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Evaluation and Management of Abnormal Uterine Bleeding

      Abstract

      Abnormal uterine bleeding (AUB) is a common condition that leads to increased health care costs and decreased quality of life. A systematic approach to AUB evaluation can simplify management and enhance women’s well-being. Abnormal uterine bleeding describes any variation from normal bleeding patterns in nonpregnant, reproductive-aged women beyond menarche lasting for at least 6 months. Ambiguous and inconsistent use of terminology and definitions to characterize AUB in the past decades necessitated a new, consensus-based approach to nomenclature and AUB evaluation. This led to the International Federation of Gynecology and Obstetrics (FIGO) System 1 in 2007, which standardized nomenclature, set parameters, and defined normal and abnormal bleeding based on the 5th to 95th percentile data from available large-scale epidemiologic studies. FIGO System 1, endorsed by several national and international societies, improved worldwide communication among educators, clinicians, and researchers. FIGO System 2, published in 2011, focused on classifications of AUB etiology into structural and nonstructural entities using the PALM-COEIN (polyp[s], adenomyosis, leiomyoma, malignancy, coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic, and not yet classified) classification system. The PALM-COEIN classification is facilitated by a complete patient history combined with appropriate imaging, histopathologic analysis, or laboratory evaluation to ensure accurate diagnostic and treatment approaches to AUB. Herein we present the systematic evaluation of AUB.

      Abbreviations and Acronyms:

      AUB (abnormal uterine bleeding), BTB (breakthrough bleeding), EIN (endometrial intraepithelial neoplasia), FIGO (International Federation of Gynecology and Obstetrics), GnRH (gonadotropin receptor hormone), HMB (heavy menstrual bleeding), IUD (intrauterine device), IV (intravenous), LNG IUS (levonorgestrel intrauterine system), MgFUS (magnetic resonance imaging–guided focused ultrasound), MRI (magnetic resonance imaging), NSAID (nonsteroidal anti-inflammatory drug), OCP (oral contraceptive pill), PALM-COEIN (polyp(s), adenomyosis, leiomyoma, malignancy, coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic, and not yet classified), SERM (selective estrogen receptor modulators), SIS (saline infusion sonohysterography), SPRM (selective progesterone receptor modulator), TVUS (transvaginal pelvic ultrasound), UAE (uterine artery embolization), vWF (von Willebrand factor)
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      Learning Objectives: On completion of this article, you should be able to (1) identify the most common etiologies of abnormal uterine bleeding in nongravid premenopausal women; (2) better understand the ideal imaging and testing required to evaluate abnormal uterine bleeding; and (3) begin management of abnormal acute and chronic bleeding.
      Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine and Science (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation. In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Jenna M. Pederson, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Laughline-Tommasco is a consultant for Allergan (for SPRM medication mentioned in text--no brand name mentioned). Dr Marnach reports no competing interests.
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      Abnormal uterine bleeding (AUB), a frequent reason for outpatient and emergency department visits in reproductive-aged women, may substantially affect quality of life. Evaluation and management of AUB incurs high health care costs, especially when including the common use of hysterectomy.
      • Showstack J.
      • Lin F.
      • Learman L.A.
      • et al.
      Randomized trial of medical treatment versus hysterectomy for abnormal uterine bleeding: resource use in the Medicine or Surgery (Ms) trial.
      Fortunately, AUB can often be managed with safe, effective, and noninvasive medical treatments focused on the source of bleeding. Hormonal contraceptives remain a common medical therapy, and the 52-mg levonorgestrel intrauterine system (LNG IUS) is increasingly used to effectively manage troublesome bleeding before a surgical approach. The etiology in reproductive-aged women is almost always benign; however, evaluation and research into AUB was limited by the inconsistent use of terminology and documentation of etiology. The International Federation of Gynecology and Obstetrics (FIGO) Systems 1 and 2 were created to provide clear terminology and nomenclature to globally facilitate the accurate diagnostic and effective treatment approaches to AUB.
      • Munro M.G.
      • Critchley H.
      • Fraser I.S.
      Research and clinical management for women with abnormal uterine bleeding in the reproductive years: more than PALM-COEIN.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      In 2007, FIGO introduced System 1, with standardized definitions and concise terminology for AUB in nonpregnant women.
      • Munro M.G.
      • Critchley H.
      • Fraser I.S.
      Research and clinical management for women with abnormal uterine bleeding in the reproductive years: more than PALM-COEIN.
      Menorrhagia, metrorrhagia, and oligomenorrhea were replaced with the nomenclature heavy menstrual bleeding (HMB), intermenstrual bleeding, and unscheduled bleeding or breakthrough bleeding (BTB) on hormone medication.
      • Munro M.G.
      • Critchley H.
      • Fraser I.S.
      Research and clinical management for women with abnormal uterine bleeding in the reproductive years: more than PALM-COEIN.
      The FIGO System 2 acronym PALM-COEIN (polyp[s], adenomyosis, leiomyoma, malignancy, coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic, and not yet classified) systematically defines the most common etiologies for AUB with structural (PALM) and nonstructural (COEIN) causes of AUB.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      The FIGO classification for AUB refers to reproductive-aged, nonpregnant women, so the first step is to evaluate for pregnancy and address whether a woman is premenopausal and postmenarche. Bleeding before menarche, after menopause, and during pregnancy requires different evaluations and is not addressed in this review. In addition, a thorough history will help distinguish gynecologic causes of bleeding from those with urinary or gastrointestinal etiologies.
      FIGO System 1 describes the 4 parameters of menstrual bleeding: regularity, frequency, duration, and volume. Normal menstrual bleeding is defined as cycles that occur every 24 to 38 days, with duration of bleeding up to 8 days.
      • Munro M.G.
      • Critchley H.
      • Fraser I.S.
      Research and clinical management for women with abnormal uterine bleeding in the reproductive years: more than PALM-COEIN.
      Regular menstrual bleeding should be 9 days or less in variation from the beginning of one menses to the beginning of the next one; however, this is age dependent so that women between 26 and 41 years old should have variation of 7 days or less in menstrual cycle length.
      • Munro M.G.
      • Critchley H.O.D.
      • Fraser I.S.
      for the FIGO Menstrual Disorders Committee
      The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions.
      For frequency terminology, amenorrhea is when menses are absent or a woman experiences no bleeding, frequent menstrual bleeding is when menses occur less than 24 days apart, and infrequent menses is when menses occur more than 38 days apart. For duration, more than 8 days of bleeding is considered prolonged menses. Volume is harder to measure: menses are determined by women to be heavy, normal, or light. Heavy menstrual bleeding is defined as excessive menstrual blood loss that interferes with a woman’s physical, social, emotional, or material quality of life.
      National Institute for Health and Care Excellence
      Heavy menstrual bleeding: assessment and management. NICE guideline (NG88).
      It can occur alone or with other symptoms. Intermenstrual bleeding is bleeding between spontaneous, predictable menses and may occur randomly through the cycle or predictably and cyclically in early, mid, or late cycle. Breakthrough bleeding may occur on hormone medications such as birth control pills/patches/rings or progesterone-only contraceptives.
      • Munro M.G.
      • Critchley H.
      • Fraser I.S.
      Research and clinical management for women with abnormal uterine bleeding in the reproductive years: more than PALM-COEIN.
      Menstrual history can be assessed using the previously listed criteria to distinguish normal menstrual bleeding from abnormal bleeding. Next, physical examination, including speculum and bimanual examinations, with or without rectal examination, can help isolate the cause of bleeding to the uterus rather than to vulvar, vaginal, cervical, or rectal sources. The PALM-COEIN classification is used herein as a systematic approach to clarifying AUB, focusing on specific evaluation and management strategies.
      • Munro M.G.
      • Critchley H.
      • Fraser I.S.
      Research and clinical management for women with abnormal uterine bleeding in the reproductive years: more than PALM-COEIN.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.

