INTRODUCTION — Women with abnormal bleeding noted in the genital area often present with a complaint of vaginal bleeding. Clinicians often attribute the bleeding to a uterine source, but it may arise from disease at any anatomic site in the lower genital tract (vulva, vagina, cervix) or upper genital tract (uterine corpus, fallopian tubes, ovaries). The source of bleeding may also be a nongynecologic site, such as the urethra, bladder, anus, or other bowel site. The differential diagnosis of genital tract bleeding is listed in the table (table 1), and varies by age group (table 2).

The differential diagnosis of genital tract bleeding in women will be reviewed here. The evaluation of women with abnormal uterine bleeding is discussed separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Evaluation and approach to diagnosis" and "Overview of the etiology and evaluation of vaginal bleeding in pregnancy" and "Approach to the patient with postmenopausal uterine bleeding".)

OVARIAN BLEEDING — Bleeding from the ovary rarely presents as vaginal bleeding and more commonly presents as intraperitoneal bleeding (eg, a bleeding corpus luteum, which may occur in anticoagulated women). Infrequently, bleeding from an ovarian mass, trauma, or infection may pass through the fallopian tube and continue to the lower genital tract.

Ovarian cancer — Vaginal bleeding represents an uncommon presentation of ovarian cancer [1,2]. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Vaginal bleeding'.)

FALLOPIAN TUBE BLEEDING — Similar to bleeding from the ovary, blood from the fallopian tube may rarely pass through the uterus and present as vaginal bleeding. However, this is unusual and most fallopian tube bleeding presents as intraperitoneal bleeding. Etiologies of fallopian tube bleeding include tubal pregnancy, neoplastic disease, trauma, and infection.

Salpingitis — Salpingitis is generally not an isolated infection, but is usually associated with pelvic inflammatory disease (PID). In women with PID, the source of bleeding may be the uterus or tube. (See 'Pelvic inflammatory disease' below.)

Hysteroscopic sterilization — A dislodged tubal microinsert may result in bleeding [3]. (See "Hysteroscopic female permanent contraception", section on 'Short-term complications and outcomes'.)

Fallopian tube cancer — Fallopian tube cancer may also present with vaginal bleeding. (See 'Ovarian cancer' above and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Vaginal bleeding'.)

UTERINE BLEEDING — The uterus is the most likely source of genital tract bleeding. The likelihood of a particular etiology of uterine bleeding depends upon the reproductive status of the patient (premenarchal, reproductive-age, postmenopausal) and the pattern of bleeding (cyclic or noncyclic).

A revised terminology system for abnormal uterine bleeding (AUB) in nongravid reproductive-age women was introduced in 2011 by the International Federation of Gynecology and Obstetrics (FIGO) [4]. The classification system is referred to by the acronym PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified (figure 1)). (See "Abnormal uterine bleeding in reproductive-age patients: FIGO System 1 terminology and symptoms and System 2 PALM-COEIN etiology classification".)

Menstruation — The uterus is the only organ for which bleeding represents a normal physiologic phenomenon (menstruation). (See "Physiology of the normal menstrual cycle".)

The characteristics of normal menstrual bleeding are (table 3) [5,6]:

●Frequency every 24 to 38 days.

●Occurs at fairly regular intervals, with a variation from the interval from first day of bleeding of one cycle to the first day of the next of less than 7 to 9 days across cycles.

●Volume of blood ≥5 to ≤80 mL; clinically, excessive blood loss is defined as a volume that interferes with the woman's physical emotional, social, and/or material quality of life.

●Duration is ≤8 days.

Molimina symptoms are often present and include an increase in thin cervical mucus secretions at mid-cycle, as well as premenstrual symptoms such as menstrual cramps, breast tenderness, fluid retention, and appetite or mood changes. The presence of molimina can help to differentiate ovulatory from anovulatory cycles. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Evaluation and approach to diagnosis", section on 'Irregular bleeding'.)

Uterine bleeding that varies from the normal characteristics is referred to as AUB.

Midcycle bleeding — In a study of women with regular menstrual cycles, mid-cycle transient spotting was reported by 4.8 percent [7]. This may be due to a rapid decrease in estradiol after the luteinizing hormone surge and in the context of the low levels of progesterone at the point in the cycle. A less likely explanation is bleeding from a corpus luteum or hemorrhagic ovarian cyst.

Pregnancy — A variety of disorders related to pregnancy can cause bleeding. All reproductive-age women with abnormal vaginal bleeding should have a pregnancy test as part of their initial evaluation. (See "Overview of the etiology and evaluation of vaginal bleeding in pregnancy".)

Ectopic pregnancy — Vaginal bleeding is a common presentation of ectopic pregnancy; the tube is the most common site of ectopic pregnancy, but other sites of extrauterine gestations include cesarean section scars, the abdomen, ovary, or cervix. In women with ectopic pregnancy, vaginal bleeding is often present in the absence of sonographic evidence of hemoperitoneum; the presumptive source of this bleeding is sloughing of the decidualized endometrium due to a failed pregnancy [8].

