Clinical Management of Abnormal Uterine Bleeding

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2 Clinical Management of Abnormal Uterine Bleeding TABLE OF CONTENTS EDITORIAL BOARD Chairman Roger P. Smith, MD Professor, Vice Chair, and Program Director Department of Obstetrics and Gynecology University of Missouri-Kansas City Truman Medical Center Kansas City, Missouri Foreword 3 Executive Summary 4 Pathophysiology of AUB 7 Diagnosing AUB 15 Treatment 27 References 38 Linda Darlene Bradley, MD Gynecologist and Director of Hysteroscopic Services Department of Gynecology and Obstetrics The Cleveland Clinic Foundation Cleveland, Ohio Raymond W. Ke, MD Associate Professor University of Tennessee Health Science Center University of Tennessee Memphis, Tennessee Julie Lubker Strickland, MD, MPH Associate Professor Department of Obstetrics and Gynecology University of Missouri-Kansas City Staff Physician The Children s Mercy Hospital Truman Medical Center Kansas City, Missouri 1 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

3 Acknowledgment The Association of Professors of Gynecology and Obstetrics (APGO) and the APGO Medical Education Foundation gratefully acknowledge Gynecare Worldwide, a Division of Ethicon, Inc., a Johnson & Johnson Company, for initially providing the educational grant that funded this module as well as Cytyc Corporation for providing an educational grant to update this module and make it available online. Author Disclosure Statement According to ACCME accreditation requirements, authors must disclose all financial associations/ special relationships with proprietary entities/ commercial supporters that may have a direct relationship to the subject matter of the educational activity. They must also disclose any discussion of unlabeled or investigational uses of products in the educational activity. Dr. Linda Bradley, Dr. Raymond Ke, and Dr. Julie Strickland have each disclosed that they do not have any financial associations/ special relationships with proprietary entities/ commercial supporters related to the subject matter of this module. Dr. Roger Smith has disclosed a consulting agreement with Proctor & Gamble, and Dr. Raymond Ke has disclosed clinical-grant funding from Serono Laboratories. Target Audience Many physicians remain unaware of the most updated diagnostic and treatment options for abnormal uterine bleeding (AUB), a disruptive condition that affects 10% to 15% of women. This module introduces practicing OB/GYNs to the various causes of and new treatments for AUB and provides better understanding about managing AUB throughout the various stages of a woman s life from childhood through post-menopause. Learning Objectives Upon completion of this continuing education activity, participants should be able to: Identify the key characteristics of normal menstrual bleeding. Describe the etiologies of ovulatory AUB and anovulatory uterine bleeding. List the different causes of abnormal uterine bleeding in women of various life-stages, from peri-menarchal women to postmenopausal women. Explain the differential diagnosis of AUB and describe diagnostic techniques used in the evaluation of AUB. State the medical and surgical treatments available for AUB in primary care and other settings. This publication was developed by Jespersen & Associates, LLC, Boston, Massachusetts. The information in this monograph reflects the views of the authors only and not APGO, MEC, Gynecare Worldwide, Cytyc Corporation, or Jespersen & Associates. All participants should verify all information and data before treating patients or utilizing therapies noted in this continuing education program Association of Professors of Gynecology and Obstetrics Priest Bridge Drive, Suite 7, Crofton, MD 21114; (410) APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

4 FOREWORD More than 10 million women in the United States currently suffer from abnormal uterine bleeding (AUB). 1 It is a debilitating and common medical problem that adversely affects a woman s daily activities and responsibilities. The high prevalence of AUB combined with its social, medical, sexual, and emotional impact demands that the clinician be thoroughly familiar with new diagnostic and therapeutic options. The impact of AUB on the patient is significant, resulting in diminished quality of life. Excessive and unpredictable uterine bleeding may cause women much anxiety and interfere with social activities, employment, sexuality, and fertility. Excessive bleeding may also result in iron-deficiency anemia and attendant fatigue. Medical evaluation and treatment for the condition can be costly, especially for the patient without health insurance. In addition, the treatments themselves may be associated with negative sequelae. Hysterectomy is a commonly used and effective treatment for AUB, but it is the most expensive surgical option available. Additionally, hysterectomy is often medically unnecessary due to the absence of pathologic uterine conditions in a large percentage of these women. Newer techniques are available for the diagnosis and management of AUB. Once learned, physicians can offer new, minimally invasive surgical procedures such as endometrial ablation, rather than hysterectomy, as the first line of therapy to symptomatic women who fail medical treatment. As a diagnostic and therapeutic technique, dilation & curettage (D&C) is now considered obsolete for the evaluation and treatment of AUB but it is unfortunately still used by many physicians for this purpose. The D&C procedure is highly inaccurate, resulting in missed diagnoses and incomplete removal of intracavitary pathologic tissue, and is associated with a high rate of false-negative findings. Lesions commonly missed with D&C are focal intracavitary lesions such as polyps, submucosal fibroids, and focal hyperplasias and focal malignancy. Even when a polyp is retrieved by D&C, the surgeon cannot ascertain if it was retrieved completely. The larger the lesion, the more likely that it may not be completely removed with D&C. 2 3 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

