Continuing Education Activity

Postmenopausal bleeding is a common complaint with a broad differential, which includes both benign and malignant conditions. This activity describes the evaluation and management of postmenopausal bleeding. It also highlights the role of the healthcare team in improving the prognosis for patients with malignant etiologies of postmenopausal bleeding.

Objectives:

• Describe the physiology of underlying various etiologies of postmenopausal bleeding.
• Explain the differential diagnosis of postmenopausal bleeding.
• Review the recommendations for the evaluation and management of postmenopausal bleeding.
• Identify patients with postmenopausal bleeding who require referral to or consultation with specialists or subspecialists.

Introduction

The average age of menopause is fifty-one years. Menopause occurs when the ovaries cease making estrogen, and the patient is no longer ovulatory. The level of the follicle-stimulating hormone is elevated after menopause, as the hypothalamic-pituitary-ovarian axis attempts to stimulate ovulation despite the ovaries no longer being able. A woman is labeled menopausal if she has gone twelve months without menses.

After a woman is postmenopausal, further vaginal bleeding is no longer considered normal. The differential diagnosis of postmenopausal bleeding includes many benign and malignant conditions, the most common of which is atrophy, but the most concerning possible etiology is endometrial cancer. As with most malignancies, early diagnosis may lead to a better prognosis. Therefore, a postmenopausal woman with vaginal bleeding should be promptly and appropriately evaluated.

Etiology

Abnormal genital bleeding is often attributed to the uterus, with postmenopausal women describing bleeding as “having a period” again despite not having had menses for quite some time. Despite this natural inclination, bleeding can arise from the perineum, vulva, vagina, cervix, or fallopian tubes. Bleeding can be related to an ovarian pathology. The etiology of bleeding may also be non-gynecologic. Bleeding from the urethra, bladder, or GI tract (anus, rectum, bowel) could be mistaken for vaginal bleeding.

The most common cause of postmenopausal bleeding is atrophy, either of the endometrium or the vaginal mucosa.[1] Other common etiologies are endometrial hyperplasia, endometrial polyps, and submucous leiomyomas. While these etiologies all lead to bleeding from a uterine source, they must be distinguished from non-gynecologic bleeding as above.

Epidemiology

Vaginal bleeding is reported in about 4-11% of postmenopausal women.[2][3][4][5] Postmenopausal bleeding accounts for approximately 5% of gynecologic office visits.[6] About 1-14% of postmenopausal bleeding will be secondary to endometrial cancer.[7]

Endometrial cancer is the most common gynecologic malignancy in the United States. In 2017, there were over 61,000 new cases of uterine cancer; there were almost 11,000 deaths.[7] Most cases of uterine cancer are endometrial in origin (92%).[7] Vaginal bleeding is the presenting sign in more than 90% of postmenopausal women with endometrial cancer.[7]

Pathophysiology

Lack of estrogen causes atrophy of the vagina and endometrium. Inside the uterus, the collapsed and atrophic surfaces of the endometrium contain scant or no fluid to prevent friction inside the cavity.[8] This leads to the development of micro-erosions of the epithelial surface, with subsequent chronic inflammation. This chronic endometritis is prone to spotting or light bleeding. A pelvic ultrasound would reveal a normal-appearing small postmenopausal uterus, small postmenopausal ovaries, and a thin endometrial stripe.

On the other hand, premalignant or malignant conditions of the endometrium often arise after unopposed estrogen. Systemic estrogen-only therapy, chronic anovulation (such as in polycystic ovarian syndrome), obesity, and estrogen-secreting tumors can lead to abnormal endometrial changes. Anovulation also leads to infrequent, insufficient shedding of the endometrium. Some women have genetic predispositions to endometrial cancer, including Lynch syndrome and Cowden disease.[9]

Histopathology

Normal proliferative endometrium contains glands that are regularly spaced and that lie within stroma at a gland: stroma ratio of 1 to 1. Atrophic endometrial cells, on the other hand, are smaller and more cuboidal than proliferative endometrium. Because atrophic postmenopausal endometrium is no longer active, there are few or no mitotic cells. The glands become cystic, appearing large and round. The stroma between glands is inactive.

Chronic endometritis can be secondary to atrophy or infection. It is diagnosed traditionally on histology by plasma cell infiltration. On hysteroscopy, one can also grossly see endometrial hyperemia, edema, or micro-polyps (measuring less than 1 mm).[10]

“Endometrial reactive changes” is terminology linked to a heterogeneous group of morphologies of the endometrium. These morphologies are associated with inciting events like infection, stromal breakdown, or recent instrumentation. They can also be seen with hormonal imbalance.

