Postmenopausal bleeding

Postmenopausal bleeding is vaginal bleeding occurring 12 months or more after the last menstrual period in a woman who has reached the menopause. Any amount counts, including spotting and blood stained discharge. Most cases are caused by atrophy of the endometrium or vagina, but endometrial cancer is found in about 5 to 10% of women, so every woman needs assessment of the endometrium, cervix, vagina and vulva.

Clinical relevance. Postmenopausal bleeding is the presenting symptom in about 90% of women with endometrial cancer, and early diagnosis gives a high chance of cure.

Anatomy and physiology. After the menopause, falling oestradiol leads to endometrial and vaginal atrophy. Endometrial pathology arises from unopposed oestrogen (obesity, hormone therapy without progestogen, tamoxifen, polycystic ovary syndrome, oestrogen secreting tumours), polyps and malignant transformation.

Classification. By source: endometrial (atrophy, polyp, hyperplasia, cancer), cervical, vaginal and vulval, ovarian (hormone secreting tumours), iatrogenic (hormone therapy, tamoxifen, anticoagulants), and non gynaecological (urinary or bowel). By pattern: first episode, recurrent, or persistent.

Key distinctions. Bleeding on sequential hormone therapy is expected as a withdrawal bleed, but unscheduled bleeding after 3 to 6 months of continuous combined therapy, or any new bleeding after a long pause, needs investigation. Bleeding on tamoxifen needs endometrial assessment irrespective of ultrasound thickness. Bleeding with a cervical or vaginal lesion needs biopsy regardless of the endometrium.

History

• Bleeding: onset, amount, colour, duration, pattern (one episode or recurrent), discharge, postcoital, association with straining or voiding, pain.
• Menopausal history: age at menopause, time since last period, symptoms.
• Hormone therapy: type (oestrogen only, sequential or continuous combined, tibolone), route, dose, adherence, duration, recent change; tamoxifen or aromatase inhibitor use.
• Risk factors for endometrial cancer: obesity, diabetes, nulliparity, polycystic ovary syndrome, prolonged unopposed oestrogen, late menopause, hypertension, family history of endometrial, colorectal or ovarian cancer (Lynch syndrome).
• Cervical screening history and previous abnormal results; HPV vaccination.
• Drugs: anticoagulants, antiplatelet agents, herbal products containing oestrogens, tamoxifen.
• Associated symptoms: pelvic pain, weight loss, abnormal discharge, bloating, urinary symptoms, rectal bleeding, vaginal dryness, dyspareunia.
• Previous pelvic radiotherapy, pessary use, trauma or foreign body, and possible abuse in older or dependent women.

Examination

• General: BMI, blood pressure, pallor, lymph nodes, abdomen for mass or ascites.
• Vulva and urethra: atrophy, ulcer, lesion, caruncle, prolapse.
• Speculum: vaginal atrophy, ulcer, laceration, pessary erosion, cervical polyp, ectropion, mass or ulcer, source of bleeding from the os.
• Bimanual and rectovaginal examination: uterine size, adnexal mass, parametrial thickening, nodularity.
• Rectal and urinary sources when the vaginal examination is normal.

Red flags

• Any postmenopausal bleeding (all women need assessment).
• Visible cervical, vaginal or vulval growth, ulcer or friable lesion.
• Pelvic mass, ascites, weight loss or bloating.
• Recurrent or persistent bleeding after a normal first assessment.
• Tamoxifen use with bleeding, Lynch syndrome, or a thickened endometrium.
• Haemodynamic instability with heavy bleeding.
• Haematuria or rectal bleeding.

Special groups. Women on tamoxifen have increased risks of polyps, hyperplasia and cancer. Women on hormone therapy: assess the regimen, and review unscheduled bleeding after 3 to 6 months of continuous combined therapy. Obese women and those with diabetes have higher cancer risk and poorer ultrasound views. Women on anticoagulants still need assessment because anticoagulation does not explain the bleeding.

Organised by source.

Endometrial and uterine

• Endometrial and vaginal atrophy (the commonest cause, about 60 to 80%).
• Endometrial polyp.
• Endometrial hyperplasia (without atypia, and with atypia).
• Serious: endometrial cancer (endometrioid, serous, clear cell, carcinosarcoma), and uterine sarcoma.
• Submucous fibroid, adenomyosis.
• Endometritis, pyometra and haematometra with cervical stenosis.
• Retained or migrated intrauterine device.

