Workup for Abnormal Uterine Bleeding with Normal Ultrasound and Hormone Levels
When ultrasound and hormones are normal but abnormal uterine bleeding persists, proceed directly to endometrial tissue sampling via office endometrial biopsy, and if this fails to yield a diagnosis or symptoms persist, advance to hysteroscopy with directed biopsy. 1
Critical Next Steps After Normal Initial Testing
Mandatory Endometrial Sampling Indications
Even with normal imaging and hormones, endometrial biopsy is mandatory if any of these risk factors are present: 2
- Age >45 years 2
- Postmenopausal status 2
- Obesity, diabetes, or hypertension 2
- Unopposed estrogen exposure or tamoxifen use 2
- Lynch syndrome or family history of endometrial/colorectal cancer 2
Office endometrial biopsy has a 10% false-negative rate, so a negative result in a symptomatic patient must be followed by fractional dilation and curettage (D&C) under anesthesia. 1
Advanced Imaging When Ultrasound is Inadequate
If the initial transvaginal ultrasound was technically limited or findings remain unclear: 3, 2
- MRI pelvis with gadolinium-based IV contrast should be obtained when the uterus is incompletely visualized or findings are indeterminate, with sensitivity up to 79% for endometrial cancer and 100% for leiomyosarcomas 3, 2
- Diffusion-weighted imaging improves diagnostic accuracy for distinguishing benign from malignant lesions by identifying abnormal signal and irregularity of the endometrial-myometrial interface 3
Saline Infusion Sonohysterography (SIS)
SIS has 96-100% sensitivity and 94-100% negative predictive value for detecting focal endometrial pathology that standard ultrasound may miss, with 97% accuracy in distinguishing polyps from submucosal fibroids. 1, 2 This should be performed when: 1
- Initial ultrasound demonstrates any focal endometrial abnormality 2
- Medical treatment has failed 1
- There is clinical suspicion for intracavitary lesions despite normal standard ultrasound 1
Hysteroscopy: The Definitive Diagnostic Step
Hysteroscopy with directed biopsy is indicated when medical treatment fails or when endometrial sampling is non-diagnostic, as it allows direct visualization of the endometrial cavity and endocervix to diagnose focal lesions possibly missed by blind endometrial sampling. 1
Hysteroscopy is particularly critical because: 1
- Endometrial biopsy sensitivity is affected by lesion type (focal vs. diffuse), lesion size, and whether uterine malformation is present 1
- Neither ultrasound nor MRI can definitively distinguish benign from malignant endometrial pathology—tissue diagnosis is mandatory 3
Common Pitfalls to Avoid
The presence of leiomyomas or adenomyosis on imaging does not exclude concurrent endometrial pathology, including malignancy. 3 Postmenopausal women with fibroids and bleeding must have endometrial cancer and uterine sarcoma excluded before any treatment. 3
Do not rely solely on endometrial thickness measurements when clinical suspicion remains high—postmenopausal women with endometrial thickness ≥5 mm require tissue sampling, but symptomatic patients with thinner endometrium may still harbor pathology. 3, 2
Endometrial biopsy may not be accurate for diagnosing malignancies of the uterine wall such as mesenchymal tumors or endometrial stromal neoplasms. 1
Medical Management Considerations
If all structural pathology is definitively excluded and tissue sampling is benign, medical therapy becomes first-line treatment: 2, 4
- Levonorgestrel-releasing intrauterine system 2, 4
- Combined oral contraceptives 2, 4
- Continuous oral progestins 2, 4
- Tranexamic acid 2, 4
- NSAIDs (may be combined with hormonal methods) 2, 4
Referral to Gynecology
Immediate referral is indicated when: 2