AUB accounts for approximately 30% of all gynecology visits [5]. Despite its frequency, AUB is a difficult diagnostic and therapeutic challenge and accounts for more than half of all hysterectomies performed in the USA. Approximately 20% of hysterectomy specimens removed for AUB have no visible pathology [6]. This suggests that many cases of AUB are potentially treatable using hormonal therapy or other systemic or local treatment modalities.

A solid understanding of the normal menstrual cycle is essential to effectively evaluate and treat women with irregularities. The concept of normal menstruation is somewhat subjective and often varies between individual women and certainly between cultures. The normal menstrual cycle occurs over a span of 4.5–8 days every 24–38 days, with cycle-to-cycle variation over 12 months of ±2 to 20 days [4]. Normal menstruation should not cause severe pain or include passage of large clots.

Peri-menarchal (age <20) and peri-menopausal (age >40) stages have tremendous cycle length variation as these age ranges have the highest prevalence of anovulatory cycles [7].

The total amount of blood lost during a normal menstrual period has been estimated to average 30 mL and should be <80 mL. In most women, 90% of all blood loss per cycle occurs within the first 3 days of menstruation [8]. However, menstrual blood loss is difficult to estimate clinically, because much of the menstrual effluent is dissolved endometrium [9]. If the patient is changing pads or tampons more than once per hour, this is considered to be outside the parameters of normal menstruation.

The different bleeding patterns of AUB often give hints to the etiology and can be used to guide the appropriate diagnostic work-up. Due to the marked variation in presentation and the possible existence of multiple causes of bleeding, presentation alone cannot be used to clinically exclude common conditions .

Dysfunctional uterine bleeding (DUB) is a term that refers to excessive uterine bleeding in cases in which no uterine pathology can be identified and is therefore a diagnosis of exclusion [10]. Due to the development of a greater understanding of AUB and the availability of more sophisticated diagnostic techniques, this term is less frequently used today.

In many cases that would have been referred to as DUB in the past, modern diagnostic techniques identify either uterine or systemic pathologies that (1) result in anovulation (e.g., hypothyroidism), (2) result from anovulation (e.g., endometrial hyperplasia or carcinoma), or (3) coexists with anovulatory bleeding but may or may not be causal (e.g., leiomyomata). Bleeding unrelated to uterine pathology can usually be determined to be a result of chronic anovulation (polycystic ovary syndrome [PCOS] and related conditions), exogenous steroid hormones (contraceptives or hormone replacement therapy), or hemostatic disorders (e.g., von Willebrand disease).

Treatment is most likely to be effective when specific causes of AUB can be identified. Since the term “DUB” is used to refer to widely divergent causes of AUB, a national consensus group recently concluded that this term is unlikely to improve diagnosis or treatment and thus no longer has any usefulness in clinical medicine [11].

AUB can be grouped according to the basic pathophysiology of the various etiologies. The clinician must keep in mind that any individual patient can simultaneously have more than one cause of uterine bleeding (◘     Table 8.2). Therefore, the work-up should include an appropriate evaluation encompassing both likely and serious anatomic and systemic etiologies.

It is important to exclude pregnancy in every case of AUB in a reproductive-aged woman, no matter how obvious any alternative diagnosis may be. Pregnancies are the most common cause of AUB in the reproductive age group, including normal pregnancies, spontaneous abortions, ectopic pregnancies, and gestational trophoblastic disease.

First-trimester bleeding occurs in up to 25% of all pregnancies and is associated with an increased risk of many common complications [12]. In approximately half of these cases, bleeding will be an early symptom of impending spontaneous abortion, whereas the remaining half will ultimately prove to have a viable pregnancy. Ectopic pregnancies currently make up 2% of all pregnancies and commonly present with AUB as one of the presenting symptoms [13]. Gestational trophoblastic disease is another pregnancy-related problem that presents as AUB in >80% of cases [14].

It is a priority for gynecologists to precisely identify uterine pathology that might contribute to uterine bleeding. Most of these diagnoses can be determined to be related to infection and neoplasm. Additionally, a common uterine pathology related to AUB is adenomyosis.

