Postmenopausal Bleeding

Etiology

PMB is often attributed to the uterus, with women mistakenly attributing bleeding to menstrual bleeding despite not having had menses for over 1 year. However, the bleeding may also arise from the urethra, vulva, vagina, cervix, or rectum. The most common cause of postmenopausal bleeding is genitourinary atrophy, accounting for 60%.[7] The etiology of PMB may also be nongynecologic (eg, the urethra, bladder, or GI tract) and mistaken for vaginal bleeding.[1] Some common underlying causes of postmenopausal bleeding include: 

• Vaginal or endometrial atrophy
• Urogenital infections (eg, endometrial tuberculosis, vaginitis, cystitis, or cervicitis)
• Medications (eg, estrogen, tamoxifen, and anticoagulants)
• Uterine leiomyomas
• Genital tract malignancies
• Vaginal foreign bodies
• Endometrial polyps
• Genitourinary atrophy
• Endometrial hyperplasia with or without atypia [1][8][4][5]

Epidemiology

Vaginal bleeding is reported in up to 10% of postmenopausal women and is the presenting symptom for approximately two-thirds of gynecologic office visits in this population.[9][2] However, the incidence of PMB may decrease with age. With the onset of menopause, bleeding is reported in approximately 40% of women per year, but 3 years after menopause, PMB decreases to 4% per year.[1] 

Endometrial cancer is the fifth most common cause of death due to malignancy in the US and the fourth most common overall cancer in females.[10] Furthermore, endometrial cancer is the most commonly diagnosed cancer in women and the most common site of uterine cancer, accounting for 92% of cases.[5][11] Over 90% of postmenopausal women with endometrial cancer present with PMB.[5] In women younger than 50, <1% of PMB is secondary to endometrial cancer. However, the incidence of PMB due to endometrial cancer increases to 24% in women older than 80.[12] The global incidence of endometrial cancer is increasing, primarily due to the increased prevalence of endometrial cancer risk factors (eg, obesity and late menopause). The number of patients diagnosed with endometrial cancer is anticipated to double by the year 2030.[2][13]

Pathophysiology

The most common etiology for postmenopausal bleeding is an atrophic endometrium. The hypoestrogenic environment following menopause leads to genitourinary atrophy. The collapsed and atrophic endometrial lining within the uterus contains scant or no fluid to prevent friction inside the cavity, causing epithelial microerosions and subsequent chronic inflammation. Chronic endometritis secondary to atrophy can present with vaginal spotting or light bleeding. Pelvic ultrasounds performed in these patients typically reveal a thin endometrial stripe with an otherwise normal appearance, a small uterus, and small ovaries.[14]

Conversely, unopposed estrogen exposure often develops premalignant or malignant endometrial conditions. Systemic estrogen-only therapy, obesity, and estrogen-secreting tumors can lead to abnormal endometrial changes. Some women have genetic predispositions to endometrial cancer, eg, Lynch syndrome and Cowden disease.[11] More recent studies demonstrate that BRCA gene mutation carriers may have a slightly increased risk of endometrial cancer, especially those with a BRCA1 mutation.[15]

Histopathology

Postmenopausal Endometrial Histologic Findings

The hypoestrogenic environment has several effects on the postmenopausal endometrium that are apparent on microscopic examination. Normal premenopausal proliferative endometrium contains regularly spaced, ordered glands lined by simple epithelial cells within the stroma with an approximate 1 to 1 gland-to-stroma ratio. Furthermore, histologically, mitotic activity is a characteristic feature of proliferative endometrium. Conversely, normal histologic findings in the postmenopausal endometrium show widely spaced glands that vary from small to cystically dilated. Moreover, the mitotic proliferative activity characteristic of a premenopausal endometrium is not apparent in postmenopausal endometrial cells.[8][4] Pathologic endometrial findings have varying histologic findings depending on the underlying etiology. For instance, the histopathology of endometrial polyps frequently shows cellular immaturity with cystic hyperplasia, while smooth muscle fibers are a characteristic finding of uterine fibroids. Both conditions have a higher risk of malignant transformation in postmenopausal women.[16][17] In women with PMB, the most concerning abnormal histologic findings are endometrial hyperplasia and carcinoma.