5 EXECUTIVE SUMMARY This monograph examines the pathophysiology of AUB, the etiologies of ovulatory AUB and anovulatory uterine bleeding in key age-groups (i.e., perimenarchal, reproductive aged, and menopausal), the diagnosis of AUB, and modern treatments available. Upon completion of this review, the reader should be able to: Identify the key characteristics of normal menstrual bleeding. Describe the etiologic bases of ovulatory AUB and anovulatory uterine bleeding. List the different causes of AUB in women of various life-stages, from peri-menarchal women to post-menopausal women. Explain the differential diagnosis of AUB and describe diagnostic techniques used in the evaluation of AUB. State the medical and surgical treatments available for AUB in primary care and other settings. Scope of AUB Abnormal uterine bleeding is a significant problem of gynecologic health that affects adolescents, women of reproductive age, and postmenopausal women. Approximately onethird of all outpatient gynecologic visits annually are for the evaluation of AUB. 3 Among adolescents, AUB is the most frequent cause of urgent admission to the hospital. 4,5 Worldwide, AUB affects about 50% of menstruating women. 6 The majority of cases of AUB occur in the 5 to 10 years prior to menopause or after menarche, when the ovaries are in an unstable responsive state. 7 Abnormal uterine bleeding and its treatment may adversely impact a woman s health (e.g., anemia, hypotension, and fatigue) and quality of life, including reductions in social, economic, and psychological well-being. 8,9 Yet, despite this fact, approximately 5 million women in the United States do not seek treatment. These women, known as silent sufferers, have a variety of reasons for not pursuing treatment of AUB. Some may have fertility concerns or experience with past ineffective therapy; others may be unaware of alternatives, or believe that their heavy bleeding is not a medical problem but a normal part of the aging process. Approximately 4 out of 5 women with AUB have no anatomic pathologic condition, and one-third of hysterectomies performed for the treatment of AUB demonstrate no abnormal finding. 10,11 Of the half-million hysterectomies performed every year in the United States, 50% or more are for the treatment of abnormal uterine bleeding. 12 Impact Rate A recent study conducted by The National Women s Health Resource Center reveals that race and ethnicity are important in determining whether women seek medical care and treatment of their heavy periods. The research is based on a poll of 653 women aged 35 to 49 years old who reported that they experience heavy periods and have not had hysterectomies. 13 Since Hispanic women are often reluctant to talk to doctors about gynecological issues, they are much less likely than others to seek aid or treatment, leaving them more vulnerable to the impact of heavy periods on their daily lives. Hispanic women are more likely to grin and bear it and are also more likely than others to cope with heavy bleeding by using over-the-counter remedies. African-American women are more susceptible to fibroids, a condition in which heavy bleeding can be a symptom. 4 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

6 Additionally, African-American women are more vulnerable to anemia. This study also revealed that African-American women are more likely than others to consult a doctor promptly, report anemic conditions, and take iron supplements as a first-line treatment. Pathophysiology of AUB Normal postovulatory menstrual bleeding is predictable and precisely regulated. The normal cycle lasts 24 to 35 days, with a usual duration of menstrual flow of 4 to 6 days, resulting in the loss of approximately 30 ml of menstrual blood. Uterine bleeding that occurs outside of normal menstruation or disruptions in cyclic menstruation is termed abnormal uterine bleeding (AUB). When AUB cannot be attributed to an anatomic, organic, or systemic pathologic condition, it has traditionally been referred to as dysfunctional uterine bleeding (DUB). However, since this form of AUB is almost always due to anovulation, the American College of Obstetrics and Gynecology (ACOG) prefers the more descriptive term anovulatory uterine bleeding. In the setting of regular ovulation, AUB is often due to an anatomic, organic, or systemic lesion or disease. Ovulatory AUB without any identifiable anatomic, organic, or systemic cause is uncommon and is generally diagnosed when excessive bleeding occurs with regular cyclic frequency of 24 to 35 days. Diagnosis The differential diagnosis of AUB includes complications of pregnancy, infection, trauma, gynecologic cancer, systemic disease, adverse effects of drugs, and iatrogenic causes. Anovulatory uterine bleeding is a diagnosis of exclusion, and other causes of uterine bleeding must first be ruled out. The most likely causes of AUB relate to the woman s reproductive age. A detailed menstrual history and physical examination can determine the woman s ovulatory status and possible cause of the bleeding, such as pathologic uterine conditions or systemic disease. Open-ended questions regarding menstrual bleeding aid in obtaining information. For example: How long do your periods last? How many pads/tampons do you go through per day? Are your periods interfering with work, leisure activities, sleep or sex? Laboratory testing can help in the evaluation of suspected coagulopathies and endocrinopathies. Pathologic uterine conditions can be evaluated by several diagnostic techniques, including endometrial biopsy, transvaginal ultrasound (TVS), hysteroscopy, saline infusion sonography (SIS), and magnetic resonance imaging (MRI). Treatment Abnormal uterine bleeding may be managed medically or surgically, and a variety of effective options exist in both treatment modalities. Medical therapy is generally preferred over surgery, especially if the woman desires future fertility and has no anatomic, organic, or systemic cause for the bleeding. Available medical treatments include supplemental cyclooxygenase, iron, antifibrinolytics, COX-inhibitors (including NSAIDs), hormonal agents (including OCs), progesterone IUDs, GnRH agonists and antagonists, and antiprogestational agents. Surgical treatments for AUB include hysteroscopic polypectomy/myomectomy, hysteroscopic endometrial ablation/resection, nonhysteroscopic global endometrial ablation and hysterectomy. Unfortunately, in 2005, hysterectomy still remains the most common surgical treatment for AUB. Hysteroscopic techniques include bipolar or monopolar resection of polyps, fibroids, and 5 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

