Abnormal uterine bleeding (AUB) includes heavy, prolonged, or excessive menstrual bleeding that both distresses a woman and interferes with her physical, emotional, social, and/or material quality of life.¹ AUB is also described as bleeding from the uterus of abnormal cycle regularity, volume, frequency, or duration.² It continues to be one of the most common gynecologic complaints,² with the prevalence varying from 10% to 35% of reproductive-age women.³ Higher prevalence is noted to occur with increasing age, particularly in perimenopause. AUB affects more than 10 million women in the United States each year. Nearly a third of gynecologic office visits and approximately 400,000 hospitalizations per year are due to AUB.^1,4 The estimated annual direct costs in the United States range from $1 billion to $1.55 billion, with indirect costs ranging from $12 billion to $36 billion.¹

A normal menstrual cycle length is defined as lasting between 21 and 35 days, with an average of 3–7 days of menstrual bleeding.⁵ Most blood loss typically occurs in the first 3 days of menses, and normal menstrual blood volume ranges from 30 to 50 mL during the entire menstrual cycle.⁵ AUB is a deviation from this normal menstrual pattern and can be defined as either acute or chronic. Acute AUB is an episode of heavy bleeding of less than 6 months duration, which is of sufficient volume to require clinical evaluation and intervention to prevent further bleeding.² Acute AUB can occur spontaneously as well as in the setting of chronic AUB.² Chronic AUB is defined as abnormal bleeding that is present for most of the previous 6 months.² Cycles associated with menstrual volume > 80 mL each month can result in iron-deficiency anemia.

In 2011, the International Federation of Gynecology and Obstetrics (FIGO) proposed a new classification system of AUB to unify the terminology used to characterize bleeding. This system eliminates older, less descriptive terms and instead divides AUB into heavy menstrual bleeding (HMB), formerly known as menorrhagia, and intermenstrual bleeding (IMB), formerly known as metrorrhagia, to avoid these confusing terms that are difficult to reproduce within a research setting.^4–6 Other terms used to describe AUB, such as dysfunctional uterine bleeding (DUB), polymenorrhea, and hypermenorrhea, are considered obsolete and should be abandoned as per the FIGO system. In addition, this classification system conveniently separates the causes of bleeding into uterine structural (PALM) and systemic (COEIN) abnormalities (Fig. 53-1). This acronym, PALM-COEIN, represents these nine etiologies and stands for Polyp, Adenomyosis, Leiomyoma, Malignancy and hyperplasia, Coagulopathy, Ovulatory dysfunction, Endometrial hemostasis, Iatrogenic, and Not otherwise classified.⁶ The abbreviations, AUB-HMG-P, for example, represent abnormal uterine bleeding with heavy menstrual bleeding due to endometrial polyps.

Normal menstruation requires both an intact hypothalamic-pituitary-ovarian (HPO) axis and effective endometrial hemostasis. Disruption of these primary pathways can lead to loss of normal menstrual cycle control. In addition, women can have more than one etiology contributing to their abnormal bleeding, which can complicate evaluation.

DIFFERENTIAL DIAGNOSIS

The pathophysiology of AUB depends on the specific etiologies of bleeding, which are described next.

Polyps

Endometrial polyps are outgrowths of endometrial tissue within the uterine cavity that can cause AUB-Polyps. Although polyps are typically benign, careful histologic examination is required to exclude the presence of malignant and premalignant lesions within them.⁷ The mechanism by which polyps cause AUB is not well understood, but it is postulated that the abnormal vasculature leads to incomplete shedding of the endometrium covering the polyps.⁷

Adenomyosis

Adenomyosis is the presence of endometrial glands and stroma within the uterine myometrium. About two-thirds of women with adenomyosis are symptomatic, with HMB being the most common symptom.⁷ Other symptoms include dysmenorrhea and dyspareunia, with the physical finding of an enlarged, tender uterus upon examination.⁷ The pathophysiology of AUB caused by adenomyosis is thought to be due to decreased contractility of the uterine myometrium.⁷ In addition, superficial adenomyosis with associated myometrial hypertrophy can cause the compression of overlying endometrium, resulting in AUB.⁷

