Approach to the patient with postmenopausal uterine bleeding

INTRODUCTION — Postmenopausal bleeding (PMB) refers to any uterine bleeding in a menopausal patient (other than the expected cyclic bleeding that occurs in patients taking combined [ie, estrogen-progestin], cyclic, postmenopausal hormone therapy). As PMB is the cardinal sign of endometrial carcinoma, all postmenopausal patients with unanticipated PMB should be evaluated for endometrial hyperplasia/carcinoma. More commonly, however, the cause of bleeding in such patients is the result of a benign condition, such as endometrial polyps or atrophy.

The etiologies and evaluation of postmenopausal patients with uterine bleeding, as well as patients near the end of the perimenopausal transition with abnormal uterine bleeding (AUB), will be reviewed here.

The evaluation and management of postmenopausal patients with a nonuterine source of vaginal bleeding, as well as premenopausal patients with AUB, are discussed separately. (See "Causes of female genital tract bleeding" and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis".)

INCIDENCE — PMB accounts for approximately 5 percent of office gynecology visits [1] and occurs in approximately 4 to 11 percent of postmenopausal patients [2-5].

The incidence appears to be inversely related to the time since menopause, with the likelihood of bleeding decreasing over time. In a prospective study including 271 Danish postmenopausal patients who completed a daily diary for one year, more patients experienced PMB after the first 12 months of amenorrhea following menopause compared with >3 years after menopause (estimated incidence of bleeding 409 per 1000 versus 42 per 1000 person-years) [2].

ETIOLOGY — The differential diagnosis of bleeding in postmenopausal patients is less broad than that for abnormal bleeding in premenopausal patients since the various causes of anovulation are not relevant. In a prospective study including 454 postmenopausal patients with uterine bleeding, the frequency of endometrial pathology was as follows [6]:

●Polyp (37.7 percent)

●Hypotrophy/atrophy (30.8 percent)

●Proliferative/secretory (14.5 percent)

●Carcinoma (6.6 percent)

●Fibroid (6.2 percent)

●Hyperplasia without atypia (2 percent)

●Hyperplasia with atypia (0.2 percent)

By comparison, the background prevalence of endometrial pathology in postmenopausal patients without bleeding is lower. In two studies including gynecologically asymptomatic breast cancer patients prior to administration of adjuvant therapy, the baseline risk of an endometrial abnormality was 17 to 18 percent [7,8]. As with postmenopausal patients with bleeding, the most common abnormalities were atrophy and polyps.

Structural abnormalities

Polyps — Endometrial polyps are localized hyperplastic overgrowths of endometrial glands and stroma that are a common cause of perimenopausal and early postmenopausal bleeding. Growth of polyps can be stimulated by estrogen therapy or tamoxifen. While the majority of polyps are benign, the incidence of malignant or hyperplastic polyps is higher in postmenopausal compared with premenopausal patients. (See "Endometrial polyps".)

Atrophy — The hypoestrogenic changes that occur in menopause cause atrophy of the endometrium and vagina. In the uterus, the collapsed atrophic endometrial surfaces contain little or no fluid to prevent intracavitary friction [9]. This results in microerosions of the surface epithelium and a subsequent chronic inflammatory reaction (chronic endometritis), which is prone to light bleeding or spotting.

Hypoestrogenic changes of the labia, vagina, urethra, and bladder are described in detail separately. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis".)

Leiomyomata uteri — Benign leiomyomata uteri (fibroids) are the most common pelvic tumors in females; however, the prevalence in postmenopausal patients is one-tenth that of premenopausal patients [10]. While fibroids may cause heavy bleeding, bulk symptoms, or pain in the reproductive years, after menopause most fibroids will decrease in size. In addition, any PMB must be assumed to arise from endometrial pathology or atrophy, and not from the fibroid itself [11]. An exception are patients on hormone replacement therapy; such treatment may stimulate fibroid growth and increase withdrawal bleeding [12].

Although rare, the diagnosis of a uterine sarcoma should be considered in postmenopausal patients in whom a fibroid is increasing in size or producing symptoms (eg, pelvic pressure, pain, bleeding); while the incidence of sarcoma is higher in such patients, it is still small. (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas".)