7 endometrial ablation. Surgical skills are easily mastered, thus avoiding complications of fluid overload and perforation. Newer nonresection techniques include thermal balloon cryoablation, circulating free fluid, bipolar mesh, and microwave energy. These techniques do not require operative hysteroscopic expertise and therefore may be simpler and faster to perform than hysteroscopic ablation. Both global and nonglobal hysteroscopic endometrial ablation are associated with low risk of complications in well-trained surgeons. Additionally, they both have excellent clinical outcomes and high patient satisfaction. 6 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

8 PATHOPHYSIOLOGY OF AUB Abnormal uterine bleeding is one of the most common complaints encountered by gynecologists and primary care physicians. Most patients who seek care are concerned when they notice a change in their normally reliable menstrual pattern. Amenorrhea or infrequent menses often elicit anxiety regarding possible pregnancy or disease. Likewise, excessive menstrual bleeding is particularly worrisome since it may interfere with physical activity, career, and sexual activity. While AUB is rarely a life-threatening event, it impacts a woman s quality of life. Heavy periods disrupt women s sex lives, personal lives, and even, in some cases, their employment. Excessive menstrual blood loss is a common complaint and has been a major contributor to the high incidence of hysterectomies performed during the later reproductive years. Characteristics of Normal Menstrual Bleeding Normal (menstrual) bleeding due to postovulatory progesterone withdrawal is stable and precisely regulated. 14 The normal menstrual cycle is so predictable that women come to expect a characteristic pattern and amount of flow. Minor variations, such as ±1 day in duration or minor deviations in expected use of napkins or tampons, color, clots, consistency of menstrual debris, and amount of flow may cause women considerable concern. 14 The characteristics of normal ovulatory menstruation are listed in Table 1. It is generally agreed that the normal menstrual cycle will be between 24 and 35 days in length, measured from the first day of menstrual flow of one cycle to the first day of the next cycle. The usual duration of menstrual flow is 4-6 days, but many women have flow for as few as 2 days or as many as 7 days. 14 A prospective 30-year study of 275,947 menstrual cycles determined that the most consistent cyclic interval was in women aged 20 to 40 years. The median cyclic interval at age 20 was 28.9 ± 2.8 days and at age 40, 26.8 ± 2.0 days. In this age-range, length of cycle varied by only 1 to 2 days each month, and the average duration of menstrual flow was between 3 and 7 days. 15 Normal menstruation also tends to be consistent in the amount of blood that is lost. The usual volume of menstrual blood loss is 30 ml, and a menstrual flow greater than 80 ml is considered abnormal. 14,16 Researchers utilize the alkalin hematin assay to objectively quantitate the amount of menstrual blood loss. One method used in clinical practice to estimate the amount of blood loss is the Table 1: Characteristics of Normal Menstruation Normal Abnormal Duration of flow 4-6 days <2 days or >7 days Volume of flow 30 ml >80mL Length of cycle days Pictorial Blood Loss Assessment Chart (PBLAC). Utilizing this chart, a woman records the amount of bleeding she experiences each month. The use of sanitary products and bleeding severity, like clots and flooding, are summed to calculate a subscore. This number provides an objective method to quantify and evaluate the amount of blood loss. While PBLAC score is a useful tool for clinical studies, it has two major limitations in clinical practice: It is difficult to use in real life and does not correlate with women s perception of menstrual bleeding. Therefore, it is virtually impossible for either the patient or her clinician to measure the volume of blood loss accurately. 7 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

9 Terminology Excessive menstrual bleeding and that which occurs outside of normal cyclic menstruation is generally described as abnormal uterine bleeding (AUB). A menstrual pattern of reduced frequency or bleeding volume is also described as AUB. Thus, the term AUB is broad and inclusive of many possible underlying causes for the bleeding. It is reflective of a symptom or sign with many possible etiologic bases. When AUB cannot be attributed to an anatomic, organic, or systemic lesion or disease, it has traditionally been referred to as dysfunctional uterine bleeding (DUB).14 However, anovulatory uterine bleeding is a more descriptive term, reflecting the fact that many of these women suffer from chronic anovulation or oligoovulation. The term DUB or anovulatory uterine bleeding is relatively narrow and exclusive; it is a diagnosis made by excluding all other possible causes, such as leiomyomas, polyps, hyperplasia, malignancy, coagulopathies, etc.14 Anovulatory uterine bleeding is usually discussed in terms of an endocrinologic derangement associated with anovulation in the absence of the influence of cyclic estrogen and progesterone upon the endometrium. Unless otherwise indicated, this monograph will use the term abnormal uterine bleeding, or AUB, to reflect all forms of uterine bleeding outside of normal cyclic menstruation. Anovulatory uterine bleeding a term preferred by the American College of Obstetrics & Gynecology (ACOG) will refer to AUB that cannot be attributed to an anatomic, organic, or systemic lesion or disease. Menses, menstrual bleeding, menstrual flow, and menstruation will be used in this document interchangeably, and each of these terms simply refers to the presence of menstrual effluent, irrespective of whether the effluent is normal or abnormal. The frequency and duration of menstrual flow are mostly stable during a woman s reproductive years, but they commonly vary at the beginning and end of this span. 17 The cycles are relatively long for about 5-7 years following menarche. 14 The length of cycle then shortens somewhat, and the cycles become increasingly regular with the advent of the reproductive years. 14 By age 25, more than 40% of cycles are 25 to 28 days in length; between the ages of 25 and 35, more than 60% of cycles are 25 to 28 days in length, 14 but, at least 20% of women of reproductive age experience irregular cycles. 17 The cycles begin to lengthen again in the 40s, as perimenopause approaches. 14 Traditional definitions associated with menstruation include the following: 14 Amenorrhea: absence of menstruation for at least three usual cyclic lengths Oligomenorrhea: cyclic length >35 days Polymenorrhea: cyclic length <24 days Menorrhagia: regular, normal intervals with excessive volume and duration of flow Metrorrhagia: irregular intervals with normal or reduced volume and duration of flow Menometrorrhagia: irregular interval and excessive volume and duration of flow Normal human menstrual function is dependent upon an intricate series of hormonal actions linking the neuronal nuclei of the hypothalamus to the pituitary gland, which subsequently stimulates the ovaries to produce sex-steroids that act upon the endometrial lining of the uterus. Appropriately, this pathway is known as the hypothalamic-pituitary-ovarian (HPO) axis. Along the HPO axis there is a complex system of positive and negative feedback signals that allow the end-organs to 8 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

