Causes of female genital tract bleeding

INTRODUCTION — Females 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 (cervix, vagina, vulva) 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. Causes of genital tract bleeding are listed in the table (table 1) and vary by age group (table 2).

Causes of female genital tract bleeding will be reviewed here. The evaluation of patients with vaginal bleeding is discussed separately:

●Nonpregnant reproductive-age patients (see "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis").

●Postmenopausal patients (see "Approach to the patient with postmenopausal uterine bleeding").

●Pregnant patients (see "Evaluation and differential diagnosis of vaginal bleeding before 20 weeks of gestation").

●Adolescent patients (see "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis").

LOWER GENITAL TRACT SOURCES

Cervical bleeding — Bleeding from the cervix often causes sporadic spotting, which commonly occurs postcoitally. A cervical lesion is often visualized on speculum examination.

Cervicitis — Postcoital bleeding is common in patients 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".)

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 [1].

Other benign 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 [2-4]. (See "Endometriosis: Clinical features, evaluation, and diagnosis", section on 'Clinical features'.)

Cervical cancer — Sporadic bleeding, postcoital spotting, and vaginal discharge that is watery, mucoid, or purulent and malodorous are often noted in patients 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 [5], 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. By contrast, traumatic vaginal lacerations can cause major internal and/or external hemorrhage.

Vaginal atrophy — Atrophic vaginitis results from estrogen deficient states, which occur in postmenopausal, postpartum lactating, and premenarchal patients. 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 "Vaginitis in adults: Initial evaluation".)

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 (eg, falling on a bicycle frame, fence, or table edge) that result in lacerations or abrasions of the labia. (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 [6]. Bleeding may occasionally occur along with significant ulceration. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Mucosal involvement'.)

Radiation therapy — Vaginal bleeding can represent a late effect of radiation therapy [7]. 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 is a less common gynecologic malignancy. 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 [8]. (See "Vaginal cancer".)

Advanced bladder or colorectal cancer may invade the vagina and cause vaginal bleeding [9], 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: Clinical manifestations and diagnosis", 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 (eg, sports or exercise related, motor vehicle). (See "Evaluation and management of female lower genital tract trauma".)

Vulvar cancer — Vulvar cancer is less common than other gynecologic malignancies. Early vulvar cancer is asymptomatic; bleeding occurs when a lesion is extensive enough to ulcerate.

Vulvar cancer and vulvar intraepithelial neoplasia 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 "Locoregional mucosal melanoma: Epidemiology, clinical diagnosis, and treatment", section on 'Vulvovaginal melanoma'.)

UPPER GENITAL TRACT SOURCES

Uterine bleeding — The uterus is the most likely source of genital tract bleeding. The likelihood of a particular etiology of uterine bleeding depends on the reproductive status of the patient (premenarchal, reproductive-age, postmenopausal) and the pattern of bleeding (cyclic or noncyclic). The characteristics of normal and abnormal uterine bleeding (AUB) bleeding are listed in the table (table 3) and are described in detail separately. (See "Normal menstrual cycle", section on 'Definitions of normal uterine bleeding (menstruation)' and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis", section on 'Definitions'.)

A revised terminology system for abnormal uterine bleeding (AUB) in nongravid reproductive-age patients was introduced in 2011 by the International Federation of Gynecology and Obstetrics (FIGO) [10]. This classification system, referred to as FIGO System 2, or the PALM-COEIN system, stratifies possible causes of AUB into nine basic categories: polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified (figure 1). An example of a worksheet to facilitate documentation is found in the table (table 4).  

Polyps (AUB-P) — Endometrial polyps are a common cause of AUB; most endometrial polyps are benign and the prevalence of endometrial polyps increases with age. Intermenstrual bleeding is the most frequent symptom, and bleeding after straining or heavy lifting can also occur. Less frequent symptoms include heavy or prolonged bleeding, postcoital bleeding, postmenopausal bleeding, prolapse through the cervical os, and unscheduled (breakthrough) bleeding during hormonal therapy. (See "Endometrial polyps".)

