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

23 biopsy. 50,51 Risk factors for endometrial cancer cited in studies include irregularity of the menstrual cycle, obesity, nulligravidity, a history of anovulation, diabetes, hypertension, and tamoxifen therapy. 50,51 Some authors have proposed that women with these risk factors should undergo endometrial biopsy for the evaluation of cancer, and women without these risk factors may not require a biopsy. 50,51 On the other hand, 50% of women ultimately diagnosed with endometrial cancer do not have any identifiable risk factors, except for age. Because endometrial cancer may have variable presentations, strong consideration for endometrial biopsy and appropriate imaging should be sought when a patient does not respond to medical therapy. Transvaginal Ultrasonography (TVS) Transvaginal ultrasound (TVS) is inexpensive, noninvasive, and a convenient technique for indirectly visualizing the endometrial cavity, myometrium, and adnexa, and measuring endometrial thickness. 49 Ultrasound may be used to identify possible abnormal endometrial conditions, such as atrophy, hyperplasia, cancer, leiomyomas, and polyps. 26 In one study involving perimenopausal women, TVS was effective in excluding endometrial carcinoma when it was performed on day 4, 5, or 6 of the menstrual cycle. 52 In evaluating women with postmenopausal bleeding, TVS is extremely helpful. Normally, the postmenopausal endometrial echo measures less than 5 mm. Fewer than 0.5% of women with an endometrial echo less than 5 mm will have endometrial cancer. In this same setting, remember that bleeding in the presence of an endometrial stripe of less than 4 mm can still be due to an endometrial polyp or endometrial atrophy. Thicknesses greater than 5 mm are associated with endometrial hyperplasia, polyps, submucosal fibroids, and endometrial cancer. Even though the endometrium is thicker in women receiving HRT, a thin endometrial echo has high negative predictive value for endometrial cancer. 53,54 The accuracy of TVS as compared to endometrial biopsy in postmenopausal women with abnormal bleeding was evaluated in one meta-analysis. 55 According to this analysis, 96% of women with endometrial cancer and 92% of women with other endometrial disease had a thickness of endometrial echo >5 mm, regardless of administration of HRT. 55 Among the women with a normal endometrium, TVS yielded false-positive results in 8% of women who did not receive HRT and 23% of women who were receiving HRT. 55 Although measurement of the endometrial echo is highly predictive of malignancy, some authors have also found that evaluation of endometrial homogeneity and heterogeneity is helpful. 56,57 When the endometrial echo is >5 mm in thickness, heterogeneous, outside of the normal size-range, indistinct, or cannot be measured, an enhanced view of the endometrium is recommended. Saline infusion sonography (SIS) or hysteroscopy should be performed to better characterize the endometrium. Focal lesions are likely to be missed with endometrial biopsy, but SIS or hysteroscopy can distinguish between focal and global lesions. A focal lesion should be directly removed. Global disease would likely be detected by a Pipelle biopsy. Due to the wide range in fluctuations of the endometrium in the reproductive years (endometrial echo in the proliferative phase of 4 to 8 mm and in the secretory phase of 8 to 14 mm), in this age-group it is difficult to establish via TVS whether pathologic conditions exist within the thickened endometrium. It is best to schedule TVS right after menses (i.e., on days 4 to 6 of the cycle), when the endometrium is thinner (i.e., less than 5 mm). Reproductive-aged women scanned during the early proliferative phase 22 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

24 characteristically have an endometrium <6 mm. When it is greater than this, physicians should strongly consider endometrial polyps, submucosal fibroids, or hyperplasia, which can be better assessed with hysteroscopy or SIS. Limitations of TVS may include problems associated with poor body habitus, skill of the operator, low signal-to-noise ratio, and lack of tissue-characterization. 38 Ultrasound may not always distinguish among a submucosal fibroid, endometrial polyp, or adenomyosis. 58 Hysteroscopy Hysteroscopy with biopsy permits visualization of the endometrial cavity, and this technique has been regarded as the gold standard for endometrial assessment. 26,59-61 However, at least one recent study has reported that the diagnostic accuracy of hysteroscopy may be limited. 61 Hysteroscopy is less sensitive than SIS in detecting endometrial hyperplasia. 62 Most diagnostic hysteroscopies are performed to evaluate abnormal uterine bleeding up to 60%, in one author s experience. 63 Hysteroscopy is also commonly used for the evaluation of infertility, recurrent loss of pregnancy, intrauterine adhesions, foreign bodies, and evaluation and treatment of proximal tubal occlusion with balloon tuboplasty Prior to hysteroscopy, D&C was the primary method of evaluating abnormal uterine bleeding, but D&C is a blind and incomplete sampling technique and has less diagnostic accuracy than hysteroscopy. 26 Without concomitant hysteroscopy, D&C is now regarded as obsolete for the evaluation of abnormal uterine bleeding. 26 By the 1990s, hysteroscopy performed in the office became practical as optics improved and the diameter of the hysteroscope decreased. 38 Diagnostic hysteroscopy can now be performed easily in an office setting, requires minimal anesthesia or sedation, and allows detection of endometrial myomas, polyps, and other lesions that may cause bleeding. 9,26,63 Additionally, diagnostic hysteroscopy can be used to obtain directed tissue biopsies of suspicious lesions and, in some cases (e.g., small polyp or myoma), can be used to remove the lesion. 9 Diagnostic hysteroscopy is particularly useful in the diagnosis of intrauterine lesions in women of reproductive age with ovulatory AUB. 9 Compared with blind sampling (e.g., D&C), diagnostic hysteroscopy is more likely to detect and identify structural abnormalities. 38 Office-based diagnostic hysteroscopy has been associated with a low (<1%) incidence of complications when performed by physicians skilled in the technique. 66 The incidence of complications may be higher when performed by those less skilled in the technique. 9 Complications may include uterine perforation, infections, excessive bleeding, and complications related to the distending medium (e.g., CO 2 embolus). 9,63 The major disadvantages of hysteroscopy in the office include the cost and maintenance of expensive equipment (e.g., camera, insufflator, hysteroscope, video equipment and sterilization instruments), the skill and training required to perform the procedure, and the cost of the procedure. 38 Despite the convenience and acceptability to the patient of hysteroscopy done in the office, most gynecologists in the US still perform hysteroscopy in the operating room. 38 Saline Infusion Sonography (SIS) Saline infusion sonography (SIS) is a relatively new technique that involves the infusion of saline into the endometrial cavity to enhance the detection of abnormalities. This technique is very useful for the evaluation of abnormal bleeding in pre-, peri- and postmenopausal 23 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