Structural abnormalities — Structural abnormalities of the uterus are a common etiology of AUB. This was illustrated in a study of 370 women aged 22 to 82 years with AUB that did not respond to treatment with progestin therapy [9]. Hysteroscopy revealed an abnormal uterine cavity in two-thirds of these women: endometrial hyperplasia (23 percent), polyps (22 percent), submucous myomata (11 percent), intracavitary synechiae (6 percent), endometrial atrophy (2 percent), and adenocarcinoma (1 percent).

When anatomic abnormalities are the cause of abnormal bleeding, cyclic menses typically occur. However, the duration and flow of menses may be altered or there may be bleeding between menstrual periods (both may occur in the same patient). Anatomic abnormalities can often be diagnosed by imaging studies, but excision is sometimes required for confirmation of the diagnosis and treatment. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Evaluation and approach to diagnosis", section on 'Secondary evaluation'.)

Leiomyoma — Leiomyomas, also known as fibroids, are the most common pelvic tumors in women. These benign tumors are clinically recognized in up to 25 percent of reproductive-age women. They are only occasionally found in adolescents. (See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history", section on 'Prevalence'.)

There are three uterine locations for fibroids: submucosal, intramural, and subserosal (figure 2). In addition, fibroids are found infrequently in the cervix or broad ligament.

Intramural fibroids may result in heavy or prolonged menstrual periods. Intermenstrual bleeding is more characteristic of submucosal fibroids, but other lesions of the cervix or uterus must be considered when this symptom is present. When fibroids are present, the uterus often feels enlarged and asymmetric on bimanual pelvic examination. (See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history", section on 'Heavy or prolonged menstrual bleeding'.)

Many women with intramural fibroids are relatively symptom free, often having become accustomed to heavier/longer than usual menses. When such women enter the perimenopausal transition and become anovulatory, the irregular bleeding that is common during perimenopause can be unusually heavy, leading such women to seek care [10,11].

Endometrial polyp — Endometrial polyps are usually benign growths that are a common cause of AUB in women in the menopausal transition and early postmenopausal women, but may occur at any time during the reproductive or postmenopausal years. The prevalence of endometrial polyps increases with age. They are rare among adolescents, and more commonly diagnosed in postmenopausal than in premenopausal women. Clinically-recognized endometrial polyps occur in approximately 6 percent of reproductive-age women. (See "Endometrial polyps".)

Intermenstrual bleeding is the most frequent symptom, occurring in approximately one-half of symptomatic cases. Bleeding after straining or heavy lifting is common. Less frequent symptoms include heavy or prolonged bleeding, postcoital bleeding, postmenopausal bleeding, prolapse through the cervical os, and unscheduled (breakthrough) bleeding during hormonal therapy. Polyps can be stimulated by estrogen therapy or tamoxifen. The uterus is typically normal on bimanual examination.

Adenomyosis — Adenomyosis is a disorder in which endometrial glands and stroma are present within the uterine myometrium, the muscular layer. This condition is estimated to affect 20 percent of women. This condition appears to be more common in parous than in nulliparous women. Adenomyosis is often present in women with uterine leiomyomas or endometriosis.

The ectopic endometrial tissue appears to induce hypertrophy and hyperplasia of the surrounding myometrium, which results in a diffusely enlarged uterus and heavy, prolonged, painful menstrual periods. (See "Uterine adenomyosis".)

Cesarean scar defect — A cesarean scar defect (also known as an isthmocele or niche) at the site of the hysterotomy is an increasingly common cause of AUB [12-17]. The usual presentation is postmenstrual spotting, which may reflect intermittent expulsion of menstrual blood retained in the defect after menstruation is completed. Poor contractility of the myometrium in the area of the hysterotomy site may also contribute to postmenstrual spotting [18]. In a prospective study that performed sonohysterograms in over 370 patients six months after cesarean delivery, 46 percent had a cesarean scar defect, and postmenstrual spotting was more common in these patients (20 versus 8 percent in patients without a defect, odds ratio 2.75, 95% CI 1.4-5.4) [19].

Arteriovenous malformation — Arteriovenous malformation (AVM) of the uterus (also referred to as enhanced myometrial vascularity [20]) is an uncommon cause of AUB [21,22]. It has been variably described as a cirsoid aneurysm, arteriovenous aneurysm, arteriovenous fistula, and cavernous hemangioma. AUB related to an AVM may be refractory to hormonal management.

Most AVMs are acquired after uterine surgery (eg, dilation and curettage [D&C; particularly in the setting of induced or spontaneous abortion], cesarean delivery, myomectomy) or are associated with neoplastic disorders (eg, gestational trophoblastic disease [GTD], endometrial adenocarcinoma) or maternal diethylstilbestrol exposure [20]. In one systematic review including 85 cases of acquired AVM, the mean time interval between uterine instrumentation (ie, D&C) and onset of hemorrhage was approximately 14 months (range <1 to 216 months) [23]. Bleeding presumably occurs when the vessels erode through or abut the endometrium. While the volume of bleeding may vary, severe bleeding with hypotension and anemia can occur.