A presumptive diagnosis can be made with imaging (eg, transvaginal ultrasound, sonohysterography, hysteroscopy); histopathologic confirmation is not required for AUB-P classification. (See "Endometrial polyps", section on 'Pelvic imaging' and "Endometrial polyps", section on 'Diagnosis'.)

Adenomyosis (AUB-A) — Adenomyosis, a disorder in which endometrial glands and stroma are present within the uterine myometrium, may result in a diffusely enlarged uterus and is often present in patients with uterine leiomyomas or endometriosis. However, the role that adenomyosis plays in the genesis of AUB is poorly understood, and data are conflicting regarding its association with heavy, prolonged, or painful menstrual periods [11-15]. (See "Uterine adenomyosis".)

A presumptive diagnosis can be made based on transvaginal ultrasound or magnetic resonance imaging (MRI); histopathologic confirmation is not required for AUB-A classification. (See "Uterine adenomyosis", section on 'Imaging' and "Uterine adenomyosis", section on 'Diagnosis'.)

Leiomyomas (AUB-L) — Leiomyomas (also referred to as myomas or fibroids) are the most common pelvic tumors in females. The majority of patients have small myomas and are asymptomatic; however many patients with leiomyomas have AUB. When leiomyomas are present, the uterus often feels enlarged and lobular/asymmetric on bimanual pelvic examination.

AUB-L is further classified based on the FIGO Leiomyoma Subclassification System (figure 2). (See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history", section on 'Terminology and location'.)

Uterine leiomyomas are discussed in detail separately. (See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history" and "Uterine fibroids (leiomyomas): Treatment overview".)

Malignancy and hyperplasia (AUB-M) — Endometrial hyperplasia or cancer of the uterus may cause AUB. Subclassification is based on histology using the appropriate World Health Organization system for hyperplasia, or the FIGO staging system for cancer [10,16-19]. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis" and "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening".)

The risk of endometrial neoplasia increases with age 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".)

Less common types of uterine cancer include uterine sarcomas (eg, endometrial stromal sarcoma, leiomyosarcoma) or gestational trophoblastic neoplasia. Rarely, the endometrium is the site of metastatic disease from a nongynecologic malignancy (eg, melanoma).

(See "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis" and "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification".)

Coagulopathy (AUB-C) — Bleeding disorders can cause AUB, usually heavy menstrual bleeding (HMB). The approach to identifying these patients starts with a structured history to assess symptoms or risk factors for coagulation disorders (table 5) [20]. Laboratory testing must confirm coagulopathy for a diagnosis of AUB-C.

Bleeding disorders are common in reproductive-age patients. Up to 15 to 29 percent of patients presenting with HMB may have some type of bleeding diathesis (eg, von Willebrand disease [VWD], immune thrombocytopenia, or platelet function defect) [20-22]. In one series including patients ages 18 to 45, bleeding disorders were diagnosed in 11 percent of patients with HMB (VWD [8/121], factor deficiencies [2/121], platelet abnormality [3/121]) but only 3 percent of patients with normal menstrual cycles [23]. Systematic reviews of HMB report an even higher prevalence of VWD (range 5 to 24 percent) [24,25]. However, the percentage of HMB attributable solely to VWD is not clear as many such patients also have uterine pathology, which may be exacerbated by the underlying coagulopathy [26].

In patients 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 menopausal estrogen 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 renal failure (platelet dysfunction), liver disease (reduced synthesis of coagulation factors), hematologic malignancy [27], anticoagulants, or chemotherapeutic agents. (See "Approach to the adult with a suspected bleeding disorder", section on 'Patient history'.)

AUB due to bleeding disorders is discussed in more detail separately. (See "Approach to the adult with a suspected bleeding disorder", section on 'Patient history' and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis", section on 'Medical history' and "Factor XI (eleven) deficiency", section on 'Heavy menstrual bleeding'.)