10 Volume of Menstrual Flow and Patients Perceptions A woman s perception of her menstrual flow whether it is too little or too much is generally unreliable. 14 As many as 15% of women with a menstrual blood loss <20 ml per cycle as measured quantitatively have reported having heavy bleeding. 18 On the other hand, one third of women with menstrual blood loss >80 ml described their bleeding as light or moderate communicate with the higher centers. To complicate matters, the ovary is subjected to numerous, and as yet not completely defined, autocrine and paracrine actions within itself that modulate external hormonal actions. Only a precise sequence of events will result in normal ovulation and menses. Late in the menstrual cycle, the arcuate nucleus of the hypothalamus generates carefully timed pulses of gonadotropinreleasing hormone (GnRH), which stimulate cells of the anterior pituitary gland to produce follicle-stimulating hormone (FSH) and, to a smaller extent, luteinizing hormone (LH). In the right proportion, FSH will recruit a cohort of ovarian follicles for development. At the same time, pituitary FSH/LH circulates back to the hypothalamus, exerting a negative feedback control on pulses of GnRH to limit recruitment of additional follicles. From this cohort of ovarian follicles, a dominant follicle is selected by the seventh day of the next menstrual cycle. It is the destiny of this one follicle to mature and proceed to ovulation, usually on the 14th day. While maturing, the dominant follicle secretes increasing amounts of estradiol, which initiates ovulation through positive feedback by causing a massive and sudden release of LH from the pituitary (LH surge). In the endometrial lining, rising levels of estradiol produced by the follicle stimulate growth of epithelial and stromal elements. This phase of growth is appropriately termed the proliferative phase and, under the influence of estradiol, the endometrium grows in height and becomes rich in progesterone receptors. Once the LH surge occurs, the ovum is released, and the follicle reorganizes to become the corpus luteum. The corpus luteum is a sub-organ within the ovary with a life-span of approximately 10 days that produces large amounts of progesterone. Under this progestagenic influence, the endometrium enters the secretory phase. Endometrial growth stops, and the stroma becomes more compact and stable. The glandular epithelium develops glycogen vacuoles to prepare for implantation of an embryo. If pregnancy fails to occur, then the corpus luteum undergoes involution and production of progesterone is withdrawn. Upon progesterone withdrawal, the endometrial lining collapses, resulting in menstruation. Once levels of progesterone and estradiol decline, the hypothalamus and pituitary escape the influence of negative feedback, and FSH levels rise again for the subsequent cycle. Progesterone withdrawal from the estrogenprimed endometrium triggers menstrual bleeding. 9 Hormone withdrawal causes an immediate, modest shrinkage of the height of endometrial tissue. As this shrinkage occurs, blood flow within the spiral vessels diminishes, and venous drainage decreases. The spiral arterioles rhythmically constrict and relax, with each successive spasm becoming more prolonged and profound. 14 Along with vasoconstriction, endometrial tissue begins to break down the binding membrane fragments, and blood is forced into the endometrial cavity. 14 A natural cleavage point exists between the basalis and spongiosum. Once that is breached, the loose, vascular, edematous stroma of the spongiosum peels 9 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

11 away. 14 Within 24 hours of the start of menstrual flow, these reactions lead to endometrial ischemia and necrosis. 14 Menstrual flow stops as a result of the combined effects of prolonged vasoconstriction, tissue-collapse, and vascular stasis. 14 With damage to tissues, thrombin is generated in the basal endometrium by the action of thromboplastins in the tissue. Thrombin, in turn, promotes the formation of fibrin and the activation of platelets to effect hemostasis. 14 At the same time as menstruation, ovarian follicular development with production of estradiol also proceeds, which begins to heal and regenerate the endometrial lining. Menstrual flow is predominantly regulated through the actions of locally released prostaglandins. Uterine contractions are caused by PGF2a and PGE2a. Thromboxane A2 (TXA2) promotes vasoconstriction, and PGI2 and PGE2a promote vasodilation. Within the endometrium, prostaglandins are produced from arachidonic acid. 22 In patients with menorrhagia, there is a demonstrated increase in endometrial arachidonic acid with a predominance of PGE2a and PGI2 over the vasoconstrictive PGF2a and TXA Figure 1 illustrates the sequence of biochemical events during a normal 28-day cycle. Etiologic Bases of Anovulatory Uterine Bleeding Anovulatory uterine bleeding is usually caused by one of three hormonal imbalances: 26 Bleeding due to estrogen withdrawal Bleeding due to estrogen breakthrough Bleeding due to progesterone breakthrough Bleeding results from an unexpected decrease in levels of estrogen. The causes are often iatrogenic, such as bilateral oophorectomy or cessation of estrogen therapy. This type of bleeding is usually isolated, self-limited, and not likely to recur if levels of estrogen remain low. 26 Some women, during the normal 10 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