Adenomyosis — Adenomyosis is a benign histologic finding of the uterus in which endometrial glands infiltrate into the myometrial wall. While it can cause pain and menorrhagia during the reproductive years, symptomatic adenomyosis does not occur after menopause in the absence of postmenopausal hormone therapy. The diagnosis may be suspected by ultrasound or magnetic resonance imaging, but can only be confirmed by pathologic examination following hysterectomy [13]. (See "Uterine adenomyosis".)

Hyperplasia and carcinoma

Endometrial hyperplasia — Endometrial hyperplasia (EH; with or without atypia) may progress to, or coexist with, endometrial carcinoma, and often presents as uterine bleeding. EH is most common in perimenopausal or early postmenopausal patients; risk factors for EH are similar to those for endometrial carcinoma (table 1). (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis".)

Endometrial carcinoma — Endometrial carcinoma is the fourth most common cancer in females in the United States; it is more common in postmenopausal compared with premenopausal patients and presents with vaginal bleeding in most patients [14-18]. In a meta-analysis including 92 studies and over 31,000 patients with PMB, the overall pooled risk of endometrial cancer was 9 percent; the risk was lower (6 percent) when only prospective or retrospective studies were included [19]. Subset analyses found higher rates of endometrial cancer in studies that excluded patients using menopausal hormone therapy (risk: 12 percent), and in patients with both PMB and a sonographic endometrial thickness ≥4 to 5 mm (risk: 19 percent; definition of a thickened endometrium varied across studies).

Increasing age, nulliparity, and diabetes mellitus are also associated with increased rates of endometrial carcinoma (table 1) [20,21]. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention".)

Choriocarcinoma as a cause of uterine bleeding in a postmenopausal patient has also been described [22].

Upper genital tract carcinomas — PMB can be a symptom from carcinomas arising in the upper genital tract (ie, fallopian tubes). In a five-year review of fallopian and ovarian carcinomas treated at a major cancer center in the United Kingdom, of the eight patients diagnosed with primary fallopian tube carcinomas, six (75 percent) presented with PMB [23]. This is discussed in more detail separately. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Vaginal bleeding'.)

Medications

Postmenopausal hormone therapy — Uterine bleeding occurs in almost all patients receiving combined (ie, estrogen-progestin), cyclic hormone therapy. While uterine bleeding can also occur in the early months of combined, continuous hormone therapy regimens, patients with continued bleeding (eg, beyond six months) require endometrial evaluation. This is discussed in detail separately. (See 'Evaluation of the endometrium' below and "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Patients on hormone therapy' and "Treatment of menopausal symptoms with hormone therapy", section on 'Side effects'.)

Other medications — Use of certain medications (eg, anticoagulants, antiplatelet therapies), herbal preparations, and dietary supplements may interfere with primary or secondary hemostasis and result in uterine bleeding (table 2). In large doses, soy and other phytoestrogens may also be associated with stimulation of the endometrial lining [24], polyp and leiomyoma growth [25], and increased rates of endometrial hyperplasia [26].

Other

Disease in adjacent organs — Inflammation of adjacent organs, such as diverticulitis, can occasionally cause a corresponding inflammation of the female upper genital tract. Similarly, a ruptured sigmoid diverticulum may fistulize into the uterus and present as uterine bleeding, discharge, and endometritis. (See "Clinical manifestations and diagnosis of acute colonic diverticulitis in adults", section on 'Fistula'.)

Post radiation therapy — Uterine bleeding can be a late effect of radiation therapy. 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. Pelvic radiation therapy can also cause hemorrhagic cystitis, proctitis, and vaginal vault necrosis, and result in significant blood loss and pain. (See "Treatment-related toxicity from the use of radiation therapy for gynecologic malignancies".)

Infection — Endometritis is an uncommon cause of PMB. Genital tuberculosis may also present as PMB, however, this is a rare cause of PMB in resource-abundant countries [27-30]. (See "Endometritis unrelated to pregnancy", section on 'Tuberculous endometritis' and "Urogenital tuberculosis", section on 'Genital tuberculosis'.)