Some AVMs are congenital and present with sudden uterine bleeding without any prior history of surgical instrumentation (image 1) [21,22]. Congenital AVMs are thought to develop from a failure of embryologic differentiation leading to abnormal vascular connections [24].

The incidence of uterine AVMs is unclear. In the systematic review above, the mean age was 30 years and the majority of women were premenopausal (96 percent) [23]. With more widespread use of pelvic ultrasound with Doppler assessment of vascular flow, AVM may be more common than previously perceived. In one cohort study including almost 320 women undergoing one or more sonographic evaluations after medically induced second-trimester abortions, 75 (24 percent) were found to have AVMs [25]. Approximately three-quarters of women with AVMs did not experience AUB, and none of those with AUB required transfusion, curettage, uterine artery embolization, or other procedures.

If an AVM is suspected in a patient with AUB and a disorder associated with AVM or a history of heavy bleeding after intrauterine instrumentation (eg, D&C), imaging studies should be performed prior to further intrauterine instrumentation [26]. Pelvic ultrasound with Doppler is typically the first-line imaging study (image 2) [20,27,28]. Magnetic resonance imaging with angiography may also be performed. Consultation with a radiologist to choose the appropriate imaging modality is suggested.

If bleeding is severe, initial management consists of hemodynamic stabilization with intrauterine tamponade (eg, with a balloon or packing material (see "Managing an episode of acute uterine bleeding")). Uterine artery embolization is the most common treatment and appears to be effective and safe (image 3A-E) [26,29-31]. Restoration of normal menstrual cycles and subsequent successful pregnancies have been reported, but patients should be counseled that embolization may result in impaired fertility and that the safety of pregnancy after embolization is uncertain [32,33]. Laparoscopic bipolar coagulation of the uterine vessels has also been successful in case reports [34]. Hysterectomy is an option if the patient does not plan future childbearing and desires definitive therapy [35]. (See "Uterine fibroids (leiomyomas): Treatment with uterine artery embolization".)

If bleeding is not severe and the patient is hemodynamically stable, conservative management may be possible. Small studies and case reports have described spontaneous resolution with expectant management and good outcomes with methylergonovine (0.2 mg intramuscularly three times a day for seven days) [36,37]. In the cohort study described above, all identified cases of AVM (following a medically induced abortion) resolved spontaneously within 150 days (mean interval 69 days) [25].

Other abnormalities — Rarely, sarcoidosis affects the female genital tract and the uterus is the most common site [38]. Women with uterine sarcoidosis may present with AUB. Most patients have concomitant pulmonary involvement. (See "Extrapulmonary manifestations of sarcoidosis", section on 'Endocrine and reproductive'.)

Ovulatory dysfunction — Ovulatory dysfunction (AUB-O) includes anovulation and oligo-ovulation and is a common cause of AUB in nonpregnant reproductive-age women. AUB-O is characteristically noted at the extremes of reproductive age (postmenarche and the menopausal transition). At any period during the reproductive years, women may develop AUB-O due to endocrine disorders (eg, polycystic ovary syndrome [PCOS]).

The pathophysiology in women with AUB-O is that sex steroids are produced but not cyclically. In anovulatory women, estrogen production unopposed by adequate progesterone production allows continued proliferation of the endometrium. Eventually, the thickened endometrium outgrows its blood supply and undergoes focal necrosis with partial shedding. Since shedding is not uniform and progesterone and prostaglandin-related changes have not occurred, bleeding is usually irregular and can be prolonged and/or heavy. In women with oligo-ovulation, some episodes of bleeding represent partial endometrial shedding and others are normal (post-ovulatory) menses, but it is often difficult to interpret in which phase the patient is.

By contrast, uterine bleeding in women with consistently ovulatory cycles is typically regular and predictable with a consistent cycle length and associated with molimina. Gonadotropin and sex steroid levels are normal and are secreted in a typical menstrual pattern (figure 3). Intermenstrual bleeding may occur in addition to the cyclic menstrual bleeding pattern. (See "Physiology of the normal menstrual cycle".)

The evaluation of women with AUB-O is discussed separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Evaluation and approach to diagnosis", section on 'Irregular bleeding'.)

Etiologies of AUB-O include (table 4):

Postmenarche and menopausal transition — Anovulation is common both at menarche and in the women in the menopausal transition, the times when ovarian function begins and declines. This results in a high prevalence of AUB during these reproductive stages.

●In postmenarchal girls, the hypothalamic-pituitary-ovarian axis is immature and consistently ovulatory cycles may not become established for several years. Thus, amenorrhea may alternate with unpredictable episodes of uterine bleeding. Less commonly, AUB in this age group may be related to other causes, such as pregnancy or a congenital defect of hemostasis. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Causes of vaginal bleeding in adolescents'.)

