2. Januari 17, 2010 Dear Doctor, Could you please advise me on treatment for my bothersome menstrual bleeding. I’m 46 years of age and mother of 3 children. I hardly can keep up my job as a teacher due to the prolonged bleeds and a lack of energy after a period. Yours sincerely, Mrs Jones © PHMvdW 2010

3. Dysfunctional Uterine Bleeding Peter van de Weijer MD PHD CCO Paramaribo Januari 24 th 2010

4. Dysfunctional Uterine Bleeding describes the spectrum of abnormal menstrual bleeding patterns that occur in women secondary after anovulation or oligo- ovulation and where no pelvic pathology or medical illness is present. Speroff L. Clinical Gynecologic Endocrinology and Infertility. 2005 Lippincott Williams & Wilkins © PHMvdW 2010

5. Januari 17, 2010 Dear Doctor, Could you please advise me on treatment for my bothersome menstrual bleeding. I’m 46 years of age and mother of 3 children. I hardly can keep up my job as a teacher due to the prolonged bleeds and a lack of energy after a period. Yours sincerely, Mrs Jones Cycle problem ? Bleeding problem ?

6. Length of the follicular + luteal phase Features of the menstrual cycle © PHMvdW 2010 Cycle length variationconsistent P5-P95 = 24 - 35 days 28 days = 15% 1 1

7. Features of the menstrual cycle © PHMvdW 2010 Cycle length 1 1 regularity 1

8. Features of the menstrual cycle © PHMvdW 2010 regularity

9. Features of the menstrual cycle © PHMvdW 2010 regularity Sex-steroid hormones Endometrium Oestrogen Progesterone Proliferative Secretory

10. Features of the menstrual cycle regularity Sex-steroid hormones

11. Features of the menstrual cycle © PHMvdW 2010 regularity Endometrium

12. Features of the menstrual cycle © PHMvdW 2010 Cycle length 1 1 regularity Variation 24 - 35 days Irregular > 20% 1

13. Features of the menstrual cycle © PHMvdW 2010 34 years of observation 25.825 person years 250.000 cycles Treloar AE et al. Variation of the human menstrual cycle through reproductive life. Int J Fert 1967;12:77-126

14. age Interval between succeeding menstruations days Treloar AE et al. Variation of the human menstrual cycle through reproductive life. Int J Fert 1967;12:77-126 © PHMvdW 2010 Features of the menstrual cycle

15. length regularity Features of the menstrual cycle © PHMvdW 2010 Bleeding

16. lengthduration regularity volumevolume Features of the menstrual cycle bleeding © PHMvdW 2010 Duration 4 – 6 days Volume 30 ml 250.000 cycles Bleeding

17. lengthduration regularity volumevolume bleeding © PHMvdW 2010 How does menstrual bleeding occur ?

18. Classical Concept Corpus luteum deficiency Oestrogen Progesterone Bleeding Vascular integrity Sex-steroid hormones ProliferativeSecretoryHistology Endometrium © PHMvdW 2010 How does menstrual bleeding occur ?

19. Bleeding Mechanisms in the Endometrium Vascular integrity © PHMvdW 2010 Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005

20. Bleeding Mechanisms in the Endometrium Vascular integrity The capillaries in the endometrium have only one thick cell layer © PHMvdW 2010

21. Bleeding Mechanisms in the Endometrium endothelial Vascular integrity Cell to cell Adhesion The capillaries in the endometrium have only one thick cell layer Tunica intima: a single layer of simple squamous endothelial cells glued by a polysaccharide extracellular matrix, surrounded by a thin layer of subendothelial connective tissue interlaced with a number of circularly arranged elastic bands called the internal elastic lamina © PHMvdW 2010

22. Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation endothelial Vascular integrity Cell to cell Adhesion © PHMvdW 2010

23. Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation endothelial Vascular integrity Collagenase Cell to cell Adhesion © PHMvdW 2010

24. Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation endothelial Vascular integrity Pro-collagenaseCollagenase Cell to cell Adhesion © PHMvdW 2010

25. Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation endothelial Vascular integrity Pro-collagenaseCollagenase MMP’s Cell to cell Adhesion Matrix Metallo Proteinase > 25 enzymes able to degrade all components of ECM 1-2-3-9 © PHMvdW 2010

26. Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation endothelial Vascular integrity Pro-collagenaseCollagenase MMP’s Cell to cell Adhesion Pro MMP’s Proteolytic cleavage by Plasmin / Gelatinase Progesteron 1-2-3-9 Cornet PB et al. Regulation of MMP-9 and activation by ovarian steroids. J Clin Metab 2005; 90 : 1001 © PHMvdW 2010

27. Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation endothelial Vascular integrity Pro-collagenaseCollagenase MMP’s Cell to cell Adhesion Pro MMP’s Proteolytic cleavage by Plasmin / Gelatinase Progesteron 1-2-3-9 Cornet PB et al. Regulation of MMP-9 and activation by ovarian steroids. J Clin Metab 2005; 90 : 1001 © PHMvdW 2010

28. Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005 Bleeding Mechanisms in the Endometrium © PHMvdW 2010

29. Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation endothelial Vascular integrity Pro-collagenaseCollagenase MMP’s Cell to cell Adhesion Pro MMP’s Proteolytic cleavage by Plasmin / Gelatinase IL-1 Progesterone withdrawal PGF 2α Ischemia Free Oxygen Radicals Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005 1-2-3-9 © PHMvdW 2010

30. How does menstrual bleeding stop ? © PHMvdW 2010

31. vasoconstriction How does menstrual bleeding stop ? PG © PHMvdW 2010

32. Platelets Thromboxane A2 Prostaglandine Synthetase Prostacyclin Vasoconstriction Promotes Aggregation Inhibits Aggregation Vasodilatation How does menstrual bleeding stop ? © PHMvdW 2010

33. vasoconstriction How does menstrual bleeding stop ? PG Clotting mechanisms Thrombin © PHMvdW 2010

34. Plasmin FibrinogenFibrinFibrin degradation PlasminogenThrombin How does menstrual bleeding stop ? © PHMvdW 2010

35. vasoconstriction How does menstrual bleeding stop ? PG Clotting mechanisms Estrogen action Thrombin © PHMvdW 2010

36. lengthduration regularity volumevolume Features of the menstrual cycle bleeding © PHMvdW 2010 Duration 4 – 6 days Volume 30 ml 250.000 cycles Bleeding

37. lengthduration regularity volumevolume Features of the menstrual cycle © PHMvdW 2010 Accompanying features

38. lengthduration regularity volumevolume Features of the menstrual cycle © PHMvdW 2010 Dysmenorrhea Prevalence 45-72% menarche + 3 yrs Severity:duration/flow Analgetics 39% y Accompanying features Dysmenorrhea

39. lengthduration regularity volumevolume Features of the menstrual cycle © PHMvdW 2010 PMS Cycle related problems 40% Prevalence PMS 2-10 % SSRI / GnRH analogue Analgetics 39% y Accompanying features Dysmenorrhea PMS

40. lengthduration regularity 4-6 days volumevolume 24-35 days 30 ml Dysmenorrhea PMS Features of the menstrual cycle bleeding © PHMvdW 2010

41. age Interval between succeeding menstruations days Changes in Cycle Pattern (climacteric) Dear Doctor, Could you please advise me on treatment for my bothersome irregular menstrual bleeding. I’m 46 years of age © PHMvdW 2010

42. Freeman EW et al. Fertil Steril 2005;83:383-92 endocrinology 3 effects Oestrogen levels Progesteron levels Endometrial growth Changes in Cycle Pattern (climacteric) © PHMvdW 2010

43. Freeman EW et al. Fertil Steril 2005;83:383-92 endocrinology Changes in Cycle Pattern (climacteric) © PHMvdW 2010

44. Freeman EW et al. Fertil Steril 2005;83:383-92 I. Oestrogen levels endocrinology © PHMvdW 2010

45. Freeman EW et al. Fertil Steril 2005;83:383-92 endocrinology I. Oestrogen levels Oestrogen levels are sustained © PHMvdW 2010

46. age Interval between succeeding menstruations days Anovulation © PHMvdW 2010 Progesteron

47. 1 15 Days of cycle 28 Progestagen day 14 -28 21 ADD Anovulation Progesterone deficiency Oestrogen surplus © PHMvdW 2010

48. How does progestagen work ?

49. © PHMvdW 2008 Effect on the Endometrium

50. Progestogen Actions on the Endometrium Progesteron Stops the oestrogen-induced growth of the endometrium © PHMvdW 2010

51. Progestogen Actions on the Endometrium Progesteron Apoptosis Suppression of Bcl-2 expression Induces apoptosis of endometrial cells © PHMvdW 2010

52. Progestogen Actions on the Endometrium Progesteron E 2 ES Bcl-2 Apoptosis + Synthesis of 17ß-hydroxysteroid dehydrogenase sulfotransferase Promotes synthesis of 17B-HDS which converts E2 into ES © PHMvdW 2010

53. 0,85 = 85% of estradiol is converted into Estrone sulphate Estrone sulphate is a non active estrogen Enzymes involved are: 17ß-hydroxysteroid dehydrogenase, sulfotransferase en sulfatase Activity of these enzymes shows large inter individual variation estradiol estrone estrone sulphate 0,85 0,014 0,54 0,21 0,05 0,15 estradiol metabolism © PHMvdW 2010

54. Progestogen Actions on the Endometrium Progesteron E 2 ES Ligand Binding domain DNA binding domain TAF-1TAF-2 Estrogen Receptor Bcl-2 Apoptosis + Synthesis of 17ß-hydroxysteroid dehydrogenase sulfotransferase Suppresses DNA synthesis through interference with the ligand binding domain © PHMvdW 2010

