Herbert L. Muncie, Jr., M.D.

1. Abnormal Uterine Bleeding (AUB) / Dysfunctional Uterine Bleeding (DUB) Herbert L. Muncie, Jr., M.D.

2. The main issues! How to control current bleeding? How to prevent future abnormal bleeding?

3. 16 year old comes in complaining of irregular heavy periods for 2 years • No medical problems and using condoms for contraception since she became sexually active 3 months ago • What can reduce current heavy bleeding? • Not currently bleeding • What can reduce her risk of future irregular heavy bleeding? Jeanie

4. Jeanie - More History

5. Interval between cycles – 21 - 28 days • Proliferative (follicular) phase – 7 - 21 days • Secretory (luteal) phase – 14 ± 2 days • Bleeding duration – 2 - 6 days • Average blood volume lost - 45 ml Jeanie - More Data

6. Maturation of endometrium relatively uncomplicated • Dependent on estrogenand progesterone • First half of cycle is estrogen- dominant • Halts menstrual flow & promotes proliferation (proliferative or follicular phase) • Second half is progesterone dominant • Stops endometrial growth, then promotes differentiation (secretory or luteal phase) Normal Menstrual Cycle

7. Interval between cycles – 21 - 28 days • Proliferative (follicular) phase – 7 - 21 days • Secretory (luteal) phase – 14 ± 2 days • Bleeding duration – 2 - 6 days • Average blood volume lost - 45 ml Normal Menstrual Cycle

8. Heavy – • > 80 ml blood loss with period • Doubtful clinical utility or significance • Changing pad > q 1 h at some point • Soaking through to her clothes • Irregular intervals– • > 35 days or < 21 days between periods • Prolonged duration • Flow > 7 days Abnormal bleeding

9. Jeanie - Follow-up Visit 3 days later

10. Dysfunctional uterine bleeding (DUB) - abnormal bleeding with no organic cause (neoplasm, inflammation, infection or pregnancy) but which can co-exist with organic pathology Abnormal uterine bleeding (AUB)- includes DUB and bleeding from structural or organic causes Definitions

11. History • Physical exam including pelvic • Diagnostic tests - • Pregnancy test • PAP smear if indicated • CBC, TSH, coagulation panel • Chlamydia, gonorrhea probe • Pelvic/transvaginal ultrasound • Endometrial biopsy in women over age 35 • Only 2% of endometrial cancers occur in women < 40 years old Assess for organic pathology

12. DUB & Bleeding Disorders • Screening for von Willebrand (vWD) disease with heavy menstrual bleeding? • ACOG recommends screening adolescents with severe menorrhagia, women whom abnormal bleeding etiology cannot be established & women undergoing hysterectomy • However, not sufficient evidence that it helps • 1% prevalence in general population

13. DUB & Bleeding Disorders • Case finding with heavy menstrual bleeding • Up to 16% have vWD [James 2009] • Consider if any of the following: • Menorrhagia since menarche • Minor wound bleeding > 5 minutes • Bleeding oral cavity/GI tract without anatomic lesion • Prolonged bleeding after dental extraction • Unexpected postsurgical bleeding

14. DUB & Bleeding Disorders • Case finding evaluation • Order CBC, PTT, PT & vWF level (ideally during menses) • No single test will establish the diagnosis • Positive family history usually necessary • Ask about any bleeding with dental procedures, T&A, peripartum bleeding • OCPs can mask type 1 vWD but don’t stop them • Patients with type O blood have 25 – 30% lower levels of vWF • In these patients with a lower level, a family history would be needed to confirm or exclude the diagnosis

15. If caused by vWD & not trying to get pregnant • Oral contraceptive would be treatment of choice • Progestin IUD alternative • Desmopressin (DDAVP®) or antifibrinolytics if pregnancy desired • Avoid NSAID with symptomatic vWD Menorrhagia – vWD treatment