●During the menopausal transition, women commonly experience intermittent episodes of anovulatory bleeding, heavy or prolonged periods, and hot flashes related to fluctuations in hypothalamic-pituitary-ovarian axis function that accompanies the natural decline in ovarian follicles [39,40]. Women in this perimenopausal reproductive stage are also more likely than younger women to have bleeding related to benign or malignant neoplasms (eg, leiomyomas, endometrial polyps, endometrial carcinoma, and sarcoma). (See "Clinical manifestations and diagnosis of menopause".)

Polycystic ovary syndrome — PCOS is a common cause of anovulation, affecting 6 percent of reproductive-age women [41]. AUB associated with PCOS is characterized by chronic unopposed estrogen stimulation of the endometrium with irregular shedding. The presence of irregular menstrual cycles (often infrequent bleeding episodes), hirsutism, acne, acanthosis nigricans, as well as (when applicable) characteristic ovarian changes on ultrasound should lead clinicians to suspect this diagnosis. (See "Diagnosis of polycystic ovary syndrome in adults".)

Other endocrine disorders — Although a less common cause of AUB-O than PCOS, thyroid disease and hyperprolactinemia (table 5) can cause ovulatory dysfunction. (See "Overview of the clinical manifestations of hyperthyroidism in adults", section on 'Genitourinary' and "Clinical manifestations of hypothyroidism", section on 'Reproductive abnormalities' and "Clinical manifestations and evaluation of hyperprolactinemia".)

Menstrual irregularities are common in women with Cushing's syndrome [42]. Menstrual abnormalities correlate with increased serum cortisol and decreased serum estradiol concentrations, but not with serum androgen concentrations. The menstrual irregularities may be due to suppression of secretion of gonadotropin-releasing hormone by hypercortisolemia. High doses of corticosteroids have a similar effect. (See "Epidemiology and clinical manifestations of Cushing's syndrome".)

Rare hormone-producing ovarian (eg, granulosa cell tumor) or adrenal tumors can lead to anovulation. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Androgen and estrogen-secreting tumors' and "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)

Liver and kidney disease represent other rare causes of anovulation and cause AUB by more than one mechanism. Liver disease can affect estrogen metabolism, synthesis of coagulation factors, and cause thrombocytopenia, thereby potentially leading to both anovulation and bleeding diathesis. Chronic renal disease is associated with both hypothalamic-pituitary-gonadal and platelet dysfunction. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Symptoms'.)

Stress and poor nutrition — Stress, significant weight loss, poor nutrition, or strenuous exercise can disturb the hypothalamic-pituitary-ovarian axis and may be causes of AUB-O. Although the menstrual pattern most characteristic of hypothalamic dysfunction is amenorrhea, some women with this entity may present with oligomenorrhea. The evaluation is the same as for other women with irregular menses. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Epidemiology and causes of secondary amenorrhea", section on 'Hypothalamic dysfunction'.)

Other etiologies

●Disorders of local endometrial hemostasis, including alterations in thrombolysis caused by local mediators that are poorly modulated in the absence of progesterone. (See 'Local endometrial hemostasis disorders' below.)

Bleeding disorders — Bleeding disorders are common in reproductive-age women. Up to 15 to 29 percent of women presenting with heavy menses may have some type of bleeding diathesis (eg, von Willebrand disease [VWD], immune thrombocytopenia, or platelet function defect) [43-45]. In addition, excessive bleeding may be due to leukemia, liver or renal failure, anticoagulants, and chemotherapeutic agents can also cause bleeding disorders resulting in AUB. (See "Approach to the adult with a suspected bleeding disorder", section on 'Patient history'.)

Bleeding disorders typically present as heavy bleeding at menarche or in women in their later reproductive years. The prevalence of different types of bleeding diatheses was illustrated in one series of women ages 18 to 45 years [46]. Bleeding disorders were diagnosed in 11 percent of patients with heavy menstrual bleeding (VWD [8/121], factor deficiencies [2/121], platelet abnormality [3/121]) but only 3 percent of women with normal menstrual cycles. Systematic reviews of heavy menstrual bleeding report a prevalence of VWD ranging from 5 to 24 percent [47,48]. However, the percentage of heavy menstrual bleeding attributable solely to VWD is not clear; many such women have uterine pathology potentially associated with abnormal bleeding, which may be exacerbated by the underlying coagulopathy [49].

In women with VWD, the menopausal transition is associated with an increased prevalence of excess bleeding due to decreasing estrogen levels. Estrogen promotes von Willebrand factor (VWF) synthesis. Conversely, patients with mild VWD who take birth control pills or estrogen replacement therapy may increase their slightly low VWF levels into the normal range and, during pregnancy, VWF levels also increase. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Changes with aging and pregnancy'.)

Bleeding defects may also be due to thrombocytopenia, renal or liver disease, or hematologic malignancy [50]. Chronic renal failure is associated with platelet dysfunction and bleeding diathesis, which can manifest as heavy menstrual bleeding. Women with liver disease may experience reduced synthesis of coagulation factors. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Symptoms'.)

The evaluation of AUB due to bleeding disorders is discussed separately. (See "Approach to the adult with a suspected bleeding disorder", section on 'Patient history' and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Evaluation and approach to diagnosis", section on 'Medical history'.)