DISTINGUISHING UTERINE FROM OTHER GENITAL TRACT BLEEDING — While vaginal bleeding is often attributed to an intrauterine source, it may arise from disease at any anatomic site in the lower genital tract (eg, vulva, vagina, cervix), upper genital tract (eg, fallopian tubes, ovaries), or a nongynecologic site (eg, urethra, bladder, anus, bowel (table 3)). (See "Causes of female genital tract bleeding".)

Nonuterine bleeding may also be caused by a foreign body (eg, pessary), consensual sexual intercourse, or sexual assault. Atrophic changes in postmenopausal patients increases the risk for both lower genital lacerations and lacerations of the cervix [31-33].

A careful history and physical examination will often permit the distinction between uterine and vaginal bleeding. (See 'History' below and 'Physical examination' below.)

DIAGNOSTIC APPROACH

Initial evaluation — The primary goal in the diagnostic evaluation of postmenopausal patients with uterine bleeding is to exclude malignancy since increasing age is a risk factor for endometrial carcinoma (table 1). A secondary goal is to exclude other intraabdominal processes (eg, diverticular disease, infection, other malignancies) and nonuterine sources of bleeding.

History — Important information that can be elicited from the patient's history includes the following:

●When did the bleeding start?

●Were there precipitating factors, such as trauma, intercourse, or intimate partner violence?

●What is the nature of the bleeding (eg, duration, quantity)?

●Are there any associated symptoms such as pain, fever, or changes in bladder or bowel function?

●Does the patient take any medications (eg, hormone replacement therapy, anticoagulants), or herbal or dietary supplements?

●Does the patient have a history of obesity or diabetes mellitus?

●Is there a family history of breast, colon, and endometrial cancer?

The answers to these questions may help direct the clinician toward one of the major categories of uterine bleeding (see 'Etiology' above). As an example, obesity, diabetes mellitus, and use of tamoxifen are risk factors for endometrial cancer; vaginal dryness and soreness with dyspareunia and bleeding after intercourse suggest atrophy. By contrast, a history of trauma, sexual assault, or intimate partner violence, which is prevalent in postmenopausal and vulnerable (eg, nursing home) populations [34], may help direct the clinician toward a nonuterine source of bleeding.

Patients with uterine bleeding and cervical stenosis may present with pain rather than bleeding, as the egress of blood from the uterine cavity is inhibited and results in hematometra. This is discussed in detail separately. (See "Causes of female genital tract bleeding" and "Overview of endometrial ablation", section on 'Complications'.)

Physical examination — A complete physical examination, including calculation of the patient's body mass index (BMI (calculator 1)) and examining the skin for ecchymosis or trauma, should be performed.

A pelvic examination is performed to help determine the bleeding site. The size and contour of the uterus, as well as tenderness (if present), as well as any suspicious lesions, lacerations, or foreign bodies should be noted; lower genital tract (eg, vulva, vagina, exocervix) causes of bleeding can usually be excluded by a normal physical examination.

Evaluation of the endometrium — Either endometrial sampling or transvaginal ultrasound (TVUS) is used as the initial test for evaluating the endometrium. Endometrial biopsy is often preferred because it results in a tissue diagnosis and has a high sensitivity, low complication rate, and low cost. A detailed discussion of these tests for the evaluation of the endometrium can be found separately. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease" and "Endometrial sampling procedures".)

Evaluation of the cervix — All patients with PMB need an evaluation for cervical cancer, as it can be difficult to distinguish between uterine and endocervical bleeding. Any visible lesions need to be biopsied, even if cervical cytology is normal. (See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing" and "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)

Additional testing for select patients — In postmenopausal patients, uterine bleeding is usually light and self-limited, and treatment is usually unnecessary once endometrial carcinoma (or premalignant histology) has been excluded.

Patients with pathology on inital evaluation — If pathology (eg, polyp, hyperplasia, malignancy) is found on initial evaluation, the patient is managed according to standard guidelines. (See "Endometrial polyps", section on 'Management' and "Endometrial hyperplasia: Management and prognosis" and "Endometrial carcinoma: Staging and surgical treatment".)