Endometrial Hyperplasia Histologic Findings

Characteristic histologic findings of endometrial hyperplasia include widespread crowding of endometrial glands, a disordered proliferation of glands, and an increased gland-to-stroma ratio. The precise ratio diagnostic of endometrial hyperplasia is debated; however, many pathologists use a gland-to-stroma ratio of 2 to 1.[4] For benign endometrial hyperplasia, gland cytology is normal, with only occasional mitotic figures found. However, on histological examination, gland crowding and abnormal gland nuclei are typically seen in endometrial intraepithelial neoplasia (EIN), considered a premalignant condition.[8][4] 

Endometrial Cancer Histologic Findings

One of the most concerning etiologies of postmenopausal bleeding is endometrial cancer, which is typically subclassified into type I or II based on histologic morphology, grade, and hormone receptors.[13][18]

• Endometrial carcinoma type 1: The most common histologic type of endometrial carcinomas, accounting for up to 90% of uterine cancers, is primarily made up of grade I or II endometrioid adenocarcinomas which involves the endometrial glands. Histologically, solid areas, maze-like glands, or appreciable cribriforming are observed. Most of these endometrioid adenocarcinomas are low-grade and confined to the uterus.[10]

• Endometrial carcinoma type 2: These are rare, high-grade, poorly differentiated, and more aggressive types of uterine cancers that include clear cell carcinoma, sarcoma, carcinosarcoma, and papillary serous histologies. Type 2 endometrial cancers have a higher risk of extrauterine disease at diagnosis and a worse prognosis than type I tumors. For instance, though only 10% of uterine cancers are papillary serous, they cause approximately 40% of deaths.[10]

History and Physical

A comprehensive history is essential when evaluating PMB to assess both underlying etiologies and establish the patient's menopausal status. Excluding a malignant etiology, primarily endometrial cancer, is the most critical aspect of PMB evaluation.[13] Clinicians should elicit a thorough history, including the following standard elements:

History of Present Illness

To evaluate the differential diagnoses for PMB and clinically confirm the patient's menopausal state, clinicians should obtain a history regarding the nature of a patient's current bleeding and any associated symptoms. Heavy menstrual bleeding or other abnormal uterine bleeding patterns may indicate structural abnormalities (eg, leiomyomas, polyps), hyperplasia, or malignancy.[19] PMB onset, duration, heaviness, and precipitating factors (eg, bleeding after intercourse or after wiping) are all essential to characterize vaginal bleeding symptoms.[13] Associated symptoms, including fever, pelvic pain, dysuria, vasomotor symptoms, dyspareunia, and vaginal dryness, should also be investigated.[20][21]

• Past medical history: Potential etiologies for abnormal bleeding include obesity, polycystic ovarian syndrome, diabetes, thyroid disease, pelvic infection, or coagulopathies. Several of these conditions are also risk factors for endometrial cancer or hyperplasia (eg, obesity and diabetes). Radiation exposure may also cause PMB.[22][13] 
• Gynecologic history: Primarily, a thorough review of the menstrual history, including the last menstrual period, is critical when assessing an individual's postmenopausal status. Menarche younger than 12 years (ie, early menarche) or menopause beginning in patients older than 55 (ie, late menopause) increase the risk for endometrial cancer.[12] Additionally, recent Pap and HPV testing may indicate cervical or endometrial etiologies.[19]
• Surgical history: Past surgical procedures can provide clinicians with potential etiologies for vaginal bleeding and menopausal amenorrhea. Recent pelvic procedures can result in postoperative bleeding, and surgically induced menopause (eg, hysterectomy, oophorectomy) can assist in definitively establishing a patient's menopausal status.[19]
• Social history: Genitourinary infections, such as sexually transmitted diseases, are also causes of PMB. Additionally, individuals who smoke have an increased risk of bladder cancer, mesh erosion, and hematuria, which may cause bleeding.[9][23] 
• Family history: Due to the increased malignancy risk, a family history of breast, gynecologic, urologic, or gastrointestinal cancers should be assessed, as well as inherited mutations (eg, Lynch or Cowden syndrome) that can predispose individuals to endometrial cancer.[13]
• Medications: Clinicians should also elicit medication history from patients as hormone replacement therapy, tamoxifen, anticoagulants, and certain herbal supplements can all affect the endometrial lining, leading to postmenopausal bleeding.[24][25][26] 