Iatrogenic

Contraception — Contraceptive methods that can cause abnormal vaginal bleeding include estrogen-progestin contraceptives, progestin-only contraceptives, and intrauterine devices (IUD). (See "Evaluation and management of unscheduled bleeding in individuals using hormonal contraception".)

●Estrogen-progestin contraceptives – Breakthrough (or unscheduled) bleeding is the most common side effect of combination hormonal contraceptives. This reflects tissue breakdown as the endometrium adjusts to a new thin state in which it is fragile and atrophic. Women should be cautioned that missing pills results in an increase in unscheduled bleeding, as well as a decrease in contraceptive efficacy. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Unscheduled bleeding'.)

●Progestin-only contraceptives – Prolonged bleeding and spotting are common side effects of progestin-only contraceptives, including depot medroxyprogesterone acetate (DMPA), the levonorgestrel-releasing intrauterine contraceptive, etonogestrel single contraceptive implant systems, and progestin-only pills. Bleeding tends to be an early side effect of these methods; many women develop amenorrhea with continued use. The mechanism of progesterone-breakthrough bleeding is endometrial atrophy due to insufficient estrogen. (See "Progestin-only pills (POPs) for contraception" and "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration" and "Etonogestrel contraceptive implant" and "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD'.)

●Copper IUD – Copper IUDs cause a foreign body reaction in the uterus that creates an inflammatory response. The endometrium may hypertrophy at the site of inflammation with normal cyclic estrogen stimulation, resulting in heavier or longer menstrual flow as well as intermenstrual bleeding.

Menopausal hormone therapy — Women who use menopausal hormone therapy may develop uterine bleeding; the frequency depends upon the regimen used, and whether or not uterine conditions including fibroids, adenomyosis, or endometrial polyps are present.

Other medications — Medications that interfere with coagulation or cause an endocrine disruption may cause AUB. Some data suggest that epidural glucocorticoid injections (40 to 80 mg of triamcinolone or methylprednisolone acetate) are associated with AUB [51]. Drugs that cause hyperprolactinemia are shown in the table (table 5).

Infection and inflammation — Infection and inflammation (endometritis or pelvic inflammatory disease [PID]). (See "Endometritis unrelated to pregnancy" and "Postpartum endometritis" and "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

Endometritis — Endometritis may be acute or chronic. The prevalence of chronic endometritis presenting with AUB is uncertain. Premenopausal women with chronic endometritis usually present with AUB, which may consist of intermenstrual bleeding, spotting, postcoital bleeding, or heavy prolonged periods. Vague, crampy lower abdominal pain may accompany the bleeding. The most common finding on physical examination is uterine tenderness or cervical motion tenderness. However, in many women with chronic endometritis, uterine tenderness is not present. Women with acute endometritis frequently have fever, while it is less common in women with chronic endometritis. (See "Endometritis unrelated to pregnancy".)

Acute endometritis occurs postpartum in women with recent complications of pregnancy: spontaneous or induced abortion, premature rupture of membranes, intrauterine procedures, retained products of conception, or cesarean delivery. Symptoms include fever, uterine tenderness, foul lochia, and leukocytosis. (See "Postpartum endometritis".)

Endometritis may also occur with PID and, uncommonly, following placement of an intrauterine contraceptive. Lower abdominal pain is the cardinal presenting symptom of PID. The onset of pain during or shortly after menses is particularly suggestive of this disorder. The abdominal pain is usually bilateral and rarely of more than two weeks' duration. (See "Intrauterine contraception: Candidates and device selection" and "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

Underlying malignancy in postmenopausal women may cause endometritis. In the setting of cervical stenosis, blood can accumulate in the uterus (hematometra) and become secondarily infected (pyometra).

Inflammation of neighboring organs, such as diverticulitis, can occasionally cause corresponding inflammation of the female upper genital tract. A ruptured sigmoid diverticulum may fistulize into the uterus and present as uterine bleeding, discharge, and endometritis.

Pelvic inflammatory disease — PID may present with AUB. As an example, in a series of 70 women (median age 24 years, range 16 to 45 years) with possible upper genital tract infection, 15 presented with AUB, underscoring that endometritis associated with PID can present with this symptom [52]. (See "Pelvic inflammatory disease: Clinical manifestations and diagnosis", section on 'Clinical features'.)

Local endometrial hemostasis disorders

●Thrombolysis – Progesterone stabilizes the endometrium and prevents unscheduled bleeding by influencing the production of key proteins. Progesterone blocks stromal cell production of matrix metalloproteinase (MMP) 1, 3, and 9. MMP 1, 3, and 9 degrade the extravascular and stromal matrix. By blocking production of the MMPs, progesterone stabilizes the stromal and vascular supporting matrix.

Progesterone also stimulates stromal cell production of tissue factor (TF), a cell surface protein that participates in the extrinsic pathway of coagulation through the binding of activated Factor VII [53]. By stimulating TF production, progesterone helps reduce the risk of unscheduled bleeding from the endometrium. Progesterone also stimulates stroma cell production of plasminogen activator inhibitor 1 (PAI-1). PAI-1 blocks fibrinolysis, thereby stabilizing clots [54].

