Abnormal Uterine Bleeding in Reproductive Age Women Charletta Ayers, MD, MPH, FACOG Associate Professor Vice Chair, Department of Obstetrics, Gynecology and Reproductive Sciences Director, Faculty Scholars Program Robert Wood Johnson Medical School Rutgers University

Abnormal Uterine Bleeding Common Clinical Problem 14- 20 % of women affected during reproductive years Impacts quality of life, emotional, sexual, social and financial burden Fraser IS, Langham S, Uhl-Hochgraeber K.Health-related quality of life and economic burden of abnormal uterine bleeding. Exp Rev Obstet Gynecol 2009;4:179-89. Matteson KA, Baker CA, Clark MA,Frick KD. Abnormal uterine bleeding, health status, and usual source of medical care:analyses usingthe Medical ExpendituresPanel Survey. J Womens Health (Larchmt) 2013;22:959-65.

Menstrual Cycle

Abnormal Uterine Bleeding (AUB) Oligomenorrhea - Interval > 35 days Polymenorrhea - Interval < 21 days Menorrhagia regular normal intervals, excessive flow > 80cc blood Metrorrhagia irregular intervals, excessive flow and duration Woolcock JG, Critchley HO, Munro MG, Broder MS, Fraser IS. Review of the confusion in current and historical terminology and definitions for disturbances of menstrual bleeding. Fertil Steril 2008;90(6):2269–80.

Abnormal Uterine Bleeding AUB is defined as bleeding from the uterine corpus that is abnormal in volume, regularity, and/or timing Present for the majority in the past 6 months. Major reason for gynecological procedures Accounts for 2/3 of all hysterectomies Kotdawala P, Kotdawala S, Nagar N. Evaluation of endometrium in peri-menopausal abnormal uterine bleeding

Treatment Options: 38 % of women of women < 40 years of age have unsupported pathology a the time of hysterectomy that are performed for AUB , uterine fibroids, endometriosis or pelvic pain Recommendations: Medical therapy should be offered if appropriate prior to surgical intervention

Abnormal Uterine Bleeding International Federation of Gynecology and Obstetrics (FIGO) Menstrual Disorder Working Group 2011 Definition of Abnormal Uterine Bleeding: Heavy Vaginal Bleeding (HMB) Inter menstrual Bleeding Combination of Both

Abnormal Uterine Bleeding (AUB) Inconsistency in Nomenclature Plethora of Potential Causes 4th most common cause for referral for Gynecological consult in Britain Federation of International Obstetrics Gynecology Association defined nomenclature/ Classification of AUB in 2011 Improve research efforts, clinical protocols PALM-COEI M.G. Munro et al. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age;/ International Journal of Gynecology and Obstetrics 113 (2011) 3–13

PALM-COEIN: AUB Classification System Polyp Adenomyosis Leiomyoma Malignancy Coagulopathy Ovulatory dysfunction Endometrial Iatrogenic Not yet classified M.G. Munro et al. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age;/ International Journal of Gynecology and Obstetrics 113 (2011) 3–13

Abnormal Uterine Bleeding Structural Non-Structural Polyps Adenomyosis Leiomyoma Malignancy & hyperplasia Coagulopathy Ovulatory Endometrial Iatrogenic Not yet classified

Evaluation of AUB is based on whether the bleeding is Acute Chronic

Evaluation of AUB Directed History Physical Examination Laboratory Testing

Evaluation of AUB Directed History Physical Examination Nature of the bleeding- Associated symptoms Chronic medical illness Medications Family History Sexual and reproductive history Physical Examination Laboratory Testing

Evaluation of AUB Directed History Physical Examination Vital signs Neck-Thyroid Abdomen Skin Bimanual exam Rectal as indicated Laboratory Testing

Evaluation of AUB Directed History Physical Examination Laboratory Testing BHCG Complete blood count with platelets Other laboratory testing as clinically indicated TSH Free testerone Prolactin PT/PTTor thrombin time or von Will brand diagnostic panel TVS or SUS Office endometrial biopsy sampling (as clinically indicated) Office hysteroscopy ( as clinically indicated)