Endometrial hyperplasia demonstrates a widespread crowding of endometrial glands. Without atypia, gland cytology is normal, and only occasional mitotic figures are found. Suppose atypia is present, as, in endometrial intraepithelial neoplasia (EIN), both gland crowding and abnormal gland nuclei are seen. EIN is considered a cancer precursor.

Endometrial cancer can be type I or type II:[11][12]

Endometrioid Adenocarcinoma Type I: This is the most common of the histologic types (more than 75% of endometrial cancers). On histology, one may see solid areas, maze-like glands, or appreciable cribiforming. Most are low grade and are confined to the uterus at diagnosis. EIN is the precursor lesion for this type of endometrial cancer.

Endometrioid Adenocarcinoma Type II: These are considered to be high grade and includes clear cell, carcinosarcoma, and papillary serous histologies. These cancers have a higher risk of extrauterine disease, and they have a worse prognosis than type I tumors. For example, 10% of uterine cancers are papillary serous, but they are responsible for nearly 40% of deaths.

History and Physical

A comprehensive history is essential in understanding postmenopausal bleeding. First, the menopausal status must be established. Questions regarding the last menstrual period, or surgical history in the case of patients who are menopausal secondary to oophorectomy, must be elicited. The patient may also have had testing at some point, such as a follicle-stimulating hormone level, that can help in establishing the diagnosis of menopause.

History of Present Illness: The nature of the patient’s prior menses and current bleeding are both essential historical elements. The previous history of heavy menses or another abnormal uterine bleeding may increase suspicion for either structural abnormalities, such as leiomyomas, or endometrial abnormalities like polyps, hyperplasia, or malignancy. Questions regarding when the patient notices her postmenopausal bleeding (in her clothing or on a pad, after intercourse, or when wiping, etc.) are important clues to the etiology of the bleeding. The heaviness of bleeding, number of bleeding days, and the constancy or intermittent nature of bleeding is also essential.

Past Medical History: The patient’s past medical history may be helpful. For example, a history of obesity, polycystic ovarian syndrome or other anovulation, diabetes mellitus, or tamoxifen use may all increase suspicion for hyperplasia or malignancy. Knowing whether the patient has had a recent Pap test, normal or abnormal, may help to identify whether cervical etiologies may be of concern. Atypical glandular cells on a Pap test may indicate endometrial pathology. A history of radiation exposure is essential to elicit.

Social History: Cervicitis may also be considered, both from the nature of the bleeding (e.g., postcoital) or due to a history of infections or partner infidelity. Also, with regards to social history, cigarette smoking may increase the risk of bladder cancer (hematuria may be mistaken for vaginal bleeding) but decreases the risk of endometrial cancer.

Family History: A family history of breast, gynecologic, urologic, gastrointestinal, or other cancers may also be elicited.

Medications: Knowing a patient’s medications is important. Postmenopausal hormone therapy, depending on the regimen, may lead to bleeding. The use of certain herbal supplements may stimulate the endometrial lining.[13][14][15] Anticoagulation may also lead to vaginal bleeding.

Physical Exam: On physical exam, it is crucial to perform a thorough evaluation of the internal and external anatomy of the genital tract. A bleeding site may be identified. Lesions on the anus, urethra, vulva, vagina, or cervix may be noted. Lacerations may be found. The shape, size, and tenderness of the uterus can aid in narrowing the differential diagnosis.

Exam findings of atrophy classically include pale, dry vaginal epithelium that is shiny and smooth and lacking rugae. Signs of inflammation include erythema or redness, petechiae, friability, discharge, visible blood vessels through the thin epithelium, or bleeding. Lastly, a general systemic examination is essential to identify signs of chronic or severe illness.

Evaluation

In addition to physical examination, evaluation of postmenopausal bleeding is directed at either diagnosing or excluding hyperplasia or malignancy. The American College of Obstetricians and Gynecologists recommend transvaginal ultrasound for initial evaluation.[7] The endometrial thickness is measured in an anterior-posterior fashion, at the area of endometrial echo of maximal thickness, on a long-axis view of the uterus.[7] An endometrial thickness of less than or equal to 4 mm has a negative predictive value greater than 99% for endometrial carcinoma. The ultrasound may also identify leiomyomas or pathology of the adnexa.