Physical Exam

On physical exam, it is crucial to thoroughly evaluate the internal and external anatomy of the genital tract. A speculum exam should be performed to visualize bleeding sites, genital lesions, lacerations, urethral prolapse, and signs of genitourinary atrophy, which typically include pale, dry vaginal epithelium with loss of rugae. Erythema, petechiae, friability, and discharge may indicate inflammation. Furthermore, clinicians can palpate for pelvic masses, abdominal distention, and enlarged lymph nodes through a bimanual exam.[13][20][6]

Evaluation

Diagnostic Studies

In addition to the clinical assessment, diagnostic evaluation of PMB is primarily directed toward excluding endometrial hyperplasia or malignancy. The American College of Obstetricians and Gynecologists (ACOG) recommends either transvaginal ultrasound or endometrial biopsy initially to evaluate low-risk women presenting for PMB; performing both studies simultaneously is unnecessary. However, endometrial biopsy is recommended as the first-line test in individuals with endometrial cancer risk factors or recurrent PMB.[5] Laboratory studies may be considered to assess for complications secondary to heavy vaginal bleeding and to help exclude differential diagnoses.[6]

Endometrial Biopsy

Endometrial sampling is a first-line test for evaluating PMB in any patient because this study provides tissue for histologic diagnosis, which is critical in identifying malignancies. Other indications for endometrial sampling in patients with PMB include:[5]

• Persistent or recurrent bleeding PMB, despite a thin endometrial stripe on ultrasound
• Risk factors for endometrial cancer (eg, obesity, smoking, exposure to unopposed estrogen)
• Endometrial lining thickness by transvaginal ultrasound of >4 mm in a woman with postmenopausal bleeding
• Inadequate visualization of the endometrium in imaging studies

ACOG also recommends performing endometrial sampling on women with abnormal uterine bleeding older than 45.[22] The primary modalities utilized for endometrial sampling include dilation and curettage (D&C) and outpatient disposable thin plastic devices inserted through the endocervical opening into the endometrial cavity without anesthesia.[27][28] Clinicians have performed D&Cs with or without hysteroscopy for years for histologic assessment as the diagnostic sensitivity for endometrial cancer exceeds 90%.[29][30] In studies, office endometrial biopsy using flexible plastic samplers has been found to have similar diagnostic accuracy.[31][32][33] However, endometrial biopsy can result in findings that are insufficient for diagnosis, with rates of sampling failure up to 54%.[5] The diagnostic accuracy of endometrial sampling correlates positively with the amount of tissue that is collected.[34] For inadequate sampling that was performed first, a follow-up ultrasound may be performed; if subsequent transvaginal ultrasound reveals a thin endometrial stripe and vaginal bleeding does not persist, further evaluation is unnecessary.[5]

Imaging Studies

Transvaginal imaging to measure endometrial thickness may also be used as a first-line modality to evaluate PMB in patients without indications for histologic assessment. The technique ACOG recommends to measure endometrial thickness consists of using the thickest portion of the endometrial stripe seen on a long-axis uterine view, measuring anterior to posterior.[5] An endometrial stripe thickness of ≤4 mm has a negative predictive value >99% for endometrial carcinoma.[35] The probability of having endometrial cancer with an endometrial stripe thickness of <4 mm is approximately 0.3%. Using this 4 mm threshold, only 1 in 339 endometrial cancers are missed, according to studies.[5] Ultrasound imaging may also identify other pathologic pelvic etiologies (eg, leiomyomas or adnexal masses). However, further evaluation with endometrial sampling is indicated if the endometrial stripe is inadequately visualized. Because endometrial imaging is not diagnostic and endometrial thickness does not always exclude malignancy, clinicians should perform an endometrial biopsy for continued or recurrent PMB, even for patients with an endometrial lining <4 mm.[5]

