Abnormal uterine bleeding

1. Abnormal uterine bleeding Leslie Ablard, M.D.

2. Quiz • 1. True or False • Most women would say periods are AWESOME!! • FALSE • 2. True or False • ABNORMAL periods are even more AWESOME!!! • FALSE

3. Definitions • Normal menstrual cycle • Interval: 28 +/- 7 days (21-35 days) • Can change from cycle to cycle • Length </= 7 days • Flow: Avg blood loss: 35ml (20-60ml) • Menorrhagia • Prolonged – more than 7 days • or • Heavy – greater than 80ml/day • CYCLIC menstruation • Aka “hypermenorrhea”

4. Definitions • Menometrorrhagia • Prolonged or heavy with breakthrough bleeding • Polymenorrhea • Bleeding occuring at intervals <21 days • Oligomenorrhea • Intervals between bleeding episodes vary from 35 days to 6 months

5. Definitions • Amenorrhea (Secondary) • No menses for 6 months or more

6. It’s Common! • Estimated 10 million women in the US • Over 2 million seen each year for menstrual abnormalities • 1/3 of gyn visits • Most common cause of emergency gyn hospital admission • Most common reason for hysterectomy • Commonly mismanaged!!!

7. Etiology • Pregnancy • Hormonal Imbalance (hypothal/pit/ovary) • Hemostatic Disorders (systemic vs local) • Reproductive Tract Pathology • Iatrogenic

8. Pregnancy • Ectopic • Spontaneous/Incomplete Abortion • Gestational Trophoblastic Disease • “Normal Pregnancy” • DON’T FORGET THE PREGNANCY TEST (you will look stupid)

9. Hormonal • Anovulation/Oligo-ovulation • PCOS/Obesity • 20% PCOS have normal BMI • Menarcheal/Perimenarcheal- immature HPA • Fully active in fetal life, suppressed in childhood, and then reactivated • Perimenopausal • insensitive ovarian follicles

10. Hormonal • Anovulation/Oligo-ovulation • Thyroid/Prolactin disorder • TRH induced increases in Prolactin- inhibits pulsatile GnRH • Hypothalamic Disorders • Anorexia, exercise induced, gonadotropin deficiency, POF • Drugs- hypothalamic depressants, steroids, herbs • Anti-dopaminergic meds- take away inhibitory dopamine on prolaction- inhibits pulsatile GnRH

11. Systemic Hemostatic Disorders • Inherited disorders • Von Willebrand disease • Hemophilias • Acquired disorders • ITP/TTP • Liver Disease • Leukemia • Iatrogenic • Anticoagulants • ASA/NSAIDS

12. Iatrogenic Causes • Medications • Hormonal • Non-hormonal • Procedures • D&C • Devices • Copper IUD (Paraguard) • Levonogestrel IUD (Mirena)

13. Reproductive Tract Disorders • Uterine Lesions • Endometrial polyps • Submucosal polyps • Endometritis • Adenomyosis • Hyperplasia or cancer

14. Anovulation or Oligo-Ovulation • Pathophysiology • In a reproductive age patient who is not having regular menses, must determine if • 1. Progesterone Deficient • 2. Estrogen and Progesterone Deficient

15. Anovulation or Oligo-Ovulation • Patholophysiology • LACK OF PROGESTERONE • Estrogen production with lack of progesterone leads to unopposed estrogen stimulation of the endometrium • Can result in irregular shedding of the endometrium resulting in unscheduled/heavy bleeding • Potential for development of endometrial hyperplasia or cancer.