25 women. In addition to abnormal uterine bleeding, SIS has been used to evaluate endometrial pathologic conditions for other indications, including the following: 38 Endometrium that is thickened, irregular, immeasurable, or poorly defined on conventional TVS Endometrium that appears irregular on TVS in women using tamoxifen Differentiation between sessile and pedunculated masses of the endometrium Recurrent loss of pregnancy Presurgical evaluation of intracavitary fibroids It has been reported that SIS is superior to TVS alone for evaluating the uterine cavity in patients with abnormal uterine bleeding. 59,61 In one study, SIS accurately identified all abnormalities except one, while TVS alone left polyps undiagnosed in 20% of cases and resulted in equivocal findings in nearly 25% of cases. 59 In another study, the rate of detection of focal intrauterine pathologic tissue using SIS was 94.1%, compared with a rate of detection of 23.5% for TVS. 61 Compared with hysteroscopy, SIS appears to be at least equally effective in detecting uterine pathologic conditions, including polyps, myomas, and adhesions, and SIS may be associated with less pain for the patient. 9,61,62,67 SIS also provides information about the myometrium and its involvement with myomas that is not possible with hysteroscopy. 9 Studies have suggested that the addition of SIS to TVS increased the sensitivity and specificity of evaluation by ultrasound sufficiently so that hysteroscopy was unnecessary in the majority (up to 90%) of women with AUB. 61,68 These authors suggested that TVS with SIS should be the first-line test in the evaluation of women with abnormal uterine bleeding, and that hysteroscopy is necessary only if results of ultrasound and of a biopsy are inconclusive. 61,68 Other authors have reported that the routine use of SIS as an alternative to diagnostic hysteroscopy in the evaluation of women with AUB could potentially lead to two-thirds of diagnostic hysteroscopies being unnecessary. 59 When used in conjunction with endometrial biopsy for the evaluation of postmenopausal women with AUB, SIS may have a sensitivity of 95% to 96.2% and a specificity of 65.7% to 98% for the detection of abnormal endometrial tissue. 38,69 The major disadvantage of SIS compared with hysteroscopy is the inability to obtain samples of lesions and other suspicious tissues. 9 Another reported disadvantage of SIS is that small irregularities caused by blood clots or endometrial protrusions have been frequently misinterpreted as polyps. 59 It may be difficult to perform SIS in patients with a uterus greater than 12 to 14 weeks in gestational size, submucosal fibroids larger than 4 to 5 cm, or large transmural fibroids. 38 Other limitations of SIS include the potential inability to thread the catheter, kinking of the catheter, endometrial pseudopolyps, the introduction of air-bubbles into the uterus, and the inability to distend the uterine cavity in cases of patulous cervix or marked intrauterine adhesions. 38 Imaging in SIS may be difficult in patients having a uterus that is markedly retroverted, retroflexed, or anteverted. 38 Magnetic Resonance Imaging (MRI) Magnetic resonance imaging (MRI) is a powerful and noninvasive technique for visualizing the endometrial cavity and uterine abnormalities. It is gaining widespread acceptance and is cost-effective in many instances for the evaluation of abnormal uterine bleeding. 38 It reliably differentiates 24 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

26 uterine anatomy, localizes pelvic pathologic conditions, and estimates the size of lesions. 38 With MRI, one can precisely localize submucosal fibroids, which may permit a skilled surgeon to resect the fibroids hysteroscopically, thereby obviating the need for hysterectomy. 38 MRI can reliably distinguish between adenomyosis and leiomyomata, and it is more sensitive and accurate than TVS and SIS for these conditions. 38 A recent study reported that MRI had a sensitivity of 1.00 for detecting submucous myomas and a higher specificity (0.91) than TVS (0.90), SIS (0.89), or hysteroscopy (0.87). 70 This study also demonstrated, however, that MRI was not superior to SIS and hysteroscopy in overall diagnostic potential of morphology in the uterine cavity, primarily because MRI failed to be reliable in diagnosing endometrial abnormalities such as polyps APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

