Abnormal Uterine Bleeding: A Primary Care Primer

ABSTRACT: A detailed menstrual cycle history is critical in women with abnormal uterine bleeding (AUB). If a patient has a history of intermenstrual bleeding, inquire about postcoital bleeding, which may occur in the setting of cervicitis, polyps, or other cervical or vaginal lesions. Metrorrhagia and menometrorrhagia imply anovulation. Recommended laboratory tests include thyroid-stimulating hormone, fasting serum prolactin level, and cultures for Neisseria gonorrhoeae and Chlamydia. In women with menorrhagia who have ovulatory cycles, ultrasonography is recommended to document uterine anatomy. Laboratory studies include measurement of hemoglobin level or hematocrit and a urinary human chorionic gonadotropin test. Postmenopausal bleeding warrants a complete assessment to rule out anatomic pathology and endometrial cancer. Options for management of AUB include oral contraceptives, NSAIDs, and hormone therapies. Key words: menstruation, metrorrhagia, menometrorrhagia, menorrhagia ____________________________________________________________________________________________________ Menstrual disorders are one of the most common complaints of women seen in primary care. Abnormal uterinebleeding (AUB) is a broad term that encompasses bleeding at abnormal or unexpected times or excessive flow at times of expected menses.1  Excessive and unpredictable cycles can cause iron deficiency anemia as well as psychological stress. In this article, we review the principal causes of AUB, as well as approaches to evaluation and treatment. Recommendations are made with reference to the strength of evidence (Box). OVERVIEW Normal menstruation occurs every 21 to 35 days and lasts approximately 4 to 6 days. Total blood loss is approximately 30 mL. Menstrual flow that exceeds 80 mL is considered excessive, based on the amount of blood loss that would produce anemia in a woman taking the recommended daily allowance of iron.2 Despite many attempts to quantify blood loss, including pictorial charts and pad collection, the assessment of abnormal uterine bleeding is primarily subjective.3  In one report, 14% of women with menstrual blood loss of less than 20 mL reported heavy bleeding, while 41% of women with menstrual loss of more than 80 mL described their bleeding as light to moderate.4  Of women who report excessive menstrual flow, only half have measurable blood loss greater than 80 mL—the formal criterion for excessive flow.5,6  Of women who meet this criterion, only two thirds have a hemoglobin level below 12 g/dL and only 44% have low iron levels.4  Thus, not all women who meet the criterion for excessive menstrual flow exhibit anemia and/or low iron levels.  Accurate diagnosis and effective medical management of women with AUB is critical. In one study, 10% of women scheduled for hysterectomy declined surgery when objective evidence showed that their cycles were normal,6  and 14 of 17 women in a smaller study accepted reassurance and opted not to have surgery when objective data showed that their blood loss was within the normal range and posed no risk to their health.7  About 20% to 33% of women who undergo hysterectomies for AUB have no anatomic abnormalities.8,9 Dysfunctional uterine bleeding (DUB) is a type of AUB that is not related to an anatomic condition, systemic disease, or pregnancy.10  Many authors define DUB as occurring only with anovulatory cycles; others consider ovulatory DUB to be a separate entity characterized by regular, predictable cycles and excessive menstrual loss. Although the exact mechanism is unclear, ovulatory DUB is thought to result from disruption of local hemostatic factors.11 PREPUBERTAL GIRLS Occasionally, newborn girls have a small amount of vaginal bleeding secondary to placental estrogenic stimulation of the endometrium. This condition is self-limited; in the absence of trauma and with a normal abdominal examination, only reassurance and follow-up are needed (strength of recommendation [SOR] level C).1  After the newborn period, girls who present with vaginal bleeding but without secondary sexual characteristics require a pelvic examination, occasionally under anesthesia, to rule out a foreign body, vaginitis, genital trauma or, very rarely, malignancy (SOR level C).1,12  In girls who manifest breast development or an unusual increase in height, an ovarian source of estrogen should be ruled out with abdominal ultrasonography.1  An evaluation for precocious puberty is recommended if a girl shows signs