Leiomyomas

Leiomyomas, or fibroids, are benign tumors of the myometrium, and they are the most common tumor in women of reproductive age. Most leiomyomas are asymptomatic, but it is estimated that 20% to `50% of women with fibroids have symptoms attributable to the them, including AUB (AUB-L), pelvic pressure, bloating, congestion, dyspareunia, and constipation. Proposed mechanisms by which leiomyomas cause AUB include increased uterine surface area, increased uterine vascularity, reduced myometrial contraction, endometrial ulceration over submucosal fibroids, and compression of venous plexus within the myometrium; however, limited evidence exists for these mechanisms.⁷

Malignancy and Hyperplasia

Currently, there are two different nomenclature systems used to classify endometrial precancer: 1. the 1994 nomenclature of the World Health Organization (WHO94) and 2. the endometrial intraepithelial neoplasia (EIN) diagnostic schema from the International Endometrial Collaborative Group. The older system characterizes histopathology based on glandular complexity and nuclear atypia with description as simple or complex hyperplasia with or without atypia. Diagnostic categories of EIN include benign endometrial hyperplasia with diffuse histologic changes caused by prolonged estrogen exposure; EIN with focal to diffuse histologic changes considered to be precancerous, and endometrial adenocarcinoma, endometrioid type, well differentiated.⁷ Endometrial hyperplasia develops in the setting of prolonged estrogen exposure typically related to anovulatory menstrual cycles. In the absence of regular ovulation, persistent estrogen effect leads to chronic endometrial proliferation and enhanced blood flow that supports the excess endometrium. Furthermore, progesterone production is limited, which results in less antiproliferative effect on the endometrium. Finally, the normal decrease in progesterone levels at the end of cycle that normally initiates shedding of excessive endometrial tissue does not occur. The end result is fragile, unstable, proliferative endometrium that can shed in a heavy, unpredictable manner.⁷ Endometrial carcinoma is classified into type I, which is associated with unopposed estrogen and is preceded by premalignant lesion, and type II, which has nonendometrioid histology with an aggressive clinical course. Endometrial malignancy causes AUB (AUB-M) because of disruption to endometrial vessels due to invasion by malignant cells and neovasculogenesis.⁷

Coagulopathy

Heavy AUB, particularly in perimenarchal girls, may be a presentation of an inherited, acquired, or iatrogenic systemic disorder of hemostasis, or AUB coagulopathy (AUB-C). Inherited coagulopathies seem to be far more common than generally recognized with an incidence ranging from 10.7% to 34%.⁸ Most early-onset cases are due to von Willebrand disease. A systematic review of the literature has determined that 13% of women of all ages with HMB have von Willebrand disease.⁸

Ovulatory Dysfunction

Heavy AUB may occur more commonly in women with ovulatory disorders (AUB-O) due to a lack of progesterone-dependent endometrial biosynthesis of local hemostatic factors, such as prostaglandin F₂α and endothelin. Thus oligo-ovulation and anovulation lead to a reduction in cyclic progesterone production, with the subsequent biosynthesis of prostaglandins and other substances that control endometrial blood loss.

There are multiple etiologies that influence the hypothalamic-pituitary-ovarian (HPO) axis and result in ovulatory dysfunction. Extremes of age, such as in perimenarchal girls and perimenopausal women, are associated with immaturity and dysmaturity of the HPO axis function, respectively. Multiple chronic diseases are known or suspected to affect the normal function of the HPO axis. Hyperprolactinemia and hypothyroidism are endocrinopathies that can result in anovulation and can be diagnosed with serum prolactin and thyroid-stimulating hormone (TSH) levels, respectively. Pharmacologic agents that affect dopamine metabolism are also known to affect ovulatory function in some women. Other hypothalamic causes of anovulation include psychological stress, rapid changes in weight, and excessive exercise. Two of the most common causes of ovarian dysfunction are obesity and polycystic ovarian syndrome (PCOS), which lead to abnormal steroid balance and androgren excess via multifactorial processes.