16. Probable diagnosis – DUB • vWF ordered to be drawn during next menses • vWF results – 35 IU/dL (low but not diagnostic) • No family history or bleeding • What can reduce her risk of future irregular heavy bleeding? • Because combination oral contraceptives (OCP) are not contraindicated • She was started on a monophasic OCP to decrease her flow and regulate her cycles Jeanie

17. A 23 year old woman complaining of heavy menstrual bleeding. Her period started 2 days ago & today is very heavy. She has to change her tampon at least every hour. • She has no medical problems • Periods are usually regular • What can reduce her current heavy bleeding? • What can she do to reduce her risk of future heavy bleeding? Fran

18. Terminology/Descriptions

19. There has been a lack of uniformity in definitions and descriptions of menstrual bleeding abnormalities • February 2005, 35 international MDs met in Washington DC to define terms • Settled on 4 key menstrual dimensions for description Terminology/Descriptions

20. Terminology/Descriptions

21. Terminology/Descriptions

22. Is It Ovulatory or Anovulatory? • With any abnormal bleeding it is helpful to determine if it is ovulatory or anovulatory • Most DUB is anovulatory • In adolescents ovulatory cycles may take up to 3 years to be established • How can you determine if it is ovulatory or not?

23. Normal Ovulatory Cyclic Function • Depends on regular pulsatile release of GnRH from hypothalamus • Which stimulates FSH & LH pulses from anterior pituitary • Pulsatile FSH & LH leads to: • Folliculogenesis (proliferative or follicular phase) • Ovulation • Corpus luteum formation which sustains luteal phase (luteal phase) • Atrophy of corpus luteum results in menses

24. Is It Ovulatory or Anovulatory? Estrogen FSH LH Progesterone Menstruation Day 14 Luteal phase Follicular phase

25. Is It Ovulatory or Anovulatory? • Anovulatory cycles • irregular intervals • no ovulatory pain • serum P4 < 3 ng/ml • 2nd half cycle • monophasic BBT • Serum LH < 25 mIU/ml • Ovulatory Cycles • regular intervals • mittelschmerz • serum P4 > 3 ng/ml • 2nd half cycle • biphasic BBT • Serum LH > 25 mIU/ml

26. Fran – more information

27. Additional information

28. Indicative of Heavy bleeding • Soaking through pad or tampon < 1 hour • Soaking through bed clothes • Below normal ferritin • Anemia • [James 2009]

29. Age • Any age • Etiologies • Anovulatory in younger & older women • Immature hypothalamic-pituitary-ovarian axis in adolescents • Fluctuating estrogen levels each end of reproductive age • Typically due to anatomic lesion (e.g. fibroid) in women 30 – 50 years old Regular heavy prolonged bleeding (Menorrhagia)

30. Etiologies • Ovulatory – either: • Corpus luteum insufficiency • Inadequate progesterone from primary ovarian failure or central/metabolic defect • Corpus luteum prolonged activity • Over stimulation of LH - irregular shedding • Do not have 14 day luteal phase Regular heavy prolonged bleeding

31. Etiologies • Up to 20% adolescents have bleeding disorder as etiology [Claessens 1981] • Consider Von Willebrand disease especially with family history of bleeding • If isolated prolonged PTT or normal PTT, PT, platelet count & fibrinogen with bleeding then specific test for VWD indicated Regular heavy bleeding

32. Outpatient treatment • Start monophasic OCP • 1 pill QID for 4 days • 1 pill TID for 3 days • 1 pill BID for 2 days then • 1 pill a day for 3 weeks • If OCP contraindicated cycle with Provera® • Give 10 mg daily for 14 days, then stop for 14 days • Continue this cycle for 3 months Acute Bleeding - Treatment

33. Outpatient treatment • Oral conjugated estrogens (Premarin®) 2.5 mg QID until bleeding is controlled • Consider giving antiemetic with medication • D&C if no response after 2 - 4 doses or sooner if needed Acute Bleeding –Treatment

