1.  Abnormal Uterine Bleeding and Associated Anomalies: Evidence and Treatment Tamara N. Fuller-Eddins, MD Assistant Clinical Professor Obstetrics and Gynecology University of South Dakota Sanford School of Medicine

2. Disclosures I have no financial relationship with a commercial entity producing health-related products and or services

3. Objectives  After this lecture, the healthcare provider should be able to  Use the “new” classification system developed by the FIGO Menstrual Disorders Working Group to describe the symptoms and etiologies related to abnormal uterine bleeding (AUB)  Identify management options for abnormal uterine bleeding  Critically evaluate medical and surgical therapies for Abnormal Uterine Bleeding and their associate anomalies as well as those not caused by structural abnormalities or systemic etiologies

4. Prevalence  Abnormal Uterine Bleeding  Alterations in the volume, amount or pattern of menstrual bleeding or blood flow  Estimated that AUB can affect 10%-35% of women  Most common group of gynecological disorders for which women seek care  Approximately 5%-10^ of women of reproductive age seek medical care for heavy bleeding Oceans Womb by Ciska Maie et al 1990 Prentice et al 1999, Lui et al 2007

5. Why do we care about AUB? Women with AUB are less likely to quantify their health as excellent or good Women with significant AUB work an average of 3.6 weeks less per year than women without AUB Average work loss from heavy bleeding is estimated to be $1692 per woman Estimated total direct cost AUB $1-1.55 billion annually Menorrhagia Healing by Barbara Bruch Costs et al 2002, Cote et al 2003, Liu et al 2007

6. Confusing definitions  The Menstrual Disorders Working Group FIGO developed a nomenclature and classification system to describe the symptoms and etiologies of AUB  Approved by the FIGO executive board and supported by ACOG  Simple symptom descriptions  Classification system for etiologies Fraser and Sungurtekin 2000; Fraser et al 2007, Munro et al 2011

7. Confusing definitions Time for clarification…  Heavy Menstrual Bleeding  Irregular and Heavy Menstrual Bleeding  DUB should no longer be used as a symptoms, sign or diagnosis ( new ICD-10) will reflect this change  Replaced with more precise categories of etiology: AUB-E and AUB-O ( more to follow)

8. Simplified clarification system FrequencyFrequent Norma Infrequent Absent < every 24 days Q 24-38 days Every 38 days RegularityRegular Irregular Variation +/- 2-20 days Variation > 20 days DurationProlonged Normal Shortened  8 days  4.5 to 8 days  < 4.5 days VolumeHeavy Normal Light  80 mls per cycle  5-80 mls per cycle  < 5 mls per cycle

9. Volume??  Traditionally, bleeding measured by volume of menstrual blood lost (> 80 mls)  Actual volume of MBL per cycle is not the main reason women seek medical attention Heavy menstrual bleeding (HMB) is defined as excessive blood loss which interfere with a woman’s physical social, emotional and/or material quality of life. It can occur alone or in combination with other symptoms. UK NICE GUIDELINES 2007

10. Abnormal Uterine Bleeding (AUB) PALM Structural Causes PolypAUB-P AdenomyosisAUB-A Leiomyoma'sAUB-L (Fibroids) Malignancy & hyperplasiaAUB-M COEIN: Nonstructural Causes CoagulopathyAUB-C Ovulatory and Endometrial AUB-O; AUB-E Iatrogenic and Not classified AUB-I; AUB-N

11. AUB-O Dysfunction  HEAVY and IRREGULAR  Absent ovulation-no corpus lutuem-ovary does not produce progesterone  (Fragile vascular endometrium with insufficient stromal support)  Continued estrogen stimulation without progesterone stimulated withdrawal bleed (As one are heals another begins bleeding) (Erratic unpredictable non-cyclic bleeding with inconsistent volume)

12. AUB-E: Endometrial Dysfunction  HEAVY AND IRREGULAR  Caused by local disturbances in endometrial function- deficiencies or excess of proteins that have an impact on coagulation  REDUCED LEVELS  Vasoconstrictors and Clotting Mechanisms  PG F@ alpha Endothelin-1  Tissue Factor pathway

13. AUB treatment modalities PALM Treat structural problems you think are causing the bleeding -Wide variety depends on problem AUB-O and AUB-E LNG IUS Oral Progestin COC’s NSAIDS Trenexaminic Acid Endometrial Ablation AUB-C Refer to treatment of the coagulopathy AUB-I and AUB-N Address the iatrogenic or other factor, may consider AUB-O and E treatment options

