What is the differential diagnosis for a female of reproductive age with a history of uterine fibroids (leiomyomas) experiencing severe vaginal bleeding for 30 days after a Depo-Provera (medroxyprogesterone acetate) injection?

Differential Diagnosis of Severe Vaginal Bleeding for 30 Days After Depo-Provera in a Patient with Fibroids

In a patient with known fibroids experiencing severe prolonged bleeding after Depo-Provera, the differential diagnosis must include: (1) Depo-Provera-induced irregular bleeding (most common), (2) fibroid-related complications (submucosal fibroid degeneration, growth, or prolapse), (3) endometrial pathology requiring biopsy, (4) pregnancy complications including ectopic pregnancy, and (5) less commonly, cervical pathology or coagulopathy.

Primary Diagnostic Considerations

Depo-Provera-Induced Bleeding Irregularities

• Irregular or prolonged bleeding is the most common side effect of Depo-Provera and represents the expected pattern in most users, particularly in early use. The FDA label explicitly states that "most women using medroxyprogesterone acetate experience disruption of menstrual bleeding patterns" including "prolonged spotting or bleeding" 1.
• While amenorrhea increases with duration of use (55% by month 12,68% by month 24), prolonged bleeding episodes are characteristic early in treatment 1.
• However, 30 days of severe bleeding exceeds typical irregular spotting and warrants investigation for organic pathology, as the FDA label mandates: "Rule out the possibility of organic pathology if abnormal bleeding persists or is severe" 1.

Fibroid-Related Complications

• Submucosal fibroids are particularly associated with abnormal uterine bleeding and can cause severe hemorrhage. Fibroids, especially the submucosal type, are associated with postpartum hemorrhage and bleeding complications 2.
• The interaction between Depo-Provera and pre-existing fibroids is complex: while one study showed Depo-Provera reduced fibroid volume by 33% and improved bleeding in 70% of patients 3, the Cochrane review found insufficient evidence that progestogens effectively treat fibroid-related symptoms 4.
• Fibroid degeneration (red degeneration, hyaline degeneration, or necrosis) can cause acute severe bleeding and pain and should be considered, particularly if accompanied by pelvic pain 2.
• Prolapsing submucosal fibroid through the cervix represents a surgical emergency requiring urgent evaluation.

Endometrial Pathology

• Endometrial biopsy is mandatory when severe or persistent abnormal bleeding occurs to exclude endometrial hyperplasia, polyps, or malignancy 5.
• Approximately 1 in 350 women undergoing surgery for presumed fibroids has unsuspected uterine sarcoma, making tissue diagnosis critical 5.
• Long-term Depo-Provera use typically causes endometrial atrophy 6, but paradoxical endometrial pathology must be excluded.

Pregnancy-Related Complications

• Pregnancy testing is mandatory as the first step, as Depo-Provera has a 6% typical-use failure rate in the first year 7.
• Ectopic pregnancy must be considered in any Depo-Provera user with abnormal bleeding or severe abdominal pain, as the FDA label specifically warns to "be alert to the possibility of an ectopic pregnancy" 1.
• Spontaneous abortion or retained products of conception can present with prolonged heavy bleeding.

Cervical Pathology

• Cervical cancer shows a nonsignificant increased risk in Depo-Provera users first exposed before age 35 (RR 1.22-1.28) 1.
• Cervical ectropion, polyps, or cervicitis can cause bleeding that may be exacerbated by hormonal changes.
• Pap smear should be current and cervical visualization performed 5.

Coagulation Disorders

• While less common, underlying coagulopathy (von Willebrand disease, platelet disorders, anticoagulant use) may be unmasked by hormonal contraception.
• Depo-Provera can interfere with coagulation factor laboratory tests 1.

Immediate Diagnostic Workup Algorithm

Step 1: Rule Out Life-Threatening Conditions

• Obtain quantitative β-hCG immediately to exclude pregnancy and ectopic pregnancy 8, 1.
• Assess hemodynamic stability and check hemoglobin/hematocrit to quantify blood loss severity 3.
• Perform pelvic examination to identify prolapsing fibroid, cervical lesions, or signs of infection 5.

Step 2: Imaging Evaluation

• Transvaginal ultrasound combined with transabdominal ultrasound is the preferred initial imaging modality to assess fibroid size, location (particularly submucosal), endometrial thickness, and exclude other pelvic pathology 5.
• If calcified fibroids are present or ultrasound is inconclusive, CT pelvis provides superior delineation of calcification patterns and helps exclude other pathology 5.
• Sonohysterography or hysteroscopy may be more sensitive for assessing endometrial cavity distortion by submucosal fibroids 2.

Step 3: Tissue Diagnosis

• Endometrial biopsy is essential if bleeding is severe or persistent to exclude hyperplasia, polyps, or malignancy 5.
• This is particularly critical given the patient's fibroid history, as tissue diagnosis helps differentiate benign from malignant pathology 5.

Step 4: Additional Laboratory Testing

• Complete blood count to assess anemia severity 3.
• Coagulation studies if history suggests bleeding disorder.
• TSH and prolactin if menstrual irregularities preceded Depo-Provera use 8.

Critical Clinical Pitfalls to Avoid

• Do not assume all bleeding in a Depo-Provera user is drug-related without excluding organic pathology, especially when bleeding is severe or prolonged beyond typical irregular spotting 1.
• Do not fail to obtain pregnancy testing, as ectopic pregnancy can be catastrophic and Depo-Provera is not 100% effective 1.
• Do not overlook the need for endometrial sampling in severe or persistent bleeding, as this is the only way to exclude endometrial pathology and occult malignancy 5.
• Do not forget that submucosal fibroids specifically cause the most severe bleeding complications and may require urgent intervention if prolapsing 2.
• Do not delay evaluation beyond initial conservative management if bleeding continues, as severe anemia can develop rapidly and impact morbidity 3.

Management Considerations Based on Diagnosis

• If Depo-Provera-induced bleeding without organic pathology: NSAIDs or short-term estrogen supplementation (such as estradiol vaginal ring) may reduce bleeding 9, though continuation of Depo-Provera should be reconsidered given severity.
• If fibroid-related: Surgical options (myomectomy, hysteroscopic resection for submucosal fibroids, or hysterectomy) may be necessary depending on fibroid location and patient fertility desires 5, 10.
• If endometrial pathology identified: Treat specific condition (polypectomy, management of hyperplasia, oncology referral if malignancy) 5.
• Selective progesterone receptor modulators (SPRMs) like ulipristal acetate represent emerging medical therapy for fibroid-related bleeding but are not appropriate for acute severe hemorrhage 2, 10.