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  1. 1. <ul><li>BY </li></ul><ul><li>Mohammad A. Emam </li></ul><ul><li>Prof. OB& GYN </li></ul><ul><li>Mansoura Faculty of Medicine </li></ul><ul><li>Mansoura integrated fertility center (MIFC) EGYPT </li></ul><ul><li> </li></ul>Progress In PCOS
  2. 2. History <ul><li>Stein and Leventhal </li></ul><ul><li>Polycystic Ovarian disease. </li></ul><ul><li>Polycystic ovarian syndrome </li></ul><ul><li>Syndrome O </li></ul><ul><li>( Metabolic) </li></ul>
  3. 3. Prevalence <ul><li>About 20% of reproductive age women demonstrate the ultrasound picture of polycystic ovaries. </li></ul><ul><li>About 5- 10 % have clinical or biochemical signs of Anovulation and androgen excess (dunaif 1995 , Norman etal 2002) </li></ul>
  4. 4. Rationale <ul><li>Knowledge base for PCOS is rapidly revived and revised Not end story </li></ul>Creation of significant Developments
  5. 5. Objective <ul><li>To highlight the progress in PCOS regarding : </li></ul><ul><ul><li>Definition . </li></ul></ul><ul><ul><li>Etiology </li></ul></ul><ul><ul><li>Path physiology. </li></ul></ul><ul><ul><li>Diagnosis </li></ul></ul><ul><ul><li>Heterogeneity of clinical presentations </li></ul></ul><ul><ul><li>Management. </li></ul></ul><ul><ul><li>Health risks. </li></ul></ul>
  6. 6. <ul><li>F rom recent publications in the relevant subjects of endocrinology, reproductive medicine, and gynaecology. </li></ul><ul><li>Medline search from 1994 till 2005 for English language articles related to PCOS and &quot;metabolic syndrome in women.&quot; </li></ul>Methods
  7. 7. Definition of PCOS
  8. 8. Definition of PCOS <ul><li>Europe view: - Ultrasound profile. </li></ul><ul><li>USA view (NIH ): - Endocrine Profile. </li></ul><ul><li>Rotterdam definition PCOS (2003). </li></ul>
  9. 9. <ul><li>PCOS could be defined when at least two of the following three features are present, after exclusion of other etiologies : </li></ul><ul><li>(i) Oligomenorrhea and or Anovulation </li></ul><ul><li>(ii) Hyperandrogenism and/or hyperandrogenemia. </li></ul><ul><li>(iii) Polycystic ovaries (sonar). </li></ul>Rotterdam , May 2003 Definition
  10. 10. <ul><li>Hyperandrogenism is the clinical manifestation of hyperandrogenemia. </li></ul><ul><li>Hyperandrogenism can exist in absence of hyperandrogenemia e.g. enhanced tissue sensitivity to androgens in many premenopausal women </li></ul>What is T he D ifference B etween Hyperandrogenism & Hyperandrogenemia?
  11. 11. Ultrasonic Criteria of PCO <ul><li>At least one of the following: </li></ul><ul><ul><ul><li>12 or more follicles measuring 2–9 mm in diameter, </li></ul></ul></ul><ul><ul><ul><li>increased ovarian volume (>10 cm 3 ). </li></ul></ul></ul><ul><li>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 . </li></ul><ul><li>The presence of a single PCO is sufficient to provide the diagnosis. </li></ul><ul><li>The distribution of follicles and a description of the stroma are not required for diagnosis. </li></ul>
  12. 12. <ul><li>Significant intra-observer and inter-observer variability . </li></ul>What are The Pitfalls Of Ultrasonic Criteria ?