Infection, in the form of endometritis, is an under-recognized cause of AUB and is often the basis of what appears to be AUB. In obvious cases of pelvic inflammatory disease, approximately 40% of patients will present with vaginal bleeding [15]. However, subclinical endometritis can also result in AUB.

Chronic endometritis was diagnosed in the past only when plasma cells were found on endometrial biopsy. More recent studies have shown an association between AUB and endometritis that manifests only as reactive changes in the surface endometrium and not in association with the presence of a particular type of inflammatory cell [16]. Other studies have verified that subclinical endometritis is a common finding in patients diagnosed with AUB and can be related to any of a number of different pathogens [17].

Cervicitis is another commonly recognized cause of AUB and is characterized by postcoital spotting. Postcoital bleeding is the most common presenting symptom in women found to have Chlamydia infections [18]. In addition to common sexually transmitted diseases (i.e., chlamydia and gonorrhea), other vaginal flora and pathogens can also cause cervicitis [19].

AUB can be a presenting symptom for gynecologic neoplasms involving the cervix, uterine fundus, or ovaries. These neoplasms can be benign (e.g., endometrial or endocervical polyps, leiomyoma) or malignant (e.g., endometrial or cervical carcinoma). Focal intracavitary lesions account for up to 40% of cases of AUB [20]. Neoplasms of the ovary can indirectly cause irregular bleeding by interfering with ovulation, as discussed below. Some of the most common neoplasms known to cause AUB are reviewed below.

These benign tumors of the myometrium are remarkably common and by age 50 can be found in almost 70% of white women and >80% of black women upon ultrasonographic examination [21]. Many of these leiomyomas are subclinical, and estimates of symptomatic leiomyomas range from 20–40%.

Submucosal and intracavitary leiomyomas that distort the uterine cavity are most likely to result in menorrhagia, presumably because of a direct effect on the adjacent endometrium. Large intramural leiomyomas can sometimes result in menorrhagia. However, the majority of leiomyomas that are intramural, subserosal, or pedunculated on the external uterine surface are not associated with AUB.

This benign condition involves the invasion of endometrium into the myometrium. Microscopic examination of the uterus reveals endometrial glands and stroma deep within the endometrium surrounded by hypertrophic and hyperplastic myometrium. This histopathologic diagnosis is found in over 60% of hysterectomy specimens [22]. Clinically, two-thirds of patients with adenomyosis will complain of menorrhagia and dysmenorrhea, and pelvic examination usually reveals a diffusely enlarged and tender uterus.

Diagnostic tests that help suggest the diagnosis of adenomyosis include both transvaginal ultrasonography and magnetic resonance imaging. The sensitivity for ultrasonography approaches 50%, and the sensitivity of MRI ranges from 80 to 100% [22]. Perhaps in the future, there will be more effective diagnostic testing for adenomyosis and treatments other than hysterectomy .

Endometrial polyps are localized overgrowths of the endometrium that project into the uterine cavity. These polyps may be broad-based (sessile) or pedunculated. Endometrial polyps are common in both pre- and postmenopausal women and are found in at least 20% of women undergoing hysteroscopy or hysterectomy [23]. The incidence of these polyps rises steadily with increasing age, peaks in the fifth decade of life, and gradually declines after menopause.

In premenopausal women complaining of AUB, studies have shown that from 5 to 33% will be found to have endometrial polyps [24]. Endometrial polyps are commonly found in patients with a long history of anovulatory bleeding, suggesting that polyps may be the result of chronic anovulation in some women. Polyps can also be found in women complaining of post-menstrual spotting or bleeding in ovulatory cycles or during cyclic hormonal therapy. Endometrial polyps in premenopausal women are almost always benign [23]. However, the risk of endometrial malignancy increases with age, and one study reported the risk of malignancy in polyps in women >65 years old was >50%.

It is unlikely that endometrial hyperplasia causes AUB. However, this condition is most often found in premenopausal women with AUB with prolonged anovulation [25]. Although endometrial hyperplasia is not in itself a health risk, it is both a precursor to and marker for concurrent endometrial cancer, particularly in the presence of atypia.