27 TREATMENT The goals of treatment for AUB are to control acute bleeding, prevent future abnormal bleeding, and minimize the risk of endometrial cancer, which is increased in association with long-term anovulation. 37 AUB may be managed medically or surgically, and a variety of effective options exist in both treatment modalities. In choosing the treatment in any particular case, one should consider the cause of the bleeding, whether the woman desires to maintain fertility, and the patient s desired outcome. Medical Treatment of AUB Medical therapy is preferred over surgical therapy for the treatment of AUB, especially if the woman desires future fertility and has no anatomic, organic, or systemic cause for the bleeding. 71 In the absence of pregnancy and anatomic pathology requiring surgical treatment, women with AUB, and especially anovulatory uterine bleeding, should be encouraged to try medical therapy as the primary option for controlling the bleeding. 8 Several medical treatments for AUB are available, including administration of any of the following: Iron Antifibrinolytics Cyclooxygenase inhibitors Progestins Estrogens plus progestins (oral contraceptives, vaginal contraceptive ring, contraceptive patches) Parenteral estrogens Androgens (Danazol) GnRH agonists and antagonists Antiprogestational agents Iron The average woman in North America ingests enough dietary iron to replace that lost in menstrual blood volumes of up to 60 ml per month. 16 Menstrual volumes that exceed 60 ml per month may lead to iron-deficiency anemia. In many women with AUB, the primary symptom is fatigue secondary to anemia. 12 The anemia may be successfully treated with daily doses of mg of iron, an essential component of medical management of the patient with AUB. In some cases, administration of iron may be the only treatment necessary. 12 Antifibrinolytics Because fibrinolysis plays an important role in hemostasis of the bleeding menstrual endometrium, the use of antifibrinolytics has been evaluated in the treatment of women with AUB. In particular, tranexamic acid (TA) and its precursors have been found to be particularly effective in reducing menstrual blood loss In trials comparing TA with progestins and cyclooxygenase (COX)- inhibitors, TA reduced menstrual blood loss by 45% to 54% In these trials, the progestin (luteal phase norethindrone 5 mg BID on days 19 through 26) actually led to a 20% increase in menstrual blood loss, while the COX-inhibitors (flurbiprofen and mefenamic acid) led to decreases of 24% and 20%, respectively In one study, a TAprecursor (Kabi 2161) reduced menstrual bleeding by 41% compared with no change in the group receiving placebos. 72 In light of such favorable data, it is easy to see why antifibrinolytics are a mainstay for the treatment of ovulatory AUB in most of the world, but it is puzzling to understand why 26 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

28 these agents are rarely administered in North America. 12 One author proposed that North American physicians may be mistakenly concerned about an increased risk of thromboembolic events in women receiving antifibrinolytics. 12 This concern is largely unwarranted. One retrospective study in a large cohort of women at enhanced risk for thromboembolic disease failed to show an association between administration of tranexamic acid and thromboembolic events. 76 Clinical trials are currently underway in the US. Cyclooxygenase (COX) Inhibitors Prostaglandins (PGs) also play a central role in normal menstrual hemostasis and may be involved in the pathogenesis of AUB. 12 Within the endometrium, cyclooxygenase (COX) converts arachidonic acid into PGs, and COX-inhibitors such as non-steroidal anti-inflammatory drugs (NSAIDs) have therefore been evaluated in the treatment of AUB. NSAIDs that have been shown to be effective in the treatment of menorrhagia include mefenamic acid, meclofemenate, diclofenac, flurbiprofen, ibuprofen, indomethacin, naproxen, and naproxen sodium. 12 Controlled comparative trials have shown, however, that other medical therapies, such as the antifibrinolytic TA, may be superior to NSAIDs in the treatment of menorrhagia. 12,74,75 Progestins Progestins are commonly administered for the treatment of AUB. 12 In North America, the agent of choice seems to be medroxyprogesterone acetate, although norethindrone is commonly prescribed in the rest of the world. 12 Progestins may be administered cyclically (usually on a monthly schedule), continuously, or locally through progestin-impregnated IUDs. 12 No randomized controlled trials have compared the efficacy of progestins with placebos for the treatment of AUB, but several trials have compared progestins with other medical therapies. 12 For women with ovulatory AUB (i.e., menorrhagia), several comparative trials demonstrated little benefit from the cyclic administration of norethindrone (10 to 15 mg/day during the luteal phase). 73,77-79 This is hardly surprising, since the mechanism of action of cyclic progestin therapy is to induce a scheduled withdrawal menses. The result is a predictable menses, but the amount of blood loss may not be diminished until therapy has been continued for several months. One trial even showed that cyclic administration of norethindrone led to a 20% increase in volume of bleeding in menorrhagic women. 73 Since ovulatory women already experience regular menses, cyclic progestin therapy offers few advantages. Continuous administration of progestins alone (i.e., without estrogens) may be more effective in the treatment of ovulatory AUB, but there are no published data evaluating this approach. 12 With this approach, the goal is to render the woman amenorrheic. Continuous progesterone therapy causes atrophy of the endometrium. While many women would welcome the total absence of menses, some may find a regular, self-limited menses a reassurance that they are not pregnant. Women with anovulatory uterine bleeding, with absence of the post-ovulatory progestagenic luteal phase, are more likely to benefit from the administration of cyclic progestins. 12 As long as their endometrium is estrogenized (as with PCOS), administration of a short course of progestin results in a selfregulated withdrawal menses. Studies have shown that the cyclic administration of norethindrone successfully restored regular and predictable menses in more than 50% of women with anovulatory uterine bleeding. 79,80 In the setting of unopposed estrogenstimulation, progestin-therapy is essential to prevent and reverse the risk of endometrial neoplasia. 27 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