14. Treatment of AUB-O and AUB-E  A small piece of the puzzle:  Other consideration: desire for future fertility, regional availability, contraindications or risk factors for adverse event costs, other treatments attempted

15. Treatment of AUB-E and AUB- O  Effectiveness varies from patient to patient based on acuity, women with ovulatory dysfunction, and women with anovulatory dysfunction  Studies can be difficult to compare and interpret, population not always clear  Most studies excluded women with irregular menses  Most studies included only women with > 80 mls MBL

16. Acute AUB  This is an episode of bleeding characterized by significant blood loss in a large quantity to warrant immediate intervention to prevent further blood loss

17. Case Scenario  A 40 yo GO non pregnant woman presents to ER with heavy vaginal bleeding for the past reported 12 days.  On examination her vitals are stable and you observer a moderate amount of bleeding. Her Hgb is 9 g/dl. She is a non-smoker and has an otherwise negative history.

18. Which of the following would not be the best first line treatment for this patient?  A. Dilation and Curettage  B. Conjugated equine estrogen 25mg IV q6 hours  C. Oral contraceptives TID x 1 week  D. Medroxyprogesterone acetate 20mg TID x 1 weeks

19. Estrogen  Use of IV Premarin in the treatment of DUB –Double blind RCT of 34 women  Compared proportion of patients in whom bleeding stopped in response to either 25 mg IV conjugated equine estrogen or IV placebo  In 5 hours, Bleeding stopped in 72% of patients who received IV estrogen therapy and in 38% who received placebo Devors et al 1982

20. COC Tapers/Cascades  Initially based on expert opinion until RCT by Munro et al October 2006  Compared COC taper and oral progestin  16 women in COC group  95% avoided surgery in the next 28 days  Average 3 days to bleeding cessation COC with 35 microgram E2/1mg norethindrone TID x 1 week then qd x 3 weeks Munro et al 2006

21. Oral Progestin  Oral progestin arm of the Munro et al study  All 17 women in MPA group avoided unplanned surgical intervention  65% stopped bleeding at 1 month follow-up with a mean time of 3 days  Medroxyprogesterone acetate 20 mg po tid x 1 week daily x 3 weeks Munro et al 2006

22. Tranexamic acid  Given its mechanism of action ( decreasing fibrinolysis) effective option for Acute AUB  Supported as a rx by experts both (PO and IV)  No studies for acute AUB  Shown to reduce intra-operative bleeding for orthopedic procedures 1.3 grams po tid x 5 days or 10 mg/hg IV q 8h for up to 5 days James et al 2011; Alshyrda et al 2011 Lethaby et al 2000;Lukes et al 2010

23. Case scenario  A 28 yo G0 non-pregnant woman seeks treatment for her heavy irregular bleeding which has been unpredictable for the last few weeks. This patient has a normal baseline transvaginal ultrasound and normal pelvic exam. She has no medical problems.

24. Which of the following are not options for this patient’s bleeding?  A. COC’s  B. Luteal phase progestin ( 10-14) d/cycles  C. LARC-IUDS  D. Trenexamic Acid  E. NSAID’S

25. Combination Oral Contraceptives  For AUB-O: May work by inhibiting the growth and development of the endometrium exogenously cycling hormones  Physiologically makes sense though evidence is limited One RCT compared the efficacy of a triphasic combination COC’s in the treatment of women with irregular bleeding (some heavy, some not) 73.2% of COC group reported bleeding was improved (vs. 39.6% of placebo group) Davis et al 2000 Cochrane Review by Hickey et al, updated 2009

26. Levonorgestrel IUS-(MIRENA)  Suppression of endometrial proliferation, inactive histology, thin endometrium and decidualization of stroma  Most studies only AUB-E  Excluded women with irregular menses suggestive of AUB-O  Probably a good chance for AUB-O as well given its mechanism of action Magnon et al, 2013

27. Levonorgestrel IUS (MIRENA)  LNG-IUS reduces MBL by 715-95%  Most effective best tolerated non-surgical option for heavy and regular menstrual bleeding  Reduction in MBL same for LNG-IUS and extended cycle oral progestin  Patient satisfaction much less for oral progestin  More effective than COC’s, luteal phase oral progestin, DEPO MPA, NSAIDS Matteson et al 2013, Lethabey et al updated 2009 Lee et al 2012, Endrikat et al 2009

28. NSAIDS  Limited studies have shown NSAIDS effective in treating heavy and regular bleeding  No difference between NSAIDS in effectiveness (Naproxen, Mefenamic acid)  Less effective than tranexamic acid  Data limited comparing to luteal phase progestin, LNG IUS, COC’s Cochrane Review by Lethaby et al updated 2009