      PALM-COEIN Classification

      Polyps

      Intermenstrual bleeding or AUB may occur in up to 67% of premenopausal women with endometrial polyps.
      • Golan A.
      • Sagiv R.
      • Berar M.
      • Ginath S.
      • Glezerman M.
      Bipolar electrical energy in physiologic solution: a revolution in operative hysteroscopy.
      Polyps may be single or multiple, measuring from a few millimeters to centimeters, and may be sessile or pedunculated.
      • Kim K.R.
      • Peng R.
      • Ro J.Y.
      • Robboy S.J.
      A diagnostically useful histopathologic feature of endometrial polyp: the long axis of endometrial glands arranged parallel to surface epithelium.
      They are localized hyperplastic overgrowths of endometrial glands and stroma around a vascular core forming a projection often from the uterine fundus and extending toward the internal os.
      • Savelli L.
      • De Iaco P.
      • Santini D.
      • et al.
      Histopathologic features and risk factors for benignity, hyperplasia, and cancer in endometrial polyps.
      The exact cause of polyps is unknown, but possible etiologies include genetic, biochemical, and hormonal factors.
      • Vanni R.
      • Dal Cin P.
      • Marras S.
      • et al.
      Endometrial polyp: another benign tumor characterized by 12q13-q15 changes.
      • Liu Z.
      • Kuokkanen S.
      • Pal L.
      Steroid hormone receptor profile of premenopausal endometrial polyps.
      The prevalence of polyps ranges from 7.8% to 34.9% of women and seems to increase with age.
      • Salim S.
      • Won H.
      • Nesbitt-Hawes E.
      • et al.
      Diagnosis and management of endometrial polyps: a critical review of the literature.
      Most endometrial polyps are benign, but a large review of more than 10,000 women suggests that the incidence of malignancy is 1.7% in premenopausal women, whereas the risk in postmenopausal women is 5.4%.
      • Lee S.C.
      • Kaunitz A.M.
      • Sanchez-Ramos L.
      • Rhatigan R.M.
      The oncogenic potential of endometrial polyps: a systematic review and meta-analysis.
      • Ferrazzi E.
      • Zupi E.
      • Leone F.P.
      • et al.
      How often are endometrial polyps malignant in asymptomatic postmenopausal women? a multicenter study.
      Risk factors for developing polyps include age, tamoxifen use, increased levels of endogenous or exogenous estrogen, obesity, and Lynch syndrome (hereditary nonpolyposis colorectal cancer).
      • Nappi L.
      • Indraccolo U.
      • Di Spiezio Sardo A.
      • et al.
      Are diabetes, hypertension, and obesity independent risk factors for endometrial polyps?.
      Endometrial polyps can be accurately diagnosed using transvaginal ultrasound (TVUS) (sensitivity, 91%; specificity, 90%), saline infusion sonohysterography (SIS) (sensitivity, 95%; specificity, 92%), diagnostic hysteroscopy (sensitivity, 90%; specificity, 93%), and hysterosalpingography (sensitivity, 98%; specificity, 35%).
      • Salim S.
      • Won H.
      • Nesbitt-Hawes E.
      • et al.
      Diagnosis and management of endometrial polyps: a critical review of the literature.
      The benefits of TVUS or SIS include the ability to visualize the adnexa, whereas polypectomy can be performed with hysteroscopy (Figure 1). Asymptomatic polyps greater than 1.5 cm and symptomatic polyps should be considered for excision and sent for pathologic examination.
      • Ferrazzi E.
      • Zupi E.
      • Leone F.P.
      • et al.
      How often are endometrial polyps malignant in asymptomatic postmenopausal women? a multicenter study.
      Figure thumbnail gr1
      Figure 1Endometrial polyp by office hysteroscopy.
      Cervical polyps occur most often in the reproductive years, especially after age 40 years.
      • Kemar H.
      • Lichtig C.
      Mullerian adenosarcoma presenting as cervical polyps: a report of seven cases and review of the literature.
      They generally arise from the endocervix potentially from inflammation and hormonal factors. Cervical polyps are rarely larger than 3 cm, are usually nonmalignant, generally are easily removable in the office, and should be sent for pathologic examination. Importantly, cervical polyps may coexist with endometrial intraepithelial neoplasia (EIN) or endometrial hyperplasia and endometrial polyps and may be mistaken for prolapsing leiomyoma.
      • Spiewankiewicz B.
      • Stelmachow J.
      • Sawicki W.
      • Cendrowski K.
      • Kuźlik R.
      Hysteroscopy in cases of cervical polyps.