12 menstrual cycle, experience recurrent midcycle bleeding or spotting just before ovulation due to a pronounced dip in levels of estradiol at that time. Anovulatory women may also experience periodic fluctuation in estradiol levels that results in withdrawal bleeding, but anovulatory uterine bleeding is usually caused by estrogen breakthrough. Prolonged deprivation of estrogen can lead to an atrophic endometrium that is friable and prone to inflammation. Postmenopausal women can often experience spotting from this condition. Estrogen breakthrough bleeding occurs with chronic and unopposed estrogenic stimulation of the endometrium. The classic example is observed in women with anovulation due to polycystic ovarian syndrome (PCOS). Without ovulation, there is no influence from progesterone on the proliferating endometrium. Eventually the unabated proliferation leads to insufficient structural support, and parts of the endometrium slough at irregular, unpredictable intervals, causing bleeding. Since this bleeding does not follow progesterone-induced maturation and subsequent withdrawal, there is no orderly sequence of endometrial shedding, such as occurs with normal menstruation. The result is not only irregular but excessive bleeding. Progesterone breakthrough bleeding occurs when the progesterone-to-estrogen ratio is relatively high. This usually occurs with the use of progesterone-only contraceptives. The endometrium atrophies and ulcerates due to the lack of estrogen and is prone to frequent irregular bleeding. 26 Ovulatory AUB Abnormal uterine bleeding without any attributable anatomic, organic, or systemic cause but associated with regular ovulation is uncommon. It is loosely named ovulatory AUB and is generally observed with regular progesterone withdrawal menses every days, but with excessive blood loss. 9,27 This uncommon form of ovulatory AUB occurs when there is loss of local endometrial hemostasis. The woman experiences regular and predictable menstruation, and usually retains existing premenstrual symptoms associated with ovulation such as dysmenorrhea, midcycle pain, breast tenderness, bloating, and irritability. Although exact mechanisms of ovulatory AUB are unknown, possible causes have been proposed. 9 As mentioned, the ratio of PGE2a:PGF2a and the level of PGI2 are increased in women with menorrhagia. 24,25 In addition, fibrinolytic activity is significantly elevated in most women with ovulatory AUB. 28,29 Anovulatory Uterine Bleeding Anovulatory uterine bleeding is defined as noncyclic menstrual blood flow that may range from spotty to excessive, is derived from the uterine endometrium, and is due to anovulatory production of sex steroids, specifically excluding an anatomic lesion. It is typically caused by estrogen withdrawal or estrogen breakthrough bleeding and occurs in the absence of the cyclic production of ovarian progesterone. 9,14 This may occur with the sustained levels of unopposed estrogen associated with PCOS, obesity, immaturity of the hypothalamic-pituitary-ovarian (HPO) axis (e.g., postpubertal teenagers), and late anovulation (e.g., women in their late 30s and 40s). 14 The mechanisms involved in anovulatory uterine bleeding are uniquely different from those with ovulatory AUB. 9 In the absence of cyclical progesterone and periodic menstruation, the endometrium becomes hyperplastic without the necessary structural support. The hyperplastic, unstructured endometrium is fragile and prone to multifocal fragmentation and bleeding. 9,14 As one site of breakdown heals, a different site may break down and bleed. The resulting bleeding is usually erratic in both timing and 11 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

13 volume of blood loss with alternating periods of amenorrhea. 9,27 In addition, local hemostatic mechanisms are hampered due to the absence of cyclical progesterone and the associated synthesis of prostaglandins and other substances necessary to control blood loss. 9 AUB Correlated with Age The usual causes of AUB vary over a woman s lifetime. Common causes of abnormal uterine bleeding in different ages are illustrated in Figure 2 and are explained in more detail below. Peri-menarchal Adolescent Women Anovulatory uterine bleeding and irregular periods are common during the first few years after menarche. This is primarily due to immaturity of the HPO axis, which renders it incapable of naturally responding to estrogen with an LH surge. 30 Regular ovulatory bleeding is usually established within 2 to 3 years after menarche, and persistence of irregular periods beyond this time warrants further investigation. 30 Coagulation disorders are not uncommon in adolescent women. 30 Such disorders may be noted by unusual bleeding from the gums, prolonged bleeding after minor cuts, and easy bruising. In one study, 19% of adolescent patients evaluated for AUB were found to have coagulation disorders. 31 This incidence was even higher if the hemoglobin was <10 g/dl (in approximately 25%) or if hospitalization was required (approximately 50%). 31 Coagulation disorders common in this age-group include: 30 von Willebrand disease (vwd) idiopathic thrombocytopenic purpura thalassemia major Fanconi anemia 12 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