  13. 13. What are Trials To Standardize Ultrasonic Criteria PCO? <ul><li>Ratio between ovarian stromal area and total area of ovarian section ( S/A)..with cut –off 0.34 for PCO diagnosis (Belasi etal 2004). </li></ul><ul><li>The use of high resolution 3D. </li></ul>
  14. 14. <ul><li>Polycystic ovaries ( PCO ), observed on ultrasound are a sign of PCOS and not by themselves diagnostic of the syndrome. </li></ul>PCO & PCOS
  15. 15. PCO VS. Multicystic Ovaries <ul><li>Polycystic ovaries </li></ul><ul><ul><li>Bilateral </li></ul></ul><ul><ul><li>Multiple cysts </li></ul></ul><ul><ul><li>Cyst diam 2-<10 mm </li></ul></ul><ul><ul><li>Stroma increased </li></ul></ul><ul><li>Multicystic ovaries </li></ul><ul><ul><li>Bilateral </li></ul></ul><ul><ul><li>Multiple cysts </li></ul></ul><ul><ul><li>Cyst diam > 10 mm </li></ul></ul><ul><ul><li>Stroma not increased </li></ul></ul><ul><ul><li>I t is better to call it Polyfollicular syndrome not PCOS </li></ul></ul>
  16. 16. Emerging & Created Phenotypes &????? Regarding Roterdam 2003 Definition
  17. 17. Phenotypes (Rotterdam) Not P C O S +/- + +/- - + Norm N. Androgen + ovulatory +PCO + + ++ ++ +++ CVS risk + + - - Abn DD - - -/+ ++ - Abn Hyperando + Anov + N.ov + + + + Norm Hyperandrogen+PCO + Ovul. * + -/+ - - Norm Anov+ PCO + N.androgen + + ++ - Irreg Classic PCOS NB PCO I.R Androgens Ovulation Menses
  18. 18. What is The significance of polycystic-appearing ovaries versus normal appearing ovaries in patients with PCOS?? <ul><li>The presence of polycystic-appearing ovaries usually correlates with the presence of insulin resistance ( Richard J 2002) . </li></ul>
  19. 19. <ul><li>Late onset congenital adrenal hyperplasia </li></ul><ul><li>DHEAS > 18mmol/l </li></ul><ul><li>17 OH Prog > 6 mmol/l </li></ul><ul><li>Ovarian + adrenal androgen secreting tumours </li></ul><ul><li>V. high teslosterone > 6mmol/l </li></ul><ul><li>Cushings Syndrome </li></ul><ul><li>- Dexamethsone suppression test </li></ul><ul><li>- 24 hours urinary cortisol </li></ul><ul><li>- DHEAS > 13 mmol/l </li></ul>Anovulation & Hyperandrogenism What is DD?
  20. 20. <ul><li>Iatrogenic and illegal androgen ingestion </li></ul><ul><li>Hypothyroidisms </li></ul><ul><li>Hyperprolactinemia. </li></ul>Anovulation & Hyperandrogenism What is DD?
  21. 21. Is Fertility Normal in patients With Ovulatory PCOS? <ul><li>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). </li></ul>
  22. 22. Asymptomatic PCO (Ovulatory + Normoandrogenic ) <ul><li>There is significantly lower levels of progesterone in the early Luteal phase. </li></ul><ul><li>This may contribute to the delay in conception in these patients. </li></ul><ul><li>May be the starting cascade of Pcos !!!!!!!!! </li></ul>
  23. 23. Pitfalls Rotterdam Definition <ul><li>doubts still exist regarding borderline groups of patients ,such as hirsute ovulatory Normoandrogenic women with PCO???. </li></ul><ul><li>Neglect role of IR </li></ul>
  24. 24. Etiology <ul><li>Speculation: </li></ul><ul><li>Complex interaction of genetic ,epigenetic and environmental factors. </li></ul><ul><li>Recently ,PCOS is mediated by ghrelin </li></ul><ul><li>( gastric peptide which is orexigenic and adipogenic) </li></ul>
  25. 25. Pathogenesis <ul><li>Three major hypothesis ( culprits ) may all interact: </li></ul><ul><ul><ul><li>Insulin resistance ( central player). </li></ul></ul></ul><ul><ul><ul><li>Hyperandrogenism & (altered Gonadotropins) </li></ul></ul></ul><ul><ul><ul><li>Recently ( target genes) : </li></ul></ul></ul><ul><ul><ul><ul><li>Genes encoding Inflammatory cytokines. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>INSR genes. </li></ul></ul></ul></ul>
  26. 26. IR ( Metabolic or Syndrome x ) What is? <ul><li>Insulin acts like a key which can open a door on the cell's surface. </li></ul><ul><li>cells do not have enough insulin receptor sites and cannot effectively burn glucose . </li></ul><ul><li>this excess glucose is then sent to the liver where it is converted to fat. </li></ul>
  27. 27. PCOS, starts in adolescence. But Unfortunately, not always diagnosed at that age.