16. Anovulation or Oligo-ovulation • Pathophysiology: • lack of ESTROGEN and PROGESTERONE • Lack of estrogen AND progestin in reproductive age women can lead to osteoprorosis, increased risk for heart disease, and reduced quality of life • Examples: anorexia nervosa, athletic amenorrhea, premature ovarian failure

17. Anovulation or Oligo-Ovulation • Progestin Challenge • Purpose: • Assess endogenous estrogen status of the patient • Is there estrogen present • From peripheral conversion (estrone) • Or Ovaries • Types: • Medroxyprogesterone acetate (Provera, MPA) 10mg for 10-12 days • Progesterone in oil 100-150mg IM • Norethindrone acetate (agestin, NETA) 5mg for 10-12 days

18. Endometrial Cancer • Most common gynecologic malignancy: est 40,100 cases/ 7,470 deaths in 2008 • Most patients between ages of 50-59 • 25% prior to menopause • 5% before age 40 • 75% stage 1 disease

19. Endometrial Cancer- Preventable • Estrogen Excess!!!! • Perimenopausal with estrogen excess • PCOS • Obesity • Postmenopausal with continued estrogen production from ovary/peripheral conversion of androstendione to estrone • TREAT WITH PROGESTINS OR PROGESTIN DOMINANT FORMULATIONS (OCs)

20. Rembember……… • Many perimenopausal patients are PROGESTRONE deficient, NOT estrogen deficient!!!

21. Management • Medical management of Profuse Bleeding • Very few published randomized trials • Estrogen only • Progestin only • Estrogen + Progestin

22. Management • Use of IV Premarin in tx of DUB • a double blind randomized controlled study • Only randomized trial assessing IV estrogen in tx of acute bleeding • 34 randomized to IV placebo solution vs IV conjugated equine estrogen (premarin) 25mg IV q 4 hrs • At 5 hrs, bleeding stopped in 72% in CEE group vs 38% in placebo group (p= 0.021) • DeVore et al: Obstet Gynecol 1982; 59: 286-91

23. Management • High dose MPA for tx of DUB in 24 Adolescents • Hospitalized for excessive uterine bleeding • Given 60-120mg MPA on day one, followed by 20mg/day x 10 days • All stopped bleeding within 4 days • Aust N Z Obstet Gynaecol 1997; 37: 228-31

24. Management • Oral MPA and Combination OCs for Acute Uterine Bleeding • Presented with acute uterine bleeding requiring emergent medical or surgical intervention • 40 subjects randomized to a 7 day treatment of • MPA 20mg TID • OCPs (1mg NTE/35 mcg EE) TID • Doses reduced to once a day for the next 3 weeks

25. Management • Patient characteristics: avg age 43, BMI 30, mean hgb 8.0 • Only one patient required surgical intervention (D&C for acute bleeding in OCP group) • Median # days to cessation of bleeding: 3 days in both groups • Cessasion of bleeding by 2 week visit in 76% in MPA and 88% in OCP group

26. Management • Mean satisfaction scores were similar • Would use medication again for bleeding if necessary • 81% in MPA group • 69% in OCP group • Median scores for bloating/cramping/nausea did not differ • Munro et al Obstet Gynecol 2006; 108: 924-9

27. Management • Progestins • High dose MPA 20mg TID • High dose NTE 5mg TID • Estrogen + Progestins (OCPs)

28. Anovulatory bleeding • PROGESTINS!!!!! • Progestins alone • Combination OCPs • Depo Provera (MPA) • Clomiphine Citrate (Clomid) or other ovulation inducing medication if pregnancy desired

29. Anovulatory Bleeding • Cyclic Progestins • MPA 10mg • NTE 5mg • Patient instructed to take for 14 days every month. Can decrease interval over time

30. Anovulatory Bleeding • Cyclic Progestins • Warn the patient that bleeding may be heavy initially but will decrease over time • Explain reason for treatment: prevention of episodic irregular/heavy bleeding and CANCER • Can modify timing of progestin therapy around activities/ events for convenience

31. Anovulatory Bleeding • OCPs • If no bleeding in over a month, consider progestin withdrawl (NETA 5mg x 12 days) before initiating OCPs to shed thickened endometrium (began OCPs on day 3 of bleeding) • Also effective in treating associated problems (acne, hirsutism)

32. Anovulatory Bleeding • DMPA (Depo Provera) • Menstrual changes occur in almost all users • Most experience unpredictable bleeding patterns in the first few months of use • ¼ will discontinue in the 1st yr for irregular bleeding • With continued use, frequency and length of bleeding episodes decreases with most becoming amenorrheic over time • ¼ will not resume regular menses for up to 1 yr