14 prothrombin deficiency Glanzmann s disease Additionally, psychosocial stress, including that associated with eating disorders, may contribute to irregular periods in adolescents. Women of Reproductive Age It is common for women of reproductive age to suffer from occasional and self-limited AUB. The reasons are unclear, but the process of normal menstruation is complex and easily deranged. Pregnancy and related complications are a common cause of bleeding in women of reproductive age and must not be overlooked. Sexually transmitted diseases (e.g., gonorrhea and chlamydia) can cause pelvic infections associated with vaginal bleeding. 30 Abnormal bleeding can also be caused by endometrial polyps or distortion of the endometrium by submucous myomas and endometrial hyperplasia. 30 Although the cause of abnormal bleeding in women of reproductive age is often benign, malignancy is always a possibility, particularly if the woman is obese or has a history of chronic oligoovulation or anovulation. 30 Perimenopausal Women Perimenopausal women have an increased incidence of anovulatory cycles due to depletion of the store of ovarian oocytes. 30 With aging, endometrial hyperplasia, cancer, polyps, or submucosal fibroids become more prevalent. Pathologic endometrial tissue should be suspected in the perimenopausal woman with abnormal bleeding. Risk factors such as obesity, hypertension, diabetes mellitus, and chronic anovulation are significantly associated with cancer in this population. 30 Menopausal Women Any vaginal bleeding or complaints of vaginal discharge in menopausal women should be considered abnormal. 30 Up to 10% of these women have been found to have cancer. 32 The most common cause of postmenopausal bleeding is due to endometrial atrophy, however, other pathology such as hyperplasia, polyps, or submucous fibroids, must be ruled out. The number of years since the last menstrual period increases the risk of malignancy, which must be aggressively excluded by thorough evaluation. 33 Anovulatory uterine bleeding is also common in this age group and may be due to various causes. By far the most common endocrinopathy is PCOS, affecting 6% of all women of reproductive age. While AUB, obesity, and hirsutism are the most common features, PCOS is a heterogeneous disorder with many different clinical appearances. Laboratory evaluations demonstrating anovulation and hyperandrogenemia assist in the diagnosis. The etiology of PCOS is also unclear, but an association with insulinresistance has been demonstrated. Excessive insulin appears to stimulate the ovarian stromal cells to produce androgens, which in turn suppress ovulation. 13 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

15 DIAGNOSING AUB The most likely causes of AUB and pathologic findings in the endometrium relate to the woman s reproductive age. 26 As a result, the approach to establishing a diagnosis of AUB depends on whether the patient is premenopausal, perimenopausal, or postmenopausal. Differential Diagnosis As explained above, anovulatory uterine bleeding is commonly defined as excessive or unexpected uterine bleeding that cannot be attributed to pelvic pathology or systemic disease. 14 It is a diagnosis of exclusion, and other possible causes of uterine bleeding must be ruled out before establishing a diagnosis of anovulatory uterine bleeding. 34 Table 2 lists all possible causes of AUB. Table 2: Differential Diagnosis of AUB Infection Cervicitis Endometritis Pyosalpinx Trauma Laceration/abrasion Foreign body Urethral prolapse Medications/Iatrogenic Causes Hepatic disease Hormones (oral contraceptives, estrogen, progesterone) Steroids Dilantin Intrauterine device Stress (emotional, excessive exercise) Smoking Cervical ectropion/eversion 14 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

16 Complications from Pregnancy Cancer Intrauterine pregnancy Cervical Ectopic pregnancy Endometrial Spontaneous abortion Ovarian Gestational trophoblastic disease Fallopian tube Placenta previa Vaginal Retained products of conception Vulvar Systemic Disease Pelvic Pathology (Benign) Hepatic disease Cervical polyps Renal disease Endometrial polyps Coagulopathies (e.g., von Willebrand disease) Endocrinopathies Hypothyroidism Leiomyoma Adenomyosis Endometrial hyperplasia Hyperprolactinemia Cushing disease Polycystic ovary syndrome (PCOS) Adrenal dysfunction/tumor Thrombocytopenia Leukemia 15 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

17 Evaluation of AUB in Premenopausal Women An algorithm for the evaluation of AUB in premenopausal women is illustrated in Figure 3. If the reproductive-age woman is not pregnant and has a normal physical examination, then anovulatory uterine bleeding is the most likely diagnosis. 26 For women of reproductive age, the first step is to determine whether the uterine bleeding is anovulatory or ovulatory. 26 Menstrual cycles can be quite variable. Patients can have alternating anovulatory cycles interspersed with ovulatory cycles. In addition, intracavitary pathologic conditions can coexist in the uterus with these problems. Anovulation is the most common cause of AUB in this age group, and is especially common in adolescents during the first few years after menarche. 26,30 Tests for TSH and prolactin can help rule out pituitary dysfunction as a cause of the anovulation. 26 Other factors may also be associated with hypothalamic-based anovulation, including loss of weight, eating disorders, stress, chronic illness, or excessive exercise. 26 A common cause of anovulation in women of reproductive age that must also be ruled out before making a diagnosis of anovulatory uterine bleeding is PCOS. As previously discussed, coagulation disorders are not uncommon in adolescents presenting with menorrhagia at menarche. One study reported that 19% of adolescents evaluated for menorrhagia were found to have an 16 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