29 The local administration of progestins through progestin-impregnated IUDs has reduced volume of bleeding in women with AUB. In trials comparing the efficacy of progestin IUDs with other medical and surgical therapies for AUB, patients who received the IUDs experienced reductions in volume of bleeding of 79% to 94%. 78,81 Of note, women preferred the IUD over other medical and surgical therapies. In one study, 76% of women elected to continue therapy with the IUD, compared to 22% of women who elected to continue treatment with oral norethindrone. 78 In other studies, 64.3% to 82% of women who received the IUDs but were also scheduled for hysterectomies elected to cancel the surgeries due to satisfaction with the IUDs. 82,83 Esrogens Plus Progestins (Oral Contraceptives) Oral contraceptives (OCs) are effective for the treatment of both ovulatory AUB and anovulatory uterine bleeding, but only a few studies have been published to support such use. 12,84 It is likely that contraceptive skin patches (Ortho Evra) and vaginal contraceptive rings (Nuvaring) would likely have the same positive impact as oral contraception, but have not been studied rigorously. Nonetheless, knowledge about the pathophysiology of AUB offers some theoretical explanations for the success of OCs in treatment. For example, women with hypothalamic menstrual irregularity may have atrophic endometrium, and the estrogen component of OCs could promote endometrial growth. 84 In women with a thickened endometrium, progesteronedominant oral contraceptives increase the number of progestin receptors, which may allow the progestin component of OCs to oppose the unopposed estrogenic endometrial growth more efficiently. 84 In ovulatory cycles, low-dose OCs suppress ovulation and, over time, thin the endometrial lining to an inactive state. The withdrawal menses seen are typically shorter in duration and decreased in amount. In anovulation, OCs level out the fluctuations in estrogen, which often initiate breakthrough bleeding. Again, OCs restore a regular pattern to the menses, and the progestin component prevents endometrial neoplasia. In addition, OCs suppress the ovarian production of androgens commonly seen in PCOS and reduce the symptoms of hyperandrogenemia. Combination OCs are also effective in adolescents with excessive uterine bleeding. Combined estrogen-progesterone therapy reduces menstrual blood flow, and estrogen raises levels of both factor VIII and vwf. A typical regimen is one tablet three times daily for 7 days, a withdrawal bleed for 5 days, and then standard pill-cycles for 2 months. 30 Treatment may then be discontinued for observation. 30 In the US, combination OCs are the most commonly prescribed medical treatment for AUB in women of reproductive age, especially for anovulatory uterine bleeding. Although dose/response studies have not identified the optimal dose of estrogen for treating AUB, it may be clinically prudent to choose a pill containing 30 or 35 µg of ethinyl estradiol, rather than one containing 20 or 50 µg, for patients with AUB. 84 Ultra-low-dose oral contraceptive pills (20 mcg) are associated with higher frequencies of breakthrough bleeding. One trial evaluated the efficacy of triphasic norgestimate ethinyl estradiol (35 µg) for the treatment of AUB. 84 Both the investigators and patients rated the triphasic OC as significantly more effective than placebo in reducing bleeding. 84 One trial compared the efficacy of a monophasic OC to two NSAIDs (mefenamic acid and naproxen) and low-dose danazol (an androgen) in the treatment of ovulatory AUB. 85 In this trial, the OC 28 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

30 provided a reduction in bleeding similar to the other medical therapies. Low-dose OCs may also be effective as add-back therapies for women taking GnRH agonists for the treatment of AUB. 12 Noncompliance is an issue that may surface with long term OC usage. Women become noncompliant with OC therapy for many reasons (i.e., concern about long-term health consequences or side effects). Parenteral Estrogens Conjugated equine estrogens (CEEs), administered by intramuscular injection or intravenous (IV) infusion, are the most widely prescribed emergent medical treatment for acute, excessive, and rapid uterine bleeding. 12 Evidence suggests that parenteral estrogens may be effective in the treatment of both ovulatory AUB and anovulatory uterine bleeding. 86 In one randomized controlled trial, IV administration of conjugated estrogens stopped the bleeding in 71% of women with AUB, compared with 38% of those who received placebos. 86 Acute bleeding in adolescent girls usually results from anovulation and inadequate stimulation of the endometrium by estrogen. 30 For severe bleeding resulting in adverse complications (i.e., anemia or hypotension), initial treatment with high-dose estrogens may be effective. Profound menorrhagia rapidly responds to high-dose intravenous CEEs, promoting rapid regrowth of endometrial tissue, covering denuded endometrium, stabilizing lysosomal membranes, and stimulating proliferation of endometrial ground substance. The administration of IV CEEs (25 mg every 4 hours) will usually result in rapid reduction of uterine bleeding. 30 For adolescents with less serious bleeding, low-dose CEEs (2.5 mg administered orally every 4 to 6 hours for 14 to 21 days) may be appropriate. 30 Once bleeding has stopped, progestins should be administered for 7 to 10 days. 30 Even in the office setting, estrogen alone or in a combination, such as in an oral contraceptive, can be useful. When the bleeding has been recurrent, estrogen can reproliferate areas of injury due to breakthrough bleeding, leading to healing and hemostasis in that portion of the endometrium. This can be followed by a course of progestin withdrawal to initiate a normal menses. Androgens Danazol, a synthetic derivative of 17a-ethinyl testosterone, has been used successfully to reduce menstrual bleeding in women with ovulatory AUB, with higher doses (eg, 200 to 400 mg/day) generally being more effective than lower doses (eg, 100 mg/day). 12,87-89 Two trials compared the efficacy of danazol with that of cyclic norethindrone in women with ovulatory AUB. 87,88 Danazol decreased menstrual volume in about half of the women, while norethindrone was not effective. 87,88 Danazol has also been shown to be more effective than mefenamic acid (an NSAID) in women with ovulatory AUB. 89 However, many women may find the adverse effects associated with danazol ( e.g., weight gain, oily skin, acne, and deepening of the voice) sufficiently unpleasant to make longterm therapy with this agent undesirable. 12 GnRH Agonist and Antagonists GnRH agonists, which create a reversible hypogonadotropic state by down-regulating GnRH-receptors, dramatically decrease production of gonadotropin by the anterior pituitary. 12 They have been evaluated primarily for stopping bleeding associated with leiomyomas, but may be effective for bleeding associated with both ovulatory AUB and anovulatory uterine bleeding. 12 Agonists to GnRH induce amenorrhea by decreasing total uterine volume by about 40% to 60%. 12 Administration of agonists has been associated with a gonadotropin flare, which 29 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