Ovulatory dysfunction (AUB-O) — AUB-O includes anovulation and oligo-ovulation and is a common cause of AUB in nonpregnant reproductive-age patients. Etiologies that may result in ovulatory dysfunction are presented in the table (table 6). AUB-O is not used to classify ovulatory dysfunction caused by drug treatment, which are classified as AUB-I (iatrogenic causes). (See 'Iatrogenic causes (AUB-I)' below.)

AUB-O can be further categorized according to the presumed primary source (and referred to by the acronym "HyPO-P") [28]:

●Type I: Hypothalamic

●Type II: Pituitary

●Type III: Ovarian

●Type IV: PCOS

The pathophysiology in patients with AUB-O is that sex steroids are not produced cyclically. In many anovulatory patients, 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 (varies by >7 to 9 days, depending on age) and can be prolonged and/or heavy (see "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis", section on 'Definitions'). In patients with oligo-ovulation, some episodes of bleeding represent partial endometrial shedding and others are normal (postovulatory) menses.

Common causes of anovulation by patient age include:

●For a few years following menarche, the hypothalamic-pituitary-ovarian axis is not fully mature and ovulatory cycles may not consistently occur. Thus, amenorrhea or infrequent menses 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 coagulopathy. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Causes of vaginal bleeding in adolescents'.)

●In reproductive-age patients, polycystic ovary syndrome (PCOS) is a common cause of anovulation. 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 "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults" and "Diagnosis of polycystic ovary syndrome in adults".)

●During the menopausal transition, patients 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 [29,30]. Such patients are also more likely than younger patients to have bleeding related to benign or malignant neoplasms (eg, leiomyomas, endometrial polyps, endometrial carcinoma). (See "Clinical manifestations and diagnosis of menopause".)

Other causes of AUB-O include:

●Thyroid disease. (See "Overview of the clinical manifestations of hyperthyroidism in adults", section on 'Genitourinary' and "Clinical manifestations of hypothyroidism", section on 'Reproductive abnormalities'.)

●Hyperprolactinemia (table 7). (See "Clinical manifestations and evaluation of hyperprolactinemia".)

●Stress and poor nutrition: Stress, weight loss, poor nutrition, or strenuous exercise can disturb the hypothalamic-pituitary-ovarian axis and may cause AUB. Although the menstrual pattern most characteristic of hypothalamic dysfunction is amenorrhea, some patients with this entity may present with infrequent (ie, >38 day) cycles. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Epidemiology and causes of secondary amenorrhea", section on 'Hypothalamic dysfunction'.)

●Cushing syndrome. (See "Epidemiology and clinical manifestations of Cushing syndrome", section on 'Menstrual irregularities'.)

●Hormone-producing ovarian (eg, granulosa cell tumor) or adrenal tumors (rare). (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults" and "Clinical presentation and evaluation of adrenocortical tumors".)

●Liver and kidney disease: 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 'Coagulopathy (AUB-C)' above.)

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

Endometrial dysfunction (AUB-E) — Patients with AUB-E have all of the following [31]:

●Predictable and cyclic menses suggestive of normal ovulation

●HMB or intermenstrual bleeding

●No other definable causes for AUB

AUB-E is primarily caused by disturbances in the molecular and cellular mechanisms responsible for regulation of the volume of blood lost at menstruation. Inflammatory or infectious endometrial disorders, such as endometritis or pelvic inflammatory disease (PID) are also included in this category:

●Local endometrial hemostasis disorders

•Thrombolysis – In ovulatory menstrual cycles, progesterone stabilizes the endometrium and prevents unscheduled bleeding by:

-Blocking stromal cell production of matrix metalloproteinase (MMP) 1, 3, and 9, which degrade the extravascular and stromal matrix [32,33].

-Stimulating 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 [34].

-Stimulating stroma cell production of plasminogen activator inhibitor 1 (PAI-1), which blocks fibrinolysis, thereby stabilizing clots [35].

