Evaluation of Abnormal Uterine Bleeding: The New Name of the Game Objectives 1) List one condition and its treatment in each PALM-COEIN category. Erin N. Saleeby, MD, MPH Medical Director - California Family Health Council Director, Women s Health Programs and Innovation Los Angeles County Department of Health Services Department of Obstetrics and Gynecology Harbor UCLA Medical Center 2) List three drug treatment options for abnormally heavy uterine bleeding. Acknowledgements & Disclosures A big thank you to Drs. Mike Policar & Ramy Eskander for sharing slide sets I have no financial i relationships to disclose Why is this important? 1/3 of all outpatient gynecologic visits #1 reason for urgent hospital admission for adolescents Affects 50% of menstruating women worldwide at some time 4 out of 5 women with AUB have no anatomic pathologic condition Accounts for 50% of hysterectomies in US A costly issue What is normal uterine bleeding? In dollars: Direct costs of > $12 billion dollars annually In quality of life: Demonstrable reduction in quality of life reported by patients with heavy uterine bleeding Age of patient Frequency Duration Flow 1
What is normal uterine bleeding? Onset of menses By 16 years old with 2 o sex characteristics Start evaluation at 14 years of age if no sexual development Cycle length: 24-35 days Menstrual days: 2-7 days Menstrual flow: 20-80 cc. per menses Average flow: 35 cc. per menses Perception vs. Reality Actual Menstrual Blood Loss Per Cycle Perception of menstrual bleeding Hallberg, L et al, G. Acta Obstet Gynecol Scand 1966;45:320-51. Traditional terminologies Menorrhagia Regular intervals, excessive menstrual blood loss amount >80mL Metrorrhagia Irregular intervals, excessive flow and duration Oligomenorrhea Interval longer than 35 days Polymenorrhea Interval less than 21 days Abnormal Vaginal Bleeding (AVB) Symptom Definitions Abnormal amount of bleeding Menorrhagia (hypermenorrhea) HMB Prolonged duration of menses Increased amount of bleeding per day Hypomenorrhea Shorter menses Less flow per day Cohen BJB et al, Obstetrical and Gynecologic Survey Abnormal Vaginal Bleeding Symptom Definitions ADOPTING A NEW LANGUAGE Abnormal timing of bleeding Frequent bleeds between menses IMB Oligomenorrhea No bleeding 36 days- 3 months Amenorrhea No bleeding for 3 cycle intervals or 6 months (in oligomenorrheic women) AUB - Abnormal Uterine Bleeding HMB - Heavy Menstrual Bleeding IMB - Intermenstrual Bleeding Menorrhagia Metrorrhagia 2
The New Normal : Proposed Terms for Vaginal Bleeding Abnormal Vaginal Bleeding Is the patient pregnant? Is it uterine? Is there a pattern or other associated symptoms? Frasier I, Fertility and Sterility 2007; 87:466-76 Hx, PE, Preg test Abnormal Vaginal Bleeding Hx, PE, Preg test Abnormal Vaginal Bleeding Preg test POS Preg test NEG Preg test POS Preg test NEG Pregnant Pregnant Pelvic Exam Location Viability GA Dating Location Viability GA Dating Uterine bleeding Cervix Non-uterine bleeding Vagina Urethra Anus Non-Uterine Conditions: Cervix Cervix Neoplasms: IMB, PCB, PMB Squamous cell carcinoma Adenocarcinoma Infections: IMB, PCB, HMB Mucopurulent cervicitis iti (chlamydia, gonorrhea, mycoplasma hominis) Benign cervical ectropion: PCB Exposed columnar epithelial cells on ectocervix Red appearance; bleeds to touch Non-Uterine Conditions: Vagina Vaginal inflammation (IMB, PCB, PMB) Atrophic vaginitis Severe vaginal trichomoniasis Trauma/ foreign body Vaginal wall laceration (PCB) Hymeneal ring tear/laceration (PCB) Vaginal foreign body (esp. pre-menarchal bleeding) Vaginal neoplasms Squamous cell cancer, clear cell (DES) Childhood tumors 3