Endometrial Hemostasis

Dysfunction in endometrial hemostasis can cause both IMB HMB (AUB-Endometrial, or AUB-E). AUB-E is primarily thought to result from incomplete or abnormal angiogenesis within the endometrium, which leads to fragile, abnormal endometrial blood vessels as well as altered endometrial vascular structure.⁷ In addition, women with persistent monthly HMB are thought to have abnormalities within the stratum basalis of the endometrium, which can produce both abnormal stratum functionalis and endometrial regeneration process, leading to irregular and heavy bleeding.⁷

Iatrogenic

Certain medications can contribute to AUB (AUB-Iatrogenic, or AUB-I). Medications that have an estrogenic effect, such as tamoxifen, can induce endometrial growth and lead to subsequent bleeding.⁷ Although often used as a treatment for AUB, progestin therapies can cause paradoxical AUB, which is thought to be due to abnormal vasculogenesis of progesterone treatment.⁷ Anticoagulation therapy also may contribute to abnormal bleeding.

Not Otherwise Classified

The category of AUB not otherwise specified (AUB-N) includes rare and future entities that do not fall into one of the previously mentioned categories.⁷ One such example is uterine arteriovenous malformations (AVM), which can cause bleeding from abnormal connections between artery and vein.¹¹ A history of curettage for the termination of pregnancy or for treatment of postpregnancy bleeding should alert the clinician to the possibility of an acquired uterine AVM.¹¹

Use of the PALM-COEIN classification system helps guide the clinical evaluation of a woman with AUB (Fig. 53-2). A focused history should include details of the current bleeding episode, such as pattern, volume, and duration of bleeding as well as anemia-related symptoms, including fatigue, palpitations, dyspnea, presyncope, or syncope. The history should target past gynecologic, menstrual, and medical history as well as current medications (e.g. steroids, contraception, anticoagulants) and pertinent family history.^2,5 Consideration must be given to possible bleeding disorders in women with a personal history of HMB since menarche, surgical, or dental bleeding, postpartum hemorrhage, and other stigmata of mucosal bleeding (as described in Table 53-2).⁴⁸

PHYSICAL EXAM FINDINGS

In the setting of acute, heavy bleeding, physical exam should focus initially on signs of hemodynamic instability based on vital signs, anemia symptoms, and hemoglobin levels as well as findings suggestive of the bleeding etiology² (Table 53-1). The clinician should look for signs of systemic illness, such as obesity indicative of ovulatory dysfunction; proptosis, goiter, and thyroid nodule indicative of thyroid disorder; spontaneous galactorrhea and vision disturbance indicative of hyperprolactinemia; hyperandrogenism with hirsutism, acne, male pattern alopecia, and acanthosis nigricans indicative of PCOS; and lanugo and Russell’s sign on the fingers, indicative of eating disorder.^2,5 Physical signs of a bleeding disorder (e.g. ecchymoses < 5 cm in diameter, petechiae, skin pallor, swollen joints) indicate possible bleeding diathesis. An abdominal exam may show a palpable mass, such as leiomyomata, ovarian neoplasm, or both; the pelvic exam must include both speculum and bimanual exams. The vulva, vagina, cervix, urethra, and anus should be inspected for the amount and location of the bleeding, as well as possible signs of genital trauma (laceration/foreign body), malignancy (vaginal or cervical mass/ulceration), infection (ulceration/discharge), vaginal atrophy, or obvious prolapsing myoma or large endometrial polyp. Additional testing, if indicated, should include Pap test in women age 21 and older if not screened within 3 years, and with high-risk HPV testing in women age 30 and older;¹² saline microscopy and 10% potassium hydroxide (KOH) prep; and chlamydia and gonorrhea deoxyribonucleic acid (DNA) probe from the endocervix or vagina. The bimanual exam assesses uterine and adnexal size, contour, consistency, and presence or absence of tenderness. Adenomyosis alone typically causes diffuse, symmetric uterine enlargement with mild tenderness. Fibroids palpate with an irregular contour with variable size and mobility, and also with possible pedunculated myomas that move separately. Likewise, the adnexa in most reproductive-aged women are small to nonpalpable, and the presence of a mass or fullness should be noted for size, contour, consistency, and tenderness.^5,8