33. Ovulatory Hypermenorrhea • Uterine bleeding controlled by prostaglandins • Abnormal prostaglandin levels in the endometrium can lead to excessive bleeding • Decrease in prostaglandin F2alpha (vasoconstrictor) and thromboxane (platelet aggregator) • Increase in prostaglandin E2 (vasodilator) and prostacyclin (platelet inhibitor)

34. Ovulatory Bleeding • NSAIDs • OCPs • Oral Progestins • DMPA • Danazol • GnRH (Lupron) • Anti-fibrinolytic agents • Progestin IUD (Mirena)

35. Ovulatory Bleeding • NSAIDs • Several studies show reduction in blood loss • Less effective than other medical modalities • Ibuprofen 800mg 3-4 x day • Naproxen sodium 550mg 3 x day • Mefenamic acid 500mg 3 x day • Meclofenamate 100mg 3 x day • Beginning day prior to or first day of menses for 3-5 days

36. Ovulatory Bleeding • Continuous OCP use (no 7 day break) should be considered as many will have unacceptable withdrawl bleeding if given 21/7 • If breakthrough bleeding on continuous OCPs, stop 3 days and then restart (3 day 90% effective in resolving BTB) Sulak et al Am J Obstet Gynecol 2006; 195: 935-41

37. Ovulatory Bleeding • Oral Progestins • MPA 10-20mg/day or NETA 5-15mg/day • Higher doses/longer intervals of cyclic progestins • Required for tx of menorrhagia as compared to anovulatory bleeding • NETA 5mg BID x 21 days starting cyle day #7 • Continuous Progestins • Without a break • NETA 5mg daily starting on day 3 of cycle, don’t take a break unless breakthrough bleeding, stop 3 days and restart or give in 24/4 fashion for predictable bleeding each month.

38. Ovulatory Bleeding • DMPA (Depo Provera) • Dose 150-250mg IM every 2-3 months • Disadvantage- high incidence of irregular bleeding

39. Ovulatory Bleeding • GnRH agonists (Lupron) • MOA: inhibits ovulation and ovarian steroid productions, inducing amenorrhea • Dose: 3.75mg IM every month or 11.25mg IM every 3 months • Often benefits short term for induction of amenorrhea and to correct severe anemia • Consider simultaneous norethendrone 5mg/d • Disadvantage to long term use • Expense • Hypoestrogenic state- need for add back for prevention of side effects

40. Ovulatory Bleeding • Antifibrinolytics • (Tranexamic Acid- Lysteda) • Approved by the FDA in the US in 2009 for tx of heavy menstrual bleeding • Commonly used throughout the world (OTC in some countries) • Effective in reducing menstrual blood loss (50%) • Concern about thromboembolic events has not been substantiated in recent studies

41. Ovulatory Bleeding • Progestin IUD (mirena) • Effective in reducing mean blood loss • Approved by FDA for treatment of heavy menstrual bleeding october 2009 • 80-90% report reduction in blood loss after 6 months, approx 30% amenorrheic

42. DUB and Fibroids • NSAIDs • Combination OCPs • Oral progestins • DMPA • Dnazol • GnRH agonists • Antifibrinolytic agents • Medicated IUDs • Selective Progesterone Receptor Modulators • Antiprogestational agents • Aromatase inhibitors

43. Procedures/Surgery • Endometrial Ablation • Hysteroscopic resection/ablation • Non-hysteroscopic ablation • Uterine Artery Embolization • Hysterectomy

44. Key Points • Many patients are progesterone deficient • Most endometrial cancer is preventable • Anovulatory bleeding is easy to treat with low dose cyclic progestins • Ovulatory bleeding can be difficult to treat (high dose progestins) unless patients can take continuous OCPs or use Mirena • If acute, profuse bleeding, consider high dose progestin therapy

45. Conclusions • Most DUB can be medically managed- today we have more options • Endometrial ablation/resection offers an alternative to hysterectomy • Most endometrial cancer is preventable- must identify those at risk and TREAT!!! (biopsy first)

46. THANK YOU