Scenario 1 32 y.o. G2P2 with acute onset of abnormal uterine bleeding with menses lasting for 9 days changing her pad q 1 hour PMH negative Medication iron daily BP 110/60 Pulse 110 wt. 56kg Pale appearing female PE unremarkable except for moderate blood in vaginal vault Labs Urine HCG negative Hgb 6.0 PLT 136 Pelvic ultrasound normal

Scenario 1 What is the working diagnosis ? How would you treat this patient?

Medical management recommendation for abnormal bleeding - O IV Conjugated equine estrogen 25 mg IV every 4- 6 hours for 24 hours Contraindicated: Pregnancy, active or previous venous/arterial thromboembolic disease , breast cancer Oral tranexamic acid Multidose combined monophasic OCP Multidose oral progestin GNRh agonist with aromatase inhibitor

Medical management recommendation for abnormal bleeding IV Conjugated equine estrogen Oral tranexamic acid 1.3 g orally every 8 h for 5 d (indicated in ovulatory women with excessive menstrual bleeding) Current or past thromboembolic disease, acquired impaired color vision (cannot be used with combined oral contraceptives) Side effects: Headaches, nausea, vomiting, diarrhea, muscle pain dysmenorrhea Multidose combined monophasic OCP Multidose oral progestin GNRh agonist with aromatase inhibitor

Medical management recommendation for abnormal bleeding IV Conjugated equine estrogen Oral tranexamic acid Multidose combined monophasic OCP monophasic pill 35 mg estradiol 3 times daily for1 week, then daily dosing for 3 wks cyclic monophasic or triphasic oral contraceptive pills, extended or continuous monophasic oral contraceptive pill, transdermal patch or vaginal ring Contraindicated : Pregnant, smoking, CAD, diabetes uncontrolled 4. Progestin 5. GNRh agonist with aromatase inhibitor

Medical management recommendation for abnormal bleeding IV Conjugated equine estrogen Oral tranexamic acid Multidose combined monophasic OCP Multidose oral progestin MPA 20 mg 3 times a day for 7 days orał MPA (2.5-10 mg) norethindrone (2.5- 5 mg), megestrol acetate (40-320 mg), or micronized progesterone (200-400 mg) Without ovulatory dysfunction, take 1 tablet daily starting day 5 for 21 d GNRh agonist with aromatase inhibitor

Medical management recommendation for abnormal bleeding IV Conjugated equine estrogen Oral tranexamic acid Multidose combined monophasic OCP Multidose oral progestin GNRh agonist with aromatase inhibitor 3.75 mg IM monthly or 11.25 mg IM every 3 months Contradictions: Pregnancy Side effects: Hot flashes, sweating, and vaginal dryness(effects minimized with add-back therapy with estrogen and progestins), trabecular bone loss with use for longer than 6 months (reversible)

Abnormal Uterine Bleeding Treatment

Scenario 2 21 y.o. female presents with history of menses q 45 days heavy for 5 days changing a pad every 1-2 hours the first 3 days with clots and flooding. PMhx significant for obesity VS normal wt. 80kg Obese female with noted hirtuism Thyroid normal Obese abdomen and bimanual pelvic exam unremarkable

Scenario 2 What is your working diagnosis? What diagnostic/labs would you order and why ?