  28. 28. The Central Player ( Insulin Resistance ) Genetics Aging Pregnancy Drugs Lifestyle Upper abdominal obesity Hyperinsulinemia Increased lipid storage Altered lipoprotein & cholesterol metabolism Altered steroid hormone metabolism PCOS Insulin Resistance
  29. 29. <ul><ul><li>The high ovarian response to insulin. </li></ul></ul><ul><ul><li>Opposed by the whole body resistance. </li></ul></ul>IR : The central paradox
  30. 31. How IR Can Be Assessed ?? <ul><li>OGTT ( the best ). </li></ul><ul><li>Fasting insulin (mu/ L) to fasting glucose (mmol/L) ( Hyperinsulinemic – euglycemic). </li></ul>
  31. 32. Emerging & Created PHENOTYPES &????????????? Regarding Pathogenesis
  32. 33. <ul><li>PCOS + IR ( 50-70 % ). </li></ul><ul><li>PCOS without IR. </li></ul>Phenotypes According to IR
  33. 34. 1) IR Phenotype of PCOS: What are the characteristics ? <ul><ul><li>Obese ( may be lean ) </li></ul></ul><ul><ul><li>Acanthosis Nigerians. </li></ul></ul><ul><ul><li>Hirsutism. </li></ul></ul><ul><ul><li>Resistance to CC, </li></ul></ul>
  34. 35. 2) PCOS Without IR: What are characteristics? <ul><li>Lean. </li></ul><ul><li>Euinsulinemic/ Euglycemic </li></ul><ul><li>Enhanced Ovarian Sensitivity to insulin ( although no Hyperinsulinemia ). </li></ul>
  35. 36. Diagnosis <ul><li>In the past (before 2003) Necessary Lab Tests or sonar </li></ul><ul><li>Recently ( after 2003)… clinically. </li></ul>
  36. 37. What is needed after clinical diagnosis PCOS? <ul><li>Body weight </li></ul><ul><li>Ideal body weight </li></ul><ul><li>Body Mass Index (BMI) </li></ul><ul><li>Lipid profile </li></ul><ul><li>Fasting blood glucose </li></ul><ul><li>Fasting insulin levels </li></ul><ul><li>Blood pressure </li></ul><ul><li>Medications </li></ul>
  38. 39. 1) Symptomatic PCOS : What is the most important parameter ? <ul><li>Any or all of these symptoms may be present: </li></ul><ul><ul><ul><li>Irregular menstrual cycles. </li></ul></ul></ul><ul><ul><ul><li>Weight gain. </li></ul></ul></ul><ul><ul><ul><li>Abnormal hair growth on the face or the body. </li></ul></ul></ul><ul><ul><ul><li>Infertility. </li></ul></ul></ul><ul><li>Increased BMI ( severity of the PCOS). </li></ul>
  39. 40. 2) Asymptomatic PCOS <ul><li>Very lean </li></ul><ul><li>Athletic women </li></ul><ul><li>May be underweight. </li></ul><ul><li>This may mask the PCOS . </li></ul><ul><ul><ul><ul><ul><li>The less symptoms, the better response to medication and treatment. </li></ul></ul></ul></ul></ul>
  40. 41. Controversy <ul><ul><li>Epilepsy & PCOS </li></ul></ul><ul><ul><li>Miscarriage & PCOS </li></ul></ul>
  41. 42. Long term risks in PCOS <ul><li>Definite </li></ul><ul><li>Type 2 diabetes </li></ul><ul><li>Dyslipidemia (Hypercholesterolemia with diminished HDL2 and increased LDL) </li></ul><ul><li>Endometrial cancer. </li></ul>
  42. 43. <ul><li>Possible </li></ul><ul><li>Hypertension </li></ul><ul><li>Cardiovascular disease </li></ul><ul><li>Gestational diabetes mellitus </li></ul><ul><li>Pregnancy-induced hypertension </li></ul><ul><li>Ovarian cancer </li></ul><ul><li>Unlikely </li></ul><ul><li>Breast cancer </li></ul>Long term risks in PCOS