Findings on ultrasound for which endometrial sampling are indicated include:

• A thickened endometrial lining greater than 4 mm
• Diffuse or focally increased echogenicity or heterogeneity
• The inability to visualize the endometrium adequately

Endometrial sampling should also be obtained in patients with persistent or recurrent bleeding, even in the setting of a thin endometrial echo.[7] It is reasonable, to begin with, endometrial sampling first rather than ultrasound, in patients with a higher pretest probability for malignancy.[7] The use of 4 mm endometrial thickness as a threshold may miss endometrial cancer for 1 in 339 patients.[7] 

The diagnostic accuracy of endometrial sampling correlates positively with the amount of tissue that is collected.[16] There are several methods of endometrial sampling. Dilation and curettage has been used for years and has a sensitivity for endometrial cancer exceeding 90%.[17][18] Office endometrial biopsy can also be performed using metal curettes or flexible plastic samplers. Both of these have been determined to be adequate methods for endometrial sampling.[19][20][21]

It is common for endometrial sampling to result in findings that are insufficient for diagnosis, with rates of sampling failure up to 54%.[7] If sampling was performed first and was inadequate, a follow-up ultrasound may be performed. If a subsequent transvaginal ultrasound shows a thin endometrium, and if bleeding has stopped, no further evaluation is necessary.[7]

A thickened endometrial echo may be caused, not by hyperplasia or malignancy, but by intracavitary lesions such as endometrial polyps. If ultrasound findings are suggestive of such lesions, or if there is a history-indicated suspicion (for example, prior polyps), additional imaging may help to identify if a polyp or other intracavitary lesion is present. Saline-infusion ultrasonography or hysterosalpingogram may be useful in these cases.

Blind sampling may miss focal lesions or intrauterine pathology, such as polyps. Mass lesions may deflect flexible endometrial sampling devices. For patients with insufficient sampling, or with persistent vaginal bleeding in whom focal lesions may have been missed, additional evaluation should be considered. Hysteroscopy with dilation and curettage or directed biopsy may be warranted in these patients.[7][12]

Treatment / Management

The etiology dictates the management of postmenopausal bleeding.

Atrophy: Bleeding is usually self-limited and requires no treatment. Vulvar and vaginal atrophy may be treated with lubricants during intercourse, topical hormones (estrogen, DHEA), oral hormonal receptor modulator (ospemifene), etc.

Polyp: Removal of the polyp may resolve the bleeding. Endometrial polyps are often benign, but they can contain hyperplasia or malignancy approximately 5% of the time.[22] Because of this, complete hysteroscopic removal should be considered. Removal is recommended, especially in patients with symptoms or at risk of malignancy (larger polyps, tamoxifen use, obesity, diabetes).[23]

Submucous Leiomyoma: Fibroids may be removed hysteroscopically or laparoscopically, or they may be ablated with various devices (some currently investigational). Some lesions are amenable to uterine artery embolization. Ultimately, if minimally-invasive approaches are unsuccessful and the patient is significantly bothered, definitive management with hysterectomy can be considered.

Cervicitis: Treatment of cervical infections is recommended, as indicated by the organism.

Cervical Cancer: Treatment is based on stage and may include surgery or radiation.

Endometritis: Administration of doxycycline can be considered. In addition to antibiotic effects, doxycycline may have anti-inflammatory effects.[24]

Endometrial Hyperplasia or Malignancy: Can be managed medically or surgically, depending on the severity. There are two ways of classifying hyperplasia, the WHO94 schema (which classifies hyperplasia based on nuclear atypia and glandular complexity) and the endometrial intraepithelial neoplasia diagnostic schema (which classifies hyperplasia as either benign, premalignant, or malignant). The EIN schema is preferred.[12]

• Benign Endometrial Hyperplasia: Observation, may resolve
• Endometrial Intraepithelial Neoplasia: Hysterectomy (total abdominal, vaginal, and minimally invasive total) is preferred. Endometrial ablation, morcellation, or supracervical hysterectomy should never be performed.[12] Medical management is an option for patients declining surgery or who desire fertility. Patients should be cautioned that a significant percentage of women with EIN have concurrent endometrial malignancy. Medical management options include:[12]
  • Medroxyprogesterone acetate
  • Depot medroxyprogesterone acetate
  • Megestrol acetate
  • Micronized vaginal progesterone
  • Levonorgestrel intrauterine device
• Endometrial Adenocarcinoma: Hysterectomy with comprehensive staging is recommended. Comprehensive staging consists of a total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and collecting pelvic washings for cytology. Staging allows for appropriate diagnosis, determination of prognosis, and to triage patients for adjuvant therapy appropriately.[9] While definitive management is recommended, especially since an accurate prognosis cannot be given without full staging, some patients choose fertility-sparing treatment (see medical management above). Candidates for conservative management must have the following:[9]
  • Strong desire for fertility-sparing
  • Patient understands and accepts the fact that data on outcomes (pregnancy-related and cancer-related) are limited
  • Well-differentiated endometrioid endometrial carcinoma, grade 1
  • No extrauterine involvement
  • No myometrial invasion
  • No contraindications to medical management

Urethral Caruncle: May initially be treated with topical estrogen, though removal may sometimes be indicated.