Non-Uterine Conditions: Other Hx, PE, Preg test Abnormal Vaginal Bleeding: Urethra (post-void bleeding) Urethral caruncle Squamous or transitional cell cancer Anus (bleeding after wiping) i External or internal hemorrhoid Anal fissure Genital warts Squamous cell cancer Preg test POS Pregnant Location Viability GA Dating Uterine bleeding Structural Cervix Non-structural Preg test NEG Pelvic Exam Non-uterine bleeding Vagina Urethra Anus FIGO System for AUB, 2011 Structural Non-Structural Munro MG, et al, FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age, Int J Gynecol Obstet (2011) AUB: Structural Conditions P: Endometrial polyp IMB or PCB in 30-50 year old woman A: Adenomyosis Dysmenorrhea, dyspareunia, chronic pelvic pain, sometimes HMB L: Leiomyoma Submucous myoma HMB; rarely IMB AUB: Structural Conditions M: Malignancy and hyperplasia Adenomatous hyperplasia (AH) atypical AH endometrial carcinoma Post-menopausal bleeding Recurrent perimenopausal metrorrhagia Chronic anovulator (PCOS) Leiomyosarcoma Post-menopausal bleeding ENDOMETRIAL POLYPS 4
POLYPS POLYPS Epidemiology Highest in the 4th & 5th decades of life Higher in Premenopausal vs Postmenopausal women (12% vs 6%) Prevalence of 10-24% in patients undergoing biopsy or hysterectomy Risk Factors Hyperestrogenic states Postmenopausal women on Tamoxifen (Up to 35%) Postmenopausal HRT Possibly increased in patients with Lynch Syndrome Presentation POLYPS AUB is the presenting symptom in 64-88% of patients with polyps Many are asymptomatic Endometrial cells noted on cytology 12% had endometrial polyps 2% had polyps + coexisiting diagnosis Clinical Course POLYPS Regression is possible (Usually for polyps < 1cm) Risk of malignancy 5% (95% benign) Higher in Postmenopausal vs Premenopausal women (5.4% vs 1.7%) Higher in bleeding polyps (4.2% vs 2.2%) Diagnostic Evaluation TvUS, SIS, Hysteroscopy (Sensitivity 91%, 95%, 90%) Found on EMB for work-up of AUB MANAGEMENT OF ENDOEMTRIAL POLYPS ADENOMYSOSIS All symptomatic polyps should be removed (Hysteroscopic Surgery) Asymptomatic Premenopausal Women Recommend removal for: Women with risk factor for hyperplasia or malignancy Polyps > 1.5cm Prolapsing polyps Infertility Asymptomatic Postmenopausal Women All polyps should be removed due to increased CA risk 5
ADENOMYOSIS Defined as the presence of endometrial glands and stroma within the myometrium Epidemiology Incidence rate of 20%* More common in parous women Uterine surgery appears to be a risk factor Pathogenesis Endomyometrial invagination vs de novo metaplasia?? Presentation ADENOMYOSIS AUB-HMB Dysmenorrhea NOT a disease of the 4th & 5th decades of life Physical exam reveals enlarged globular uterus Diagnostic Evaluation Definitive diagnosis is by HISTOLOGICAL exam MRI is the most superior imaging modality (Junctional zone) TvUS good imaging study and less expensive (80% sensitivity and specificity) TREATMENT OF ADENOMYOSIS LEIOMYOMA Only Definitive treatment is hysterectomy Uterine Artery Embolization Reduction in uterine size by up to 25% Symptomatic improvement in up to 60% of women at 3-5 yr f/u Endometrial ablation / resection helpful Progestin therapy effective, but symptoms usually return within 6 mos of discontinuation Combine Estrogen/Progestin therapy is of debatable efficacy LEIOMYOMA Definition: Benign monoclonal tumor arising from the smooth muscle of the myometrium. (Malignant transformation on the order of 5/100,000) Epidemiology Most common benign pelvic tumor in female Up to 77% of patient s had myomas on hysterectomy specimen Risk Factors: Race (African Americans > Caucasians; 55% vs 35%) Early menarche Parity decreases risks of myoma formation Obesity, Diet (red meats), Alcohol, Caffeine, Smoking LEIOMYOMA Presenting Complaints: Abnormal Uterine Bleeding Degree of bleeding determined by location of myoma more than size Pelvic Pressure / Pain Bulk symptoms Dyspareunia / Dysmenorrhea Degeneration / Torsion Reproductive Dysfunction 6