Patients with recurrent bleeding — For patients with recurrent or persistent bleeding, further diagnostic evaluation (eg, dilation and curettage with hysteroscopy, saline infusion sonography) is indicated. Persistent bleeding can be a sign of endometrial carcinoma, even in the setting of a "benign" endometrial biopsy or thin (ie, ≤4 mm) endometrial stripe on TVUS. (See 'Evaluation of the endometrium' above and "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Postmenopausal patients with bleeding'.)

Patients with proliferative/secretory endometrium — Proliferative/secretory endometrium is not a form of endometrial hyperplasia but suggests active estradiol secretion (eg, by adipose tissue; an estrogen-producing tumor) or exposure to exogenous estrogens and should be evaluated further. This is discussed in detail separately. (See "Endometrial hyperplasia: Management and prognosis", section on 'Proliferative endometrium'.)

When to refer — Referral to a gynecologist is appropriate for patients who have persistent bleeding, if there is suspicion of malignancy, if surgery (eg, dilation and curettage) is required, or if the primary care clinician is not comfortable performing endometrial sampling. If saline infusion sonography or hysteroscopy is indicated and the initial clinician lacks the experience or resources to perform these procedures, referral to a gynecologist with the needed experience and equipment is also appropriate.

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)")

SUMMARY AND RECOMMENDATIONS

●Definition – Postmenopausal bleeding (PMB) refers to any uterine bleeding in a menopausal patient (other than the expected cyclic bleeding that occurs in patients taking combined [ie, estrogen-progestin], cyclic, postmenopausal hormone therapy). (See 'Introduction' above.)

●Causes

•Structural abnormalities – Endometrial polyps and atrophy are the most common causes of PMB; leiomyomata and adenomyosis should not cause PMB in the absence of postmenopausal hormone therapy. While polyps and leiomyomata are typically benign, malignancy can occur. (See 'Structural abnormalities' above.)

•Hyperplasia and carcinoma – Endometrial carcinoma is the cause of PMB in approximately 6 to 9 percent of patients overall. For patients who are not taking menopausal hormone therapy, the risk is higher (approximately 12 percent). PMB is also common in patients with endometrial hyperplasia. (See 'Hyperplasia and carcinoma' above.)

•Medications – Uterine bleeding occurs in almost all patients receiving combined (ie, estrogen-progestin), cyclic hormone therapy; it is also common in the early months of continuous hormone therapy regimens. Other medications (eg, anticoagulants, antiplatelet therapies), herbal preparations, and dietary supplements may also result in uterine bleeding (table 2). (See 'Medications' above.)

•Other – Inflammation of adjacent organs (eg, diverticulitis) and infection (eg, endometritis) are uncommon causes of PMB. (See 'Other' above.)

●Initial evaluation – The primary goal in the diagnostic evaluation of postmenopausal patients with uterine bleeding is to exclude malignancy since increasing age is a risk factor endometrial carcinoma (table 1). Either endometrial biopsy or transvaginal ultrasound (TVUS) is used as the initial test for evaluating the endometrium; in our practice, we typically perform endometrial biopsy due to its high sensitivity, low complication rate, and low cost. (See 'Initial evaluation' above and "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Postmenopausal patients with bleeding'.)

A secondary goal is to exclude other intraabdominal processes (eg, diverticular disease, infection, other malignancies) and nonuterine sources of bleeding (eg, foreign body, trauma). (See 'Disease in adjacent organs' above and 'Distinguishing uterine from other genital tract bleeding' above.)

●Additional testing – Uterine bleeding in postmenopausal patients is usually light and self-limited and treatment is usually unnecessary once cancer has been excluded. However, further diagnostic evaluation (eg, dilation and curettage with hysteroscopy, saline infusion sonography) is indicated for recurrent or persistent bleeding as this can be a sign of endometrial carcinoma. (See 'Additional testing for select patients' above.)

●Referral – Referral to a gynecologist is appropriate for patients who have persistent bleeding, if there is suspicion of malignancy, if surgery (eg, dilation and curettage) is required, or if the primary care clinician is not comfortable performing endometrial sampling. (See 'When to refer' above.)