of pubertal development before age 8 years (SOR level D).13 ADOLESCENTS AUB is the most frequent cause of urgent admission to the hospital among adolescent girls.3  By far the most common cause of AUB in this age group is anovulation attributable to immaturity of the hypothalamic-pituitary axis. However, other causes of heavy bleeding—including complications of pregnancy and bleeding disorders—must be considered. Up to 80% of adolescents are anovulatory for the first year after menarche, and about 50% of adolescents are anovulatory for the first 2 years of menses.10,14 Persistence of anovulation beyond 2 to 3 years of menarche warrants further investigation (SOR level C).1 Although anovulatory cycles are normal during the onset of menarche, most adolescents do not experience excessive bleeding. The incidence of bleeding disorders among adolescents evaluated for excessive bleeding is about 12% to 33%.6,15  One report found that 25% of adolescents who present with a hemoglobin level of less than 10 g/dL had an underlying coagulation disorder.15  Another study demonstrated that 13% of women of all ages who presented with menorrhagia had bleeding disorders.16 Because the prevalence of bleeding disorders in adolescents is significant, screening with coagulation studies (such as prothrombin time or partial thromboplastin time) and a platelet count is warranted (SOR level B). Adolescents with significant menstrual blood loss—defined as a hemoglobin level of less than 10 g/dL or bleeding that warrants hospitalization—should also have a ristocetin cofactor assay of von Willebrand factor before hormone therapy is initiated (SOR level B).17,18 WOMEN OF REPRODUCTIVE AGE AND OLDER WOMEN After pregnancy is ruled out, a detailed history of a patient’s menstrual cycles is critical. Determine the cycle length and bleeding duration, and attempt to quantify the amount of flow. Women often describe their cycles as “irregular” whether they are experiencing intermenstrual bleeding or menometrorrhagia. Intermenstrual bleeding. This is a pattern of unpredictable, usually light, bleeding or spotting between regular cycles. If a patient has a history of intermenstrual bleeding, ask about postcoital bleeding, which may occur in the setting of cervicitis, polyps, or other cervical or vaginal lesions. Recurrent spotting at day 14 in a normal ovulatory cycle occurs in some women as the estrogen level dips; in the absence of other risk factors, only reassurance is required (SOR level D).3 Contraceptive modalities, including inert intrauterine devices (IUDs), progesterone-only contraceptives, and combination oral contraceptive pills (OCPs), frequently cause intermenstrual bleeding. Even one missed pill can cause breakthrough bleeding. An increased progesteroneto- estrogen ratio can result in thinning and denudation of the endometrial lining. Breakthrough bleeding has become more common with the use of lower doses of estrogen. However, even in OCPs that contain higher doses, bleeding can occur as a result of the saturation of estrogen receptors by progesterone, which greatly reduces the concentration of estrogen.19 The physical examination of a patient with intermenstrual bleeding includes a thorough inspection of the perineal area to detect other possible causes of bleeding, including urinary or GI sources. The speculum examination, in which all surfaces of the vaginal walls are viewed, also focuses on identification of specific sites of potential blood loss. A cervix that is friable because of inflammation is a frequent source of intermenstrual spotting. Therefore, in addition to cervical cultures and a Papanicolaou smear, consider a potassium hydroxide evaluation and a saline wet slide preparation. Depending on the patient’s age and other risk factors, endometrial cavity evaluation for focal hyperplasia or cancer may be warranted. Metrorrhagia/menometrorrhagia. These conditions imply anovulation. In the absence of ovulation, unopposed estrogen causes proliferation of the endometrium, which eventually outgrows its structural support and sloughs.3  Therefore, women with anovulatory cycles often have episodes of amenorrhea or very light cycles interspersed with very heavy bleeding. Determine the length of anovulation, and obtain a detailed history to determine whether a secondary cause of anovulation (Table 1) might be present. Findings such as acanthosis nigricans, obesity, striae, hirsutism, and acne may support androgenic causes. Any complaint of AUB warrants a thorough pelvic examination. Cultures