Januari 17 2010 Dear Doctor Could you please
- Slides: 74
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 © PHMvd. W 2010
Dysfunctional Uterine Bleeding Peter van de Weijer MD PHD CCO Paramaribo Januari 24 th 2010
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 © PHMvd. W 2010
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 ? © PHMvd. W 2010
Features of the menstrual cycle Cycle length 1 Length of the 1 follicular variation © PHMvd. W 2010 + luteal phase consistent P 5 -P 95 = 24 - 35 days 28 days = 15%
Features of the menstrual cycle Cycle length regularity 1 © PHMvd. W 2010 1 1
Features of the menstrual cycle regularity © PHMvd. W 2010
Features of the menstrual cycle regularity Sex-steroid hormones Oestrogen Progesterone Endometrium Proliferative © PHMvd. W 2010 Secretory
Features of the menstrual cycle regularity Sex-steroid hormones
Features of the menstrual cycle regularity Endometrium © PHMvd. W 2010
Features of the menstrual cycle Cycle length regularity 1 1 1 Variation 24 - 35 days Irregular > 20% © PHMvd. W 2010
Features of the menstrual cycle Treloar AE et al. Variation of the human menstrual cycle through reproductive life. Int J Fert 1967; 12: 77 -126 34 years of observation 25. 825 person years 250. 000 cycles © PHMvd. W 2010
Features of the menstrual cycle Interval between succeeding menstruations days age © PHMvd. W 2010 Treloar AE et al. Variation of the human menstrual cycle through reproductive life. Int J Fert 1967; 12: 77 -126
Features of the menstrual cycle Bleeding regularity length © PHMvd. W 2010
Features of the menstrual cycle Bleeding regularity length Duration 4 – 6 days Volume 30 ml 250. 000 cycles © PHMvd. W 2010 v o l u m e duration bleeding
How does menstrual bleeding occur ? regularity length v o l u m e duration bleeding © PHMvd. W 2010
How does menstrual bleeding occur ? Classical Concept Sex-steroid hormones Histology Endometrium Vascular integrity © PHMvd. W 2010 Corpus luteum deficiency Oestrogen Progesterone Proliferative Secretory Bleeding
Bleeding Mechanisms in the Endometrium Vascular integrity © PHMvd. W 2010 Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005
Bleeding Mechanisms in the Endometrium The capillaries in the endometrium have only one thick cell layer Vascular integrity © PHMvd. W 2010
Bleeding Mechanisms in the Endometrium 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 Cell to cell Adhesion internal elastic lamina endothelial Vascular integrity © PHMvd. W 2010
Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation Cell to cell Adhesion endothelial Vascular integrity © PHMvd. W 2010
Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation Cell to cell Adhesion endothelial Collagenase Vascular integrity © PHMvd. W 2010
Bleeding Mechanisms in the Endometrium Extra Cellular Matrix Degradation Cell to cell Adhesion endothelial Pro-collagenase Collagenase Vascular integrity © PHMvd. W 2010
Bleeding Mechanisms in the Endometrium Matrix Metallo Proteinase > 25 enzymes able to degrade all components of ECM MMP’s 1 -2 -3 -9 Extra Cellular Matrix Degradation Cell to cell Adhesion endothelial Pro-collagenase Collagenase Vascular integrity © PHMvd. W 2010
Bleeding Mechanisms in the Endometrium Progesteron Pro MMP’s Proteolytic cleavage by Plasmin / Gelatinase 1 -2 -3 -9 Extra Cellular Matrix Degradation Cell to cell Adhesion endothelial Pro-collagenase Collagenase Vascular integrity © PHMvd. W 2010 Cornet PB et al. Regulation of MMP-9 and activation by ovarian steroids. J Clin Metab 2005; 90 : 1001
Bleeding Mechanisms in the Endometrium Progesteron Pro MMP’s Proteolytic cleavage by Plasmin / Gelatinase 1 -2 -3 -9 Extra Cellular Matrix Degradation Cell to cell Adhesion endothelial Pro-collagenase Collagenase Vascular integrity © PHMvd. W 2010 Cornet PB et al. Regulation of MMP-9 and activation by ovarian steroids. J Clin Metab 2005; 90 : 1001
Bleeding Mechanisms in the Endometrium © PHMvd. W 2010 Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005
Bleeding Mechanisms in the Endometrium Ischemia Progesterone withdrawal PGF 2α Free Oxygen Radicals Pro MMP’s Proteolytic cleavage by Plasmin / Gelatinase IL-1 1 -2 -3 -9 Extra Cellular Matrix Degradation Cell to cell Adhesion endothelial Pro-collagenase Collagenase Vascular integrity © PHMvd. W 2010 Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005
How does menstrual bleeding stop ? © PHMvd. W 2010
How does menstrual bleeding stop ? vasoconstriction © PHMvd. W 2010 PG
How does menstrual bleeding stop ? Prostaglandine Synthetase Thromboxane A 2 Prostacyclin Promotes Aggregation Inhibits Aggregation Vasoconstriction © PHMvd. W 2010 Platelets Vasodilatation
How does menstrual bleeding stop ? vasoconstriction PG Clotting mechanisms © PHMvd. W 2010 Thrombin
How does menstrual bleeding stop ? Fibrinogen Fibrin degradation Plasmin Thrombin © PHMvd. W 2010 Plasminogen
How does menstrual bleeding stop ? vasoconstriction PG Clotting mechanisms Estrogen action © PHMvd. W 2010 Thrombin
Features of the menstrual cycle Bleeding regularity length Duration 4 – 6 days Volume 30 ml 250. 000 cycles © PHMvd. W 2010 v o l u m e duration bleeding
Features of the menstrual cycle Accompanying features regularity length © PHMvd. W 2010 duration v o l u m e
Features of the menstrual cycle Accompanying features regularity length Dysmenorrhea Prevalence 45 -72% menarche + 3 yrs Severity: duration/flow Analgetics © PHMvd. W 2010 39% y Dysmenorrhea duration v o l u m e
Features of the menstrual cycle Accompanying features regularity length PMS Cycle related problems 40% Prevalence PMS 2 -10 % SSRI / Gn. RH analogue Analgetics © PHMvd. W 2010 39% y Dysmenorrhea duration PMS v o l u m e
Features of the menstrual cycle regularity length 24 -35 days duration v o l u m e 4 -6 days 30 ml Dysmenorrhea PMS bleeding © PHMvd. W 2010
Changes in Cycle Pattern (climacteric) Dear Doctor, Could you please advise me on treatment for my Interval between succeeding menstruations bothersome irregular menstrual bleeding. I’m 46 years of age days age © PHMvd. W 2010
endocrinology Changes in Cycle Pattern (climacteric) 3 effects Oestrogen levels Progesteron levels Endometrial growth Freeman EW et al. Fertil Steril 2005; 83: 383 -92 © PHMvd. W 2010
endocrinology Changes in Cycle Pattern (climacteric) Freeman EW et al. Fertil Steril 2005; 83: 383 -92 © PHMvd. W 2010
endocrinology I. Oestrogen levels Freeman EW et al. Fertil Steril 2005; 83: 383 -92 © PHMvd. W 2010
endocrinology I. Oestrogen levels are sustained Freeman EW et al. Fertil Steril 2005; 83: 383 -92 © PHMvd. W 2010
Progesteron Interval between succeeding menstruations Anovulation days age © PHMvd. W 2010
Oestrogen surplus Anovulation Progesterone deficiency ADD Progestagen 1 © PHMvd. W 2010 15 Days of cycle 21 day 14 -28 28
How does progestagen work ? © PHMvd. W 2010
Effect on the Endometrium © PHMvd. W 2008
Progestogen Actions on the Endometrium Progesteron Stops the oestrogen-induced growth of the endometrium © PHMvd. W 2010
Progestogen Actions on the Endometrium Progesteron Suppression of Bcl-2 expression Apoptosis Induces apoptosis of endometrial cells © PHMvd. W 2010
Progestogen Actions on the Endometrium Bcl-2 Apoptosis Progesteron + Synthesis of 17ß-hydroxysteroid dehydrogenase sulfotransferase E 2 ES Promotes synthesis of 17 B-HDS which converts E 2 into ES © PHMvd. W 2010
estradiol metabolism estradiol 0, 15 0, 05 0, 85 0, 014 estrone sulphate 0, 54 estrone 0, 21 • 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 © PHMvd. W 2010
Progestogen Actions on the Endometrium Bcl-2 Apoptosis Progesteron + Synthesis of 17ß-hydroxysteroid dehydrogenase sulfotransferase E 2 ES TAF-1 DNA binding. Ligand Binding TAF-2 domain Estrogen Receptor Suppresses DNA synthesis through interference with the ligand binding domain © PHMvd. W 2010