In anovulatory menstrual cycles, the absence of a regular cyclical progesterone stimulus results in excessive production of MMP 1, 3, and 9, decreased production of TF and PAI-1, thereby leading to unpredictable menstrual bleeding in both timing and amount. In ovulatory cycles with excessively high estradiol and abnormally low progesterone secretion (commonly observed in perimenopausal women), a similar pattern of dysfunctional protein secretion and bleeding may occur. Women with heavy menstrual bleeding, even those with ovulatory cycles, have been demonstrated to have elevated endometrial concentrations of tissue plasminogen activator and plasmin, which reduce the stability of the clots. Tranexamic acid is an inhibitor of plasminogen and the plasminogen activator-plasmin complex. Administration of tranexamic acid to women with heavy menstrual bleeding results in the stabilization of fibrin and reduces the amount of menstrual bleeding [55]. (See "Managing an episode of acute uterine bleeding", section on 'Tranexamic acid'.)

●Prostaglandins – Women with heavy menstrual bleeding have been reported to have increased expression of cyclooxygenases (COX-1, COX-2) and increased endometrial responsiveness to stimulation by prostaglandins [56]. This suggests that increased prostaglandin production and/or increased responsiveness to prostaglandins contribute to the pathophysiology of heavy menstrual bleeding. Treatment of women with heavy menstrual bleeding with anti-prostaglandin agents (eg, nonsteroidal anti-inflammatory drugs) has been reported to reduce the quantity of menstrual bleeding. However, a meta-analysis concluded that antiprostaglandin agents such as mefenamic acid were less effective than a levonorgestrel intrauterine system or tranexamic acid in reducing menstrual bleeding in women with heavy menstrual bleeding [57]. (See "Abnormal uterine bleeding: Management in premenopausal patients", section on 'Nonsteroidal anti-inflammatory drugs'.)

Uterine cancer — Women in the United States have a 2.6 percent lifetime risk of developing uterine cancer. Endometrial neoplasia is far more common than uterine sarcoma. The risk of endometrial neoplasia increases with age (1.5 percent of cases occur from ages 20 to 34 years and 19.0 percent from ages 45 to 54 years) and with exposure to endogenous or exogenous estrogen unopposed by a progestin (eg, obesity, anovulation, menopausal use of estrogen alone, or tamoxifen). (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention" and "Approach to the patient with postmenopausal uterine bleeding".)

Sarcomas of the uterus constitute only 3 to 5 percent of all uterine tumors. These cancers arise from the stroma of the endometrium (endometrial stromal sarcomas) or the myometrium. They may look and feel like benign leiomyomas; diagnosis is characteristically made at the time of hysterectomy. Women with leiomyosarcomas usually present with heavy prolonged bleeding or postmenopausal bleeding and a uterine mass. (See "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis".)

GTD represents an uncommon cause of AUB. (See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)

Rarely, the endometrium is the site of metastatic disease from nongynecologic malignancy (eg, melanoma).

CERVICAL BLEEDING — In contrast to abnormal bleeding from the uterine corpus, which is often heavy and associated with menses, cervical lesions typically cause sporadic spotting, which commonly occurs postcoitally. In addition, cervical lesions can be visualized on speculum examination.

Cervicitis — Postcoital bleeding is common in women with cervicitis due to nonspecific inflammatory changes or ulcerative sexually transmitted diseases. Strawberry red spots on the cervix with bleeding on contact are pathognomonic for Trichomonas vaginalis infection. (See "Acute cervicitis".)

Polyps — Cervical polyps may cause postcoital spotting and sporadic bleeding, although they are often asymptomatic. The majority are benign endocervical polyps, which can be seen on visual examination of the cervix and endocervix. (See "Benign cervical lesions and congenital anomalies of the cervix", section on 'Polyps'.)

Ectropion — Ectropion is the normal physiologic presence of endocervical glandular tissue on the exocervix. This tissue can be friable, readily bleeding upon contact, such as during intercourse or cervical cancer screening. (See "Benign cervical lesions and congenital anomalies of the cervix", section on 'Ectropion'.)

Pelvic organ prolapse — Defects in pelvic floor support can lead to herniation of the anterior, posterior, or apical portion of the vagina. If part or all of the vagina and cervix is exteriorized, bleeding occasionally occurs secondary to ulceration, trauma and infection. This type of bleeding often occurs after straining. (See "Pelvic organ prolapse in females: Epidemiology, risk factors, clinical manifestations, and management".)

Cervical trauma — Bleeding can occur after both consensual sexual intercourse and sexual assault and may be the result of a cervical laceration. In one retrospective review including 114 sexual assault victims presenting to an acute care hospital, injuries to the cervix were found in 12 percent of patients [58].