Cervical

• Cervical polyp and ectropion.
• Cervicitis, including trichomoniasis, chlamydia and herpes simplex virus.
• Cervical intraepithelial neoplasia.
• Serious: cervical cancer.

Vaginal and vulval

• Atrophic vaginitis and vaginal trauma.
• Vaginal foreign body and pessary erosion, prolapse with ulceration.
• Vulvovaginal lichen sclerosus with fissures.
• Serious: vaginal cancer, vulval cancer, vaginal intraepithelial neoplasia.
• Radiation vaginitis and fistula.

Ovarian and hormonal

• Oestrogen secreting ovarian tumour (granulosa cell tumour, thecoma).
• Ovarian cancer (rarely presents with bleeding).
• Exogenous oestrogens: hormone therapy, tibolone, tamoxifen, herbal products, topical oestrogen creams.

Iatrogenic and systemic

• Hormone therapy related bleeding (sequential or continuous combined regimens).
• Tamoxifen related endometrial change.
• Anticoagulants and antiplatelet agents (unmask lesions but do not explain bleeding without investigation).
• Bleeding disorders and thrombocytopenia.

Non gynaecological sources (mistaken for vaginal bleeding)

• Urethral caruncle and prolapse.
• Haematuria from bladder cancer, stones or infection.
• Haemorrhoids, anal fissure, rectal cancer and inflammatory bowel disease.

Stepwise reasoning

1. Establish the source by speculum examination and exclude non gynaecological sources.
2. Measure the endometrium with transvaginal ultrasound in every woman.
3. Sample the endometrium (outpatient biopsy or hysteroscopy) when thickness is over 4 mm, when ultrasound cannot be completed, when bleeding recurs or persists, or when risk is high.
4. Assess the cervix and vagina and biopsy any lesion.
5. Stage promptly when cancer is found.

Tests

• Transvaginal ultrasound: endometrial thickness 4 mm or less has a negative predictive value over 99% for endometrial cancer when bleeding is a first episode in a woman not on hormone therapy; thickness over 4 mm needs sampling. Features suggesting disease: focal thickening, irregular margin, heterogeneity, cystic change and increased vascularity. Ovarian masses, fibroids and fluid are also assessed.
• Endometrial biopsy by pipelle or similar device: high sensitivity for endometrial cancer when the whole cavity is abnormal (about 90 to 99%) but misses focal lesions such as polyps; a non diagnostic or insufficient sample needs hysteroscopy or ultrasound confirmation of a thin endometrium.
• Hysteroscopy with directed biopsy: for persistent or recurrent bleeding despite a normal ultrasound or biopsy, a focal lesion, polyps, a thickened endometrium with an unsuitable sample, and bleeding on tamoxifen. Outpatient hysteroscopy is preferred; use general anaesthesia when it cannot be tolerated.
• Tamoxifen: investigate every episode of bleeding with hysteroscopy and biopsy regardless of thickness (endometrial thickness is raised by subendometrial cystic change and has limited accuracy).
• Hormone therapy: ultrasound thresholds are less reliable, and unscheduled bleeding after 3 to 6 months of continuous combined therapy, or any bleeding on sequential therapy not at the expected time, needs endometrial assessment.
• Cervical examination and cytology or HPV test if due (a normal test does not exclude cancer); colposcopy and biopsy for any visible cervical lesion.
• Vulval and vaginal biopsy of any ulcer, plaque or mass.
• Full blood count and ferritin; coagulation screen if bleeding disorder is suspected; HbA1c if diabetes is suspected.
• Urine dipstick and culture, and cystoscopy for haematuria; colonoscopy for rectal bleeding.
• MRI pelvis for endometrial or cervical cancer staging, myometrial invasion and adnexal masses; CT chest, abdomen and pelvis for staging; CA 125 only when ovarian or serous cancer is suspected.
• Genetic assessment (immunohistochemistry for mismatch repair proteins, microsatellite instability) for endometrial cancer, particularly under age 60 or with family history, for Lynch syndrome.

Limitations. Ultrasound thickness thresholds do not apply on tamoxifen or in some hormone therapy users. Blind sampling misses focal lesions. Thickness can be hard to measure with fibroids, adenomyosis or obesity. A normal endometrium does not exclude cervical or vulval disease.

Immediate steps. Control heavy bleeding with resuscitation, tranexamic acid 1 g orally three times daily for up to 4 days (reduce for renal impairment: serum creatinine 120 to 249 micromol/L, 1 g twice daily; 250 to 500 micromol/L, 1 g once daily; over 500 micromol/L, 500 mg once daily; contraindicated with active thromboembolism) or intravenously 1 g over 10 minutes, and urgent gynaecology assessment when unstable. Arrange urgent assessment within 2 weeks for all women. Explain that most causes are benign.