31 may induce bleeding in the second week after starting therapy. Cost and significant sideeffects (e.g., osteopenia, vasomotor symptoms) may limit the suitability of use of GnRH-agonists for the treatment of AUB. 30 Antagonists to GnRH may also create a hypogonadotropic state and may be effective for treating bleeding associated with both ovulatory AUB and anovulatory uterine bleeding. Antagonists, however, would not be associated with the gonadotropin flare associated with agonists. 12 Antiprogestational Agents The antiprogestational agent mifepristone, at a dosage of 50 mg/day, has been reported to induce amenorrhea in subjects with leiomyomas. 12 Administration of the agent has been shown to reduce the number of progesterone receptors in the myometrium, but not the number of estrogen receptors. 12 This suggests that its ability to induce amenorrhea is a result of its antiprogestational activity. 12 Asoprinil is currently being evaluated in Phase II trials for treatment of leiomyoma and is associated with decreasing menstrual flow and increased rates of amenorrhea. Clinical Application of Medical Therapy With the availability of several proven medical therapies for AUB, knowing when and in whom to use any one particular agent may be confusing. When deciding on a therapeutic regimen, the physician should consider the patient s desire for conception or contraception, as well as whether the AUB is ovulatory or anovulatory in nature. Additionally, some medications may be contraindicated in certain women. For example, oral contraceptives are contraindicated in women over 35 years of age with cardiovascular risk factors, including cigarette-smoking, thrombotic disease, breast cancer, hepatitis, and coagulopathies. 9 Ovulatory AUB Women with ovulatory AUB have a number of medical options for treatment. If contraception is desired, combination OCs reduce menstrual blood loss by about 50% and would be a good initial therapy. 12 Progestin IUDs, which reduce menstrual blood loss by 80% to 90%, would be another good choice. 12 For women who desire fertility, the antifibrinolytic agent tranexamic acid (TA) would be an effective and apparently safe treatment (when available). 12 A dosage of 1g four times daily for days 1 through 4 of the menses reduces menstrual bleeding by about 50%. 12 Such a regimen would be particularly attractive for women who desire to limit treatment to a few days per month. 12 Use of NSAIDs would also be effective at reducing menstrual blood loss, but not quite as effective as use of TA. Use of NSAIDs would, however, also be effective for reducing dysmenorrhea. 12 Use of agonists to GnRH may also be an effective treatment for women with ovulatory AUB. In one study, a GnRH-agonist was combined with add-back treatment (cyclic estrogen-progestin) for vasomotor symptoms and prevention of osteopenia. 90 The women in this study experienced a significant reduction in bleeding volume, and 90% were willing to continue therapy beyond 12 months. 90 Anovulatory Uterine Bleeding Because the mechanisms involved in anovulatory uterine bleeding are unique, the strategies for medical treatment for these women differ significantly from those for women with ovulatory AUB. 12 If possible, the cause of anovulation should be identified and treated, which would allow ovulation and 30 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

32 regular menses to resume. 12 Cyclic progestins and combination OCs are usually effective in women with anovulatory uterine bleeding, because these agents ameliorate the basic deficit of luteal-phase progesterone. 12 Cyclic progestins may be ideal for those patients with contraindications to use of combination OCs, such as women over the age of 35 who smoke, those with other cardiovascular risk factors, or those with a history of recurrent deep vein thrombosis. 30 Use of GnRH agonists is an effective but expensive treatment for anovulatory uterine bleeding. 12 Some evidence suggests that short-term treatment with GnRH may provide lasting benefits, which would help reduce overall costs associated with therapy. 91 In one study, 3 months of goserelin therapy resulted in reduced bleeding in 21 of 38 women (55%) evaluated 4 months after the cessation of therapy. 91 Women with anovulatory uterine bleeding are less likely to benefit from antifibrinolytics and NSAIDs than women with ovulatory AUB, because these agents target mechanisms specific to ovulatory women. Although they haven t been studied in use for women with anovulatory uterine bleeding, progestin IUDs and continuous systemic progestins could be expected to cause troublesome breakthrough-bleeding. 12 Surgical Treatment of AUB When medical therapy fails, surgical treatment of AUB is common, with hysterectomy being the most common technique employed. 92 Several techniques for endometrial ablation are also commonly used, and others are under clinical investigation. For many women, endometrial ablation may be more appropriate than hysterectomy. As stated previously, D&C is now considered obsolete for the evaluation of AUB, because the results of surgical therapy are transient, and it is therefore obsolete as a treatment for AUB as well. Diagnostic D&C is highly inaccurate, resulting in missed diagnoses and incomplete removal of intracavitary pathologic conditions. Use of D&C will not be discussed further as a treatment for AUB in this paper, because several more appropriate surgical procedures exist, and these are outlined below. The main surgical therapies for the treatment of AUB include the following: Hysterectomy Hysteroscopic endometrial ablation (several techniques) Nonhysteroscopic endometrial ablation (several techniques) Hysterectomy Hysterectomy is the most common surgical treatment for AUB. Of the approximately 550,000 hysterectomies performed each year in the United States, up to 40% of them may be performed for the treatment of AUB. 92,93 Moreover, up to 50% of the uterine specimens demonstrate no histologic abnormality. 94 Multiple techniques are used to perform hysterectomies, including: total abdominal hysterectomy (TAH), vaginal hysterectomy (VH), laparoscopically-assisted vaginal hysterectomy (LAVH), laparoscopic supracervical hysterectomy (LSH) and total laparoscopic hysterectomy (TLH). 91 Abdominal hysterectomy (AH) generally costs more and is associated with greater morbidity than VH. 95 The LAVH was developed to reduce the costs and morbidity associated with AH. 91 Studies indicate that outpatient LAVH is a safe and well-accepted alternative to traditional inpatient hysterectomy. 96 Both LSH and TLH are slowly gaining in popularity as techniques and tools for performing these procedures improve. Potential advantages 31 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