Diagnosis LEIOMYOMA Physical exam Imaging TvUS (95% sensitivity), SIS Diagnostic Hysteroscopy MRI Best modality to distinguish between adenomyosis vs leiomyoma vs adenomyoma Best used for pre-op surgical planning HSG Natural History 7-40% regress over 6 months to 3 yrs AVERAGE growth rate 1.2cm/2.5yrs LEIOMYOMA Menopause can lead to shrinkage of some myomas Subtypes Cervical Serosal / Subserosal Intramural Submucosal 0: Intracavitary 1: < 50% Intramural 2: > 50% Intramural TREATMENT OPTIONS FOR LEIOMYOMA MALIGNANCY / HYPERPLASIA Dependent on patient and desires for fertility Dependent on predominant symptomatology Dependent of size and location of the leiomyoma(s) Medical Management MIGS UAE Myomectomy Hysterectomy New ablative technology Hyperplasia: Abnormal proliferation of endometrial glands than may result in progression to cancer or may co-exist with endometrial cancer Simple vs Complex (refers to glandular /stromal architecture) Presence or absence of nuclear atypia MALIGNANCY / HYPERPLASIA Presenting symptom is nearly always abnormal uterine bleeding Diagnosis i made by endometrial sampling Reproducibility between different pathologists can be an issue EMB RESULT: NEOPLASMS Endometrial polyp Simple endometrial hyperplasia Gland proliferation and crowding, but no atypia Reversible with continuous progestin exposure Atypical endometrial lhyperplasia Hyperplasia with nuclear atypia of gland cells Premalignant; often not reversible with progestin Endometrial carcinoma Stromal invasion of malignant glands 7
ENDOMETRIAL CA MANAGEMENT OPTIONS Most common GYN malignancy in the US 50k new cases annually with 8200 deaths Average age is 61yo Type 1 vs Type 2 Adenocarcinoma is the most common type Age distribution 20-34: 1.5% 35-44: 6% 45-54: 19% 55-64: 32.6% 65-74: 22.6% 75-84: 13.5% >85 yo: 4.8% Medical Management Hormonal Progestin treatment Use of Mirena IUD Surgical Management Hysterectomy P A L M Structural Causes AUB C O E I N Non-Structural Causes COEIN: Coagulopathy Clotting factor deficiency or defect Liver disease Congenital (Von Willebrands Disease) Platelet deficiency (thrombocytopenia) with platelet count <20,000/mm 3 Idiopathic thrombocytopenic purpura (ITP) Aplastic anemia Platelet function defects COEIN: Coagulopathy Screen for underlying disorder of hemostasis if any of Heavy menstrual bleeding since menarche One of the following Post-partum hemorrhage Bleeding associated with surgery Bleeding associated with dental work Two or more of the following Bruising 1-2 times per month Epistaxis 1-2 times per month Frequent gum bleeding Family history of bleeding symptoms COEIN: Ovulatory Anovulation Age: peri-menarche and perimenopuse PCOS Stress Hypothyroidism Munro M, Int J Gynecol Obstet (2011) 8
Normal Ovarian Hormone Cycle Estrogen Precipitous drop of E+P Synchronous Universal Withdrawal Bleed Abnormal Ovarian Hormone Cycles Estrogen Amenorrhea Progesterone Progesterone E withdrawal bleed ovulation menses anovulation Menometrorrhagia: heavy, irregular bleeding COEIN: Ovulatory Mainly due to anovulatory bleeding Age-related: peri-menarche, perimenopause Estrogenic: unopposed exogenous or endogenous estrogen Androgenic: PCOS; CAH, acute stress Systemic: Renal disease, liver disease Diagnosis of exclusion HMB/IMB not due to by anatomic lesion, medications, pregnancy COEIN: Ovulatory Hyperthyroidism or hypothyroidism Bleeding can be excessive, light, or