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.

•Prostaglandins – Patients with HMB may have increased expression of cyclooxygenases (COX-1, COX-2) and increased endometrial responsiveness to stimulation by prostaglandins [36].

●Inflammatory or infectious endometrial disorders – Infection and inflammation (endometritis or PID) can result in AUB. Endometritis may be acute (pregnancy-related or unrelated to pregnancy) or chronic. (See "Postpartum endometritis" and "Endometritis unrelated to pregnancy".)

Etiologies may include:

•Chlamydia trachomatis [31,37] or PID. In a series of 70 patients (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 [38]. (See "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

•Instrumentation following an intrauterine procedure, including placement of an intrauterine contraceptive (uncommon). (See "Intrauterine contraception: Management of side effects and complications", section on 'Infection and/or pelvic inflammatory disease'.)

•Malignancy and/or cervical stenosis – Underlying endometrial cancer in postmenopausal patients may also 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.

Iatrogenic causes (AUB-I) — Iatrogenic causes of AUB include:

●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. Patients 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, 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 patients develop amenorrhea with continued use. The mechanism of progesterone-breakthrough bleeding is endometrial atrophy due to insufficient estrogen. (See "Contraception: Progestin-only pills (POPs)" and "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration" and "Contraception: Etonogestrel 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. (See "Intrauterine contraception: Background and device types", section on 'Copper IUD'.)

●Menopausal HT – Patients who use menopausal hormone therapy (HT) may develop uterine bleeding; the frequency depends upon the regimen used, and whether uterine conditions including fibroids, adenomyosis, or endometrial polyps are present. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Side effects'.)

●Anticoagulants. (See "Management of bleeding in patients receiving direct oral anticoagulants".)

●Other – Medications that 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 [39]. Drugs that cause hyperprolactinemia are shown in the table (table 7). (See 'Ovulatory dysfunction (AUB-O)' above and "Causes of hyperprolactinemia".)

Not otherwise classified (AUB-N) — AUB-N encompasses additional entities that may cause AUB and include:

●Cesarean scar defect – A cesarean scar defect (also known as an isthmocele or niche) at the site of a prior hysterotomy (or less commonly, myomectomy) incision is an increasingly common cause of AUB [40-46]. 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 [47]. When symptoms (eg, postmenstrual bleeding) are present, the term "cesarean scar disorder" may be used [48].

In a prospective study including over 370 patients evaluated with sonohysterography six months after cesarean birth, patients with (46 percent) versus without a cesarean scar defect were more likely to have postmenstrual spotting (20 versus 8 percent, odds ratio [OR] 2.8, 95% CI 1.4-5.4) [49].

●Arteriovenous malformation – Arteriovenous malformation (AVM) of the uterus is a rare cause of AUB in which arteries and veins directly connect, rather than going through capillaries [50,51]. Direct connection of these vessels results in enlarged, tangled-appearing vascular structures with turbulent flow. AVM has been variably described as a cirsoid aneurysm, arteriovenous aneurysm, arteriovenous fistula, and cavernous hemangioma.

Some AVMs are acquired and present with sudden uterine bleeding after surgical instrumentation (eg, dilation and curettage in a nonpregnant patient), while others are congenital and occur without any prior history of surgical instrumentation (image 1) [50,51]. Congenital AVMs are thought to develop from a failure of embryologic differentiation leading to abnormal vascular connections [52].

If an AVM is suspected in a patient with AUB, imaging studies should be performed prior to further intrauterine instrumentation [53]. Pelvic ultrasound with Doppler is typically the first-line imaging study (image 2) [54-56]. MRI with angiography may also be performed.

AUB related to an AVM may be refractory to hormonal management. Management of patients with AVMs and AUB is discussed separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management", section on 'Structural lesions'.)

●Enhanced myometrial vascularity – It is important to different AVM from enhanced myometrial vascularity (EMV), which is its own diagnostic entity and usually occurs in the setting of retained products of conception following delivery (presenting as delayed postpartum hemorrhage) or pregnancy loss/termination (all trimesters) (image 3) [57,58]. As the use of vaginal ultrasound with Doppler assessment of uterine vascularity is becoming more widespread, the diagnosis of EMV is increasing.

Management of patients with EMV is with expectant management or dilation and curettage; this is distinct from those with AVM and is discussed in detail separately. (See "Retained products of conception in the first half of pregnancy", section on 'Management' and "Secondary (late) postpartum hemorrhage", section on 'Management'.)

●Other – Rarely, sarcoidosis affects the female genital tract and the uterus is the most common site [59]. Patients with uterine sarcoidosis may present with AUB. Most patients have concomitant pulmonary involvement. (See "Overview of extrapulmonary manifestations of sarcoidosis".)

Fallopian tube bleeding — 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 PID. In patients with PID, the source of bleeding may be the uterus or the fallopian tube. (See 'Endometrial dysfunction (AUB-E)' above.)

Hysteroscopic sterilization — A dislodged tubal microinsert may result in bleeding [60]. (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' below and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Vaginal bleeding'.)

Ovarian bleeding — Similar to bleeding from the fallopian tube, 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 patients). 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 [61,62]. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Vaginal bleeding'.)

NONGENITAL TRACT DISEASE — Diseases of the tissue and organs surrounding the female genital tract may initially be mistaken for genital tract bleeding; nongenital tract sources include: 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: Terminology, evaluation, and approach to diagnosis", section on 'Gynecologic and obstetric history'.)

SPECIAL POPULATIONS

Children — Common causes of vaginal bleeding prior to menarche include vaginal foreign bodies (eg, toilet paper, pencil erasers), urethral prolapse, bacterial infections, trauma (including sexual assault), 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".)

Pregnant patients — Bleeding from the vagina is a common event at all stages of pregnancy; the source is virtually never fetal. Causes of vaginal bleeding in pregnant patients are discussed in detail separately. (See "Evaluation and differential diagnosis of vaginal bleeding before 20 weeks of gestation".)

Vaginal bleeding is also a common presentation of ectopic pregnancy; in such patients, the presumptive source of this bleeding is sloughing of the decidualized endometrium rather than bleeding from the tube itself [63,64]. While the fallopian tube is the most common site of ectopic pregnancy, other sites of extrauterine gestations include the abdomen, ovary, or cervix. Cesarean scar pregnancies can also occur. (See "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Vaginal bleeding' and "Ectopic pregnancy: Epidemiology, risk factors, and anatomic sites", section on 'Anatomic sites'.)

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

●Sources – Females 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 (cervix, vagina, vulva) 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 (table 1 and table 2). (See 'Introduction' above.)

●Lower genital tract sources – Causes of cervical, vaginal, and vulvar bleeding include trauma, infection, neoplasia, and genital manifestations of systemic disease. Bleeding from these areas often causes sporadic or postcoital bleeding, but hemorrhage can occur. A lesion is often visualized on examination. (See 'Cervical bleeding' above and 'Vaginal bleeding' above and 'Vulvar bleeding' above.)

●Upper genital tract sources

•Uterus – The uterus is the most likely source of genital tract bleeding. The etiology of uterine bleeding depends on the reproductive status of the patient (premenarchal, reproductive-age, postmenopausal) and the pattern of bleeding (cyclic or noncyclic). Possible causes of abnormal uterine bleeding (AUB) are divided into nine basic categories: polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified (figure 1). (See 'Uterine bleeding' above.)

Uterine bleeding is also a common event at all stages of pregnancy; the source is virtually never fetal. Ectopic pregnancy must also be considered. (See 'Pregnant patients' above.)

•Fallopian tube – 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.)

•Ovary – Although bleeding from the ovary usually collects intraperitoneally, vaginal bleeding 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.)

●Nongenital tract bleeding – 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.