The single most important disease to identify early in the evaluation of a peri- or postmenopausal woman with AUB is endometrial cancer. Approximately 20% of endometrial cancer is diagnosed in women before menopause and 5% before the age of 40 years [26]. After the menopause, approximately 10% of women with AUB will be found to have endometrial cancer, and the incidence rises with each decade of life thereafter.

These soft, fleshy growths originate from the mucosal surface of the endocervical canal. They usually arise from a stalk and protrude through the cervical os, although some may be broad-based. They usually range in size from 3 to 20 mm, but occasionally can be larger.

Endocervical polyps are known to be more frequent in women on oral contraceptives and with chronic cervicitis; however, the etiology remains unclear. Microscopically, endocervical polyps consist of a vascular core surrounded by a glandular mucous membrane and may be covered completely or partially with stratified squamous epithelium. In some polyps, the connective tissue core may be relatively fibrous. Endocervical polyps removed from women taking oral contraceptives often show a pattern of microglandular hyperplasia [27].

Endocervical polyps are relatively common in sexually active women, but are rare before menarche. Many endocervical polyps are asymptomatic and are discovered incidentally on visual examination of the cervix. In other instances, these polyps can manifest as intermenstrual and/or postcoital spotting .

Cervical dysplasia can be found in up to 17% of women presenting with postcoital spotting, and 4% will have invasive cancer [28]. In the absence of a visible lesion, Papanicolaou smears and colposcopy (if indicated) are important diagnostic tools. In the presence of a visible cervical lesion, it is critical to biopsy the lesion to confirm the clinical diagnosis.

Many women experience heavy or irregular menstrual bleeding that is not caused by an underlying condition of the uterus. Anovulatory bleeding is one of the most common underlying causes; however, a number of other unrelated causes, such as exogenous hormones and bleeding disorders, must also be considered (◘     Table 8.3).

Hormonal therapy is one of the most common causes of AUB. Specifically, irregular bleeding is the most common symptom of women receiving contraceptive therapy and hormone replacement therapy (see ►     Chap. 10) and the most common reason for discontinuation of these therapies.

Approximately ten million women in the USA use some type of hormone contraception, including combination oral contraceptives, progestin-only pills, depot medroxyprogesterone acetate injections, progestin-containing intrauterine devices, subdermal levonorgestrel implants, transdermal combination hormone patches, and intravaginal rings. In addition to being a common reason to visit primary care physicians and gynecologists, AUB is the major reason for contraception discontinuation and subsequent unplanned pregnancy.

During the first 3 months of combination oral contraceptive use, as many as one-third of women will experience AUB. For the vast majority of women, the most effective treatment approach is patient reassurance and watchful waiting. As the uterus adapts to the new regimen of hormonal exposure, the monthly withdrawal bleeding becomes regular, lighter, and less painful than natural menstruation in most women.

If abnormal bleeding persists beyond 3 months while a patient is on hormonal contraceptives, other common causes should be excluded. In young, sexually active women, sexually transmitted diseases should be excluded, because in one study, almost one-third of women on oral contraceptives who experienced abnormal bleeding were found to have otherwise asymptomatic Chlamydia trachomatis infections [29]. If no cause for AUB other than hormonal therapy is found, treatment options include the use of supplemental estrogen or changing to an oral contraceptive with a different formulation that has a different progestin or higher estrogen content.

Women using progestin-only contraceptives have a greater risk of continued AUB than those using combined oral contraceptives. Prolonged exposure to progestins results in a microscopic condition sometimes called “pseudoatrophy ” (see the section on Endometrial Atrophy). When reassurance is not sufficient, administration of supplemental estrogen during these bleeding episodes is sometimes useful .

Abnormal or absent ovulation is a common cause of AUB during the reproductive years. A brief description of normal menstrual physiology (which is covered in depth in Chap. 1) is useful in understanding anovulation as an underlying cause of AUB.