33 over other hysterectomy methods include decreased morbidity and significantly improved recovery time. 97 Hysteroscopic Endometrial Ablation Use of the hysteroscope has been incorporated into several techniques for endometrial ablation, which appear to be the surgical treatments of choice for managing AUB. 98 These techniques, however, require specialized training and surgical expertise, and they involve a significant learning curve. 98 These techniques have also been associated with serious adverse effects, including fluid overload (see below), uterine perforation, infection, hemorrhage, thermal injuries, and death. 98 The first hysteroscopic ablative techniques employed the Nd:YAG laser, in which laser energy is transmitted to the endometrium through a flexible quartz fiber passed through the hysteroscope. Tissue-necrosis reaches a depth of 4 mm to 5 mm. 92 Following endometrial ablation with the Nd:YAG laser, the vast majority of patients (>90%) experienced a significant reduction in uterine blood flow. 92 Approximately half had amenorrhea, and the other half had either hypomenorrhea or normal menstrual flow. 92 In one study, more than 80% of the patients considered the procedure successful, and failures and complications of treatment were infrequent (8% and 4%, respectively). 99 In clinical practice, electrosurgical techniques of hysteroscopic endometrial ablation have superseded the laser technique. 92 Electrosurgical techniques include rollerball coagulation, resection with a loop electrode, and electrosurgical vaporization. 92 In rollerball ablation, an electrode with a large surface area (ball, barrel, ovoid, or bar) is passed over the endometrium to coagulate the tissue. In another technique, an electrosurgical loop electrode is used to resect endometrial tissue. Potential advantages of this technique include availability of tissue for histologic analysis and a lower risk of concealed endometrial hyperplasia or carcinoma. 92 Electrosurgical vaporization is a relatively new technique, in which a fairly large electrode with multiple edges is used to vaporize endometrial tissue. For all three electrosurgical techniques for endometrial ablation (i.e., rollerball coagulation, loop resection, and vaporization), clinical outcomes are equally high, with about 90% of patients experiencing a significant reduction in volume of bleeding. 92 Failures and complications of treatment are generally low, and a majority of the failures that are retreated experience a successful outcome. 92 Electrical surgical procedures can be performed utilizing monopolar or bipolar equipment. Electrosurgical techniques that use an electrolyte-free, low-viscosity solution for distention of the endometrial cavity employ monopolar technology. Media commonly used in distention for this purpose include 3% sorbitol, 1.5% glycine, 5% mannitol, and solutions of sorbitol and mannitol. 92 Each of these solutions may be absorbed into the systemic circulation and may lead to dilutional hyponatremia and hypoosmolality when safety parameters are not followed. 100,101 In rare cases, long-term morbidity and death due to fluid overload have been reported. 92 Thus, rigorous management of fluids is critical for the safety of electrosurgical endometrial ablation. 92 More recently, bipolar technology, which is used in the presence of normal saline or lactated ringers, provides a greater margin of safety when performing longer and more complex hysteroscopic resections of myomas or endomyometrial resection. These fluids are not associated with hyponatremia. Nevertheless, surgeons must still monitor fluid deficits in order to reduce the risks of pulmonary or cardiac overload. 32 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