for Neisseria gonorrhoeae and Chlamydia and a recent cervical smear are also required. However, perineal, vaginal, and cervical lesions and inflammation are unlikely to cause the pattern of bleeding observed with anovulatory cycles. Question the patient to confirm the absence of ovulatory symptoms, such as premenstrual discomfort, breast tenderness, mood changes, and bloating. Obtain a 21-day progesterone level if ovulation cannot be determined by history.20 Other recommended laboratory studies include tests for pregnancy, thyroid-stimulating hormone, and fasting serum prolactin (SOR level B). Only one third of women with hyperprolactinemia have galactorrhea, and subclinical hypothyroidism and hyperthyroidism may both cause abnormal bleeding.18  Obtain a hematocrit or hemoglobin level if bleeding is excessive. Testing for androgenic causes with a luteinizing hormone (LH)– to–follicle-stimulating hormone (FSH) ratio and free testosterone may be indicated by the history.21  A low FSH level may also indicate a hypothalamic cause, and elevated levels of both LH and FSH may indicate ovarian failure.21  Endometrial cavity evaluation is sometimes warranted, especially if the patient has received long-standing unopposed estrogen therapy. Menorrhagia. In women who are found to be ovulatory by history or laboratory testing, attempt to determine the extent of menstrual loss, possibly with use of pictorial charts.7 Heavy ovulatory bleeding is less common than anovulatory bleeding and indicates impaired hemostasis either locally—as in the setting of submucosal fibroids or ovulatory DUB— or from a systemic coagulopathy.12  A history of alcoholism or liver disease, easy bruising or bleeding, heavy menses since menarche, or a family history of bleeding disorders may prompt further workup for coagulopathy. If the patient has undergone major surgery without excessive bleeding, a hereditary coagulation disorder is unlikely.22 Note any extensive bruising or ecchymosis. Submucosal fibroids cannot be ruled out by examination and are the only fibroids thought to interfere with local hemostasis. Ultrasonography is therefore recommended to document uterine anatomy (SOR level B). Hemoglobin or hematocrit level and a urinary human chorionic gonadotropin test are the only universally recommended laboratory studies. Other tests may be considered depending on the history. One report found that in women aged 30 to 49 years with menorrhagia, the incidence of an inherited bleeding disorder was 17%. This suggests that coagulation studies may be warranted in women with documented menorrhagia in the absence of anatomic pathology (SOR level C).23  Perimenopausal and postmenopausal bleeding. Vaginal bleeding after menopause in a woman who is not taking hormone replacement therapy or 12 months after the initiation of hormone replacement therapy warrants a complete assessment to rule out anatomic pathology. A thorough pelvic examination, including cervical smear, should be followed by an evaluation of the uterine cavity (SOR level B). Endometrial cancer is the fourth most common cause of malignancy in women; most cases occur in postmenopausal women.24  An endometrial tissue evaluation is indicated in postmenopausal women with vaginal bleeding to rule out hyperplasia and cancer. Pipelle endometrial sampling is as accurate as dilation and curettage and is easily performed in the office.25  However, Pipelle sampling is nondiagnostic in 2% to 38% of cases, is uncomfortable, and often misses focal hyperplasia or polyps.24 A large meta-analysis demonstrated that transvaginal ultrasonography (TVUS) showing a thin endometrial stripe (5 mm or less) has negative predictive value comparable to that of endometrial Pipelle sampling (96% vs 97.5%) and is an acceptable alternative (SOR level A).2  Moreover, other pathologic conditions, such as atypical or focal hyperplasia and polyps, may be detected with TVUS.24  The specificity of TVUS decreases to 77% in women using hormone replacement therapy. The falsenegative rate of TVUS (8%) also compares favorably with that of Pipelle sampling (5% to 15%), which suggests that neither test excludes endometrial cancer with complete certainty.24,26 Therefore, if an identifiable source of bleeding is not found in a postmenopausal woman, referral to a gynecologist for possible hysteroscopy or saline infusion sonohysterography is warranted (SOR level B).26,27 Although abnormal bleeding in perimenopausal women is often attributable to anovulatory cycles, 10% to 20% of cases of endometrial