Each month, the endometrium of normally ovulating women is exposed to physiologic levels of estradiol (50–250 pg/mL), accompanied in the last 14 days of each cycle by progesterone (mid-luteal phase >12 nmol/L). The result is a structurally stable endometrium 5–20-mm thick as measured by transvaginal ultrasound.

Withdrawal of progesterone and estrogen results in menstruation, which involves the breakdown and uniform shedding of much of the functional layer of the endometrium, which is enzymatically dissolved by matrix metalloproteinases [30]. Normal menses occur every 28 ± 7 days, with duration of flow of 4 ± 2 days, and a blood loss of 40 ± 40 mL [31]. Hemostasis is achieved by a combination of vasoconstriction of the spiral arterioles and normal coagulation mechanisms.

Irregularity or absence of ovulation is common among reproductive-aged women not using hormonal contraception. In the perimenarchal years, adolescents often have anovulatory cycles as part of the maturation process, but only occasionally do they complain of clinically significant AUB. In the perimenopausal years, anovulatory cycles again become more common for many women. These episodes of endometrial exposure to unopposed estrogen increase the risk of not only AUB but also endometrial hyperplasia and endometrial cancer. During the intervening years, both chronic and intermittent intervals of anovulation can occur, usually as a result of a treatable underlying condition.

Anovulation results in AUB as a result of chronic exposure of the endometrium to estrogen, without the effect of cyclic exposure to postovulatory progesterone. Endometrium that is exposed to unopposed estrogen becomes abnormally thickened and structurally incompetent. The result is asynchronous shedding of portions of the endometrium unaccompanied by vasoconstriction.

The bleeding associated with unopposed estrogen exposure is usually heavy. Since the blood has not been lysed by endometrial enzymes, blood clots are often passed, resulting in increased menstrual cramping in many women. Prolonged periods of bleeding also appear to predispose to subclinical endometritis, which can further exacerbate bleeding, and is often unresponsive to hormonal therapy .

The most common cause of chronic anovulation is a disorder that can present with a constellation of symptoms and is referred to as PCOS (see ►     Chap. 8). PCOS is a heterogeneous endocrine and metabolic disorder that affects 6–10% of reproductive age women [32]. This syndrome is diagnosed when a woman without an underlying condition is found to have two out of the following three criteria: (1) oligo- or anovulation, (2) clinical and/or biochemical evidence of hyperandrogenemia, and (3) polycystic ovaries [33]. These women have circulating estrogen levels in the normal range, but anovulatory progesterone levels.

PCOS is believed to result from insulin resistance in many women [32]. In today’s culture, insulin resistance is often the result of obesity. However, only 70% of women with PCOS are obese [33]. Insulin resistance will be found in approximately 75% of women with PCOS who are obese, but <40% of those who are not obese [34].

The mechanism whereby insulin resistance results in PCOS is intriguing [35]. Insulin increases production of androgens by both the ovaries (primarily androstenedione and testosterone) and adrenal gland (primarily dehydroepiandrosterone). In the ovary, insulin increases androgen secretion by both theca cells, which are LH-dependent, and ovarian stroma cells. These increased androgens contribute to hirsutism and may contribute to the increased body mass often seen in PCOS patients. These androgens can be aromatized peripherally in both fat and muscle to estrogen (primarily estrone), which acts on the pituitary to increase secretion of LH, which in turn stimulates the ovaries to secrete more androgens in concert with insulin. The positive-feedback loop that results is believed to be the cause of many cases of PCOS. The accuracy of this interpretation is supported by the observation that in many overweight patients, either weight loss or the use of an insulin-sensitizing agent (e.g., metformin) will simultaneously improve insulin resistance and restore regular ovulatory cycles [35].

Some patients that are oligo- or anovulatory can have an underlying systemic disease, which makes these patients clinically indistinguishable from PCOS. Although some diseases can be detected with appropriate testing, not all of these systemic conditions can be treated such that the symptoms completely resolve.