A thickened endometrial stripe may be caused by hyperplasia, malignancy, and intracavitary lesions (eg, leiomyomas and endometrial polyps). For ultrasound findings suggestive of intracavitary lesions or history-indicated suspicion (eg, previous polyps), additional imaging may be useful, including saline-infused ultrasonography or hysterosalpingogram. Pelvic CT and MRI are sometimes used to characterize better urogenital pathology noted on ultrasound.[4] However, hysteroscopy with dilation and curettage is the gold standard as diagnostic sampling and therapeutic excision for some etiologies of PMB (eg, endometrial polyps) can be performed simultaneously. Furthermore, blind endometrial sampling without hysteroscopy may miss focal lesions or intrauterine pathology, such as polyps, and mass lesions may deflect flexible disposable devices. Consequently, further imaging evaluation should be considered for patients with insufficient sampling or persistent vaginal bleeding in whom focal lesions may have been missed; hysteroscopy with dilation and curettage or directed biopsy may be warranted.[5][18]

Laboratory Studies

A CBC, TSH, and coagulation studies (eg, prothrombin time and partial thromboplastin time) should be considered for individuals with PMB to help exclude some differential diagnoses and assess for secondary anemia due to abnormal bleeding.[6] Vaginal cultures for sexually transmitted diseases and other genital infections should be considered if clinically indicated. In women who have undergone early menopause (ie, older than 40), a pregnancy test is typically performed also.[22] Papanicolaou smears are not diagnostic but can suggest PMB etiologies (eg, cervicitis, sexually transmitted diseases, cervical and endometrial cancers).[6]

Treatment / Management

The underlying cause primarily directs the treatment of PMB. However, other clinical factors, including patient comorbidities and preferences, as well as PMB characteristics (eg, heaviness and duration), are considered when determining management.[4][20][36]

Genitourinary atrophy: Bleeding is usually self-limited and requires no treatment. Vaginal dryness may be treated with nonhormonal vaginal moisturizers and lubricants to maintain sexual activity. Vulvar and vaginal atrophy symptoms can be effectively reversed by topical estrogen and are the preferred pharmacologic therapy for genitourinary atrophy. Oral hormone replacement and hormonal receptor modulators (eg, ospemifene) also may be considered if there is no improvement with other treatments.[20]

Endometrial polyps: Thirty percent of PMB cases are caused by endometrial polyps; however, polyps can be asymptomatic. Furthermore, the severity of PMB is not affected by the number or size of polyps. One percent of all endometrial polyps are malignant, most commonly occurring in postmenopausal women.[16] Therefore, endometrial polyps in symptomatic postmenopausal women should be removed and histologically assessed. Surgical excision should be considered in asymptomatic women at higher risk of malignancy (eg, large polyps, tamoxifen use, obesity, or diabetes).[37] Hysteroscopic polypectomy is the preferred treatment because the clinician can obtain directed biopsies and excise polyps at once.[16](A1)

Uterine leiomyoma: Typically, leiomyomas (ie, fibroids) are benign and regress during menopause and may not need treatment if patients are asymptomatic. A small percentage of fibroids are malignant, primarily in postmenopausal women. Occasionally, benign leiomyomas may grow or become symptomatic even in postmenopausal patients, particularly in obese women, due to peripheral conversion of estrogen from adipose stores.[38] In women with PMB found to have uterine fibroids with an otherwise normal evaluation, pharmacologic (eg, aromatase inhibitors and selective estrogen receptor modulators) or surgical (eg, myomectomy and hysterectomy) therapy may be considered. However, leiomyosarcomas can not be definitively excluded through laboratory or imaging studies, and symptomatic postmenopausal women are at higher risk; therefore, clinicians should thoroughly counsel patients and determine management through shared decision-making.[38][39](B2)

Genitourinary infection: For sexually transmitted diseases and other genital infections, treatment is guided by vaginal culture results.[22][6] Clinicians may consider oral doxycycline to treat endometritis.[40]

Cervical, vaginal, and vulvar carcinomas: Most treatment modalities for these PMB etiologies include surgery and chemoradiotherapy based on the stage.[41][42](B2)

Endometrial hyperplasia or malignancy: Endometrial hyperplasia is classified as benign endometrial hyperplasia or intraepithelial neoplasia. Management of hyperplasia consists of surgical and nonsurgical therapies; the treatment approach is individualized based on clinical factors (eg, comorbid conditions). However, endometrial carcinoma requires surgical treatment and staging by gynecologic oncology specialists. Additionally, chemotherapy and radiation may be indicated for some patients.[18][4](B3)