Familial Heterogeneous disorder Scenario 2 Polycystic Ovarian Syndrome Familial Heterogeneous disorder Prevalence: 4- 12 % of reproductive women Ghana 518,925 *(estimate) Hyperandrogenism Ovulatory dysfunction Polycystic ovaries *http://www.rightdiagnosis.com/p/pcos/stats-country.htm

Ovulatory Dysfunction Causes Anovulation PCOS Menopausal Transition Hypothyroidism Hyperprolactinemia Mental Stress Obesity Extreme weight Loss Extreme exercise Gonadalsteroids Drugs impacting dopamine metabolism – phenothiazines and Tricyclic antidepressants Unpredictable timing of bleeding and variable flow Luteal out of phase events -absence of predictable progesterone production

Medical Management Recommendation for PCO Combined monophasic OCP Metformin Improving the sensitivity of peripheral tissue to insulin Start with 500 mg daily to a max of 2500 mg per day Weight loss American College of Obstetricians and Gynecologists. Management of acute abnormal uterine bleeding nonpregnantreproductive-aged women. ACOG Committee opinion no. 557. Obstet Gynecol 2013;121:891-6; b Guzick DS, Wing R, Smith D, Berga SL, Winters SJ. Endocrine consequences of weight loss in obese, hyperandrogenic anovulatory women. Fertil Steril 1994;61:598-604.Adapted from

Scenario 3 41 o G4P4 presents with heavy vaginal bleeding past 6 months lasting 6 days. PMHx unremarkable Family history unremarkable PE Female in no acute distress VS normal wt 53 kg Thyroid normal/ Abdomen normal Bimanual exam normal

Scenario 3 What is the appropriate evaluation for this patient ? What is your differential diagnosis?

Scenario 3

Polyp Lesions usually benign Present or absent Atypical or malignant features rare Present or absent

Polyp Identification Dimensions Location Number Morphology Histology

Operative Hysteroscopy

Scenario 3

Leiomyoma Benign fibromuscular tumors of the myometrium Prevalence up to 70% Caucasian and 80- % women with African Ancestry Primary Classification Present or Absent Secondary Involving Endometrial Cavity Tertiary Sub endometrial Submucososal Size Fibroids (leiomyoma) represent the most common tumour of women; by the age of 50, almost 70% of white women and >80% of black women will have developed at least one fibroid Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine leiomyoma in black and white women: ultrasoundevidence. Am J Obstet Gynecol 2003;188:100e7.

Adenomyosis Relationship between adenomyosis and AUB is unclear Prevalence is 5%-70% Endometrial tissue beneath the endometrial –myometrial interface Identified by histopathology by hysterectomy specimen MRI Ultrasound

Scenario 4 49 yo female with menses q 39- 45 for the past 6 months . With her last period lasting 14 days, presents to the office for evaluation. Directed History Labs/Imaging

Transvaginal Ultrasound:

Endometrial Biopsy NICE recommends endometrial sampling in women with Persistent inter-menstrual Bleeding or aged 45 years with treatment failure Excise clinical judgement for those women aged <40 years with HMB at risk for premalignant changes Obesity PCOS NICE. Clinical Guideline 44; Heavy menstrual bleeding 2007. National Institute for Health and Clinical Excellence (NICE); Available at: http://www.nice.org.uk/nicemedia/pdf/CG44FullGuideline.pdf.

Endometrial Biopsy

Malignancy and hyperplasia Relatively uncommon but are important potential causes of AUB Blind endometrial biopsies should no longer be performed as the sole diagnostic strategy in perimenopausal with AUB. A single-stop approach, especially in high risk women (Obesity, diabetes, family history of endometrial, ovarian or breast cancer) combining the office hysteroscopy, directed biopsy in presence of a focal lesion vacuum sampling of endometrium in normal looking endometrium, Midlife Health. 2013 Jan;4(1):16-21 10.4103/0976-7800.109628. Evaluation of endometrium in peri-menopausal abnormal uterine bleeding. Kotdawala P, Kotdawala S, Nagar N.