How does progestagen work ? Stops the oestrogen-induced growth of the endometrium Induces apoptosis of endometrial cells Promotes synthesis of 17 B-HDS which converts E 2 into ES Suppresses DNA synthesis through interference with the ligand binding domain © PHMvd. W 2010
How to treat anovulatory bleeding problems ? Acute Heavy Bloodloss Chronic Menorrhagia © PHMvd. W 2010
Acute Heavy Bloodloss High dose Progestagens ( Norethisteron 5 mg 2 -3 dd 1 / 10 days) or 4 tabs OC during 5 days or tranexamic acid 1 -1. 5 g tds or ( curettage ) © PHMvd. W 2010
Acute Heavy Bloodloss High dose Progestagens than Regulate Cycle for at least 3 months © PHMvd. W 2010
Acute Heavy Bloodloss Dydrogesteron 10 mg MPA 10 mg Lynestrenol 5 mg Norethisteron 5 mg Medrogeston 5 mg P P normal dose day 15 -28 cycle 10 days High dose M © PHMvd. W 2010 OAC during 3 months M M M Speroff L. Clinical Gynecologic Endocrinology and Infertility. 2005 Lippincott Williams & Wilkins
How to treat menstrual bleeding problems ? Acute Heavy Bloodloss Chronic Menorrhagia © PHMvd. W 2010
How to treat menstrual bleeding problems ? If cycle and bleeding problems are present first correct cycle Progestagens OCC Ultrasound If bleeding problems still persist Progestagen day Hysteroscopy 14 -28 exclude anatomical / systemic pathology 1 Lab examination Oral contraceptive If bleeding problems still persist treat bleeding problems 1 15 Days of cycle © PHMvd. W 2010 21 PGSI Antifibrinolytics Surgery 28
How to treat menstrual bleeding problems ? If cycle and bleeding problems are present first correct cycle Progestagens OCC If bleeding problems still persist exclude anatomical / systemic pathology Ultrasound Hysteroscopy Lab examination If bleeding problems still persist treat bleeding problems PGSI Antifibrinolytics Surgery © PHMvd. W 2010
How to treat menstrual bleeding problems ? If cycle and bleeding problems are present first correct cycle Progestagens OCC If bleeding problems still persist exclude anatomical / systemic pathology Ultrasound Hysteroscopy Lab examination If bleeding problems still persist treat bleeding problems PGSI Antifibrinolytics Progestagens Surgery © PHMvd. W 2010
How to treat menstrual bleeding problems ? vasoconstriction © PHMvd. W 2010 PG Synthetase inhibitors
Prostaglandine Synthetase PG Synthetase inhibitors Thromboxane A 2 Prostacyclin Promotes Aggregation Inhibits Aggregation Vasoconstriction © PHMvd. W 2010 Platelets Vasodilatation
Endometrium & Bleeding Thromboxane A 2 Promotes Reduction in blood loss (%) Aggregation Vasoconstriction ©PHMvd. W 2010 2005 © PG Synthetase inhibitors PGSI : Prostaglandin Synthetase Inhibitors Prostacyclin naproxen 500 mg bd ibuprofen 400 mg tds Inhibits diclofenac 50 mg tds Platelets Aggregation Vasodilatation
How to treat menstrual bleeding problems ? vasoconstriction Clotting mechanism © PHMvd. W 2010 PG Synthetase inhibitors Antifibrinolytics
How to treat menstrual bleeding problems ? Fibrinogen Fibrin degradation Plasmin Antifibrinolytics Thrombin Clotting © PHMvd. W 2010 Plasminogen
How to treat menstrual bleeding problems ? Antifibrinolytic drugs tranexamic acid 1 -1. 5 g tds Reduction in blood loss (%) Antifibrinolytics © PHMvd. W 2010
How to treat menstrual bleeding problems ? vasoconstriction Inactive endometrium Clotting mechanism © PHMvd. W 2010 PG Synthetase inhibitors Progestagen Antifibrinolytics
How to treat Dysfunctional Uterine Bleeding ? Progestagen Reduction in blood loss (%) © PHMvd. W 2010
Progestagen oral continuous Progestagen IUD Gn. RH analoques Danazol OC Progestagen oral sequential 1 © PHMvd. W 2010 3 15 Days of cycle 21 28
How to treat menstrual bleeding problems ? If cycle and bleeding problems are present first correct cycle Progestagens OCC If bleeding problems still persist exclude anatomical / systemic pathology Ultrasound Hysteroscopy Lab examination If bleeding problems still persist treat bleeding problems PGSI Antifibrinolytics Progestagens Surgery © PHMvd. W 2010
Health care for Women © PHMvd. W 2010
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