Other conditions — Ectopic endometriosis can be found in the cervix, especially if the patient has a history of cervical procedures (such as cone biopsy). Postcoital bleeding, intermenstrual bleeding, as well as acute bleeding due to cervical endometriosis have been reported [59-61]. (See "Endometriosis: Pathogenesis, clinical features, and diagnosis", section on 'Physical examination'.)

Cervical cancer — Sporadic bleeding, postcoital spotting, and vaginal discharge that is watery, mucoid, or purulent and malodorous are often noted in women with cervical cancer. Accordingly, cervical cytology and biopsy, when indicated, should not be postponed in this setting. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

Direct extension from other pelvic tumors, such as uterine cancer, can cause cervical bleeding. Choriocarcinoma commonly can extend to the cervix, causing bleeding. Rarely, leukemias, lymphomas [62], and other nongynecologic cancers involve the cervix.

VAGINAL BLEEDING — As with cervical lesions, vaginal lesions typically cause sporadic or postcoital bleeding and can be visualized on speculum examination. Traumatic vaginal lacerations can cause major internal and/or external hemorrhage.

Vaginal atrophy — Atrophic vaginitis results from estrogen deficient states, which occur in postmenopausal women, postpartum lactating women, and premenarchal girls. Bleeding or spotting, which may be related to sexual activity, may occur. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis".)

Vaginitis and vaginal ulcers — Vaginal infection or inflammation may lead to friability of the vaginal mucosa with bleeding. (See "Approach to females with symptoms of vaginitis".)

Ulcerative diseases with vaginal involvement (eg, lichen planus) can cause postcoital bleeding. Genital ulcers may be caused by infection, but non-infection-related etiologies should also be considered. (See "Approach to the patient with genital ulcers".)

Benign growths — Gartner duct cysts, vaginal polyps, and aberrant glandular tissue (vaginal adenosis) rarely lead to vaginal bleeding in the absence of friction and trauma. (See "Congenital anomalies of the hymen and vagina".)

Vaginal trauma — Bleeding from the vagina or vulva can occur from genital tract trauma related to intercourse (eg, tearing of an intact hymen during coitarche or laceration of the vaginal fornix mucosa), foreign bodies that cause ulceration (eg, neglected tampon, pessary, sexual aids), sexual assault, pelvic trauma (eg, from a motor vehicle accident), and straddle-type injuries that result in lacerations or abrasions of the labia (eg, falling on a bicycle frame, fence, or table edge). (See "Evaluation and management of female lower genital tract trauma".)

Female circumcision or infibulation reduces the vaginal opening. Vaginal bleeding and lacerations can occur when intercourse is attempted. (See "Female genital cutting".)

Toxic epidermal necrolysis and Stevens-Johnson syndrome — Toxic epidermal necrolysis and Stevens-Johnson syndrome may be caused by a variety of drugs, particularly antibiotics. Vulvar and vaginal tissues are commonly involved in this acute and extensive destruction of the skin [63]. Bleeding may occasionally occur along with significant ulceration. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Mucosal lesions'.)

Radiation therapy — Vaginal bleeding can represent a late effect of radiation therapy [64]. Obliterative endarteritis and the vascular narrowing of aging and arteriosclerosis lead to devascularization of the radiated tissues. Tissue necrosis causes viscus perforation, tissue sloughing, and bleeding. Hemorrhagic cystitis and proctitis can lead to significant blood loss. Vaginal vault necrosis may cause uncontrolled bleeding and pain. (See "Treatment-related toxicity from the use of radiation therapy for gynecologic malignancies".)

Vaginal cancer — Primary vaginal cancer constitutes 1 to 2 percent of gynecologic malignancies. The majority of patients present with vaginal bleeding, either postmenopausal or postcoital. Other symptoms include a watery, blood-tinged, or malodorous vaginal discharge or a vaginal mass. The upper posterior vaginal wall is the most frequent site of vaginal cancer. It is important to carefully palpate the lateral, anterior, and posterior vaginal walls since the lesion may be obscured by the speculum blades during examination [65]. (See "Vaginal cancer".)

Advanced bladder or colorectal cancer may invade the vagina and cause vaginal bleeding [66], and the vagina may be the site of metastatic disease from distant organs.

VULVAR BLEEDING — As with cervical and vaginal lesions, vulvar lesions typically cause sporadic bleeding and can be visualized on physical examination.

Infection — Sexually transmitted diseases can cause characteristic lesions on the vulva, some of which may bleed easily on contact (friability). Examples include the syphilitic chancre (although this usually produces drainage that is more serous than bloody), herpes simplex virus, Haemophilus ducreyi (Chancroid), granuloma inguinale (Donovanosis), and lymphogranuloma venereum. Pediculosis pubis (ie, pubic lice or "crabs") can also cause a small amount of bleeding. (See "Approach to the patient with genital ulcers" and "Pediculosis pubis and pediculosis ciliaris".)

Benign lesions — Benign lesions, such as sebaceous (epidermal) cysts, condylomata, and angiokeratoma, may occasionally bleed due to trauma related to friction from clothing or scratching. (See "Vulvar lesions: Diagnostic evaluation" and "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers".)