Conditions that result in signs and symptoms identical to PCOS can be divided into two groups. The first group includes conditions that cause hyperandrogenemia, which in turn can interfere with ovulation and result in a clinical picture identical to PCOS [36]. These include adult-onset congenital adrenal hyperplasia, Cushing’s syndrome and disease, and androgen-secreting neoplasms of the ovary or adrenal gland. Adult-onset congenital adrenal hyperplasia should be suspected whenever PCOS symptoms occur simultaneously with menarche. Cushing’s and androgen-secreting tumors should be suspected when hyperandrogenism and ovulation dysfunction present rapidly in a woman with previously normal menstrual cycles.

The second group consists of any systemic condition that can interrupt ovulation. Both hypothyroidism and hyperprolactinemia are relatively common conditions that can have no other symptoms other than interfering with ovulation. Simple blood tests can screen for these conditions in the initial evaluation of PCOS. In addition, any serious systemic disease can interfere with ovulation—most notably, renal failure and chronic liver disease. These systemic disorders can also affect hemostasis. Patients with serious systemic diseases, however, usually manifest significant symptoms in addition to ovulatory dysfunction and AUB [37].

Endometrial atrophy from any cause can result in AUB and is usually described as spotting. The significance of this type of AUB is that it is indistinguishable from the earliest symptoms of endometrial cancer and thus must be carefully evaluated in the peri- and postmenopausal woman.

Hypoestrogenemia is most commonly the result of surgical or natural menopause. Although natural menopause occurs at an average age of approximately 51 years, 2% of women undergo premature menopause before the age of 40 years. Hypoestrogenemia also occurs in women with normal ovaries who lack gonadal hormonal stimulation due to pituitary or hypothalamic pathology, descriptively grouped together as having hypogonadotropic hypogonadism. Causes of this condition include hypothalamic amenorrhea, usually secondary to conditions such as anorexia nervosa, repetitive or prolonged strenuous exercise, or starvation, and the relatively uncommon pituitary failure. Hypoestrogenemia can also occur secondary to hyperprolactinemia.

Histologically, hypoestrogenemia leads to atrophy of both endometrial glands and stroma. Scanty, small glands can be seen in dense stroma. The result is thinning of the endometrium, which can be <5-mm thick by transvaginal ultrasonography.

Prolonged exposure to exogenous progestins, with or without estrogen, can also result in endometrial atrophy. Long-term use of combined oral contraceptives results in poorly developed glands lined by a single layer of low columnar to cuboidal cells. Secretory changes are minimal, but stromal decidualization is present, resulting in discordance between small inactive glands and decidualized stroma. Numerous granular lymphocytes are often present. Progestin-only contraception results in endometrial atrophy with sparse, narrow glands lined by flattened epithelium in a spindle-cell stroma without decidual reaction. Women with hyperandrogenemia can develop a similar clinical and histological picture.

A surprisingly common cause of menorrhagia is one of the several inborn or acquired conditions that can interfere with the body’s normal hemostatic mechanisms.

Von Willebrand disease and less common disorders of platelet function and fibrinolysis are characterized by excessive menstrual bleeding that begins at menarche and is usually regular. As many as 20% of adolescents who present with menorrhagia significant enough to cause anemia or hospitalization have a bleeding disorder, and should therefore undergo an evaluation for coagulopathy. However, it is important to remember that most AUB in this age group is probably due to anovulation [38].

The most common bleeding disorder is von Willebrand disease, which affects 1–2% of the population [39]. This hereditary deficiency (or abnormality) of the von Willebrand factor results in decreased platelet adherence, with von Willebrand factor interacting with platelets to form a platelet plug. A fibrin clot will then form on this plug. There are three main types of von Willebrand disease. The mild form (type 1) is responsible for over 70% of cases and is characterized by an absolute decrease in the protein. The mechanism by which an abnormal factor leads to bleeding at the level of the endometrium is unclear. The vast majority of women with this disease report AUB, specifically menorrhagia. The prevalence of this disorder in adults can range from 7 to 20%. Other inherited conditions include thrombocytopenias and rare clotting factor deficiencies (e.g., factor I, II, V, VII, X, XI, XIII).