  43. 44. Long Term Risks Of PCOS PCOS CVD Gout Obesity Hypertension Infertility Endometrial Cancer Gallbladder Disease NIDDM
  44. 45. How is PCOS treated? <ul><li>Till now there is no cure for PCOS . </li></ul><ul><li>The target is to: </li></ul><ul><ul><ul><ul><ul><li>Try causative ttt. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>prevent further problems. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>HOW????? </li></ul></ul></ul></ul></ul>
  45. 46. Causative ttt <ul><li>Life- style modifications: </li></ul><ul><ul><ul><li>Diet modification </li></ul></ul></ul><ul><ul><ul><li>Weight loss </li></ul></ul></ul><ul><ul><ul><li>Exercise </li></ul></ul></ul><ul><ul><ul><li>Psychosocial support. </li></ul></ul></ul><ul><ul><ul><li>Cessation smoking. </li></ul></ul></ul><ul><ul><li>Improve IR ( Metformin) </li></ul></ul>
  46. 47. Targets for treatment PCOS
  47. 48. A weight loss of only 5% of total body weight is associated with: <ul><li>Decreased insulin levels </li></ul><ul><li>improved menstrual function </li></ul><ul><li>reduced hirsutism and acne </li></ul><ul><li>lower testosterone levels. </li></ul>
  48. 49. Drug Therapy: Insulin-Sensitizing Agents (Metformin) <ul><li>Potential Disadvantages </li></ul><ul><li>Gastrointestinal disturbance in 1/3 of patients </li></ul><ul><li>Generalized feeling of unwell ness </li></ul><ul><li>Decreased absorption of vitamin B-12 </li></ul><ul><li>Lactic acid buildup </li></ul><ul><li>Potential Advantages </li></ul><ul><li>↑ glucose tolerance </li></ul><ul><li>↑ insulin sensitivity </li></ul><ul><li>↓ blood lipid levels </li></ul><ul><li>↑ weight loss or stabilization </li></ul><ul><li>Improved fat distribution </li></ul><ul><li>↓ blood pressure </li></ul><ul><li>↓ androgen levels </li></ul><ul><li>Restoration of regular menses </li></ul><ul><li>Postponement of diabetes </li></ul>
  49. 50. Laparascopic Treatment of Polycystic Ovaries: Is Its Place Diminishing? <ul><li>Laparascopic ovarian drilling and Metformin improve ovulatory dysfunction and pregnancy rate to a similar extent. </li></ul><ul><li>The advantages of Metformin continue beyond conception: </li></ul><ul><ul><ul><li>It reduces the miscarriage rate </li></ul></ul></ul><ul><ul><ul><li>Decreases the likelihood of developing gestational diabetes. </li></ul></ul></ul>
  50. 51. Proposed APPROACH FOR ttt of PCOS
  51. 52. <ul><li>Gynecologists should categorize any case of PCOS ,depending on : </li></ul><ul><li>Rotterdam definition </li></ul><ul><li>IR or not </li></ul><ul><li>Asymptomatic or symptomatic </li></ul>Conclusions
  52. 53. Conclusions <ul><li>Treatment of PCOS should be directed towards causative rather than symptomatic especially if IR is proved as the central player !!!! </li></ul>Conclusions
  53. 54. <ul><li>NOW We Can Decide That Polycystic Ovary Syndrome is An Open Door for Dietetics Professionals </li></ul>Conclusions
  54. 55. <ul><li>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 </li></ul>Recommendations
  55. 56. T elfax 0020502319922 & 0020502312299 Email. [email_address] Prof. DR. MOHAMMAD EMAM Thank you