cancer occur in premenopausal women.28 How to identify women who are at risk for endometrial cancer or hyperplasia is still a subject of debate. Most clinicians use age as a criterion for evaluating the uterine cavity. However, the incidence of endometrial cancer is 2% to 5% in women younger than 40 years.29 Risk stratification based on factors other than age may therefore be appropriate.30  Risks include longstanding anovulation, obesity, nulliparity, diabetes mellitus, hypertension, tamoxifen therapy, and a family history of colon cancer.28,29,30  Weight of more than 90 kg was shown to have the highest predictive value for endometrial hyperplasia or carcinoma; it correlated better than age older than 45 years in one study.28  Another study showed irregular cycles to be a better predictor of hyperplasia on biopsy than age.31  Consider endometrial cavity evaluation at an earlier age in obese women and in those with anovulatory cycles (SOR level B).18,28  Larger studies are needed to determine whether women older than 40 years who have AUB and no other risk factors can be managed with watchful waiting. Recent studies have shown that a thin endometrial stripe on ultrasonography is also sufficient to exclude hyperplasia or cancer in premenopausal women.31  Initial screening with TVUS on day 4 to 6 of a woman’s cycle decreases the need for endometrial biopsy by 65%. This method reduces costs and detects focal abnormalities that may have been missed by biopsy (SOR level B).31  Moreover, it better distinguishes premenopausal women whose lesions require more focal hysteroscopic sampling from those with globally thickened endometrial tissue, who are more appropriate candidates for Pipelle sampling.31 MEDICAL MANAGEMENT Options for medical management of AUB include OCPs and other hormone therapies, as well as NSAIDs. OCPs. These are the most widely prescribed agents for AUB in the United States; they are effective for both menorrhagia and metromenorrhagia. However, there is little highquality evidence to support their use. One small trial showed that a monophasic OCP was equivalent to NSAIDs and low-dose danazol for menorrhagia.32  A more recent randomized controlled trial showed that a triphasic preparation containing 35 μg of estrogen reduced blood loss in DUB more effectively than placebo.33 OCPs are considered first-line treatment in anovulatory cycles for women who also desire contraception (SOR level B).34  No evidence supports the superiority of monophasic over triphasic agents. OCPs are also widely used for acute bleeding in hemodynamically stable women who have an acceptable hematocrit or as a way to add progesterone in women whose acute bleeding has already been stabilized by estrogen, although only anecdotal evidence supports their use in this setting. The typical regimen is estrogen, 35 μg bid to q6h, for 5 to 7 days (SOR level D).34 NSAIDs. In a Cochrane metaanalysis, 5 of 7 randomized controlled trials showed that NSAIDs were an effective treatment for menorrhagia (SOR level B).35  However, a trial that compared NSAIDs with other treatments showed that both danazol and tranexamic acid (an antifibrinolytic) were more effective for menorrhagia.36,37  There are few studies that compare combination OCPs with NSAIDs, and there is no evidence that any one NSAID is superior to another. NSAIDs are a readily available treatment option for menorrhagia—especially in the case of desired fertility—when used during menses or with concurrent dysmenorrhea (SOR level B). NSAIDs are also an option for first-line treatment of women who have breakthrough bleeding associated with OCPs (SOR level D) or bleeding associated with copper or other inert IUDs (SOR level C).10,34 Women with anovulatory cycles are unlikely to respond to NSAIDs.4 Antifibrinolytics. A number of randomized controlled trials show that tranexamic acid is a more effective treatment of menorrhagia than NSAIDs and cyclic progestins (SOR Level A).4  Antifibrinolytics decrease blood loss by 40% to 60% and are taken only 4 days per month.38 Strong evidence supports the safety of antifibrinolytics; a large Scandinavian trial that followed 238,000 women for 19 years dispelled the notion of a theoretical increased risk of thromboembolic disease, even in high-risk women.39,40 Although tranexamic acid is the mainstay of treatment of menorrhagia in the rest of the world, it is not available in the United States. This option would be particularly appealing for women who desire fertility. No randomized controlled trials have