Hematuria: Acute cystitis may be treated with antibiotics. The appropriate specialist should manage concerns for bleeding from renal etiologies or bladder masses/malignancy.

Gastrointestinal Bleeding: Bleeding hemorrhoids may be managed with topical treatments or with removal. Constipation can be treated with hydration, stool softeners, etc. Bleeding from more proximal in the gastrointestinal tract may necessitate specialist referral for additional evaluation.

Medications: If phytoestrogens are suspected of causing stimulation of the endometrial lining, they can be stopped, and further endometrial evaluation may be performed as above. In patients taking postmenopausal hormone replacement, the regimen may be adjusted. Postmenopausal hormone therapy may also lead to uterine abnormalities as above, and if so, they should be treated as indicated. If anticoagulants are leading to vaginal bleeding, medical management with progestins may control bleeding until the anticoagulant course is complete. Longer-term solutions may need to be discussed in patients on lifelong anticoagulation.

Differential Diagnosis

The differential diagnosis of postmenopausal bleeding includes both gynecologic and non-gynecologic etiologies, both benign and potentially malignant:

• Atrophy: Lack of estrogen can lead to bleeding from within the uterine cavity or from the vagina or vulva if lacerations or fissures occur
• Malignancy: Cancer may bleed from the fragility of the blood vessels within it or invasion into nearby blood vessels
  • Cervical
  • Endometrial
  • Sarcoma
  • Fallopian Tube
  • Ovarian
  • Vaginal
  • Vulvar
• Polyps: Bleeding may be due to apical necrosis and venous stasis caused by stromal congestion inside the[25]
  • Endometrial
  • Cervical
• Endometrial Hyperplasia
• Uterine Leiomyomata: Can put pressure on the opposing uterine walls or endometrial, or disrupt the normal vasculature of the uterine myometrium
• Adenomyosis: May disrupt the tissues of the myometrium and endometrium
• Infection: Can cause inflammation and irritation, leading in turn to bleeding
  • Cervical
  • Uterine
  • Vaginal
  • Urinary
  • Gastrointestinal
• Endometritis: Can be infectious (see above), or noninfectious secondary to epithelial micro-erosions leading to chronic inflammation
• Medications
  • Herbal Supplements: Phytoestrogens may stimulate the endometrial lining and subsequent bleeding
  • Anticoagulation: Can lead to increased bleeding than would otherwise be seen in a given situation
  • Postmenopausal Hormone Therapy: Estrogen may cause the proliferation of the endometrium, leading in turn to hyperplasia or malignancy. If hormone regimens include progestins, bleeding may be an intended result (cyclical therapy regimens) or a result of hormonal imbalance.
• Post-Radiation Effects: Devascularization of radiated tissues can lead to necrosis, perforation, tissue sloughing, and bleeding. Hemorrhagic cystitis or proctitis can be significant. Vaginal vault necrosis can also lead to pain or uncontrolled bleeding.[26]
• Disease in Adjacent Organs: Bleeding from structures near the vagina can be mistaken for vaginal bleeding
  • Urethra
    • Caruncle
    • Diverticulum
    • Urethritis
  • Bladder
    • Cystitis
    • Malignancy
    • Renal disease leading to hematuria
  • Bowel
    • Anal fissure
    • Constipation
    • Hemorrhoid
    • Diverticulitis
    • Colitis
    • Infection
    • Polyps or malignancy

Staging

Postmenopausal bleeding, as such, is not a staged condition. However, endometrial cancer, which is one cause of postmenopausal bleeding, does have staging criteria. Endometrial cancer is staged as follows:[9]

Stage I: The tumor is limited to the uterine corpus

• IA = No myometrial invasion, or invasion into less than have of myometrial thickness
• IB = Invasion into half or more of the myometrium

Stage II: The tumor invades the cervical stroma but doesn't extend beyond the uterus

Stage III: The tumor has spread locally or regionally

• IIIA = Invades serosa or adnexa
• IIIB = Involves vagina or parametria
• IIIC = Has metastasized to lymph nodes
  • IIIC1 = Pelvic lymph nodes
  • IIIC2 = Para-aortic nodes (pelvic nodes involved or not)