34 Nonhysteroscopic Endometrial Ablation Nonhysteroscopic endometrial ablation mandates an excellent preoperative evaluation, since a device is inserted without concomitant hysteroscopy. Nonresectoscopic techniques for endometrial ablation are attractive for several reasons. First, they require relatively little skill and experience to perform successfully and safely, as opposed to resectoscopic techniques, which require precise eye and hand coordination. 92 Additionally, because they don t require distention media, the risk of fluid overload is obviated. Furthermore, these techniques may be performed relatively quickly in the office or clinical environment. 92 A number of nonhysteroscopic ablative techniques have been approved by the FDA. These are reviewed briefly below. Some of these technologies are described as global ablation techniques, as they are designed to ablate the entire endometrium simultaneously. Others are operative in that they require interpretation of, and reaction to, monitoring throughout the procedure. Balloon Ablation - This technique is a thermal ablative system that utilizes a silicone intrauterine balloon filled with a solution of dextrose and water, which is heated to 87 C for 8 minutes. Clinical trials have demonstrated that balloon ablation resulted in clinical outcomes (e.g., bleeding response and patient satisfaction) similar to those achieved with rollerball electrosurgical ablation and hysteroscopic endometrial resection. 98,102,103 The ThermaChoice Uterine Balloon Therapy System is approved for use in the US. 92 Circulating free fluid A newer technique known as hydrothermablation involves the use of heated free fluid. The procedure includes a hysteroscope used to visualize the endometrial cavity during the procedure, although the hysteroscope does not contribute to the procedure per se. This device, the HydroThermAblator Endometrial Ablation System, is currently approved by the FDA for clinical use. Preliminary results from one study suggested that efficacy of hydrothermablation was similar to that achieved with rollerball electrosurgical endometrial ablation. 92,104 Cryoablation One cryotherapeutic endometrial ablative device, the Her Option Uterine Cryoablation Therapy System, was approved by the FDA for clinical use in April Data from postcryoablation studies of hysterectomy indicate that cryoablation can uniformly destroy the endometrium to a depth of 9 mm to 12 mm. 105 Preliminary data indicate that cryoablation is safe and effective for the treatment of AUB and may potentially be performed with a paracervical block and less anesthesia than rollerball electrosurgical ablation. 106 Intra-procedural pelvic ultrasound is required to monitor treatment when the cryoprobe is used. Preliminary data also indicate that more than one freeze-cycle, and as many as four cycles, leads to higher rates of good patient outcomes. 107 In the FDA clinical trial, pretreatment with leuprolide acetate was employed. 107 Bipolarelectrodes One bipolar device (the NovaSure System) employs electrodes utilizing a combination of electrosurgical vaporization and desiccation/ coagulation. 92 Suction is required to remove steam and vapor from the endometrial cavity. 92 Therapy with the device reportedly lasts for less than 2 minutes on average. One significant advantage is that success and amenorrhea rates comparable to those of rollerball can be achieved without hormonal 33 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

35 pretreatment of the endometrium and can be scheduled at anytime of the menstrual cycle. The device was approved by the FDA in 2001 for clinical use. Microwave Microwave energy (Microwave Endometrial Ablation system) was the last device approved for endometrial ablation by the FDA in It differs from other devices because it can treat a larger uterine cavity (up to 12 to14 cm size) and can be used in the presence of fibroids and polyps up to 3 cm in size. Both success and amenorrhea rates exceeding those of rollerball in the pivotal trial were unaffected by the presence of fibroids up to 3 cm in size. 108 When fibroids were separately analyzed, amenorrhea and hypomenorrhea was sustained in the presence of fibroids too. In one study involving women followed for 3 years, 84% of the patients were satisfied with the treatment. 109 Another study compared microwave therapy with hysteroscopic endometrial resection. 110 After 12 months of follow-up, patients were equally satisfied with both treatments. 110 for intent-to-treat groups from separate studies as reported in documents for FDA Summary of Safety and Effectiveness Data (SSED) for each device. These data do not reflect head-to-head comparison of the devices, so caution should be used when comparing efficacy of the devices based on these data. Diode laser - The use of a low-power Nd:YAG diode laser has been proposed as a safe and effective technique for endometrial ablation. 92 A preliminary study has reported that this technique results in relatively high rates of amenorrhea.112 However, high costs of equipment associated with the laser may prevent use of the technique in clinical practice. 92 Table 4 presents data comparing the ThermaChoice Uterine Balloon Therapy System, Hydro ThermAblator Endometrial Ablation System, Her Option Uterine Cryoablation Therapy System, and the NovaSure System (bipolar electrode device). The data presented in this table were collected 34 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

36 For any endometrial ablation procedure, commonly reported post-operative events include the following: Cramping/pelvic pain: Post-treatment cramping can range from mild to severe. The cramping will typically last a few hours, but may continue beyond the first day after the procedure. Nausea/vomiting: Usually occurs immediately following the procedure and can be managed with medication. Vaginal discharge. Vaginal bleeding/spotting. Relative Costs Associated with Surgical Treatments Because the rates of success for various hysteroscopic and nonhysteroscopic endometrial ablative techniques are similar and high around 90% of women experience a satisfactory reduction in menstrual bleeding cost of surgical therapies may play a significant role in determining procedures of choice. Several studies comparing the costs of hysterectomy to endometrial ablation have been conducted. 111 Among hysterectomy techniques, vaginal hysterectomy (VH) is the least costly, followed by abdominal hysterectomy (AH) and laparoscopic hysterectomies (LAVH, LSH, TLH). 111 The laparoscopic techniques result in fewer inpatient days, but overall costs are increased, largely due to the use of disposable rather than nondisposable surgical supplies. 111,112 Hysteroscopic endometrial ablative techniques cost about 50% less than hysterectomy (in direct hospital costs). 111 The economic savings associated with endometrial ablation may be even greater if indirect costs, such as reduced morbidity and faster return of the patient to work, are considered APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