Atrophic vaginitis and endometrial atrophy

• Vaginal oestrogen: oestradiol 10 microgram vaginal tablet nightly for 2 weeks, then twice weekly; maximum one tablet daily; review at 3 months; contraindicated with undiagnosed vaginal bleeding (use after the work up is complete), active venous thromboembolism and active liver disease. Alternatively oestriol 0.5 mg vaginal pessary nightly for 3 weeks then twice weekly, or oestriol 0.1% cream 0.5 g daily for 2 to 3 weeks then twice weekly.
• Vaginal moisturiser every 2 to 3 days and water based lubricant during intercourse when hormonal treatment is not suitable.
• Report any further bleeding, which needs reassessment.

Endometrial polyp. Hysteroscopic removal with histology (most symptomatic polyps are removed in postmenopausal women because of malignancy risk); tamoxifen related polyps are removed.

Endometrial hyperplasia

• Without atypia: levonorgestrel 52 mg intrauterine system for at least 6 months (first line); review with endometrial biopsy at 6 months and then every 6 to 12 months until two consecutive negative biopsies. Alternative: medroxyprogesterone acetate 10 to 20 mg orally daily, or norethisterone 10 to 15 mg orally daily, for at least 6 months; monitor for mood change, weight gain and bleeding. Weight loss and glycaemic control.
• With atypia: total hysterectomy with bilateral salpingo oophorectomy (a fertility sparing approach is for women who wish to conceive); medical treatment with the levonorgestrel intrauterine system and biopsies every 3 months for those who are not surgical candidates.
• Stop unopposed oestrogen; add a progestogen or switch to a combined regimen.

Endometrial cancer. Staging with MRI pelvis and CT, multidisciplinary review, and surgery (total hysterectomy with bilateral salpingo oophorectomy, with lymph node assessment by sentinel node biopsy or lymphadenectomy as stage directs). Adjuvant radiotherapy, chemotherapy, hormonal therapy or immunotherapy are given by oncology, selected by molecular and histological features.

Refer to gynaecological oncology within 2 weeks.

Cervical, vaginal and vulval cancer. Urgent referral for staging and treatment (surgery, chemoradiation).

Hormone therapy related bleeding. Sequential therapy: bleeding is expected during the progestogen phase or in the days after it; investigate when heavy, prolonged, or at unexpected times. Continuous combined therapy: unscheduled bleeding often settles within 3 to 6 months; after that, or if heavy, investigate. Options after exclusion of pathology: change the progestogen dose, route or type, or switch to a levonorgestrel intrauterine system with oestrogen alone.

Tamoxifen. Investigate every episode with hysteroscopy and biopsy. Remove polyps hysteroscopically and treat hyperplasia with a levonorgestrel 52 mg intrauterine system. Review the need for tamoxifen with oncology in women with hyperplasia with atypia or cancer.

Pessary erosion and prolapse ulceration. Remove the pessary, treat with vaginal oestrogen (oestradiol 10 microgram vaginal tablet nightly for 2 weeks, then twice weekly), and review after 2 to 4 weeks before refitting.

Anticoagulated women. Investigate in the same way. Do not stop anticoagulation without specialist advice.

Non gynaecological causes. Urological or colorectal referral for haematuria and rectal bleeding. Monitoring. Review results within 2 weeks. If the first assessment is normal and bleeding recurs, repeat assessment with hysteroscopy. Follow women on hyperplasia treatment with endometrial biopsy at 6 months and then every 6 to 12 months. Review women on hormone therapy yearly.

Women on tamoxifen are followed with regular review and a low threshold for hysteroscopy.

Referral and escalation. Refer urgently within 2 weeks to a gynaecology rapid access service for all women with postmenopausal bleeding. Refer to gynaecological oncology for confirmed or suspected cancer. Refer to urology or colorectal services for non gynaecological bleeding. Refer to genetics for suspected Lynch syndrome.

Admission criteria. Heavy bleeding with haemodynamic instability, severe anaemia needing transfusion, pyometra with sepsis, suspected cancer with obstruction or sepsis.

Discharge and follow up. Outpatient assessment for most women. Provide a clear date for results and a named contact.

Safety netting. Return for heavier or recurrent bleeding, pain, fever, offensive discharge, weight loss, bloating, or any delay in the urgent assessment.