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 1 st 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