What are the causes, management, and potential pitfalls of dysfunctional uterine bleeding (DUB)?

Dysfunctional Uterine Bleeding: Causes, Management, and Pitfalls

Definition and Critical Distinction

Dysfunctional uterine bleeding (DUB) is NOT a generic term for all abnormal uterine bleeding—it specifically refers to bleeding caused by ovarian endocrinopathy (anovulation or ovulatory dysfunction) after excluding all structural pathology, pregnancy, medications, systemic disease, and coagulopathy. 1

This is a diagnosis of exclusion that requires systematic evaluation using the PALM-COEIN classification system to rule out other causes first. 2, 3

Causes and Mechanisms

Primary Mechanism

• Anovulation is the most common cause of DUB, resulting from progesterone deficiency and an immature or dysfunctional hypothalamic-pituitary-ovarian axis. 4, 5
• Two distinct mechanisms produce DUB: estrogen withdrawal bleeding and inappropriately sustained estrogen production (estrogen breakthrough bleeding). 1

High-Risk Populations

• Adolescents: Anovulation is extremely common in the first 2-3 years post-menarche due to hypothalamic-pituitary-ovarian axis immaturity. 5
• Perimenopausal women: Anovulation is frequent, but structural causes (especially malignancy) must be ruled out first. 3

Underlying Conditions to Exclude

• Adolescence, perimenopause, lactation, pregnancy 2
• Hyperandrogenic conditions (PCOS) 2
• Hypothalamic dysfunction 2
• Hyperprolactinemia 2
• Thyroid disease 2
• Primary pituitary disease 2
• Premature ovarian failure 2
• Iatrogenic causes and medications 2

Diagnostic Algorithm

Initial Assessment

• Test for pregnancy (β-hCG) in ALL reproductive-age women—this is mandatory before proceeding. 6
• Assess hemodynamic stability; urgent evaluation is needed if bleeding saturates a large pad/tampon hourly for ≥4 hours. 6
• Measure thyroid-stimulating hormone and prolactin levels to exclude endocrine causes. 2, 6

Imaging Strategy

• Combined transabdominal and transvaginal ultrasound with Doppler is the first-line imaging study to identify structural causes (polyps, adenomyosis, leiomyomas, malignancy). 6
• Saline infusion sonohysterography has 96-100% sensitivity and can distinguish leiomyomas from polyps with 97% accuracy. 2, 6
• MRI should be considered when ultrasound incompletely visualizes the uterus or findings are indeterminate. 6

Endometrial Sampling Indications

• Endometrial biopsy is mandatory in patients with risk factors for endometrial cancer: age >45 years, postmenopausal status, obesity, diabetes, hypertension, unopposed estrogen exposure, tamoxifen use, Lynch syndrome. 3, 6
• Endometrial biopsy is preferred over dilation and curettage because it is less invasive, safer, and lower cost. 2
• Critical caveat: Endometrial biopsy sensitivity is affected by lesion type (focal vs. diffuse), size, and location—focal lesions may be missed. 2

Management Algorithm

Medical Management (First-Line)

Medical therapy should always be attempted before surgical intervention unless contraindicated or structural pathology requires surgery. 3, 6

For Anovulatory DUB:

• Combined oral contraceptives (COCs) are first-line for most patients, providing cycle regulation and reducing bleeding. 2, 4, 5
• Cyclic progestins (oral or depot) are appropriate alternatives, especially when estrogen is contraindicated. 2, 4, 5
• Progestin-only contraception including levonorgestrel-releasing intrauterine system is highly effective. 2, 4

For Ovulatory DUB (Menorrhagia):

• NSAIDs are most effective for ovulatory menorrhagia, reducing bleeding by 20-50%. 3, 7
• Tranexamic acid (antifibrinolytic) is a non-hormonal alternative that significantly reduces bleeding. 3, 5
• Levonorgestrel IUS is the most effective medical treatment for menorrhagia. 7

Additional Options:

• GnRH agonists/antagonists (elagolix, linzagolix, relugolix) effectively reduce bleeding and fibroid volume when fibroids coexist. 3
• Danazol is effective but has significant side effects limiting use. 4, 5

Surgical Management (When Medical Therapy Fails)

If medical treatment fails, is contraindicated, or not tolerated, or if concomitant significant intracavitary lesions exist, surgery is appropriate. 2

• Endometrial ablation is a uterus-sparing option for completed childbearing. 2, 7
• Hysterectomy provides definitive resolution of all symptoms and significantly better health-related quality of life compared to other therapies. 3, 6
• The least invasive surgical route should be chosen based on uterine size and surgical expertise. 3

Referral Indications

• Failed medical management 6
• Endometrial sampling showing hyperplasia or malignancy 6
• Postmenopausal bleeding with endometrial thickness ≥4 mm 6

Critical Pitfalls and Caveats

Diagnostic Pitfalls

• Never assume DUB without excluding structural pathology—this is the most common error. The PALM-COEIN system exists specifically to prevent missing structural causes. 2, 3
• Endometrial biopsy can miss focal lesions (polyps, submucosal fibroids); if bleeding persists despite treatment, hysteroscopy is indicated for direct visualization. 2
• Transvaginal ultrasound cannot always completely evaluate the endometrium; when visualization is incomplete, proceed to MRI or endometrial sampling. 3
• In postmenopausal women, endometrial thickness <4 mm has nearly 100% negative predictive value for cancer, but ≥4 mm requires tissue diagnosis. 6

Treatment Pitfalls

• Estrogen therapy is contraindicated in anovulatory bleeding except for profuse bleeding unresponsive to progestins, because it increases risk of endometrial hyperplasia and cancer. 1
• Avoid NSAIDs and tranexamic acid in patients with cardiovascular disease due to association with MI and thrombosis. 6
• In patients on antiplatelet therapy, reassess the indication and consider discontinuation if appropriate before starting hemostatic agents. 6
• GnRH agonist/antagonist effects are temporary—symptoms return after discontinuation, making them unsuitable as definitive long-term therapy. 3

Age-Specific Considerations

• Adolescents: Anovulation is physiologic in the first 2-3 years post-menarche; avoid overtreatment but monitor for severe anemia. 5
• Perimenopausal women: Higher risk for endometrial hyperplasia/cancer; lower threshold for endometrial sampling. 3, 8
• Postmenopausal women: Endometrial cancer is the primary concern; any bleeding requires evaluation. 3

Coexisting Pathology

• Adenomyosis frequently coexists with DUB (common in women in their 40s), presenting with heavy menstrual bleeding, dysmenorrhea, and dyspareunia, contributing to menorrhagia and anemia. 3
• When adenomyosis coexists, medical management may be less effective, and hysterectomy may be required for definitive treatment. 3