55. How does progestagen work ? Stops the oestrogen-induced growth of the endometrium Induces apoptosis of endometrial cells Promotes synthesis of 17B-HDS which converts E2 into ES Suppresses DNA synthesis through interference with the ligand binding domain © PHMvdW 2010

56. How to treat anovulatory bleeding problems ? Acute Heavy Bloodloss Chronic Menorrhagia © PHMvdW 2010

57. Acute Heavy Bloodloss High dose Progestagens ( Norethisteron 5 mg 2-3dd 1 / 10 days) or 4 tabs OC during 5 days or tranexamic acid 1-1.5 g tds or ( curettage ) © PHMvdW 2010

58. High dose Progestagens than Regulate Cycle for at least 3 months Acute Heavy Bloodloss © PHMvdW 2010

59. OAC during 3 months P normal dose day 15-28 cycle P 10 days High dose M MMM Dydrogesteron 10 mg MPA 10 mg Lynestrenol 5 mg Norethisteron 5 mg Medrogeston 5 mg Speroff L. Clinical Gynecologic Endocrinology and Infertility. 2005 Lippincott Williams & Wilkins Acute Heavy Bloodloss © PHMvdW 2010

60. Acute Heavy Bloodloss Chronic Menorrhagia © PHMvdW 2010 How to treat menstrual bleeding problems ?

61. If cycle and bleeding problems are present first correct cycle If bleeding problems still persist exclude anatomical / systemic pathology If bleeding problems still persist treat bleeding problems Progestagens OCC Ultrasound Hysteroscopy Lab examination PGSI Antifibrinolytics Surgery 1 15 Days of cycle 21 28 Progestagen day 14 -28 Oral contraceptive 1 © PHMvdW 2010 How to treat menstrual bleeding problems ?

62. If cycle and bleeding problems are present first correct cycle If bleeding problems still persist exclude anatomical / systemic pathology If bleeding problems still persist treat bleeding problems Progestagens OCC Ultrasound Hysteroscopy Lab examination PGSI Antifibrinolytics Surgery © PHMvdW 2010 How to treat menstrual bleeding problems ?

63. If cycle and bleeding problems are present first correct cycle If bleeding problems still persist exclude anatomical / systemic pathology If bleeding problems still persist treat bleeding problems Progestagens OCC Ultrasound Hysteroscopy Lab examination PGSI Antifibrinolytics Progestagens Surgery © PHMvdW 2010 How to treat menstrual bleeding problems ?

64. vasoconstriction PG Synthetase inhibitors © PHMvdW 2010 How to treat menstrual bleeding problems ?

65. Platelets Thromboxane A2 Prostaglandine Synthetase Prostacyclin Vasoconstriction Promotes Aggregation Inhibits Aggregation Vasodilatation PG Synthetase inhibitors © PHMvdW 2010

66. Endometrium & Bleeding Platelets Thromboxane A2 © PHMvdW 2005 Prostacyclin Vasoconstriction Promotes Aggregation Inhibits Aggregation Vasodilatation PG Synthetase inhibitors PGSI : Prostaglandin Synthetase Inhibitors naproxen 500 mg bd ibuprofen 400 mg tds diclofenac 50 mg tds Reduction in blood loss (%) © PHMvdW 2010

67. vasoconstriction PG Synthetase inhibitors Clotting mechanism Antifibrinolytics © PHMvdW 2010 How to treat menstrual bleeding problems ?

68. Plasmin FibrinogenFibrinFibrin degradation Plasminogen Antifibrinolytics Thrombin Clotting © PHMvdW 2010 How to treat menstrual bleeding problems ?

69. Antifibrinolytics Reduction in blood loss (%) Antifibrinolytic drugs tranexamic acid 1-1.5 g tds © PHMvdW 2010 How to treat menstrual bleeding problems ?

70. vasoconstriction PG Synthetase inhibitors Clotting mechanism Antifibrinolytics Inactive endometrium Progestagen © PHMvdW 2010 How to treat menstrual bleeding problems ?

71. Reduction in blood loss (%) Progestagen How to treat Dysfunctional Uterine Bleeding ? © PHMvdW 2010

72. 1 15 Days of cycle 28 3 OC 21 Progestagen oral continuous Progestagen IUD GnRH analoques Danazol Progestagen oral sequential © PHMvdW 2010

73. If cycle and bleeding problems are present first correct cycle If bleeding problems still persist exclude anatomical / systemic pathology If bleeding problems still persist treat bleeding problems Progestagens OCC Ultrasound Hysteroscopy Lab examination PGSI Antifibrinolytics Progestagens Surgery © PHMvdW 2010 How to treat menstrual bleeding problems ?

74. Health care for Women © PHMvdW 2010