Endometrial Hyperplasia

Endometrial Hyperplasia Progressing to Endometrial Cancer "In 159 cases (90%), the endometrial histologic results of curettage agreed with those of the Pipelle biopsy. All three cases of endometrial cancer were identified by Pipelle aspiration. In seven cases (4%), the Pipelle aspiration failed to detect hyperplasia. Sonographic endometrial thickness of more than 5 mm slightly increased the sensitivity and slightly decreased the specificity of Pipelle aspiration from 82 to 92% and from 99 to 96%, respectively Goldchmit R. Katz Z. Blickstein I. Caspi B. Dgani R. The accuracy of endometrial Pipelle sampling with and without sonographic measurement of endometrial thickness. Obstetrics & Gynecology. 82(5):727-30, 1993 Nov. Abstract.  Full text available to Fellows, Members and Trainees here. Kavak Z, Ceyhan N, Pekin S. Combination of vaginal ultrasonography and pipelle sampling in the diagnosis of endometrial disease. Australian and New Zealand Journal of Obstetrics and Gynaecology 1996;36(1):63–6. Abstract. Map of Medicine. Endometrial cancer. 2011. Simple Hyperplasia 1% Complex Hyperplasia 3% Simple Hyperplasia w/Atypia 8% Complex Hyperplasia with atypia 29 % Incidence of endometrial cancer -147 per 100,000 women in Ghana

Scenario 5 19 y.o. not sexually active female presents with feeling weak and light headed. Pt with noted menses every 24-28 days lasting 10 days. Pt reports changing her pad q 1 hour and missing school at least 2 days each month. In ER Hgb 5.4 and GYN consult called . Directed history

Coagulopathy Von Will brand Disease World Federation of Hemophilia reports 1 in every 10,00 people has a bleeding disorder worldwide Platelet Function Disorders Obstet Gynecol. 2005 Jan;105(1):61-6. Age and the prevalence of bleeding disorders in woman with menorragia. Philipp CS, Faiz A, Dowling N, Dilley A, Michaels LA, Ayers C, Miller CH, Bachmann G, Evatt B, Saidi P.

Von Willebrand Disease Inherited deficiency or dysfunction of von Willebrand factor Defective platelet adhesions, slightly decreased VIII activity Mild or moderate bleeding tendency in in most type 1 and type II patients Diagnosis: von Will brand antigen, factor VIII, ristocetin cofactor activity , platelet function analysis Treatment: DDAVP (Type1) Intermediate purity factor VII concentrate (types II, III)

Endometrial Causes Disorder of the endometrium Predictable and cyclic menstrual bleeding Ovulatory cycles No other causes defined Deficiencies in local production of vasoconstrictors - endothelin -1 and prostaglandin F2alpha Accelerated lysis of endometrial clot secondary to excessive production of plasminogen activator Increased production of prostaglandin E2 and prostacyclin which increase vasodilation Infection/endometrial inflammation – not well defined

Not yet explained Unclear etiology of bleeding Diagnosis of exclusion

Assessment of AUB Evaluation is necessary for AUB in a perimenopausal Woman Determine Bleeding is from cervical canal R/O Pregnancy/ Other source of bleeding R/O Anemia - Full Blood Count including platelets Determination of ovulatory status Screening for systemic disorders Structured History

Evaluation of the endometrium TVUS Endometrial sampling –Hysteroscopy Cultures as needed Evaluation of the endometrial cavity TVUS 100% sensitive for polyps Office hysteroscopy Myometrial evaluation TVUS and transabdominal ultrasound Determine relationship of myoma to the cavity and myometrium MRI – not practical as a routine test

Summary Reproductive females with AUB need evaluation Evaluate and examine Base testing and treatment options on presumed/confirmed etiology of the AUB

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Medical Therapy Combined OCP Progesterone Levonorgestrel intra-uterine device Tranexamic acid Reduce blood loss by 34% to 59% Antinflammatory medication– Naproxen/Mefenamic acid Reduce bleeding by 22% - 46% Androgens Limit 6 months Decrease bleeding up to 80% GnRH agonist

Workup History Exam Directed Lab work up CBC/ Ferritin Prolactin TSH PAP Endometrial Biopsy Ultrasound Saline sonohystogram

Iatrogenic Medical intervention or devices causes AUB IUD 25% of women complained of spotting in first 6 months of use Gonadal steroid therapy –breakthrough bleeding