irregular Only severe, uncorrected thyroid disease causes abnormal bleeding patterns Normal pattern when corrected to euthyroid 1 o hypothyroidism assoc. with 2 o amenorrhea Low T 4 high TRH high TSH normal T 4 high PRL amenorrhea + galactorrhea COEIN: Endometrial Idiopathic Unexplained menorrhagia Endometritis Post-partum Post-abortal t endometritis Endometritis component of PID In teens, PID commonly presents with abnormal bleeding (menorrhagia, IMB) Any teen with abnormal bleeding + pelvic pain requires bimanual exam to evaluate for PID COEIN: Iatrogenic Conditions Anticoagulants Over-anticoagulation: HMB Therapeutic levels will not cause bleeding problems Chronic steroids, opiates Progestin-containing contraceptives Intrauterine Contraception (IUC) "Normal" side effect PID, pregnancy (IUP or ectopic), perforation, expulsion 9
COEIN: Not Classified TREATMENT OF AUB: Non-structural AVM Myometrial hypertrophy Diagnosis of exclusion AVB: History Is the patient pregnant? Pregnancy symptoms, esp. breast tenderness Intercourse pattern Contraceptive use Is it uterine? Coincidence with bowel movement and wiping, during or after urination Pain or irritation of vagina, introitus, vulva, perinuem, or anal skin AVB: History Is bleeding ovulatory or anovulatory? Bleeding pattern: regular, irregular, none Molimenal symptoms: only in ovulatory cycles Previous history of menstrual disorders Recent onset weight gain or hirsuitism Menopausal symptoms History of excess bleeding; coagulation disorders Current and past medications; street drugs Chronic medical illnesses or conditions Nipple discharge from breasts AVB: Physical Exam General: BMI > 30 Skin: acne, hirsutism, acanthosis nigricans; bruising Breasts: galactorrhea Abdomen: uterine enlargement, abdominal pain Pelvic exam Vulva and perineum Anal and peri-anal skin Speculum: vaginal walls and cervix Bimanual: uterine enlargement, softness, masses AVB: Laboratory Urine highly sensitive pregnancy test Quantitative B-hCG is unnecessary CBC or HgB POCT Find severe anemia; baseline value for observation Platelet estimation (detect thrombocytopenia) TSH, Prolactin Amenorrhea or recurrent anovulatory bleeds only FSH, LH levels are unnecessary 10
Hemostasis evaluation: consult with a hematologist before ordering coag tests!! Kouides PA Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding Fertil Sterility 2005;84:1345 51. AVB: Imaging Studies Mainly for evaluation of ovulatory AUB if no response to treatment or suspect anatomic defect Not useful for demonstrating or excluding hyperplasia in premenopausal women Saline infusion sonogram (SIS) helpful for polyps, sub-mucus myomata 80% sensitivity, 69% specificity compared to hysteroscopy Who Needs an EMB? Purpose: detect endometrial hyperplasia or cancer Menopausal woman Any postmenopausal bleeding, if not using HT Unscheduled bleeding on continuous-sequential hormone therapy Bleeding > 3 mo after start of continuouscombined hormone therapy Endometrial stripe > 5 mm (applies to postmenopausal woman only) Pap smear: any endometrial cells or AGC Pap Who Needs an EMB? Premenopausal Women Major change in bleeding prior bleeding pattern Prolonged HMB/IMB (3 months or more) Chronic anovulation Unexplained post-coital or intermenstrual bleeding Endometrial cells on Pap smear in anovulatory premenopausal woman Abnormal glandular cells (AGC) Pap Abnormal endometrial cells Older than 35 years old < 35 years old with abnormal bleeding AVB: Presentation-based Management HMB IMB Postmenopausal bleeding (PMB) Note: a menstrual calendar will help to differentiate these conditions Management of Acute Bleeds Substitute a pharmacologic luteal phase for missed physiologic luteal phase If minimal bleeding for a few days Rx MPA 10-20 mg QD (or microp, 200 BID) x10d Bleeding stops < 3 days; menses after progestin ended Moderate or heavy bleeding > 3 days Monophasic OC taken BID-TID x 7 days, then daily OC for 3 weeks (or longer) Using OC taper and then stopping is illogical Torrential bleed: surgical curettage (MUA) 11