Vulvar lichen sclerosus occasionally may result in bleeding and, rarely, hemorrhage. (See "Vulvar lichen sclerosus", section on 'Clinical manifestations and natural history'.)

Blistering and ulcerative diseases — Bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, pemphigus vulgaris, and pemphigus vegetans are autoimmune blistering dermatologic disorders that can develop on the vulva. Erosions are usually seen due to the fragile nature of lesions and frictional trauma. Older lesions may be cloudy or hemorrhagic. Beçhet syndrome is a systemic vascular disorder that can cause genital ulcers. (See "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers".)

Vulvar trauma — The vulva may bleed from trauma due to forceful sexual activity/assault or accidents (sports or exercise related, motor vehicle). (See "Evaluation and management of female lower genital tract trauma".)

Vulvar cancer — Vulvar malignancies account for 3 to 5 percent of gynecologic cancers. Early vulvar cancer is asymptomatic; bleeding occurs when a lesion is extensive enough to ulcerate.

Vulvar cancer and vulvar intraepithelial neoplasia (VIN) are often misdiagnosed. Delay may be related to patient embarrassment, denial, reluctance to be examined, or health care practitioners who prescribe topical medications to a patient with vulvar complaints without performing a physical examination. All ulcers associated with skin thickening or mass must be biopsied. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment" and "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)".)

Vulvar melanoma presents with a hyperpigmented lesion, which may bleed. (See "Mucosal melanoma", section on 'Vulvovaginal melanoma'.)

NONGENITAL TRACT DISEASE — Diseases of the tissue and organs surrounding the female genital tract may be the source of bleeding: urethra (eg, urethritis, diverticulum, urethral prolapse or caruncle, or atrophy), bladder (eg, cancer, stone, or infection), anus (eg, hemorrhoids, anal cancer), bowel (eg, inflammatory bowel disease, rectal cancer), or dermatologic conditions of the perineum or skin beyond the vulva. (See "Urethral caruncle" and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Evaluation and approach to diagnosis", section on 'Gynecologic and obstetric history'.)

GENITAL TRACT BLEEDING IN CHILDREN — Common causes of vaginal bleeding prior to menarche include vaginal foreign bodies (eg, toilet paper or pencil erasers), urethral prolapse, bacterial infections, and condyloma. Less commonly, bleeding may result from a reproductive tract neoplasm, such as sarcoma botryoides. (See "Evaluation of vulvovaginal bleeding in children and adolescents" and "Overview of vulvovaginal conditions in the prepubertal child".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal uterine bleeding".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Abnormal uterine bleeding (Beyond the Basics)" and "Patient education: Heavy or prolonged menstrual bleeding (menorrhagia) (Beyond the Basics)" and "Patient education: Absent or irregular periods (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Women with abnormal bleeding noted in the genital area often present with a complaint of vaginal bleeding. Clinicians often attribute the bleeding to a uterine source, but it may arise from disease at any anatomic site in the lower genital tract (vulva, vagina, cervix) or upper genital tract (uterine corpus, fallopian tubes, ovaries). The source of bleeding may also be a nongynecologic site, such as the urethra, bladder, or anus or other bowel site (table 1 and table 2). (See 'Introduction' above.)

●Bleeding from the ovary usually collects intraperitoneally, rather than presenting as vaginal bleeding, but this may occur if blood passes through the fallopian tube and continues to the lower genital tract. Etiologies of ovarian bleeding include benign neoplasms and ovarian cancer. (See 'Ovarian bleeding' above.)

●Fallopian tube bleeding may rarely present as vaginal bleeding. Etiologies of fallopian tube bleeding include ectopic pregnancy and salpingitis, typically as part of pelvic inflammatory disease. (See 'Fallopian tube bleeding' above.)

●The uterus is the most likely source of genital tract bleeding. The etiology of uterine bleeding depends upon the reproductive status of the patient (premenarchal, reproductive-age, postmenopausal) and the pattern of bleeding (cyclic or noncyclic). (See 'Uterine bleeding' above.)

●Uterine bleeding is the cardinal sign of endometrial cancer; it is also a common symptom of a variety of disorders related to pregnancy. Other common causes of abnormal uterine bleeding (AUB) include structural abnormalities (eg, fibroids, adenomyosis, and endometrial polyps), ovulatory dysfunction, and side effects of contraceptives. (See 'Uterine bleeding' above.)

●Causes of cervical, vaginal, and vulvar bleeding include trauma, infection, neoplasia, and genital manifestations of systemic disease. (See 'Cervical bleeding' above and 'Vaginal bleeding' above and 'Vulvar bleeding' above.)

●Diseases of the urethra (eg, urethritis, diverticulum), bladder (eg, cancer, stone, infection), and bowel (eg, inflammatory bowel disease, hemorrhoids) may cause bleeding that is misdiagnosed as genital tract bleeding. (See 'Nongenital tract disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Annekathryn Goodman, MD, MPH, MS, who contributed to earlier versions of this topic review.