      Adenomyosis

      Adenomyosis is a disorder in which endometrial glands and stroma are present focally or globally through the uterine musculature, causing hypertrophy of the surrounding myometrium. Prevalence is predicted to be 5% to 70% of women.
      • Dueholm M.
      Transvaginal ultrasound for diagnosis of adenomyosis: a review.
      Most cases occur in multiparous women in the fourth to fifth decades of life.
      • Levy G.
      • Dehaene A.
      • Laurent M.
      • et al.
      An update on adenomyosis.
      Whereas adenomyosis is asymptomatic in one-third of cases, women may present with HMB, irregular bleeding, dysmenorrhea, or dyspareunia. Evidence supports that the pathologic features of adenomyosis are related to abnormal gene expression, increased angiogenesis and proliferation, decreased apoptosis, impaired cytokine expression, local estrogen production, resistance to progesterone, increased nerve density, and immunologic oxidative stress.
      • Benagiano G.
      • Brosens I.
      • Habiba M.
      Structural and molecular features of the endomyometrium in endometriosis and adenomyosis.
      Definitive diagnosis is by histologic examination at hysterectomy; however, specific TVUS and magnetic resonance imaging (MRI) criteria help establish the diagnosis.
      • Cunningham R.K.
      • Horrow M.M.
      • Smith R.J.
      • Springer J.
      Adenomyosis: a sonographic diagnosis.
      • Reinhold C.
      • McCarthy S.
      • Bret P.M.
      • et al.
      Diffuse adenomyosis: comparison of endovaginal US and MR imaging with histopathologic correlation.
      Transvaginal ultrasound may include echogenic striations, myometrial cysts, globular uterus configuration or asymmetrical thickening of the myometrium, and heterogeneity of the myometrium leading to poor definition of the endometrial-myometrial interface (sensitivity, 89%; specificity, 89%).
      • Cunningham R.K.
      • Horrow M.M.
      • Smith R.J.
      • Springer J.
      Adenomyosis: a sonographic diagnosis.
      Given that adenomyosis increases uterine vascularity, a pattern of penetrating vessels can be seen at color Doppler ultrasound.
      • Cunningham R.K.
      • Horrow M.M.
      • Smith R.J.
      • Springer J.
      Adenomyosis: a sonographic diagnosis.
      T2-weight MRI findings may show diffuse or focal endometrial-myometrial junctional zone widening of 12 mm or more, islands of heterotopic endometrial tissue, cystic dilation of heterotopic glands, and punctate hyperintense foci of hemorrhage (sensitivity, 86%; specificity, 86%)
      • Reinhold C.
      • McCarthy S.
      • Bret P.M.
      • et al.
      Diffuse adenomyosis: comparison of endovaginal US and MR imaging with histopathologic correlation.
      (Figure 2). In a systematic review by Pontis et al,
      • Pontis A.
      • D’Alterio M.N.
      • Pirarba S.
      • de Angelis C.
      • Tinelli R.
      • Angioni S.
      Adenomyosis: a systematic review of medical treatment.
      effective medical therapies for adenomyosis include suppressive hormonal treatments such as continuous contraceptive hormones, high-dose progestins, selective estrogen receptor modulators (SERMs), selective progesterone receptor modulators (SPRMs), the 52-mg LNG IUS, aromatase inhibitors, danazol, and temporary use of gonadotropin receptor hormone (GnRH) agonists. The review concluded that if amenorrhea was achieved, there was no statistically significant difference between medical therapies in terms of pain relief. However, adverse effects and costs vary widely between various treatments. The most promising medical therapy per the authors is the LNG IUS, given its effectiveness and low-profile adverse effects.
      • Pontis A.
      • D’Alterio M.N.
      • Pirarba S.
      • de Angelis C.
      • Tinelli R.
      • Angioni S.
      Adenomyosis: a systematic review of medical treatment.
      When endometrial ablation has been performed, adenomyosis is a predictor of treatment failure due to bleeding, with a failure rate of 20%.
      • Shazly S.A.
      • Famuyide A.O.
      • El-Nashar S.A.
      • Breitkopf D.M.
      • Hopkins M.R.
      • Laughlin-Tommaso S.K.
      Intraoperative predictors of long-term outcomes after radiofrequency endometrial ablation.
      In nonrandomized studies, uterine artery embolization (UAE) and MRI-guided focused ultrasound (MgFUS) seem to be promising treatments for adenomyosis, although they were approved by the Food and Drug Administration primarily for leiomyoma therapy.
      • Taran F.A.
      • Stewart E.A.
      • Bruker S.
      Adenomyosis: epidemiology, risk factors, clinical phenotype and surgical and interventional alternatives to hysterectomy.
      • Cheung V.Y.
      Current status of high-intensity focused ultrasound for the management of uterine adenomyosis.
      Taran et al
      • Taran F.A.
      • Stewart E.A.
      • Bruker S.
      Adenomyosis: epidemiology, risk factors, clinical phenotype and surgical and interventional alternatives to hysterectomy.
      reported improved symptoms in 50% to 90% of women in several small studies undergoing UAE followed for 1 or more years. Use of MgFUS resulted in a 25% to 66% reduction in bleeding over 12 months in women with adenomyosis.
      • Cheung V.Y.
      Current status of high-intensity focused ultrasound for the management of uterine adenomyosis.
      Hysterectomy remains definitive therapy for women failing medical treatments.
      Figure thumbnail gr2
      Figure 2Adenomyosis of the uterus by magnetic resonance imaging.