34. What can reduce her current heavy bleeding? • Started on combination OCP 1 pill qid for 4 days • Bleeding subsided significantly in 12 hours Fran – 23 year old

35. Inpatient treatment • Conjugated Estrogens (Premarin®) 25 mg IV Q 4 H until bleeding is controlled • Give antiemetic prophylactically • D&C if no response after 2 - 4 doses or sooner if needed Acute Bleeding – Treatment

36. Inpatient treatment • Simultaneous with IV Conjugated Estrogens (Premarin®)start monophasic OCP • 1 pill QID for 4 days • 1 pill TID for 3 days • 1 pill BID for 2 days then • 1 pill a day for 3 weeks • If OCP contraindicated cycle with Provera® • Give 10 mg daily for 14 days, then stop for 14 days • Continue this cycle for 3 months Acute Bleeding - Treatment

37. After the acute bleeding is controlled. • What can she do to reduce her risk of future heavy bleeding? Fran

38. Evaluation • ACOG does not recommend routine CBC, TSH or prolactin • Endometrial sampling rarely necessary since regular bleeding is less concerning for endometrial cancer Regular heavy bleeding

39. NSAIDs • Inhibit prostaglandin which increases platelet aggregation • Increase uterine vasoconstriction • Mefenamic acid (Ponstel®) 500 mg tid had 30-50% decrease in flow • Naproxen 375 mg bid effective Menorrhagia - Treatment

40. Tranexamic acid (Lysteda®) • Two 650 mg tablets tid • Stabilizes a protein that helps blood clot • Concern about increased risk of clots has not been confirmed in ongoing studies • Caution if combined with oral contraceptive • Contraindicated with history or increased risk of thrombosis or VTE Menorrhagia - Treatment

41. Treatment • Danazol 200 mg qd acceptable short-term • Synthetic androgen, suppresses LH & FSH which suppresses ovulation • Can start low 100 mg/d & titrate up • Rare side effects if < 600 mg/d Menorrhagia - Treatment

42. Treatment • Levonorgestrel-releasing IUD (Mirena®) • Improved health quality of life [Hurskainen 2004] • Reduces blood loss more than NSAID, Danazol, OCPs, oral progesterone [Kaunitz 2010] Menorrhagia

43. Unlikely to be beneficial • Oral progesterone (longer cycle) • Likely to be ineffective or harmful • Oral progesterone (luteal phase) Menorrhagia – treatment

44. What can she do to reduce her risk of future heavy bleeding? • Because she did not want to become pregnant & had no contraindications to OCP • She was started on a monophasic combination OCP & will return in 3 months • She was given a prescription for mefenamic acid to be used if her next period was heavy Fran

45. 47 year old female with hypertension & type 2 diabetes • Complains of irregular heavier periods for the past 7 months • Married, non-smoker, BTL at age 32 • Ht 63”; Wt 187 lbs; BMI 30.5; BP 146/92; P 74 • What other information do you need? • What tests do you want to order? Joan

46. More information

47. Probable diagnosis is anovulatory DUB • Probably perimenopausal etiology • What can be done about the irregular menses? • What can be done to decrease the duration and excessive flow? Joan

48. Etiology • Get decrease in estrogen & cannot initiate LH surge, therefore anovulatory • FSH level > 40 IU/L suggest impending ovarian failure • LH-FSH ratio > 2 compatible with chronic anovulation Irregular Heavy Menstrual Bleeding (Menometorrhagia)

49. Treatment • None medically required if that is only issue • OCPs will regulate menses if patient wants birth control & no contraindications • If OCP contraindicated cycle with Provera® • Give 10 mg daily for 14 days, then stop for 14 days • Continue this cycle for 3 months • Postmenstrual bleeding – “endometritis” • Doxycycline 100 mg bid for 10 days Irregular menstrual bleeding

50. Treatment – for non-acute active bleeding • Therapy indicated for these patients: • Bleeding > 7 days • Anemia from blood loss • Interferes with normal life activities Irregular Heavy Menstrual Bleeding