Mechanism of Chemical Curettage High dose OCs x 7 days Estrogen - E stabilizes EM - P matures EM OCs Progesterone anovulation Oral MPA and COCs for Acute Uterine Bleeding (AUB) Munro MG, et al Obstet Gynecol 2006;108:924-9 40 women with non-anatomic AUB randomized to MPA 20 mg TID, then QD for 3 weeks vs COC (1 mg nor + 35 mcg EE) TID x1 week, QD x3 wks Results Median time to bleeding cessation was 3 days Cessation in 88% OC group, 76% in MPA group Surgery avoided in 100% MPA, 95% COC subjects Compliance similar in both groups Would use again 81% MPA, 69% COC Recurrent HMB Differential diagnosis Endometrial polyp Submucus myoma Coagulpathy: vwd, ITP, liver disease Idiopathic Diagnostic Coag panel: consult with hematologist Saline Infusion Sonography (SIS) Hysteroscopy NOT endometrial biopsy or pelvic US alone Management of Recurrent AUB Pregnancy: cycle with clomiphene or metformin Contraception: cycle with OC Not interested in pregnancy or contraception MPA or microp first 10-14 days each month or every other month if pt prefers fewer menses Place LNG-IUS (Mirena) Consider endometrial ablation if childbearing completed Perimenopausal bleeding Once hyperplasia excluded, the goal is cycle control Low estrogen dose OC Cyclic sequential EPT Recurrent HMB Submucous myoma (fibroids) Medical: OCs, progestins, tranexamic acid LNG-IUS (Mirena) Myomectomy Laparoscopy, hysteroscopy, or laparotomy Uterine artery embolization (UAE) Hysterectomy (VH, LAVH, LASH) GnRH-a (Lupron) is given for 1-3 months only To facilitate surgery by reducing myoma volume To induce amenorrhea to treat severe anemia LNG-IUS and Fibroids Small studies with mixed results Mercorio (2003): 75% persistent menorrhagia Starczewski (2000): 92% reduced bleeding Recommendations Off-label use; may violate precaution regarding cavity depth and distortion of uterine cavity Reasonable to attempt treatment with Mirena Documentation of informed consent content a must 72 12
Tips for IUC Insertion in Women with Fibroids Determine fibroid location by ultrasound Fundal fibroids (intramural, sub-serous) that do not distort uterine cavity do not preclude IUC use Large sub-mucous fibroids, especially in lower uterine segment, contraindicate IUC use Evaluate for other pathology, e.g., polyp Ultrasound guidance may facilitate safe placement No data on efficacy, but probably not compromised with LNG-IUS or with Cu-T if fundal placement Recurrent HMB Idiopathic HMB Oral contraceptives (extended regimen or cycle) NSAIDS (before and during menses) Ibuprofen (400 mg tid), naproxen sodium (275 mg every 6 hours after a loading dose of 550 mg) LNG intrauterine system (Mirena) Tranexamic acid (Lysteda) Endometrial ablation Hysterectomy (VH, LAVH, LASH) Tranexamic Acid (Lysteda) for HMB FDA: treatment of cyclic heavy menstrual bleeding Mechanism of action is antifibrinolytic Use: 1,300 mg (two 650 mg tablets) TID for up to 5 days Contraindications Active thromboembolic disease History or intrinsic risk of DVT Cautions Concomitant therapy with OCs may further increase the risk of blood clots, stroke, or MI Women using CHC should use only if a strong medical need and benefit outweighs risk of TE event Menorrhagia Medical Therapy: Bleeding Reduction with LNG-IUS vs NSAID and Tranexamic Acid Milsom et al. Am J