      Leiomyoma

      Leiomyomas (also called myomas or fibroids) are benign monoclonal tumors arising from smooth muscle cells of the myometrium that develop during the reproductive years.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      They are the most common pelvic tumors, with an estimated lifetime prevalence of 70% in white women and more than 80% in black women.
      • Stewart E.A.
      Clinical practice: uterine fibroids.
      Risk factors for developing leiomyomas include African American race, early menarche, early oral contraceptive use, low parity, obesity, diet (increased consumption of meats, increased glycemic index or load, consumption of alcohol), hypertension, and family history.
      • Stewart E.A.
      • Cookson C.L.
      • Gandolfo R.A.
      • Schulze-Rath R.
      Epidemiology of uterine fibroids: a systematic review.
      Symptoms include painful menses or HMB and bulk-related symptoms such as pelvic pressure, urinary frequency, bowel symptoms, or reproductive dysfunction (infertility or obstetrical complications such as adverse outcomes related to leiomyoma location).
      • Stewart E.A.
      Clinical practice: uterine fibroids.
      Clinical diagnosis may be based on results of pelvic examination (although normal findings do not exclude the presence of submucosal leiomyoma as a cause of AUB), with pelvic ultrasound as the standard confirmatory test. The FIGO classification of leiomyoma location helps define the relationship of leiomyomas in reference to the endometrium or the visceral peritoneum (serosal layer)
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      (Figure 3). Submucous (subendometrial) or types 0, 1, and 2 leiomyomas can be diagnosed by using either SIS or hysteroscopy.
      • Munro M.G.
      • Critchley H.
      • Fraser I.S.
      Research and clinical management for women with abnormal uterine bleeding in the reproductive years: more than PALM-COEIN.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      In addition, MRI can show the relationship of leiomyomas to both the endometrium and the visceral peritoneum. The use of gadolinium can identify devascularized (degenerated) leiomyomas, and MRI can also be used to determine whether uterine-sparing treatments are an option.
      • Stewart E.A.
      Clinical practice: uterine fibroids.
      Although MRI may demonstrate features concerning for leiomyosarcoma, no preoperative testing can definitively rule out this rare malignancy.
      • Stewart E.A.
      Clinical practice: uterine fibroids.
      Figure thumbnail gr3
      Figure 3Uterine leiomyoma, intrauterine and subserosal-posterior uterus, by transvaginal pelvic ultrasound.
      The many treatment options for leiomyomas can help individualize therapy to symptoms. Asymptomatic leiomyomas usually do not need to be treated, except in some cases associated with fertility treatments. When HMB is the only symptom, medical therapies may be highly effective, including tranexamic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), contraceptive hormones, danazol, GnRH agonists, aromatase inhibitors, SERMs, and SPRMs.
      • Stewart E.A.
      Clinical practice: uterine fibroids.
      In a review by Talaulikar,
      • Sinai Talaulikar V.
      Medical therapy for fibroids: an overview.
      tranexamic acid reduced bleeding by 30% to 60%, and the LNG IUS significantly decreased bleeding while increasing ferritin and hematocrit levels. A uterus with leiomyomas is at increased risk for expulsion of the LNG IUS, and the LNG IUS may be challenging to place in women with larger leiomyomas. The GnRH agonists can be used preoperatively to reduce leiomyoma volume, correct anemia, and reduce intraoperative blood loss.
      • Stewart E.A.
      Clinical practice: uterine fibroids.
      A review of SPRMs shows them to be beneficial for improving quality of life, decreasing HMB, and creating amenorrhea, but they are not available in the United States currently for leiomyomas.
      • Murji A.
      • Whitaker L.
      • Chow T.L.
      • Sobel M.L.
      Selective progesterone modulators (SPRMs) for uterine fibroids.
      For submucous leiomyomas, hysteroscopic myomectomy may be the best therapeutic option for AUB.
      • Stewart E.A.
      Clinical practice: uterine fibroids.
      Endometrial ablation can be performed in women with leiomyomas who have a normal uterine cavity or in conjunction with hysteroscopic myomectomy to reduce HMB; ablation is reserved for women who have completed childbearing.
      • Loffer F.D.
      Improving results of hysteroscopic submucosal myomectomy for menorrhagia by concomitant endometrial ablation.
      For women with bulk symptoms with or without HMB, the goal is to decrease bleeding and shrink leiomyomas. Uterine-sparing options include myomectomy, UAE, MgFUS, or laparoscopic radiofrequency ablation.
      • Stewart E.A.
      Clinical practice: uterine fibroids.
      All of these treatment options have been shown to improve symptoms. In comparing treatments, reintervention risk after 36 months was 1.2% for abdominal myomectomy, 7.4% for UAE, 34.7% for high-intensity focused ultrasound (includes both MRI and ultrasound guided), and 3.2% for hysteroscopic myomectomy.
      • Sandberg E.M.
      • Tummers F.H.M.P.
      • Cohen S.L.
      • van den Haak L.
      • Dekkers O.M.
      • Jansen F.W.
      Reintervention risk and quality of life outcomes after uterine-sparing interventions for fibroids: a systematic review and meta-analysis.
      Oral SPRMs seem to be promising as medical therapy that lowers bleeding and decreases leiomyoma size; 1 SPRM is available outside of the United States.
      • Stewart E.A.
      Clinical practice: uterine fibroids.
      • Murji A.
      • Whitaker L.
      • Chow T.L.
      • Sobel M.L.
      Selective progesterone modulators (SPRMs) for uterine fibroids.
      Additional long-term medical treatments are anticipated in the future. Hysterectomy remains the treatment for leiomyoma symptoms after childbearing is completed and when other options fail.

      Malignancy and Premalignant Conditions

      Malignancy of the vagina or uterus (including the cervix) can cause abnormal bleeding. Thus, it is important to discern the etiology of any AUB through examination of the vulva, vagina, and cervix with Pap test screening or tissue sampling, as indicated by the American College of Obstetricians and Gynecologists guidelines.
      American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Gynecology
      Practice Bulletin No. 168: cervical cancer screening and prevention.
      In older premenopausal and menopausal women, AUB may be secondary to EIN (subtype: simple or benign hyperplasia vs [the more worrisome] subtype: atypical hyperplasia with progression to or concurrent with endometrial malignancy).
      Practice Bulletin No. 149: endometrial cancer.
      Women have a 2.8% lifetime risk of developing endometrial cancer, which accounts for 63,000 new cases in the United States yearly.
      American Cancer Society
      Key statistics for endometrial cancer.
      Fortunately, 70% of cases are found at an early stage given that most women (75%-90%) with malignancy present with AUB.
      Practice Bulletin No. 149: endometrial cancer.
      Endometrioid (adenocarcinoma) is the most common type of malignancy; papillary serous, clear cell, mucinous, and carcinosarcoma are rarer but more aggressive endometrial cancers. The risks for EIN and malignancy include unopposed estrogen with an intact uterus, obesity, diabetes mellitus, hypertension, nulliparity, and tamoxifen use.
      Practice Bulletin No. 149: endometrial cancer.
      American Cancer Society
      Key statistics for endometrial cancer.
      Women with Lynch syndrome have a 27% to 71% lifetime risk of endometrial cancer and, thus, require close endometrial surveillance until risk-reducing hysterectomy.
      The American College of Obstetricians and Gynecologists recommends that all women with AUB older than 45 years and women younger than 45 years who have additional risk factors for EIN undergo endometrial sampling.
      Committee on Practice Bulletins–Gynecology
      Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women.
      The sensitivity for endometrial cancer by endometrial sampling using the Pipelle device in premenopausal women is 91%, and the sensitivity for diagnosis of EIN (subtype: atypical endometrial hyperplasia) is 81%.
      • Dijkhuizen F.P.
      • Mol B.W.
      • Brolmann H.A.
      • Heintz A.P.
      The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis.
      In a systematic review of hysteroscopy for the diagnosis of endometrial cancer, sensitivity was 86% and specificity was 99%; in the diagnosis of EIN, sensitivity was 78% and specificity was 96%.
      • Clark T.J.
      • Voit D.
      • Gupta J.K.
      • Hyde C.
      • Song F.
      • Khan K.S.
      Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia: a systematic quantitative review.
      Endometrial intraepithelial neoplasia (subtype: benign hyperplasia without atypia) can be treated with oral progestins or LNG IUS and followed with endometrial surveillance; EIN (subtype: atypical) and endometrial malignancy are best treated with hysterectomy.
      Practice Bulletin No. 149: endometrial cancer.