29. Endometrial Ablation  1 st generation Resectoscopic  Rollerball  Transcervical endometrial resection  2 nd generation; Non-Resectoscopic  Heated fluid (Hydrothermal Ablation)  Thermal Balloon ablation  Microwave  Cryotherapy  Radiofrequency bipolar

30. Global endometrial ablation  Most studies: only heavy and regular bleeding  Satisfaction: 50%-90%  Amenorrhea: 13%-64%  Failure rate: 8%-42% No difference between resectoscopic and global methods in bleeding reduction and QOL Matteson et al; 2012 Dickerson et al 2007, ACOG PB 2007 Penninx et al 2011; Cochrane review by Lethaby et al 2009

31. Success and Failure of Ablations  Predictors of amenorrhea  > 45yo  Uterine length > 9 cm  Endometrial stripe < 4mm  Predictors of failure  < 45yo  Parity greater than or equal to 5  History of dysmenorrhea El-Nashar et al 2009

32. Hysterectomy versus Ablation  Hysterectomy better  Bleeding reduction at 1 year  Satisfaction at 2 yrs post-op  Some evidence of improved health status  Ablation better  Surgery duration, hospital stay and recovery time  Most adverse events ( both major and minor)  Overall “costs” but not cost-effectiveness Dickerson et al 2007; Cochrane review by Lethaby et al 2009

33. Summary Points  Must consider the etiology behind the patient’s heavy bleeding Some treatments:  Effective for irregular bleeding, not regular bleeding  Only studied for regular bleeding-but does that mean the WON’T work for irregular bleeding  Man studies only include patient with confirmed MBL > 80 mls  Research in this area by small sample size variety of comparison groups, limited number of studies

34. Summary Points  Active AUB  IV estrogen, multiple pill regimens of progestin and COC;’s appear to be effective, TCS also effective  AUB-E-Heavy and regular  LNG IUS and ablation-most effective TX  Shown effective-COC’s, TXA, 21 day Progestin, NSAID’s  AUB-O Heavy and irregular  Cyclic COC’s, luteal phase progestin  Limited date on other treatments (most studies excluded irregular bleeders

35. Key references  References listed on slides by author and year of publication  Key references to review:  Systematic Reviews  Clinical Guidelines on Heavy Menstrual Bleeding. National Institute of Clinical Excellence National Collaborating Centre for Women’s and Children’s Health 2007  Matteson KA, Rahn DD. Wheeler TL 2 nd Siddiqui N. Casiano E. Harvey H. Marntik M, Sung VW. Balk EM. Society of Gynecologic Surgeons Systematic Review Group. A systematic review comparing hysterectomy with less-invasive treatments for abnormal uterine bleeding. J Minim Invasive Gynecol 2012 JAN 19 (1) 13-28

36. Key references  Systematic reviews continued  Marjoribanks J. Lethaby A. Farquhar C. Surgery versus therapy for heavy menstrual bleeding. Cochrane Database if Systematic Reviews 2006 Issue 2. Art. No : CD003855 DQI 10. 1001/14651858. CD003855 pub2.  Lethaby A. Shepperd S. Farquhar C, Cooke I. Endometrial resection and ablation verus hysterectomy for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 1999 Issue 2 Art No CD000329 Doi: 10. 1002/14651858 CD000329.  Hickey M, Higham HM, Fraser I. Progestogens versus oestrogens and progestogens for irregular bleeding associated with anovulation. Cochrane Database of Systematic Reviews 2007, Issue 4 Art No: CD001895. DOI: 10. 1002/14651858. CD001895.pub2.  Lethaby A, Irvine G, Cameron I. Cyclical progestogens for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 1998 Ussye 4. Art NO: CD001016.DOI: 10. 1002/14651858 CD001016. (2)

37. Original Research Lukes AS, Moore KA, Muse KN, Gersten JK, Hecht, BR, Edlunc M, et al Tranexamic acid treatment for heavy menstrual bleeding. ARCT Obstet Gynecol 2010, 116 (4) 865-75 Jensen JT, Parks S, Mellinger U, Machlitt A, Fraser IS. Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogist. A RCT Obstet Gynecol 2011; 117(4) 777-87. Munro, MG, Critchley HOD, Broder, MS, Fraser IS. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in non gravid women of reproductive age. Int J Gynecol Obstet 113 (20110, 3-13. Penninx JP, Herman MC, Mol BW Bongers MY. Five-year follow-up after comparing bipolar endometrial ablation with hydrothermal ablation for menorrhagia. Obstet Gynecol 2011 DEC; 118(6) 1287-92