18 underlying coagulation disorder (e.g., von Willebrand disease, prothrombin deficiency, etc.). 31 Ovulatory AUB is less common in premenopausal women than anovulatory uterine bleeding, but it may occur. 26 Ovulatory AUB manifests as regular cyclic bleeding. Although extensive laboratory testing for ovulation is costly and sometimes impractical (i.e., testing for serum progesterone LH surge or charting of basal body temperature), the typical patient who ovulates notes changes in vaginal secretions, premenstrual tension syndrome, and premenstrual breast tenderness. The clinical history of a regular menstrual cycle with the characteristic premenstrual molimina complaints (e.g., dysmenorrhea, midcycle pain, unilateral pelvic pain, and premenstrual symptoms) often correlates with an ovulatory menstrual cycle. The ovulatory patient with abnormal bleeding should be thoroughly evaluated for uterine pathology (e.g., leiomyomas, adenomyosis, or endometrial polyps) and coagulation disorders (eg, von Willebrand disease in adolescents). 26 As mentioned, ovulatory AUB without any attributable anatomic, organic or systemic disease is uncommon. Evaluation of AUB in Perimenopausal Women An algorithm for the evaluation of AUB in perimenopausal women is illustrated in Figure 4. As women approach menopause, the cycles shorten and may become intermittently anovulatory. 26 The risk of endometrial cancer is low (<1%) in women under 40 years of age. In these women, the most common causes of bleeding will not be endometrial cancer or even endometrial hyperplasia, but 17 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

19 intracavitary pathologic conditions, including endometrial polyps or submucosal fibroids. However, all perimenopausal women with persistent abnormal uterine bleeding should be evaluated for endometrial hyperplasia or cancer. 26 Techniques for evaluating endometrial pathologic conditions include endometrial biopsy, transvaginal ultrasonography (TVS), hysteroscopy, and saline infusion sonography (SIS) and MRI. 26 These techniques are reviewed in greater detail below. Evaluation of AUB in Postmenopausal Women An algorithm for the evaluation of AUB in postmenopausal women is illustrated in Figure 5. The most common cause of postmenopausal bleeding is endometrial atrophy, followed by iatrogenic bleeding often due to hormone replacement therapy (HRT). Women receiving sequential HRT may expect to have scheduled withdrawal bleeding when finishing the progesterone component of the pills. Additionally, women on HRT can experience irregular bleeding due to missed pills, drug interactions, or malabsorption. 26 Up to 40% of women receiving continuous combined HRT have irregular bleeding in the first 4 to 6 months of therapy APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

20 The traditional recommendation has been to wait for 6 to 9 months of bleeding before performing a formal workup. This, however, will often lead to cessation of HRT because of the inconvenience, annoying bleeding, and fear of endometrial cancer. Therefore, a more circumspect approach is advocated. In order to keep the patient compliant with therapy, a workup should be performed sooner in patients who are inconvenienced by HRT bleeding. Once the patient understands that the bleeding is not due to a malignancy, she is more likely to continue with medical therapy. Further evaluation may also be considered if the bleeding does not stop within 3 weeks after the cessation of HRT. 35 Hysteroscopy and transvaginal ultrasonography (TVS) are very useful in the evaluation of postmenopausal bleeding, and may eliminate the need for endometrial biopsy. Endometrial cancer and endometrial hyperplasia are less common causes of postmenopausal bleeding. Of all postmenopausal women with bleeding, up to 10% may have endometrial cancer. 32,36 Other causes of AUB in the postmenopausal woman may include cervical lesions, ovarian cancer, tubal cancer, and pathologic tissue in the vagina. 26 History and Physical Examination The examination of women with abnormal uterine bleeding must focus on identifying the site of bleeding. 9 Bleeding that the patient thinks originates in the genital tract may actually originate in the urinary tract or gastrointestinal tract. 9 On the other hand, genital bleeding may not originate in the uterus, but in the vulva, vagina, cervix, and, in rare cases, the fallopian tubes. 9 The clinical evaluation of a woman with AUB should begin with a detailed menstrual history. 9 The history can help determine the patient s ovulatory status and the impact of bleeding on her lifestyle. 9 Molimina may provide clues indicative of ovulation. 9 The history can also be used to uncover congenital or acquired coagulopathy. 9 The physical examination should attempt to identify the cause of abnormal bleeding. 9 For ovulatory women, the examination should focus on detecting myometrial and intracavitary uterine pathologic conditions (endometrial polyps and fibroids). If the patient is having regular, predictable bleeding, then one can assume that the HPO axis is normal and search for other structural causes. Conditions such as coagulopathy must be considered but are not common especially if the history does not point to bruising, easy bleeding, family history of coagulopathy, or prior problems with surgery. Evidence of coagulopathy (e.g., bruising) and features such as hepatopathy and splenomegaly may suggest systemic disease as the underlying cause of the bleeding. 9 For anovulatory women, the skin and general body habitus may provide some clues about the cause of anovulation. 9 For example, obesity, hirsutism, and acanthosis nigricans may suggest PCOS. 9 A careful visual and manual pelvic examination can be used to identify non-genital-tract causes of bleeding (e.g., anal fissures) as well as anatomic causes of genital bleeding such as vaginal lacerations, cervical polyps, or uterine enlargement suggestive of pregnancy or adenomyosis. 9 Laboratory Tests in the Evaluation of AUB The hemoglobin, hematocrit, and platelet count should be assessed in all patients with AUB. 9 The need for additional laboratory testing should be dictated by the history and physical examination. 9 A sensitive urinary 19 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