      Coagulopathy

      Inherited bleeding disorders, especially von Willebrand disease (vWF), are identifiable in 5% to 24% of women with HMB.
      • Shankar M.
      • Lee C.A.
      • Sabin C.A.
      • Economides D.L.
      • Kadir R.A.
      Von Willebrand disease in women with menorrhagia: a systematic review.
      Coagulopathy should be considered in women with heavy, prolonged menses from an early reproductive age; a history of frequent bruising, epistaxis, gum/dental bleeding, postpartum hemorrhage, and severe surgical bleeding; and a family history of these issues. Heavy menses may be seen with factor deficiencies (factors VIII and IX are most common, factors VII and XI are less frequent) and platelet disorders.
      • Shankar M.
      • Lee C.A.
      • Sabin C.A.
      • Economides D.L.
      • Kadir R.A.
      Von Willebrand disease in women with menorrhagia: a systematic review.
      • James A.H.
      • Manco-Johnson M.J.
      • Yawn B.P.
      • Dietrich J.E.
      • Nichols W.L.
      Von Willebrand disease: key points from the 2008 National Heart, Lung and Blood Institute guidelines.
      An acquired coagulopathy should be considered in the setting of leukemia, aplastic anemia, renal or liver disease/failure, sepsis, and disseminated intravascular coagulopathy and in women taking drugs that affect coagulation or platelet function, such as NSAIDs and herbal remedies, anticoagulants, and chemotherapeutic agents.
      Evaluation should begin with a history to assess symptoms and risk factors for a coagulopathy, followed by confirmatory testing.
      Committee on Practice Bulletins–Gynecology
      Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women.
      • Shankar M.
      • Lee C.A.
      • Sabin C.A.
      • Economides D.L.
      • Kadir R.A.
      Von Willebrand disease in women with menorrhagia: a systematic review.
      Evaluation for a suspected coagulopathy should begin with a complete blood cell count or platelet count for thrombocytopenia, prothrombin (prothrombin time/international normalized ratio), activated partial thromboplastin time followed by, when indicated, plasma vWF antigen, plasma vWF activity (ristocetin cofactor activity, vWF:RCo and vWF collagen binding), factor VIII, and other factor testing.
      Committee on Practice Bulletins–Gynecology
      Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women.
      • Shankar M.
      • Lee C.A.
      • Sabin C.A.
      • Economides D.L.
      • Kadir R.A.
      Von Willebrand disease in women with menorrhagia: a systematic review.
      Inherited coagulopathies and HMB can be treated with factor replacement and desmopressin acetate as well as hormone therapy as follows.
      American College of Obstetricians and Gynecologists
      ACOG committee opinion no. 557: management of acute abnormal bleeding in nonpregnant reproductive-aged women.
      Medical therapy for acquired coagulopathies with HMB may include intravenous (IV) conjugated equine estrogens (Premarin; Pfizer Inc) 25 mg every 4 to 6 hours for 24 hours, combined oral contraceptives (monophasic continuous pills containing 35 μg of ethinyl estradiol) 3 times daily for 7 days (then daily thereafter), or medroxyprogesterone acetate 20 mg orally 3 times daily for 7 days (then daily for 3 weeks).
      • Devore G.R.
      • Owens O.
      • Kase N.
      Use of intravenous Premarin in the treatment of dysfunctional bleeding: a double-blind randomized control study.
      • Munro M.G.
      • Mainor N.
      • Basu R.
      • Brisinger M.
      • Barreda L.
      Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial.
      Tranexamic acid may be considered for acute AUB using 10 mg/kg IV (maximum of 600 mg per dose) or 1.3 g orally 3 times daily for 5 days.
      • Lukes A.S.
      • Moore K.A.
      • Muse K.N.
      • et al.
      Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an international expert panel.
      Intrauterine tamponade using a 26F Foley catheter infused with 30 mL of saline solution may control bleeding.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an international expert panel.
      In women treated with IV Premarin for HMB, 72% had controlled bleeding; in women taking oral contraceptive pills (OCPs) as above, 88% had controlled bleeding compared with 76% using medroxyprogesterone acetate.
      • Devore G.R.
      • Owens O.
      • Kase N.
      Use of intravenous Premarin in the treatment of dysfunctional bleeding: a double-blind randomized control study.
      • Munro M.G.
      • Mainor N.
      • Basu R.
      • Brisinger M.
      • Barreda L.
      Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial.
      For chronic bleeding, NSAIDs, the 52-mg LNG IUS, combined OCPs (monthly or extended cycle), progestin therapy (oral, intramuscular, or subdermal), or tranexamic acid with menses may be useful.
      American College of Obstetricians and Gynecologists
      ACOG committee opinion no. 557: management of acute abnormal bleeding in nonpregnant reproductive-aged women.
      When medical therapies fail for coagulopathies, endometrial ablation or hysterectomy may be warranted after childbearing is completed.