37 Hysterectomy is, however, a one-time procedure offering complete resolution of abnormal uterine bleeding, while endometrial ablation may require a repeated procedure or eventual hysterectomy, increasing its overall costs. One study of long-term outcomes revealed that 5 years following endometrial ablation, about 80% of women had no further surgery and 91% had not had a hysterectomy. 113 Indeed, in a recent study published in the British Medical Journal, a reduction in number of hysterectomies by almost 15,000 per year has been realized in the UK over the interval from 1995 to 2003, a large portion of which has been attributed to the availability and adoption of endometrial ablation. 114 There are a variety of causes and treatment options available. Clinicians need to keep abreast of the latest diagnostic and management techniques in order to effectively monitor the many facets of AUB. In another cost-analysis of endometrial ablation versus hysterectomy, Brumstead and colleagues estimated that a rate of failure of 53% would be required before the economic advantage of endometrial ablation is lost. 115 Since the failure-rate of endometrial ablation is estimated to be about 10% to 20%, it appears that the economic advantage of endometrial ablation is sustained over time. 113 Conclusion Abnormal uterine bleeding is a widespread, often undisclosed, medical problem affecting women of all ages. For women, this problem is not just a medical issue, but a quality-of-life issue. 36 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

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44 replacement therapy for dysfunctional uterine bleeding. Br J Obstet Gynaecol. 1996;103: Colacurci N, De Placido G, Mollo A, et al. Short-term use of goserelin depot in the treatment of dysfunctional uterine bleeding. Clin Exp Obstet Gynecol. 1995;22: Munro MG. Abnormal uterine bleeding: surgical management Part III. J Am Assoc Gynecol Laparosc. 2001;8: Brooks PG, Clouse J, Morris LS. Hysterectomy vs resectoscopic endometrial ablation for the control of abnormal uterine bleeding. A cost comparative study. J Reprod Med. 1994;39: Cooper JM, Erickson ML. Global endometrial ablation technologies. Obstet Gynecol Clin North Am. 2000;27: Kovac SR. Hysterectomy outcomes in patients with similar indications. Obstet Gynecol. 2000;95: Manko LG. Outpatient laparoscopic hysterectomy. Obstet Gynecol. 2001;97:21S. 97. Anderson TL, Lindsay JH, Daniell JF. Performing laparoscopic supracervical hysterectomy. OBG Management. 1999;11: Gervaise A, Fernandez H, Capella- Allouc S, et al. Thermal balloon ablation versus endometrial resection for the treatment of abnormal uterine bleeding. Hum Reprod. 1999;14: Garry R, Shelly-Jones D, Mooney P, et al. Six hundred endometrial laser ablations. Obstet Gynecol. 1995;85: Istre O, Shahaa K, Schjoensky AP, et al. Changes in serum electrolytes after transcervical resection of endometrium and submucous fibroids with the use of 1.5% glycine for irrigation. Obstet Gynecol ;80: Kim AH, Keltz MD, Arici A, et al. Dilutional hyponatremia during hysteroscopic myomectomy with sorbitol-mannitol distention medium. J Am Assoc Gynecol Laparosc. 1995;2: Meyer WR, Walsh BW, Grainger DA, et al. Thermal balloon and rollerball ablation to treat menorrhagia: a multicenter comparison. Obstet Gynecol. 1998;92: Grainger DA, Tjaden BL, Rowland C, et al. Thermal balloon and rollerball ablation to treat menorrhagia: twoyear results of a multicenter, prospective, randomized clinical trial. J Am Assoc Gynecol Laparosc. 2000;7: Brooks PG. A clinical comparison between hydrothermablation and rollerball ablation to treat menorrhagia: a multicenter clinical trial. Obstet Gynecol. 2000;95:S Dobak JD, Williams J, Howard R, et al. Endometrial cryoablation with 43 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

45 ultrasound in women undergoing hysterectomy. J Am Assoc Gynecol Laparosc. 2000;7: Coddington C, Duleba A, Soderstrom R, Townsend D, Willems J. Data on 222 patients from a multicenter study using Cryogen first option uterine cryoblation therapy in women with abnormal uterine bleeding. Obstet Gynecol. 2001;97:21S Sanders B. Preliminary outcomes of longer freeze cycles in the treatment of women with abnormal uterine bleeding using CryoGen first option uterine cryoblation therapy. Obstet Gynecol. 2001;97:14S Cooper JM, Anderson TL, Fortin CA, Jack SA, Plentl MB. Microwave Endometrial Ablation vs.rollerball electroablation for menorrhagia: A multicenter randomized trial. J Am Assoc Gynecol Laparosc. 2004;11: Hodgson DA, Feldberg IB, Sharp N, et al. Microwave endometrial ablation: development, clinical trial and outcomes at three years. Br J Obstet Gynaecol. 1999;106: Gynecol Clin North Am. 2000;27: Daniell JF, Anderson TL. Hysterectomy and Health Care in America: Finding the Balance Between Costs and Outcomes. In: Bean J and Sipkoff, ed. Hospital Strategies in Managed Care Faulkner and Gray; O'Conner H, Magos A. Endometrial resection for the treatment of menorrhagia. NEJM. 1996;335: Reid PC, Mukri F. Trends in number of hysterectomies performed in England for menorrhagia: examination of health episode statistics, 1989 to BMJ. 2005;330: Brumstead JR, Blackman JA, Badger GJ, et al. Hysteroscopy versus hysterectomy for the treatment of abnormal uterine bleeding: a comparison of cost. Fertil Steril. 1996;65: Cooper KG, Bain C, Parkin DE. Comparison of microwave endometrial ablation and transcervical resection of the endometrium for treatment of heavy menstrual loss: a randomised trial. Lancet. 1999;354: Hidlebaugh DA. Cost and quality-oflife issues associated with different surgical therapies for the treatment of abnormal uterine bleeding. Obstet 44 APGO Educational Series Clinical Management of Abnormal Uterine Bleeding

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