• Benign endometrial hyperplasia: Also referred to as nonatypical endometrial hyperplasia, this type of hyperplasia is typically managed with hormonal therapy and/or curettage.[4] 
• Endometrial intraepithelial neoplasia: The approach to treatment depends on various clinical factors, including patient preferences. Generally, in postmenopausal women, fertility conservation is not desired; therefore, minimally invasive hysterectomy with bilateral salpingectomy is the preferred treatment. Shared decision-making should be utilized when determining if bilateral oophorectomy is also performed.[4] Medical management is an option for patients who are declining surgery or are poor surgical candidates. Patients should be cautioned that many women with EIN have concurrent endometrial malignancy. If medical treatment is chosen, repeat endometrial sampling to assess therapeutic response should be done in 3 to 6 months for a minimum of 1 year. Nonsurgical therapies include:[4]
  • Megestrol 80 mg orally twice a day
  • Depot medroxyprogesterone acetate 150 mg intramuscularly every 3 months
  • Micronized vaginal progesterone 100 to 200 mg daily
  • Levonorgestrel intrauterine device, 52 mg
  • Medroxyprogesterone acetate orally 10 to 20 mg daily
• Endometrial adenocarcinoma: Definitive treatment with hysterectomy and comprehensive staging is the standard of care. Prognosis and appropriate adjuvant therapy are determined by staging.[11][4]

• Hematuria: Genitourinary atrophy can lead to asymptomatic microscopic hematuria. Because the risk of urinary malignancy is lower in women without risk factors (eg, smokers, no gross hematuria) than in men, ACOG only recommends evaluation in asymptomatic low-risk women if urine microscopy shows >25 red blood cells per high-power field. Clinical findings and diagnostic studies consistent with acute cystitis should be treated with appropriate antibiotics.[43]
(B3)

• Gastrointestinal Bleeding: The differential diagnoses for PMB include gastrointestinal etiologies (eg, hemorrhoids and diverticulitis), which can be mistaken for vaginal bleeding. Management may consist of surgery, anti-inflammatories, or antibiotics. Recurrent or severe bleeding may necessitate referral to a gastrointestinal specialist for additional evaluation and treatment.[44]
(A1)

• Medications: Postmenopausal hormone replacement therapy frequently causes PMB for the first 2 to 3 months after initiation, which spontaneously resolves in most women. However, clinicians should evaluate for endometrial pathology in women with persistent or recurrent PMB following the first few months of therapy. For anticoagulants leading to vaginal bleeding, progestin therapy may improve bleeding until anticoagulants can be discontinued. Longer-term solutions may need to be discussed in patients on lifelong anticoagulation.[3]

Differential Diagnosis

Clinicians evaluating patients with PMB must consider the various differential diagnoses that have a similar presentation to PMB which may arise from nongynecologic (eg, the urethra, bladder, or GI tract) or gynecologic areas.[1] Common conditions that should also be considered when evaluating PMB include:[1][8][4][5]

• Urogenital infections (eg, endometritis, vaginitis, cystitis, or cervicitis) [45]
• Uterine leiomyomas
• Genital tract malignancies
• Vaginal foreign bodies
• Gastrointestinal conditions (eg, diverticulitis, colitis, hemorrhoids, malignancy)
• Genitourinary atrophy
• Radiation effects on adjacent organs (eg, hemorrhagic cystitis, proctitis, necrosis) [46]

Prognosis

PMB has a favorable prognosis, as the most common etiologies are benign and treatable. Furthermore, the prognosis for the most common malignant PMB etiology, endometrial cancer, is significantly better than other cancers, with a 5-year survival rate of 90%.[11] In patients diagnosed with endometrial hyperplasia who underwent hysterectomy, approximately 43% had undiagnosed concurrent endometrial carcinoma.[4]

Complications

The primary complication of PMB is secondary anemia, which occurs in approximately 10% of postmenopausal women.[47] Other complications that may occur are typically associated with the underlying etiology. For instance, genitourinary atrophy can decrease quality of life due to reduced sexual intimacy and self-esteem, while uterine fibroids may cause pelvic discomfort.[48][38] Management of PMB etiologies, such as pharmacologic therapy of endometrial hyperplasia with megestrol, can also be associated with adverse effects, including weight gain, nausea, venous thromboembolism, and continued vaginal bleeding.[4]