Stage IV: The tumor has invaded bladder, bowel, or has spread distantly

• IVA = Invades bladder or mucosa of the bowel
• IVB = Distant spread (intra-abdominal metastases, inguinal lymph nodes)

Prognosis

Overall the prognosis of postmenopausal bleeding is favorable because the most common etiologies are benign. Once the etiology of bleeding is identified, treatment can be instituted. Even in cases where endometrial cancer is diagnosed, the prognosis is better compared to many other malignancies. Over 70% of endometrial cancer cases are diagnosed at stage I, with an associated survival rate at five years of 90%.[9]

Caution is warranted in patients who are diagnosed with endometrial hyperplasia. Some patients with endometrial hyperplasia may have undiagnosed concurrent endometrial carcinoma. One study found certain risk factors increase this risk:[27]

• Age 40-59, with an odds ratio of 3.07
• Age ≥60, with an odds ratio of 6.65
• Body mass index ≥35 kg/m(2), with the odds ratio 2.32
• Diabetes mellitus, with an odds ratio of 2.51
• Endometrial intraepithelial neoplasia, with the odds ratio 9.01, p=0.042

In this study, the presence of more risk factors was correlated with an increased risk of concurrent carcinoma.[27]

• No risk factors = 0%
• 1 risk factor = 7%
• 2 risk factors = 17.6%
• 3 risk factors = 35.8%
• 4 risk factors = 45.5%

Complications

Atrophy, though benign, can lead to decreased quality of life, decreased sexual intimacy, and lowered self-esteem.[11] Loss of vaginal elasticity and rugae can lead to narrowing and shortening of the vagina. Fragile tissues may tear and bleed or lead to fissures. Narrowing of the introitus or fusion of the labia minora may occur. Care must be taken to solve these issues after evaluation for more life-threatening etiologies is done.

Failure to evaluate postmenopausal bleeding may lead to delayed diagnosis of endometrial cancer. Though endometrial cancer, when diagnosed in early stages, has a good prognosis, later-stage endometrial cancer has a poorer prognosis. Endometrial cancer cases that involve extra-uterine spread account for more than half of uterine cancer-related deaths and have survival rates as low as 5 to 15%.[11]

Consultations

One may consider a consultation with the medical specialty appropriate to the etiology of the postmenopausal bleeding. An obstetrician-gynecologist is necessary to evaluate and manage many vulvar, vaginal, cervical, and uterine etiologies. A urologist may be more appropriate; on the other hand, if the bladder or urethra is the cause of bleeding.

Consultation with a gynecologic oncologist should be done for patients with a gynecologic malignancy as the etiology of postmenopausal bleeding. Ovarian, fallopian tube cancers, and uterine sarcomas require subspecialist care. It is generally acknowledged that the prognosis is better for patients with gynecologic malignancies who are cared for by gynecologic oncologists.[11] They have the best understanding of the various treatment options and the nuances of management to best aid each individual in determining their optimal plan of care.

Gynecologic oncology referral is especially recommended for the following clinical scenarios:[11]

• At the patient’s initial procedure, the option to adequately surgically stage is not available.
• Histology preoperatively is a high risk for extrauterine spread (grade 3, clear cell, papillary serous, carcinosarcoma).
• Unexpected endometrial cancer is found after hysterectomy.
• Evidence is present of endometrial cancer spread to the cervix or outside the uterus (lymph nodes, ovary).
• Recurrent disease.
• The patient is considering non-surgical management.

Deterrence and Patient Education

Perimenopausal patients should be counseled regarding expectations for the menopausal transition years. Doctors can discuss with them how their bodies may change as their hormones change. This counseling can include how to manage menopausal symptoms, vaginal dryness, changes in metabolism, osteoporosis prevention, etc. Patients should also be counseled regarding expectations for their menses, including what is concerning during the menopausal transition and that any bleeding after menopause is considered abnormal. Patients should be encouraged to get medical attention if their perimenopausal bleeding is abnormal or if they experience postmenopausal bleeding. Providers should ask postmenopausal patients about bleeding at their routine appointments, rather than depending on them to volunteer the information.

Enhancing Healthcare Team Outcomes

Care of gynecologic malignancies, including uterine or endometrial cancer and precancer, should be coordinated with gynecologic oncologists. While a general gynecologist is capable of performing a hysterectomy or inserting an intrauterine device, the subtleties and nuances of various management options are best understood by a subspecialist with advanced training and expertise. For example, the performance (or not) of lymphadenectomy is within the auspices of a gynecologic oncologist. Research is clear that care from high-volume surgeons in likewise high-volume institutions, such as that care provided by gynecologic oncologists, provides improved patient outcomes.[28] [Level 2]