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

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

Jeanie 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 - More History Question Answer When did her last period start? 10 days ago When was her PMP? How irregular are her periods? 6 weeks ago, usually every 6 - 8 weeks How heavy is the bleeding with most periods? Will sometimes have to change her tampon every hour, has soaked her clothes at times Is this heavy bleeding unusual? Has had heavier periods for almost 2 years, lasting 4 - 5 days

Normal general physical No bruising or petechia Jeanie - More Data Physical Exam Tests ordered Results Ht - 64 in; Wt - 126 BMI - 21.6 BP 106/68; P 70 Pregnancy test Negative Normal general physical No bruising or petechia CBC Coagulation panel TSH - reflex Pending Pelvic exam - normal GC/Chlamydia probe 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 Maturation of endometrium relatively uncomplicated Dependent on estrogen and 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 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

Abnormal bleeding Heavy – Irregular intervals– Prolonged duration > 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

Jeanie - Follow-up Visit 3 days later Tests ordered Results CBC Hgb – 10.6 g/dL Hct – 31% MCV – 76 fl Platelet count 215,000 Coagulation panel PT – 12 sec INR – 1.1 aPTT – 22 sec TSH 1.76 mU/L GC/Chlamydia probe Negative

Definitions 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

Assess for organic pathology 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

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

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

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

Menorrhagia – vWD treatment 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

Probable diagnosis – DUB Jeanie 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

Fran What can reduce her current heavy bleeding? 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?

Terminology/Descriptions Does Fran Have Definition Hypomenorrhea Abnormally reduced menstrual flow Oligomenorrhea Infrequent periods with normal flow Menorrhagia Regular periods with heavy flow Metrorrhagia Irregular periods with normal flow Menometrorrhagia Irregular heavy periods

Terminology/Descriptions 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 Dimension Categories Regularity Irregular Regular Absent Frequency Frequent Normal frequency Infrequent Duration Prolonged Normal Shortened Volume Heavy Light

Terminology/Descriptions Old terminology Regularity Frequency Duration Volume Hypomenorrhea Regular Normal Light Oligomenorrhea Irregular Infrequent Menorrhagia Prolonged Heavy Metrorrhagia Frequent Menometrorrhagia

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?

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

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

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

Oligomenorrhea – Infrequent regular Age Adolescents End of reproductive years Etiology Most often anovulatory Rarely ovulatory

Oligomenorrhea – Infrequent regular Anovulatory etiology Adolescents Failure of established cyclic estrogen pattern due to lack of maturity hypothalamic-pituitary-ovarian (H-P-O) axis

Oligomenorrhea – Infrequent regular Etiology (continued) End of reproductive years Failure estrogen to increase or decrease in a regular manner Estrogen is necessary for target tissue responsiveness Without adequate estrogen, tissues fail to respond to progesterone therapy

Oligomenorrhea – Infrequent regular Treatment No treatment required Medroxyprogesterone (Provera®) 10 mg for 5 days to induce menses If no menses within 5-7 days after completing Provera® Give estrogen prior to repeating progesterone If patient wants regular periods Combination oral contraceptive (OCP) Use if also desires birth control

Fran – more information Answer Vital signs Ht – 67”; Wt – 146 lbs; BMI 22.9 BP 124/76; P 88; T 98.8 (O) Any other symptoms? A little dizzy when standing Contraception Used OCP until 6 months ago Using condoms past 4 weeks Physical exam Normal general exam Pelvic – active bleeding from os Uterus small nontender No adenexal mass

Additional information Tests ordered Results Stat CBC Hgb – 11.6 g/dL Hct – 34% MCV – 76 fl Pregnancy test Negative TSH Results pending GC/Chlamydia probe

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

Regular heavy prolonged bleeding (Menorrhagia) 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 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 bleeding 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

Acute Bleeding - Treatment 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 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

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

Acute Bleeding – Treatment 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 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

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

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

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

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

Fran 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

Joan 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?

Pelvic – uterus 6 week size More information Results LMP PMP Duration of flow 12 days ago 37 days before LMP 8 days PMH: Hypertension Type 2 diabetes Medications: Lisinopril/HCTZ Metformin, ASA Physical exam General exam normal Pelvic – uterus 6 week size Tests ordered CBC TSH Pelvic ultrasound Pap smear

Joan 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?

Irregular Heavy Menstrual Bleeding (Menometorrhagia) 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 menstrual bleeding 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 Heavy Menstrual Bleeding 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 Treatment Combination oral contraceptives To reduce bleeding slowly over several days Give standard OCP dosing To reduce bleeding quickly in 24 hours 1 pill qid for 5-7 days then 1 pill bid for three weeks May need to pre-medicate with antiemetic

Treatment Menorrhagia – EBM For women considering hysterectomy, placement of levonorgestrel-releasing IUD resulted in similar outcomes & was more cost effective InfoRetriever Randomized controlled trial after 5 years found no difference in outcomes (SOR 1b) http://www.infopoems.com/irsearch/search_details.cfm?ID=60625&ResultKey=E&title=Progesterone%20IUD%20effective%20for%20menorrhagia

Summary of MedicalTherapies – Irregular Heavy Prolonged Bleeding Drug Mean reduction blood loss (%) Women benefiting (%) Levonorgestrel IUD 94 100 Oral PG (day 5-25) 87 86 Danazol 50 76 NSAIDs 29 51 OCP 43 Oral PG (day 12-26) -4 18

Joan Follow-up visit CBC Hgb – 11.1 g/dL Hct – 33.4% MCV – 88 fl TSH Tests ordered Results CBC Hgb – 11.1 g/dL Hct – 33.4% MCV – 88 fl TSH 2.6 mU/L (nl – 0.45 – 4.5) Pelvic ultrasound Diffuse uterine enlargement Endometrial stripe < 4 mm Ovaries normal appearance

Menometrorrhagia - EBM Various types of surgery or IUD hormone device are effective in reducing heavy bleeding & suit most women better than oral medications Cochrane Review Controlled randomized trials Surgery reduced bleeding better at 1 yr. than medical therapy & IUD equally effective to surgery Oral therapy suits minority of women http://www.cochrane.org/reviews/en/ab003855.html

Joan Treatment Options Oral contraceptive Will control bleeding & make her regular Not contraindicated NSAIDS Would reduce flow but not effect regularity Progestine IUD Would control flow & frequency Would obviate the need for more invasive procedure Surgical options Ablative therapies would be a reasonable option

Key Points - DUB History determines the pattern & probable etiology Four aspects: Regularity, frequency, duration & volume Always assess for organic etiology Pregnancy test, STDs, infection, etc Assess desire for contraception Oral contraceptive can frequently control the problem

Key Points - DUB Provide medical therapy that is effective and lowest risk for patient NSAIDs usually safe, OCPs, progesterone IUD, then surgery Discuss progesterone IUD for significant bleeding in older women who want to avoid surgery Surgery is final therapeutic option Multiple new modalities are effective

What Questions do you have?

References - Dysfunctional Uterine Bleeding Claessens EA et al. Acute adolescent menorrhagia. Am J Obstet Gynecol 1981;139:277-80. Hurskainen R et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia. JAMA 2004;291:1456-1463. James A et al. Von Willebrand disease and other bleeding disorders in women: Consensus on diagnosis and management from an international expert panel. Am J Obstet Gynecol 2009;201:12. Kaunitz AM et al. Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding. Obstet Gynecol 2010;116:625-32.