      Ovulatory Dysfunction

      Ovulatory dysfunction includes not ovulating on a regular basis or infrequently, which may lead to amenorrhea but more likely results in irregular bleeding. Anovulation occurs most commonly in the early reproductive years and later perimenopausal years. Episodes of bleeding range from light and infrequent for 2 or more months to episodes of unpredictable and extreme HMB requiring intervention.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      • Hale G.E.
      • Hughes C.L.
      • Burger H.G.
      • Robertson D.M.
      • Fraser I.S.
      Atypical estradiol secretion and ovulation patterns caused by luteal out of phase (LOOP) events underlying irregular ovulatory menstrual cycles in the menopause transition.
      When HMB is associated with anovulation, the loss of luteal progesterone results in persistent proliferative endometrium, which seems to be associated with reduced local levels of prostaglandin F2a, a necessary factor for efficient endometrial hemostasis.
      • Smith S.K.
      • Abel M.H.
      • Kelly R.W.
      • Baird D.T.
      The synthesis of prostaglandins from persistent proliferative endometrium.
      A different disorder, generally manifesting in the later reproductive years, can occur in ovulatory women: the luteal-out-of-phase event. These women ovulate but recruit follicles early in the luteal phase, resulting in high circulating estradiol levels and associated HMB.
      • Hale G.E.
      • Hughes C.L.
      • Burger H.G.
      • Robertson D.M.
      • Fraser I.S.
      Atypical estradiol secretion and ovulation patterns caused by luteal out of phase (LOOP) events underlying irregular ovulatory menstrual cycles in the menopause transition.
      Although there is no identifiable cause, ovulatory dysfunction can occur with polycystic ovarian syndrome, obesity, hypothyroidism, hyperprolactinemia, anorexia, extreme exercise, and significant weight loss.
      Committee on Practice Bulletins–Gynecology
      Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women.
      In women with AUB consistent with ovulatory dysfunction, evaluation should be directed toward identifying treatable causes, which may include thyroid function testing.
      Committee on Practice Bulletins–Gynecology
      Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women.
      Human chorionic gonadotropin, prolactin, and follicle-stimulating hormone testing should be considered for prolonged amenorrhea in younger women. Follicle-stimulating hormone levels can fluctuate daily. In obese women, prolonged amenorrhea due to anovulation and exposure to unopposed endogenous estrogen increases the risk of EIN and endometrial cancer; consideration for endometrial sampling/assessment is important.
      Practice Bulletin No. 149: endometrial cancer.
      American Cancer Society
      Key statistics for endometrial cancer.

      Endometrial Disorders

      Endometrial disorders are due to primary dysfunction of local endometrial hemostasis.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      Women present with predictable and cyclic menses suggestive of normal ovulation but have HMB. Etiology is not completely defined, but there are likely deficiencies in vasoconstriction (endothelin-1, prostaglandin F2a) and excessive production of plasminogen, leading to accelerated lysis of clot.
      • Nordengren J.
      • Pilka R.
      • Noskova V.
      • et al.
      Differential localization and expression of urokinase plasminogen activator (uPA), its receptor (uPAR), and its inhibitor (PAI-1) mRNA protein in endometrial tissue during the menstrual cycle.
      This latter phenomenon may be improved using tranexamic acid given its antifibrinolytic action.
      • Lukes A.S.
      • Moore K.A.
      • Muse K.N.
      • et al.
      Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial.
      Other therapies for HMB include NSAIDs, oral/ring or patch combined contraceptives (monophasic, monthly, or extended cycle), progestins (oral, intramuscular, subdermal), the 52-mg LNG IUS, and danazol, with surgical interventions such as endometrial ablation or hysterectomy when warranted.
      American College of Obstetricians and Gynecologists
      ACOG committee opinion no. 557: management of acute abnormal bleeding in nonpregnant reproductive-aged women.
      In addition, endometrial inflammation or endometritis may play a role, as seen in Chlamydia trachomatis or ureaplasma infections. Sources of infection are easily treated after cultures with appropriate antibiotic regimens.
      Committee on Practice Bulletins–Gynecology
      Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women.

      Iatrogenic

      The most common iatrogenic causes of AUB are due to hormone therapy such as OCPs or intramuscular, intrauterine, or subdermal contraceptives, which can cause BTB.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      Corticosteroid-related drugs that may cause BTB are GnRH agonists, aromatase inhibitors, SERMS, and SPRMs. Systemic agents (ie, antidepressants) that contribute to disorders of ovulation, such as those that interfere with dopamine metabolism or cause hyperprolactinemia, may also lead to AUB.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      Anticoagulants (warfarin, heparin, and direct oral anticoagulants) may cause HMB, prolonged menses, and postmenopausal bleeding. Treatment may not be necessary for minor BTB due to hormones. Breakthrough bleeding may initially be seen when estrogen-containing OCPs are used in a continuous manner without inert pills taken or in the first 4 to 6 months of OCP or LNG IUS use; only reassurance may be required.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      Use of the subdermal implant has more associated BTB than other hormonal contraceptives and may improve with low-dose estrogen when not contraindicated (oral estradiol 1 mg daily for 10 days), short-course NSAIDs, or doxycycline 100 mg twice daily for 10 days.
      • Curtis K.M.
      • Jatlaoui T.C.
      • Tepper N.K.
      • et al.
      U.S. selected practice recommendations for contraceptive use, 2016.