compared antifibrinolytics with OCPs. Women with anovulatory cycles are unlikely to benefit from antifibrinolytics.34 Clomiphene citrate. There is no evidence from randomized controlled trials to support the effectiveness of this agent for AUB. However, it is recommended by the American College of Obstetrics and Gynecology and other groups as an option for women with idiopathic anovulatory bleeding who desire fertility (SOR level C).4,11,19 Etrogens. High-dose estrogens are the most widely used treatment for acute AUB. However, only one randomized controlled trial exists that shows intravenous estrogen to be superior to placebo (cessation of bleeding in 71% of women, compared with 38% in the placebo group).41 Nevertheless, conjugated equine estrogens, 25 mg q4h IV for a maximum of 24 hours, are considered first-line treatment for acute AUB, even when bleeding is attributable to presumed anovulatory cycles and excess estrogen (SOR level B).4,18 Once acute bleeding has subsided, progestins are usually added, either alone or in a combination OCP. Because nausea and vomiting are common side effects of high-dose estrogen treatment, antiemetics are often required. Oral estrogens are also used to rebuild a denuded endometrium attributable to excess progesterone. One week of supplemental estrogen (ethinyl estradiol, 20 μg/d) may alleviate OCP-induced breakthrough bleeding that persists for 3 months. Other options include conjugated estrogens, 0.625 to 1.25 mg/d, and estradiol, 0.5 to 1 mg/d for 1 to 2 weeks. This therapy is therefore recommended as an alternative to NSAIDs as first-line treatment in bleeding caused by OCPs (SOR level C).10 Progestins. A Cochrane metaanalysis showed that cyclic oral progestins were less effective than tranexamic acid, danazol, or a progesteroneimpregnated IUD for menorrhagia.35 There are no trials that have compared these agents with placebo. However, cyclic oral progestins taken approximately 10 days per month are effective in decreasing menstrual loss attributable to unopposed estrogen in at least 50% of anovulatory women (SOR level B).42 Continuous local progestins.  Progesterone-impregnated IUDs are a promising tool in the management of AUB. Several high-quality randomized trials have shown that results obtained with the IUD are highly satisfactory43-45  and, in some cases, superior to those obtained with medical and surgical treatments (SOR level B).44,45 Reported reductions in bleeding ranged from 79% to 94%.43,45  In one small study, 64% of women scheduled for hysterectomy for menorrhagia canceled their surgery because of satisfaction with the IUD, compared with only 14.3% treated with other modalities.45 Women are often more satisfied with the IUD than other similarly effective medical therapies. In one study, 76% of women who were given an IUD wanted to continue with it, compared with only 22% of those who were given progesterone, despite similar reductions in blood flow.46  Another small randomized trial showed that satisfactory results were obtained with the progesterone IUD, compared with hysteroscopic endometrial resection.43  Neither the progesterone-impregnated IUD nor continuous local progestins have been evaluated in anovulatory women. Androgens. Danazol, an androgenic compound often prescribed by gynecologists, is an effective treatment for menorrhagia.34  However, because of masculinizing side effects, only half of women in one study were willing to continue the medication.36 Gonadotropin-releasing hormone agonists. These agents are occasionally used as a temporizing treatment for menorrhagia secondary to uterine fibroids. They are also used as an alternative to parenteral estrogen in acute severe bleeding; however, there are no studies supporting this approach, and heavy bleeding often develops 1 to 2 weeks after use.34 Antiprogestational agents. There may be an important role for these agents in reducing fibroid growth. In one small study, the antiprogestin RU-486, 50 mg/d, stopped bleeding attributable to uterine fibroids; it produced amenorrhea and a 50% reduction in fibroid size.47  More largescale studies are required to confirm these results. However, the use of this agent as an abortifacient may make availability and further research challenging. Dr Miller is a thirdyear resident in family medicine at Camp Pendleton Naval Hospital in California and a lieutenant in the United States Navy. Dr Holman is adjunct associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md. 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