Obstet Gynecol 1991;164:879-83. Meta-Analysis: Mirena vs. Ablation for Heavy Menstrual Bleeding No difference between rates of treatment failures 21.2% LNG-IUS vs. 17.9% endometrial ablation Both methods resulted in similar improvements in quality of life Less need for analgesia/anesthesia in LNG-IUS group Ablation requires additional effective contraception Kaunitz, et al. OG. 2009 May;113(5):1104-16b. 1 st Generation Treatment: Rollerball Endometrial Ablation Technique Hysteroscopy, with fluid distention of endometrium Rollerball electrocautery of EM, fundus in strips Advantages Direct visualization of the endometrial cavity Permits removal of polyps, submucous fibroids Disadvantages Requires general or regional anesthesia Risk of fluid overload, burn injuries, perforation Training and expertise in hysteroscopy 13
Global Endometrial Ablation Bipolar Dessication (NovaSure ) Cryoablation (Her Option ) Thermal Balloon (Thermachoice, Caviturm ) Microwave Endometrial Ablation (Microsulis) Hydrothermal Ablation (Hydro ThermAblator ) Radiofrequency Thermal Balloon Endometrial Ablation vs Hysterectomy Advantages Office procedure or outpatient surgery Very low rate of major complications Rapid post operative recovery period Less time consuming and costly vs hysterectomy Disadvantages Amenorrhea in 50-70%, but >95% have less bleeding May fail over time; 2nd ablation required in 5-10% Reduces fertility, but not highly effective contraception Cervical, endometrial cancer may occur (vs hysterectomy) Postmenopausal Bleeding (PMB) Differential Diagnosis Hormonal Exogenous estrogens: hormone therapy (HT) Endogenous estrogens: acute stress, estrogensecreting ovarian tumor Anatomic Atrophic vaginitis, foreign body Endometrial hypoplasia (atrophy) Endometrial hyperplasia Uterine cancer: endometrial adenocarcinoma, corpus sarcoma Cervical cancer: squamous, adenocarcinoma Postmenopausal Bleeding: Evaluation If not using HT, evaluation is required by either Endometrial biopsy, or Endovaginal ultrasound (normal stripe is < 5 mm) If using HT, endometrial biopsy (EMB) to evaluate Cont Combined -EPT: persistent bleeding > 3 months after HT initiation Cont Sequential -EPT: persistent unscheduled bleeding Single episode of PMB; limited time and volume; explained Observation is an acceptable option If recurrent, endometrial evaluation is mandatory Postmenopausal Bleeding: Management Atrophic vaginitis: topical estrogen Chronic endometritis: + antibiotics Polyp: observe or hysteroscopic excision Depends upon size, persistent bleeding symptoms Cystic hyperplasia or endometrial atrophy Observe or very low estrogen dose CC-EPT Simple endometrial hyperplasia Continuous high dose progestin; re-biopsy in 4 mos Atypical endometrial hyperplasia: hysterectomy Endometrial cancer: hysterectomy + XRT P A L M Structural Causes AUB: HMB/IMB C O E I N Non-Structural Causes 14
References Kaunitz, et al. Meta-Analysis: Mirena vs. Ablation for Heavy Menstrual Bleeding. Obstet Gynecol 2009 May;113(5):1104-16b. Pitkin J. Dysfunctional uterine bleeding. BMJ 2007;334:1110 Munro MG, et al. Oral MPA and COCs for Acute Uterine Bleeding Obstet Gynecol 2006;108:924-9 Dubinsky TJ. Value of sonography in the diagnosis of abnormal vaginal bleeding. J Clin Ultrasound. 2004 Sep;32(7):348-53 Learman LA, et al, Hysterectomy y versus expanded medical treatment for abnormal uterine bleeding: clinical outcomes in the medicine or surgery trial. Obstet Gynecol 2004;103(5 Pt 1):824-33 Daniels RV, Abnormal vaginal bleeding in the nonpregnant patient. Emerg Med Clin North Am. 2003;21(3):751-72 Lethaby A, et al. Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev. 2007;(4):CD000400 15