      Not Yet Classified

      This group of entities causing AUB is poorly defined, inadequately examined, and generally rare.
      • Munro M.G.
      Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years.
      They include arteriovenous malformation, myometrial hypertrophy, and uterine isthmocele secondary to cesarean delivery scar defect. Imaging such as TVUS and MRI may be helpful.

      When to Evaluate

      Not all AUB needs treatment, but it does require evaluation with a thorough medical history and physical examination. Laboratory testing should include a complete blood cell count and ferritin level measurement when HMB is an issue, with additional studies such as human chorionic gonadotropin, coagulation tests, hormonal tests, and imaging as indicated. Addressing quality of life and potential anemia as well as discussing that obesity and ovulatory dysfunction may increase the risk of EIN and malignancy are key discussion points for treatment. In premenopausal nongravid women, menses should occur at least 4 times yearly except in women receiving hormonal contraception.

      Management of Acute AUB

      It is important to understand the management of acute AUB (Table). After control of acute AUB, the underlying etiology can be determined using the PALM-COEIN classification. Medical management of acute and life-threatening HMB includes IV Premarin 25 mg every 4 to 6 hours for 24 hours along with antiemetic agents.
      • Devore G.R.
      • Owens O.
      • Kase N.
      Use of intravenous Premarin in the treatment of dysfunctional bleeding: a double-blind randomized control study.
      If bleeding does not lessen significantly within 8 hours, treatment should be changed to a different approach. In addition, caution should be used in giving IV or oral estrogen to women with cardiovascular disease, hypertension, venous thromboembolism, breast cancer, tobacco use after age 35 years, or migraines with aura. Oral treatments for HMB are monophasic 35-μg estrogen-containing OCPs given 3 times daily for 7 days, with 1 tablet daily thereafter, or medroxyprogesterone acetate 20 mg 3 times daily for 7 days with 20 mg daily for the next 3 weeks.
      • Munro M.G.
      • Mainor N.
      • Basu R.
      • Brisinger M.
      • Barreda L.
      Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial.
      Tranexamic acid can alternatively be used if no history of venous thromboembolism or cerebral vascular disease as 10 mg/kg IV (maximum of 600 mg per dose) or 1.3 g orally 3 times daily for 5 days.
      • Lukes A.S.
      • Moore K.A.
      • Muse K.N.
      • et al.
      Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial.
      In addition, intrauterine tamponade with a 26F Foley catheter infused with 30 mL of fluid may be used to control acute bleeding.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an international expert panel.
      TableManagement of Abnormal Uterine Bleeding
      Data from Committee on Practice Bulletins–Gynecology. Practice bulletin no. 110: noncontraceptive uses of hormonal contraceptives. Obstet Gynecol. 2010; 115(1):206-218; American College of Obstetrics and Gynecology Committee on Practice Bulletins–Gynecology. Practice bulletin no. 136: management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013; 122(1):176-185; and Obstet Gynecol.
      American College of Obstetricians and Gynecologists
      ACOG committee opinion no. 557: management of acute abnormal bleeding in nonpregnant reproductive-aged women.
      Acute bleedingChronic bleeding
      Conjugated equine estrogen 25 mg IV every 4-6 h for 24 h with IV antiemetic agentsIbuprofen 600 mg every 6 h or 800 mg every 8 h; naproxen 500 mg initially and repeat 3-5 h later, then 250-500 mg twice daily; mefenamic acid 500 mg 3 times daily (all with food)
      Monophasic 35-μg estrogen-containing OCP 3 times daily for 7 d, then 1 dailyMonophasic 30- to 35-μg estrogen-containing OCP daily with or without inert pills
      Medroxyprogesterone 20 mg or norethindrone 20 mg 3 times daily for 7 dMedroxyprogesterone 5-10 mg or norethindrone 5-10 mg daily
      Tranexamic acid 10 mg/kg IV (maximum, 600 mg per dose) or 1.5 g orally every 8 h for 5 dDepot medroxyprogesterone 150 mg subcutaneously every 3 mo

      Levonorgestrel 19.5- to 52-mg intrauterine devices for 5 y (19.5-mg LNG IUS is a slightly smaller device)

      Etonogestrel subdermal implant for 3 y

      Tranexamic acid 1.5 g orally every 8 h for 5 d with menses
      IV = intravenous; LNG IUS = levonorgestrel intrauterine system; OCP = oral contraceptive pill.

      Summary

      Abnormal uterine bleeding in nongravid reproductive-aged women accounts for frequent visits to primary care and emergency department providers. After a complete history and examination with pregnancy excluded, clinicians can feel comfortable in beginning an assessment of AUB using the PALM-COEIN terminology with management directed toward etiology to improve quality of life. Women with challenging AUB warranting further evaluation and management should be referred to gynecologists.

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