Infertility.

40. 2) Asymptomatic PCOS Very lean Athletic women May be underweight. This may mask the PCOS.

41.  Controversy Epilepsy & PCOS Miscarriage & PCOS

42. Long term risks in PCOS Definite Type 2 diabetes Dyslipidemia (Hypercholesterolemia with diminished HDL2 and increased LDL) Endometrial cancer.

43. Possible Hypertension Cardiovascular disease Gestational diabetes mellitus Pregnancy-induced hypertension Ovarian cancer Unlikely Breast cancer Long term risks in PCOS

44. Long Term Risks Of PCOS Gout (deposits of sodium urate crystals in small joints and surrounding tissues) due to increased uric acid levels (associated with obesity). Gallbladder disease due to ? HDL & ? triglycerides (associated with the five �F�s��female, fat, forty, fair, fertile). Endometrial cancer caused by proliferation of uterine cells in response to increased levels of estrogen. If this proliferation is left unopposed by progesterone, periodic loss of endometrium at menstruation is prevented and a build-up of the endometrium occurs. Fat cells have the ability to convert precursor hormones in the blood to estrogens. Obesity due to increased lipogenesis (associated with high levels of insulin). NIDDM due to glucose intolerance and hyperinsulinemia. Hypertension and CVD due to ? triglycerides, ? LDL cholesterol, and ? HDL cholesterol. Infertility due to anovulation or other menstrual disturbances.Gout (deposits of sodium urate crystals in small joints and surrounding tissues) due to increased uric acid levels (associated with obesity). Gallbladder disease due to ? HDL & ? triglycerides (associated with the five �F�s��female, fat, forty, fair, fertile). Endometrial cancer caused by proliferation of uterine cells in response to increased levels of estrogen. If this proliferation is left unopposed by progesterone, periodic loss of endometrium at menstruation is prevented and a build-up of the endometrium occurs. Fat cells have the ability to convert precursor hormones in the blood to estrogens. Obesity due to increased lipogenesis (associated with high levels of insulin). NIDDM due to glucose intolerance and hyperinsulinemia. Hypertension and CVD due to ? triglycerides, ? LDL cholesterol, and ? HDL cholesterol. Infertility due to anovulation or other menstrual disturbances.

45. How is PCOS treated? Till now there is no cure for PCOS. The target is to: Try causative ttt. prevent further problems.

46. Causative ttt Life- style modifications: Diet modification Weight loss Exercise Psychosocial support. Cessation smoking. Improve IR ( Metformin)

47. Targets for treatment PCOS

48. A weight loss of only 5% of total body weight is associated with:

49. Drug Therapy: Insulin-Sensitizing Agents (Metformin) Potential Disadvantages Gastrointestinal disturbance in 1/3 of patients Generalized feeling of unwell ness Decreased absorption of vitamin B-12 Lactic acid buildup

50. Laparascopic Treatment of Polycystic Ovaries: Is Its Place Diminishing? Laparascopic ovarian drilling and Metformin improve ovulatory dysfunction and pregnancy rate to a similar extent. The advantages of Metformin continue beyond conception: It reduces the miscarriage rate Decreases the likelihood of developing gestational diabetes.

51. Proposed APPROACH FOR ttt of PCOS

52. Gynecologists should categorize any case of PCOS ,depending on : Rotterdam definition IR or not Asymptomatic or symptomatic Conclusions

53. Conclusions Treatment of PCOS should be directed towards causative rather than symptomatic especially if IR is proved as the central player !!!!

54. NOW We Can Decide That Polycystic Ovary Syndrome is An Open Door for Dietetics Professionals Conclusions

55. The pathogenesis of altered ovarian morphology in asymptomatic PCO should be evaluated by 3D and Doppler ultrasonic in those apparently normal women where up to 20% of fertile women have PCO on ultrasound Recommendations