What is the appropriate work‑up for irregular menstrual bleeding in a reproductive‑aged woman?

Work-Up for Irregular Menstrual Bleeding in Reproductive-Aged Women

Begin with a serum β-hCG pregnancy test in every reproductive-age woman presenting with irregular bleeding, regardless of contraceptive use or perceived pregnancy risk, before proceeding with any further evaluation. 1, 2

Immediate Assessment

• Assess hemodynamic stability first: urgent evaluation is required when bleeding saturates a large pad or tampon hourly for ≥4 hours. 1, 2
• Perform a speculum examination to identify cervical or vaginal sources of bleeding (cervical polyps, erosion, cervicitis, vaginal trauma, or infection). 1, 3

Laboratory Work-Up

• Order thyroid-stimulating hormone (TSH) and prolactin levels to screen for thyroid dysfunction and hyperprolactinemia, which are common endocrine causes of anovulatory bleeding. 1, 2, 4
• Obtain a complete blood count with platelet count to evaluate for anemia and underlying coagulopathy (particularly von Willebrand disease in adolescents or women with lifelong heavy bleeding). 1, 5
• Consider coagulation studies (PT, PTT, von Willebrand panel) in women with menorrhagia since menarche, family history of bleeding disorders, or failure of medical therapy. 4, 5

Imaging Studies

• Transvaginal ultrasound (TVUS) with Doppler is the first-line imaging modality to detect structural causes including polyps, adenomyosis, leiomyomas, and endometrial hyperplasia or malignancy. 1, 2, 6
• Saline infusion sonohysterography (SIS) should be performed when TVUS is inconclusive or when focal lesions are suspected, as it has 96–100% sensitivity and 94–100% negative predictive value for detecting endometrial polyps and submucosal fibroids. 1, 4, 7
• MRI is reserved for cases where ultrasound incompletely visualizes the uterus or findings remain indeterminate. 2

Endometrial Sampling Indications

Perform endometrial biopsy in the following scenarios:

• Age ≥35 years with recurrent anovulation or irregular bleeding 2, 4
• Any age with risk factors for endometrial cancer: obesity, diabetes, hypertension, unopposed estrogen exposure, tamoxifen use, Lynch syndrome, or polycystic ovary syndrome 1, 2, 4
• Women younger than 35 years with chronic anovulation plus obesity and diabetes (the combination markedly increases cancer risk from persistent unopposed estrogen) 2
• Excessive bleeding unresponsive to first-line medical therapy 2, 4

Classification Framework (PALM-COEIN)

Use the FIGO classification system to organize your differential diagnosis:

Structural causes (PALM):

• Polyp
• Adenomyosis (frequently coexists with fibroids in women in their 40s, causing heavy bleeding, dysmenorrhea, and dyspareunia) 1, 8
• Leiomyoma (fibroids)
• Malignancy and hyperplasia 1, 8, 2

Non-structural causes (COEIN):

• Coagulopathy (von Willebrand disease most common)
• Ovulatory dysfunction (most common in perimenopausal women and those with PCOS)
• Endometrial factors
• Iatrogenic (anticoagulants, antipsychotics, antiepileptics, IUDs)
• Not yet classified 1, 8, 2

Common Pitfalls to Avoid

• Do not rely solely on endometrial biopsy to exclude focal lesions such as polyps or submucosal fibroids; blind sampling can miss these lesions, and SIS or hysteroscopy is required for definitive evaluation. 1
• Do not skip pregnancy testing even in patients using contraception or reporting irregular cycles; ectopic pregnancy and trophoblastic disease can be life-threatening if diagnosis is delayed. 2, 3
• Do not omit TSH and prolactin testing even when imaging reveals structural pathology, because coexisting endocrine disorders require specific therapy distinct from standard bleeding management. 2
• In women on anticoagulation (especially NOACs like rivaroxaban), recognize that up to 70% experience heavy menstrual bleeding, and reassess the necessity of ongoing antiplatelet therapy. 9, 8

Referral Criteria

Refer to gynecology when:

• Medical management fails after an adequate trial 1, 2
• Endometrial sampling reveals hyperplasia with atypia or malignancy 2, 4
• Endometrial thickness is ≥4 mm on ultrasound with persistent postmenopausal bleeding 2
• Hysteroscopic evaluation is needed when bleeding persists despite therapy and focal lesions may have been missed by sampling 1