LABORATORY FINDINGS

Laboratory evaluation is necessary in all women who present with AUB and should be guided by the PALM-COEIN classification system (see Fig. 53-1).² Basic laboratory testing includes complete blood count (CBC), urine pregnancy test, and ABO blood type and crossmatch, if indicated.² Additional assessment should be guided by the suspected etiology of bleeding. For women with possible bleeding disorder or AUB-C (Table 53-2), the laboratory workup should begin with coagulation studies such as prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen. For women at high risk for a bleeding disorder based on a personal and family history positive screen (see Table 53-2), specific testing includes von Willebrand factor (VWF) antigen, factor VIII function assay, and ristocetin cofactor assay.^2,5 A hematology consult is also recommended. Other testing includes thyroid function tests, prolactin, markers of ovulatory dysfunction such as follicle-stimulating hormone (FSH), and liver function tests.^2,5 Serum iron, total iron-binding capacity, and ferritin levels can be used to assess anemia associated with AUB.² Endometrial sampling should be obtained in women age 45 and older or any age with risk factors, such as chronic anovulation, infertility, diabetes, obesity (> 90 kg), family history of endometrial cancer, or prolonged exposure to unopposed estrogen or tamoxifen (Fig. 53-3)^2,13,49. A smaller study, however, found that only irregular menstrual cycles and age 40 years and older were associated with an increased risk of endometrial neoplasia,¹⁴ which is consistent with the precursor mechanism of chronic anovulation and unopposed estrogen exposure for the development of endometrial hyperplasia and endometrial intraepithelial neoplasia (EIN).

IMAGING STUDIES

In the acute setting, transvaginal ultrasound (TVUS) is the most reliable imaging tool used to assess for endometrial and myometrial abnormalities, such as adenomyosis and myomas (Fig. 53-4). In addition, TVUS can suggest ovarian causes of AUB such as PCOS⁵ and ovarian neoplasm. The ultrasound criteria for PCOS include either ≥ 12 follicles measuring 2 to 9 mm in diameter, or increased ovarian volume > 10 cm³ in one or both ovaries.¹⁵ Uterine or adnexal masses that extend out of the pelvis mandate abdominal ultrasound to fully delineate these structures (Fig. 53-2). Computed tomography (CT) scan of the abdomen and pelvis can be warranted for indeterminate ultrasound images, concern for malignancy, or evaluation of other causes of abdominal-pelvic masses. Outpatient imaging, including TVUS, saline infusion sonohysterography (SIS), and hysteroscopy, are commonly used to assess for anatomic causes of AUB;⁵ SIS uses normal saline to distend the uterine cavity, which allows resolution of intracavitary lesions, such as polyps and myomas.⁵ Hysteroscopy permits direct visualization of the endometrium, looking for global changes, such as atrophy or diffuse hyperplasia, as well as focal intracavitary lesions, such as polyps, submucous myomas, and hyperplasia/malignancy.^2,5 However, SIS and hysteroscopy are not first-line treatments for evaluation of acute AUB due to difficult visualization from intrauterine clot and debris. Likewise, a thickened endometrium can interfere with the accuracy of SIS, obscuring intracavitary lesions, or creating false-positive lesions.⁸