21 assay for pregnancy should be performed in women who have a relatively short history of bleeding or who are at risk for pregnancy. 9 Recently, ACOG recommended screening for von Willebrand disease (vwd) in women, especially those with excessively heavy menses and those scheduled for endometrial ablation. The platelet function screen (PFA-100), when normal, effectively excludes platelet dysfunction and vwd. Increasingly, the platelet function screen will decrease the need for the extensive and costly tests utilizing a peripheral smear, prothrombin time (PT), activated partial thromboplastin time (APTT), and vwd panel. In the past, a vwd panel was ordered when the PT and APTT was normal. 9 If ovulatory status is uncertain, luteal phase progesterone may be measured. 9 Tests for thyroid-stimulating hormone (TSH), serum prolactin, and serum testosterone may also be helpful if indicated by the clinical picture. 9 In sexually active women, cultures for infection, especially Chlamydia, Neiserria gonorrhea, and wet prep microscopic evaluation for Trichomonas vaginalis, may be helpful. 34 A Pap test should also be performed to screen for cervical dysplasia. 34 Diagnostic Techniques in the Evaluation of AUB There are several techniques available for evaluating AUB; these may be used to rule out anatomic or organic causes (e.g., carcinoma, endometrial polyps) of the abnormal bleeding. Diagnostic techniques reviewed below include: Endometrial biopsy Transvaginal ultrasonography (TVS) Hysteroscopy Saline infusion sonography (SIS) Magnetic resonance imaging (MRI) Endometrial Biopsy Endometrial biopsy is a safe, relatively simple procedure that can be performed during the initial office visit. 26 It is widely used for excluding endometrial cancer, especially in peri- and postmenopausal women. 26 A biopsy, when properly timed, may also be used to determine if the bleeding is ovulatory or anovulatory. 37 An endometrial biopsy performed during the expected postovulatory interval (day 18 or beyond) can be used to date the endometrium and determine if it is synchronous (glands and stroma in harmony). A biopsy showing secretory changes in the endometrium provides absolute confirmation that the patient is ovulatory. 37 A drawback to the utility of endometrial biopsy is that it is not a sensitive technique for detecting structural abnormalities, such as polyps or fibroids. 38 Also, biopsy performed at the onset of bleeding may not be helpful because of the extensive stromal breakdown that occurs and the limited information it would provide. Pain associated with office-based endometrial sampling is generally minimal, but some women may unpredictably experience substantial pain. 9 The routine use of a nonsteroidal agent (ibuprofen, naprosyn) 1 to 2 hours before, alone or in combination with local anesthesia, may minimize discomfort associated with endometrial biopsy. 9 Several techniques may be used to obtain endometrial samples. Unfortunately, hospitalbased dilation & curettage (D&C) without concurrent hysteroscopic visualization, is still performed even though it should be discouraged. It is no longer considered the gold standard for evaluation of abnormal bleeding, except in patients who have had a miscarriage. A diagnostic D&C is highly 20 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

22 inaccurate, resulting in missed diagnoses and incomplete removal of intracavitary pathologic tissue, and is associated with a high false-negative rate. Studies dating back at least 30 years have shown that D&C is inadequate for diagnosis of intrauterine disorders, especially endometrial polyps and submucous myomas. 2,38 A recently reported retrospective study demonstrated that D&C failed to detect intrauterine disorders in 248 of 397 (62.5%) women. 2 Office-based sampling techniques have been shown to be at least equivalent to D&C in sensitivity and rate of positive diagnosis/effectiveness, while being less intrusive and more cost-effective. 2,39-41 Several sampling devices are available for office-based endometrial biopsy, including disposable devices (e.g., Pipelle catheter, Tis-u-Trap, Accurette, and Z-sampler), and reusable instruments (e.g., Novak Curette, Randall Curette, and Vabra Aspirator). 9,42 Although the Vabra Aspirator may sample a greater proportion of the endometrium than the Pipelle catheter, it is more expensive, cumbersome to use, painful for the patient, and has not been shown to be more reliable at diagnosis. 9,43,44 At least two studies have shown that the Novak Curette and Pipelle catheter have equivalent sensitivity, with the Pipelle causing less discomfort to the patient. 9,45,46 The use of the Pipelle catheter for performing a biopsy has limitations. 38 The endometrial surface area that can be sampled is small (4.5% to 15%), a 4% to 10% chance of cervical stenosis may complicate or prevent a biopsy, and up to 70% of biopsy samples are nondiagnostic. 38,43,47 Additionally, the detection of endometrial cancer with the Pipelle catheter depends on the total surface area of the tumor. For instance, endometrial cancer that co-exists within a polyp may be missed. It may also be missed if the endometrial cancer is located near the tubal ostia or involves less than 5% of the cavity. The endometrial Pipelle biopsy will not detect submucosal fibroids, and only small portions of a polyp may be sampled. Patients with persistent symptoms despite a normal biopsy require further evaluation. The results of most endometrial biopsies fall into one of several categories (see Table 3). Endometrial hyperplasia with atypia is the most important risk factor for endometrial cancer. 48 Approximately 25% of patients with atypia have been reported to develop endometrial cancer, compared with only 2% of patients without atypia. 48 A finding on biopsy of normal secretory endometrium indicates that the patient is having ovulatory cycles, and abnormal uterine bleeding is therefore most likely due to a cause other than anovulation. 49 Table 3: Possible Endometrial Biopsy Findings Proliferative, secretory, benign, or atrophic endometrium Inactive endometrium Chronic endometritus Tissue insufficient for analysis No endometrial tissue seen Simple or complex (adenomatous) hyperplasia without atypia Simple or complex (adenomatus) hyperplasia with atypia Endometrial adenocarcinoma Some studies have attempted to define women at low risk for endometrial cancer who may not need to undergo endometrial 21 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding