Overview of causes of genital tract bleeding in women INTRODUCTION Abnormal bleeding noted in the genital area is often attributed

d to a uterine source, but 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 organ, such as the urethra, bladder, or bowel. The differential diagnosis of genital tract bleeding is listed in the table (table 1). It is useful to separate these causes according to age group (table 2) and site (see below). An overview of the differential diagnosis of genital tract bleeding in women will be reviewed here. The evaluation and management of women with this complaint are discussed separately. (See "Initial approach to the premenopausal woman with abnormal uterine bleeding" and "Terminology and evaluation of abnormal uterine bleeding in premenopausal women" and "Postmenopausal uterine bleeding".) UTERINE BLEEDING The likelihood of a particular etiology of uterine bleeding depends upon the age of the patient and the pattern of bleeding (cyclic or noncyclic). Pregnancy Bleeding is a common symptom of a variety of disorders related to pregnancy. All reproductive age women with vaginal bleeding should have a pregnancy test as part of their initial evaluation. (See "Overview of the etiology and evaluation of vaginal bleeding in pregnant women".) Menstruation The uterus is the only organ for which bleeding can be a normal physiologic phenomenon (menstruation). (See "Physiology of the normal menstrual cycle".) Normal menstrual bleeding is characterized by [1]: Duration between two and seven days Flow less than 80 mL Occurring in cycles of 24 to 35 days

Moliminal symptoms are often present and include an increase in thin cervical mucus secretions at mid-cycle and premenstrual symptoms such as menstrual cramps, breast tenderness, fluid retention, and appetite or mood changes. (See "Evaluation of the menstrual cycle and timing of ovulation".) Menorrhagia Excessive menstrual blood flow is termed menorrhagia. Menorrhagia may be due to local disturbances in prostaglandins (elevated endomyometrial vasodilatory prostaglandins and decreased vasoconstrictive prostaglandins), or may be related to any of the uterine etiologies described below. (See "Chronic menorrhagia or anovulatory uterine bleeding".) Anovulation In premenopausal nonpregnant women, anovulation is a common cause of abnormal uterine bleeding (AUB). Anovulatory bleeding is characterized by noncyclical bleeding of variable flow and duration. Molimina are typically absent. Many women with chronic anovulation have an adequate amount of biologically active estrogen since androgens can be converted peripherally to estrogens in the absence of normal ovarian function; however, their anovulatory cycles lack the progesterone secretion normally present in the luteal phase. This puts them at risk of developing endometrial hyperplasia and endometrial cancer. (See "Classification and diagnosis of endometrial hyperplasia" and "Endometrial carcinoma: Epidemiology and risk factors", section on 'Risk factors'.) Causes of anovulation are listed in the table (table 3). Anovulation should be suspected in the following settings:

Adolescents Anovulatory cycles are the most common cause of AUB in adolescent girls due to a slowly maturing hypothalamic-pituitary axis during the first two to three postmenarchal years [2]. (See "Definition and evaluation of abnormal uterine bleeding in adolescents", section on 'Abnormal uterine bleeding (AUB) in adolescents' and "Differential diagnosis and approach to the adolescent with abnormal uterine bleeding" and "Management of abnormal uterine bleeding in adolescents".) Menopausal transition Anovulation is also a common cause of AUB in women in the menopausal transition. Ovulatory cycles and the normal cyclic production of estrogen and progesterone become disturbed as women approach menopause. Ovulation occurs intermittently, interspersed with anovulatory (estrogen only) cycles of varying length. As a result, menses become irregular. The duration and volume of blood loss can be short and light, but prolonged heavy bleeding can occur during longer periods of anovulation. (See "Clinical manifestations and diagnosis of menopause".) Polycystic ovary syndrome Chronic anovulation in reproductive-age women is most often attributable to an endogenous disorder, such as the polycystic ovary syndrome (PCOS), which is characterized by oligomenorrhea (irregular infrequent menstrual cycles) and hyperandrogenism (hirsutism, acne, and male pattern balding). Obesity and insulin resistance are common. Women with PCOS have an adequate amount of biologically active estrogen since androgens can be converted peripherally to estrogens even in the absence of normal ovarian function, but low levels of progesterone. Thus, constant mitogenic stimulation of the endometrium leads to endometrial hyperplasia, intermittent estrogen unscheduled (breakthrough) bleeding, and menorrhagia. (See "Diagnosis of polycystic ovary syndrome in adults" and "Treatment of polycystic ovary syndrome in adults".) Endocrine disorders Endocrine disorders may be associated with hormonal changes that affect ovulation. These disorders are uncommon causes of AUB, with the exception of polycystic ovary syndrome, which occurs in 6 percent of reproductive age women [1]. Both hypo- and hyper- thyroid activity are associated with AUB. Women with hypothyroidism, even when subclinical, may have heavy or prolonged uterine bleeding [3]. Hypothyroidism can cause hyperprolactinemia; this usually results in amenorrhea and galactorrhea, but women may develop anovulatory bleeding prior to amenorrhea. Hyperthyroidism may cause anovulation due to alterations in sex hormone binding globulin [4]. (See "Overview of the clinical manifestations of hyperthyroidism in adults" and "Clinical manifestations of hypothyroidism".) Menstrual irregularities are common in women with Cushing's syndrome [5]. 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".) Hormone secreting adrenal and ovarian tumors are rare causes of anovulation and menstrual irregularities. (See individual topic reviews). Endocrine changes leading to anovulation may also be caused by strenuous exercise/activity (eg, running, ballet dancing), sudden weight change, or significant stress.

Other disorders The level or activity of sex hormones may be affected by disorders unrelated to endocrine glands, such as advanced liver or renal disease, that alter hormone metabolism or binding. Anovulation and AUB may result. Neoplasia and other disorders of the hypothalamus and pituitary often cause anovulation, but amenorrhea is more common than AUB because estrogen levels are low. (See "Etiology, diagnosis, and treatment of secondary amenorrhea".) Anatomic abnormalities A significant number of women who complain of abnormal uterine bleeding have uterine abnormalities. This was illustrated in a study of 370 women aged 22 to 82 years with abnormal uterine bleeding unresponsive to treatment with progestin therapy [6]. Hysteroscopy revealed an abnormal uterine cavity in two-thirds of these women: endometrial hyperplasia (23 percent), polyps (22 percent), submucous myomata (11 percent), synechiae (6 percent), endometrial atrophy (2 percent), and adenocarcinoma (1 percent). When anatomic abnormalities are the cause of abnormal bleeding, cyclic menses with molimina typically occur. However, the duration and flow of the menstrual period may be altered or there may be bleeding between menstrual periods. Anatomic abnormalities can often be diagnosed by imaging studies, but excision is sometimes required for confirmation of the diagnosis and treatment. (See "Terminology and evaluation of abnormal uterine bleeding in premenopausal women".) Polyp Uterine polyps are usually benign endometrial growths of unknown etiology that are a common cause of abnormal uterine bleeding in women in the menopausal transition and early postmenopausal women. Irregular bleeding is the most frequent symptom, occurring in about one-half of symptomatic cases. Bleeding after straining or heavy lifting is common. Less frequent symptoms include heavy or prolonged bleeding, postmenopausal bleeding, prolapse through the cervical os, and unscheduled (breakthrough) bleeding during hormonal therapy. Polyps can be stimulated by estrogen replacement or tamoxifen. The uterus is typically normal on bimanual examination. (See "Endometrial polyps".) Fibroids Leiomyomas, also known as fibroids, are the most common pelvic tumors in women, occurring in approximately 25 percent of those who are of reproductive age. There are three uterine locations for fibroids: submucosal, intramural, and subserosal (figure 1). Intramural and submucosal fibroids distort the endometrial cavity, resulting in heavy or prolonged menstrual periods. Intermenstrual bleeding can also occur, but this is less likely and other lesions of cervix or uterus must be considered. The uterus often feels enlarged and asymmetric on bimanual examination. (See "Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas (fibroids)".) Adenomyosis Adenomyosis is a disorder in which endometrial glands and stroma are present within the uterine musculature. 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. The diagnosis may be suspected by ultrasound or magnetic resonance imaging, but can only be confirmed by pathologic examination following hysterectomy. (See "Uterine adenomyosis".) Hysterotomy scar Endometrial abnormalities related to previous hysterotomy (particularly cesarean delivery) can lead to postmenstrual or intermenstrual bleeding [7-10]. Other structural abnormalities Case reports have described sarcoidosis of the endometrium detected during the evaluation and treatment of AUB. A rare cause of heavy uterine bleeding is a congenital or acquired uterine arteriovenous malformation [11]. This lesion should be suspected when an invasive procedure (eg,

endometrial biopsy, curettage) for unexplained uterine bleeding seems to aggravate the problem. Color Doppler studies can confirm the presence of abnormal blood flow, but pelvic arteriography is the standard for diagnosis. Uterine arteriovenous malformations have traditionally been treated with hysterectomy, but uterine artery embolization is often effective and may preserve fertility [11]. (See "Interventional radiology in management of gynecological disorders".) Malignancy Uterus Adenocarcinoma of the endometrium is the most common gynecologic cancer in women over 45 years of age; it is rarely seen before age 35. All women who experience postmenopausal uterine bleeding in the absence of estrogen therapy must be evaluated for endometrial cancer since age is a significant risk factor for this disorder. (See "Endometrial carcinoma: Epidemiology and risk factors" and "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 requires a hysterectomy. Women with leiomyosarcomas usually present with heavy prolonged bleeding or postmenopausal bleeding and a uterine mass. (See "Uterine sarcoma: Classification, clinical manifestations, and diagnosis".) Other Bleeding from fallopian tube cancer can track through the uterus, but this is a rare cause of uterine bleeding. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Subacute presentation'.)

Abnormal uterine bleeding can also be a symptom of ovarian cancer or gestational trophoblastic disease. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis" and "Gestational trophoblastic disease: Epidemiology, clinical manifestations and diagnosis".) Rarely, the endometrium is the site of metastatic disease from nongynecologic malignancy (eg, melanoma). Endometritis and pelvic inflammatory disease Endometritis may be acute or chronic. Premenopausal women with chronic endometritis usually present with abnormal uterine bleeding, 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. Women with acute endometritis frequently have fever, while it is less common in women with the chronic process. (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 after placement of an intrauterine contraception or with pelvic inflammatory disease. Lower abdominal pain is the cardinal presenting symptom of pelvic inflammatory disease. 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 "Overview of intrauterine contraception" and "Clinical features and diagnosis of pelvic inflammatory disease".) In contrast, endometritis in postmenopausal women is commonly associated with underlying malignancy. 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. Bleeding diatheses Women with bleeding diatheses usually present with abnormal uterine bleeding, particularly increased flow, but other genital tract bleeding may occur [12]. In one series of women age 18 to 45 years, bleeding disorders were diagnosed in 11 percent of patients with menorrhagia (von Willebrand disease [8/121], factor deficiencies [2/121], platelet abnormality [3/121]), but only in 3 percent of controls without abnormal uterine bleeding [13]. In another series, 19 percent of adolescents with abnormal uterine bleeding had a coagulation disorder, with an even higher risk in those with hemoglobin less than 10 g/dL or requiring hospitalization (25 and 50 percent, respectively) [14]. Abnormal genital bleeding in women and adolescents with bleeding diatheses may be associated with other mucosal bleeding (eg, epistaxis). (See "Approach to the adult with epistaxis" and "Evaluation of epistaxis in children".) von Willebrand disease is a relatively common inherited bleeding disorder that is characterized by a deficiency of a plasma protein that stabilizes factor VIII. It should be suspected in young women who present with menorrhagia from the onset of menarche, particularly if there is a family history of coagulopathy. (See "Clinical presentation and diagnosis of von Willebrand disease".) Thrombocytopenia due to immune thrombocytopenia (ITP), hypersplenism, or systemic diseases, such as chronic renal failure, may cause menorrhagia. Uremia also causes anovulatory menstrual bleeding. Women with acute leukemia or who are undergoing chemotherapy for malignancy may develop a bleeding diathesis and heavy, prolonged uterine bleeding. (See "Heavy or irregular uterine bleeding during chemotherapy".) Advanced liver disease may cause reduced synthesis of vitamin K-dependent clotting factors, fibrinogen, and antithrombins. Anticoagulants enhance the volume of blood loss from menstruation or AUB. Menorrhagia has been reported in women taking SSRIs, presumably related to the effect of these agents on platelets [15]. (See "Unipolar depression in adults and selective serotonin reuptake inhibitors (SSRIs): Pharmacology, administration, and side effects", section on 'Bleeding'.)

Drugs Contraception Contraceptive techniques that can cause abnormal vaginal bleeding include combination hormonal contraceptives, intrauterine contraception, and progestin-only contraceptives. Combination hormonal contraceptives Intermenstrual (breakthrough) bleeding is the most common side effect of combination hormonal contraceptives. Its occurrence does not indicate a decrease in efficacy (unless the patient has been noncompliant), but reflects tissue breakdown as the endometrium adjusts to a new thin state in which it is fragile and atrophic. Unscheduled (breakthrough) bleeding is related to a relatively high progesterone-to-estrogen ratio and was less of a problem when high doses of estrogen

were used because estrogen stabilizes the endometrium. The frequency of bleeding is independent of the type of progestin [16,17], and is increased in women who smoke cigarettes, probably due to the accelerated metabolism of estrogen caused by smoking [18]. Women should be cautioned that missing pills results in an increase in unscheduled bleeding, as well as a decrease in contraceptive efficacy. (See "Risks and side effects associated with estrogen-progestin contraceptives".) Progestin-only contraceptives Prolonged bleeding and spotting are common complications of progestin-only contraceptives, such as depotmedroxyprogesterone acetate (Depo-Provera), the levonorgestrel-releasing intrauterine contraceptive, implantable progestin rods (eg, Implanon), and progestin-only pills. Bleeding tends to be an early complication of these methods; many women develop amenorrhea with continued use. The mechanism of progesterone-breakthrough bleeding is endometrial atrophy and ulceration due to insufficient estrogen. (See "Overview of contraception"and "Overview of intrauterine contraception", section on 'Levonorgestrelreleasing IUDs'.)

Copper IUC Copper IUCs 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 intermenstrual bleeding. (See "Overview of intrauterine contraception", section on 'TCu380A (copper) IUD'.) Postmenopausal hormone therapy Postmenopausal women who take postmenopausal hormone therapy may develop uterine bleeding; the frequency depends upon the regimen used. (See "Preparations for postmenopausal hormone therapy", section on 'Doses and bleeding patterns with estrogen regimens' and "Postmenopausal uterine bleeding".) Other Drugs that can cause hyperprolactinemia may also cause abnormal uterine bleeding (table 4). Although severe hyperprolactinemia results in amenorrhea, mild degrees of hyperprolactinemia may cause oligomenorrhea and menstrual abnormalities. (See "Clinical manifestations and diagnosis of hyperprolactinemia".) Chemotherapy-induced thrombocytopenia can cause menorrhagia, while antipsychotic drugs may lead to anovulation and irregular bleeding. Ruptured ovarian cyst Symptoms include pain and light uterine bleeding (due to a drop in ovarian hormone levels). (See "Evaluation and management of ruptured ovarian cyst".) CERVICAL BLEEDING In contrast to abnormal bleeding from the 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 easily visualized on speculum examination. Cancer Sporadic bleeding, postcoital spotting, and vaginal discharge that is watery, mucoid, or purulent and malodorous are common signs of cervical cancer. Therefore, women with these symptoms should not have cervical cytology postponed. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".) Direct extension from other pelvic tumors, such as uterine cancer, is the most common source of cervical involvement by metastatic tumors. Choriocarcinoma has a relatively high rate of cervical involvement. Rarely leukemias, lymphomas, and other nongynecological cancers involve the cervix. Cervicitis Postcoital bleeding is common in women with cervicitis due to nonspecific inflammatory changes or ulcerative sexually transmitted diseases. A strawberry red cervix with

bleeding on contact is pathognomonic for Trichomonas vaginalis infection. (See "Acute cervicitis".) Polyps Cervical polyps commonly cause postcoital spotting and sporadic bleeding. The majority are benign endocervical polyps, which can be seen on visual examination of the cervix and endocervix. (See "Congenital cervical anomalies and benign cervical lesions".) Ectropion Ectropion is the normal physiologic presence of endocervical glandular tissue on the exocervix. This tissue is friable and readily bleeds upon contact, such as during intercourse or cervical cancer screening. (See "Congenital cervical anomalies and benign cervical lesions", 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 can occur secondary to ulceration, trauma and infection. This type of bleeding often occurs after straining. (See "An overview of the epidemiology, risk factors, clinical manifestations, and management of pelvic organ prolapse in women".) Endometriosis Ectopic endometriosis can be found in the cervix, especially if the patient has a history of cervical procedures (such as cone biopsy). These endometriotic implants will bleed during menses. Diagnosis is made by biopsy. (See "Pathogenesis, clinical features, and diagnosis of endometriosis".) Vasculitis Isolated necrotizing arteritis is a rare lesion, usually localized to the cervix [19]. Clinical manifestations include menorrhagia or postmenopausal bleeding. Isolated vasculitis involving the cervix, as well as other sites in the female genital tract, is another rare lesion that may be associated with bleeding [20]. VAGINAL BLEEDING As with cervical lesions, vaginal lesions typically cause sporadic or postcoital bleeding and can be easily visualized on speculum examination. Trauma is an exception; vaginal trauma can be associated with major internal and/or external hemorrhage. Vaginitis and vaginal ulcers Vaginal infection or inflammation may lead to significant irritation of the vaginal lining, which then bleeds. (See "Approach to women with symptoms of vaginitis".) Atrophic vaginitis is an estrogen deficiency state, which occurs in premenarchal girls, postpartum lactating women, and postmenopausal women. Bleeding or spotting may occur. (See "Clinical manifestations and diagnosis of vaginal atrophy".) Ulcerative diseases with vaginal involvement 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".) Primary and metastatic cancer Primary vaginal cancer constitutes 1 to 2 percent of gynecological 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 [21]. (See "Vaginal cancer".) Up to 20 percent of children under age 10 with vaginal bleeding have a reproductive tract neoplasm, such as sarcoma botryoides. (See "Rhabdomyosarcoma and undifferentiated sarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis" and "Vulvovaginal complaints in the prepubertal child".)

Advanced bladder or colorectal cancer may invade the vagina and cause vaginal bleeding [22], and the vagina may be the site of metastatic disease from distant organs. Radiation therapy Vaginal bleeding can be a late effect of radiation therapy [23]. 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. Vaginal trauma Bleeding from the vagina or vulva can occur from genital tract trauma related to intercourse (eg, tearing of an intact hymen during intercourse), 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 rail, fence, or table edge). (See "Evaluation and management of lower genital tract trauma in women".) Female circumcision or infundibulation reduces the vaginal opening. Vaginal bleeding and lacerations can occur when intercourse is attempted. (See "Female genital cutting (circumcision)".) Fistulas Vesicovaginal or rectovaginal fistulas related to childbirth, gynecologic surgery, or complications of cancer and cancer therapy can present with vaginal bleeding. (See "Urogenital tract fistulas in women" and "Rectovaginal, anovaginal, and colovesical fistulas".) Benign growths Gartner's duct cysts, polyps, and aberrant glandular tissue (termed vaginal adenosis) rarely lead to vaginal bleeding in the absence of friction and trauma. (See "Diagnosis and management of congenital anomalies of the vagina".) Toxic epidermal necrolysis and Stevens-Johnson syndrome Toxic epidermal necrolysis and Stevens-Johnson syndrome may be caused by a variety of drugs, particularly antibiotics. The vulvar and vaginal regions are commonly involved in this sudden and extensive destruction of the skin [24]. Bleeding may occur along with significant ulceration. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Clinical manifestations; pathogenesis; and diagnosis".) VULVAR BLEEDING As with cervical and vaginal lesions, vulvar lesions typically cause sporadic bleeding and can be easily visualized on physical examination. Infection Sexually transmitted diseases can cause characteristic lesions on the vulva, some of which may produce a bloody discharge or bleed easily on contact. Examples include the syphilitic chancre (although this usually produces more serous than bloody drainage), herpes simplex virus, Haemophilus ducreyi (Chancroid), granuloma inguinale (Donovanosis), and lymphogranuloma venereum. (See "Approach to the patient with genital ulcers".) Benign lesions Benign lesions, such as sebaceous (epidermal) cysts, condylomata, and angiokeratoma, may bleed due to trauma related to friction from clothing or scratching. (See "Diagnostic evaluation of vulvar lesions" and "Differential diagnosis of vulvar lesions".) Malignant and premalignant lesions 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 are often misdiagnosed. Delay may be related to patient embarrassment, denial, reluctance to be examined, or the tendency of health care practitioners to 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: Clinical manifestations, diagnosis, and pathology" and "Vulvar intraepithelial neoplasia".) 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 lower genital tract trauma in women".) NONGENITAL TRACT DISEASE Diseases of the urethra (eg, urethritis, diverticulum, urethral prolapse [caruncle]), bladder (eg, cancer, stone, or infection), and bowel (eg, inflammatory bowel disease, hemorrhoids) may cause bleeding that is misdiagnosed as genital tract bleeding. These disorders should be considered in women with bleeding unrelated to the menstrual cycle, especially when there is no obvious genital tract etiology. Systemic diseases that may present with vulvar involvement include Crohn's disease, Behcet's syndrome, pemphigoid, erosive lichen sclerosus, and lymphoma. Trauma is a common cause genital tract 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 th th language, at the 5 to 6 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 th th at the 10 to 12 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 information: Abnormal uterine bleeding (Beyond the Basics)" and "Patient information: Menorrhagia (excessive menstrual bleeding) (Beyond the Basics)" and "Patient information: Absent or irregular periods (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS The source of abnormal bleeding may be from a problem anywhere in the lower genital tract (vulva, vagina, cervix), upper genital tract (uterine corpus, fallopian tubes, ovaries), or from nearby organs (urethra, bladder, bowel). (See 'Introduction' above.) The likelihood of a particular etiology for uterine bleeding depends upon the patient's reproductive age (premenarchal, adolescent, menopausal status), the pattern of bleeding (heavy, light, prolonged, cyclic or noncyclic), and the occurrence of associated symptoms (eg, pain, fever) and medical conditions. (See 'Uterine bleeding' above.) Bleeding is a common symptom of a variety of disorders related to pregnancy; therefore, all reproductive age women with uterine bleeding should have a pregnancy test as part of their initial evaluation. Other common causes of abnormal uterine bleeding include heavy menses, anovulation, anatomic abnormalities (eg, polyps, fibroids, adenomyosis), and side effects of contraceptives. Bleeding is the cardinal symptom of endometrial cancer. Vulvar, vaginal, and cervical bleeding can usually be visualized by physical examination. Causes 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.

Initial approach to the premenopausal woman with abnormal uterine bleeding INTRODUCTION Abnormal uterine bleeding (AUB) can be caused by a wide variety of local and systemic diseases or related to drugs (table 1). However, most cases are related to pregnancy, structural uterine pathology (eg, fibroids, polyps, adenomyosis), anovulation, a disorder of hemostasis, or neoplasia. Trauma and infection are less common. The differential diagnosis will change based upon age, reproductive status, and intercurrent illness. A relevant differential diagnosis and focused workup is established by the following key questions: Where is the bleeding coming from? What is the woman's age? Is she sexually active? Could she be pregnant? What is her normal menstrual cycle like? Are there symptoms of ovulation? What is the nature of the abnormal bleeding (frequency, duration, volume, relationship to activities such as coitus)? When does it occur? Are there any associated symptoms? Does she have a systemic illness or take any medications? Has there been a change in weight, possibly associated with an eating disorder, excessive exercise, illness, or stress? Is there a personal or family history of a bleeding disorder?

The initial approach to the woman with AUB will be reviewed here. The evaluation of women with AUB is discussed separately. (See "Terminology and evaluation of abnormal uterine bleeding in premenopausal women" and "Postmenopausal uterine bleeding".) An overview of the differential diagnosis of abnormal genital tract bleeding can also be found elsewhere. (See "Overview of causes of genital tract bleeding in women".) CONFIRM THAT BLEEDING IS UTERINE Diseases of the urethra (eg, urethritis), bladder (eg, cancer or urinary tract infection), vagina, vulva, and bowel (eg, inflammatory bowel disease or hemorrhoids) may cause bleeding that is mistaken for uterine bleeding. These disorders should be considered and evaluated for in patients with bleeding that is unrelated to the menstrual cycle in whom there is no obvious uterine etiology. Management depends upon the specific lesion. (See "Overview of causes of genital tract bleeding in women".) HOW OLD IS THE PATIENT? Premenopausal women range in age from menarche (age 10 to 14 years) to the onset of menopause (age 46 to 55 years). Within this group, there are three broad age divisions based upon hypothalamic-pituitary-ovarian axis (HPO) function. Changes in HPO function are a common cause of AUB at the extremes of reproductive age. Women between the ages of 40 and menopause (the menopausal transition) commonly experience intermittent periods of anovulatory cycles, skipped periods, heavy or prolonged periods, and hot flashes related to fluctuations in HPO function accompanying the natural decline in follicular number. (See"Clinical manifestations and diagnosis of menopause".) Women in this age group are also more likely than younger women to have bleeding related to

benign and malignant growths (see individual topic reviews on uterine polyps, leiomyomas, adenomyosis, endometrial cancer, and sarcoma). Women aged 20 to 40 years typically have a mature HPO axis that generally produces regular menstrual cycles. AUB in this age group is due to a wide range of ovulatory and anovulatory etiologies. (See 'Is bleeding anovulatory or ovulatory?' below.) In the first decade after menarche, the HPO axis is immature; therefore, a teenager often does not ovulate with each cycle, which can lead to periods of amenorrhea alternating with polymenorrhea. However, AUB can be related to other causes, such as pregnancy or a congenital defect of hemostasis. (See"Differential diagnosis and approach to the adolescent with abnormal uterine bleeding".) IS THE PATIENT PREGNANT? Pregnancy should be considered in any female with AUB from menarche to menopause. Women who are pregnant are evaluated primarily for pregnancy related causes of bleeding, but the possibility of a concurrent nonpregnancy related etiology should be kept in mind. (See"Overview of the etiology and evaluation of vaginal bleeding in pregnant women".) WHEN DOES THE BLEEDING OCCUR? Menstrual bleeding Menorrhagia refers to excessive or prolonged menstrual bleeding occurring at regular intervals, although the term is also used in women with excessive anovulatory bleeding. The diagnosis should be suspected based on the answers to the questions listed in the table (table 2). The most common cause of menorrhagia in premenopausal women is distortion of the endometrial architecture from a submucous leiomyoma, endometrial polyp, or adenomyosis and menopausal transition-associated anovulatory cycles. Additional causes are listed in the table (table 3). Although endometrial polyps may cause menorrhagia, intermenstrual bleeding is the more common clinical manifestation. (See "Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas (fibroids)" and "Endometrial polyps" and "Uterine adenomyosis".) Hemostatic defects should be considered if menorrhagia began at menarche or is associated with other signs of a bleeding diathesis [1-3]. In one series of women age 18 to 45 years, bleeding disorders were diagnosed in 11 percent of patients with menorrhagia (von Willebrand disease [8/121], factor deficiencies[2/121], platelet abnormality [3/121]), but only 3 percent of controls with normal vaginal bleeding [1]. Systematic reviews of studies of women with menorrhagia reported the prevalence of von Willebrand disease ranged from 5 to 24 percent [4,5]. However, the percentage of menorrhagia attributable solely to von Willebrand disease is not clear; many such women have uterine pathology potentially associated with bleeding which may be aggravated by the underlying coagulopathy [6]. (See "Approach to the adult patient with a bleeding diathesis" and "Clinical presentation and diagnosis of von Willebrand disease".) Bleeding defects can also be due to thrombocytopenia or renal or liver disease. Chronic renal failure is associated with platelet dysfunction and bleeding diathesis, which can manifest as menorrhagia. Liver disease can affect synthesis of coagulation factors. The Tcu-380A (Paragard) intrauterine contraception (IUC) is associated with iatrogenic menorrhagia, in contrast, the levonorgestrel IUC actually decreases menstrual blood loss. (See "Overview of intrauterine contraception".) A rare cause of menorrhagia is a congenital or acquired uterine arteriovenous malformation [79]. This lesion should be particularly suspected when an invasive procedure for unexplained

bleeding seems to aggravate the problem. The diagnosis can be established by color flow Doppler or angiography. Chronic endometritis and endometrial cancer can cause menorrhagia; however, endometritis more commonly present as intermenstrual bleeding and endometrial cancer more commonly presents as irregular uterine bleeding. (See "Endometritis unrelated to pregnancy" and "Endometrial carcinoma: Epidemiology and risk factors".) Management of menorrhagia is discussed separately. (See "Chronic menorrhagia or anovulatory uterine bleeding".) Intermenstrual bleeding Intermenstrual bleeding may be related to a variety of etiologies (table 4), some of which are discussed below: Use of hormonal contraception. Breakthrough bleeding is the most common side effect of hormonal contraception. Factors which increase the incidence of breakthrough bleeding include noncompliance, taking a low dose oral contraceptive pill at a different time each day, use of medications that alter the metabolism of sex steroids, and use of progestin-only contraception. (See "Risks and side effects associated with estrogenprogestin contraceptives" and "Overview of contraception".) Presence of an intrauterine contraceptive device (see "Overview of intrauterine contraception"). Cervical polyps or ectropion (see "Congenital cervical anomalies and benign cervical lesions") Endometrial polyps (see "Endometrial polyps") Genital tract cancer (see individual topic reviews on vaginal, cervical, endometrial, fallopian tube, and ovarian cancer). Endometrial and cervical cancer are the most common malignancies associated with AUB. Infection, most commonly endometritis, but cervicitis and some types of vaginitis can cause bloody discharge (see "Endometritis unrelated to pregnancy" and "Acute cervicitis" and "Trichomoniasis") Endometrial abnormalities related to previous endometrial trauma (including cesarean delivery [10-12]) Physiologic intermenstrual bleeding at the time of expected ovulation is secondary to the brief abrupt decline in estradiol that follows its preovulatory surge. Postcoital bleeding suggests the presence of cervical disease (eg, infection, benign or malignant lesions) (see "Postcoital bleeding in women")

Management depends upon the specific lesion. IS BLEEDING ANOVULATORY OR OVULATORY? It is useful to determine whether the woman is ovulating because the etiologies of anovulatory and ovulatory bleeding are generally different. Bleeding in ovulating women Ovulatory AUB is typically cyclic, but heavy or prolonged. AUB in ovulating women is usually due to an anatomic or physical lesion (eg, polyp, fibroid, adenomyosis, neoplasm, foreign body), hemostatic defect, infection, trauma, or local disturbances in prostaglandins (elevated endomyometrial vasodilatory prostaglandins and decreased vasoconstrictive prostaglandins). Gonadotropin and sex steroid levels are normal, however, checking gonadotropin levels is rarely indicated as ovulation can generally be documented clinically, based on regular cyclic menses with molimina (eg, breast tenderness, bloating or pelvic discomfort, mood changes, thin vaginal discharge). (See "Overview of causes of genital tract bleeding in women", section on 'Uterine bleeding'.)

Anovulatory bleeding Anovulatory uterine bleeding refers to unpredictable endometrial bleeding of variable flow and duration. It is the most common cause of AUB. In anovulatory women, sex steroids are produced, but not cyclically so bleeding is irregular. In particular, chronic 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, prolonged, and heavy. Cause Anovulation is common both at menarche and in the women in the menopausal transition, the times when ovarian function begins and declines. However, it can occur at anytime during the reproductive years and has many causes (table 5).

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder associated with anovulation, affecting 6 percent of reproductive aged women [13]. It is characterized by chronic unopposed estrogen stimulation of the endometrium with irregular shedding. The presence of obesity, hirsutism, acanthosis nigricans, and irregular menstrual cycles should lead to a suspicion of this diagnosis. (See "Diagnosis of polycystic ovary syndrome in adults".) Thyroid dysfunction and elevated prolactin levels are other common endocrine disorders related to anovulation. Stress, significant weight loss, and exercise can disturb then hypothalamic-pituitary-ovarian axis and are not uncommon causes of anovulation. (See"Amenorrhea and infertility associated with exercise".) Rare estrogen-producing ovarian tumors (eg, granulosa cell tumor) can lead to anovulation, as can psychopharmacologic drugs that interfere with the neurotransmitters responsible for release and inhibition of hypothalamic hormones. Liver and kidney disease are other rare causes of anovulation and cause AUB by more than one mechanism. Liver disease can affect both estrogen metabolism and synthesis of coagulation factors, thereby potentially leading to both anovulation and bleeding diathesis. Chronic renal disease is associated with both hypothalamicpituitary-gonadal and platelet dysfunction. (See"Reproductive and sexual dysfunction in uremic women", section on 'Hormonal disturbances in uremic premenopausal women'.) Another possible etiology of irregular menstrual bleeding is celiac disease [14]. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Menstrual and reproductive issues'.) Diagnosis The clinical diagnosis of anovulation is based upon the characteristic noncyclic bleeding pattern, the absence of signs of ovulation, and exclusion of anatomic lesions that can cause endometrial bleeding. The diagnosis can be difficult because many patients (especially women in the menopausal transition) have anovulatory cycles interspersed with ovulatory cycles.

The absence of secretory endometrial changes from lack of progesterone stimulation is the histologic hallmark of anovulation. When this occurs from unopposed estrogen stimulation over a prolonged period, the proliferative endometrium can become hyperplastic and ultimately progress to a precancerous lesion (endometrial hyperplasia with cytological atypia) or cancer. (See "Classification and diagnosis of endometrial hyperplasia".)

If bleeding is thought to be anovulatory, subsequent evaluation is directed toward detecting the cause and excluding the presence of a structural lesion. Ideally, the cause of anovulation can be identified and treated so that normal cyclic menses can be established. Management Control of acute moderate to severe anovulatory bleeding is discussed in detail separately. (See "Chronic menorrhagia or anovulatory uterine bleeding".) If regular ovulatory cycles cannot be established, then medical management to regulate bleeding episodes and prevent endometrial hyperplasia is important. (See "Chronic menorrhagia or anovulatory uterine bleeding", section on 'Initial approach to management' and "Management of endometrial hyperplasia", section on 'Mechanism of progestin therapy'.) If medical management is ineffective, then surgery (endometrial ablation, myomectomy, hysterectomy) can be considered as a last resort, but precludes future childbearing. (See "An overview of endometrial ablation" and "Prolapsed uterine leiomyoma (fibroid)" and "Hysteroscopic myomectomy" and "Overview of hysterectomy" and "Abdominal myomectomy", section on 'Indications'.) Drug related uterine bleeding Medications can cause AUB in a variety of ways: (1) they may interfere with hemostasis, which usually results in menorrhagia, (2) they may affect the concentration of endogenous or exogenous hormones, which could result in fluctuating hormone levels with breakthrough bleeding, (3) they may interfere with the HPO axis, which could result in anovulation. Drugs associated with AUB include: hormonal contraceptives, postmenopausal hormone therapy, digitalis, anticonvulsants, anticoagulants, corticosteroids, psychopharmacologic agents, and others. AMENORRHEA Amenorrhea refers to absence of bleeding for at least three usual cycle lengths. (See "Etiology, diagnosis, and treatment of primary amenorrhea" and "Etiology, diagnosis, and treatment of secondary amenorrhea".) 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 th th language, at the 5 to 6 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 th th at the 10 to 12 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 information: Abnormal uterine bleeding (Beyond the Basics)" and "Patient information: Menorrhagia (excessive menstrual bleeding) (Beyond the Basics)" and "Patient information: Absent or irregular periods (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS Abnormal uterine bleeding is caused by a wide variety of local and systemic diseases or related to drugs (table 1). (See 'Introduction' above.)

Women who are pregnant are evaluated primarily for pregnancy related causes of bleeding, but the possibility of a nonpregnancy related etiology should be kept in mind. (See 'Is the patient pregnant?' above.) It is useful to determine whether the woman is ovulating because the etiologies of anovulatory and ovulatory bleeding are generally different. (See 'Is bleeding anovulatory or ovulatory?' above.) Bleeding in ovulating women is usually due to an anatomic or physical lesion (eg, polyp, fibroid, adenomyosis, neoplasm, foreign body), hemostatic defect, infection, trauma, or local disturbances in prostaglandins. (See 'Bleeding in ovulating women' above.) Anovulatory bleeding is common both at menarche and during the menopausal transition, the times when ovarian function begins and declines. However, it can occur at anytime during the reproductive years and has many causes (table 5). (See 'Anovulatory bleeding' above.) The most common cause of menorrhagia in premenopausal women is distortion of the endometrial architecture from a submucous leiomyoma, endometrial polyp, or adenomyosis and menopausal transition anovulatory cycles. Additional causes are listed in the table (table 3). (See 'Menstrual bleeding' above.) Intermenstrual bleeding is usually related to estrogen or progestin breakthrough (in women using hormonal contraception) or to an endometrial polyp. However, a variety of etiologies are possible (table 4). (See 'Intermenstrual bleeding' above