What is the differential diagnosis for a 25-year-old woman with severe bilateral leg pain for 1 year, also diagnosed with Polycystic Ovary Syndrome (PCOS)?

Differential Diagnosis for Severe Bilateral Leg Pain in a 25-Year-Old Woman with PCOS

The differential diagnosis should prioritize musculoskeletal causes (overuse syndromes, compartment syndrome), vascular etiologies (thrombosis given PCOS-associated hypercoagulability), neurologic conditions (peripheral neuropathy from insulin resistance, lumbar radiculopathy), and metabolic disorders, while recognizing that PCOS itself does not directly cause bilateral leg pain but creates risk factors for several of these conditions.

Primary Differential Considerations

Vascular Etiologies

• Venous thromboembolism (DVT): Women with PCOS have increased risk of vascular thrombosis due to insulin resistance, dyslipidemia, and metabolic syndrome 1. The chronic nature (1 year) makes acute DVT less likely, but chronic venous insufficiency or post-thrombotic syndrome should be considered.
• Polycythemia vera: Although rare, this can present as bilateral leg pain with discoloration and has been documented to cause complex regional pain syndrome 2. Check complete blood count with hemoglobin and hematocrit levels.

Metabolic and Endocrine Causes

• Insulin resistance complications: PCOS patients frequently have insulin resistance independent of BMI, which can lead to peripheral neuropathy 1, 3. Screen with 2-hour oral glucose tolerance test (75g glucose load) 1.
• Type 2 diabetes mellitus: All women with PCOS should be screened for diabetes and glucose intolerance given demonstrated increased risk 1. Diabetic neuropathy can cause bilateral lower extremity pain.
• Thyroid disease: Must be excluded as it can mimic PCOS symptoms and cause myalgias 1. Measure TSH levels 3.

Musculoskeletal Causes

• Chronic exertional compartment syndrome: Consider if pain worsens with activity. PCOS patients often engage in vigorous exercise for weight management 1.
• Obesity-related mechanical pain: Calculate BMI and waist-to-hip ratio, as central obesity is common in PCOS and can cause mechanical lower extremity pain 1, 3.
• Myopathy: Screen for Cushing's syndrome if patient has buffalo hump, moon facies, hypertension, abdominal striae, or proximal myopathies 1.

Neurologic Causes

• Lumbar radiculopathy or spinal stenosis: Bilateral presentation suggests central pathology.
• Peripheral neuropathy: Beyond diabetic causes, evaluate for other metabolic or inflammatory neuropathies.
• Complex regional pain syndrome (CRPS): Characterized by pain, discoloration, sweating, allodynia, and hyperalgesia 2. Though typically post-traumatic, can occur spontaneously.

Inflammatory and Autoimmune Conditions

• Inflammatory myopathy or vasculitis: Consider if constitutional symptoms present.
• Fibromyalgia: Chronic widespread pain syndrome that can affect lower extremities bilaterally.

Critical Diagnostic Workup

Laboratory Evaluation

• Metabolic screening: Fasting glucose followed by 2-hour oral glucose tolerance test (75g) to detect diabetes and glucose intolerance 1, 3.
• Lipid panel: Fasting lipoprotein profile including total cholesterol, LDL, HDL, and triglycerides, as PCOS patients have dyslipidemia risk 1.
• Complete blood count: Rule out polycythemia vera (hemoglobin >180 g/L, hematocrit >47%) 2.
• TSH and prolactin: Exclude thyroid disease and hyperprolactinemia 1, 3.
• Inflammatory markers: ESR and CRP if inflammatory etiology suspected.

Physical Examination Findings

• Anthropometric measurements: Calculate BMI and waist-to-hip ratio to assess central obesity 1, 3.
• Skin examination: Look for acanthosis nigricans (neck, axillae, under breasts, vulva) indicating insulin resistance 1, 3.
• Vascular assessment: Check for edema, discoloration, temperature changes, and pulses in lower extremities 2.
• Neurologic examination: Assess for sensory deficits, motor weakness, reflexes, and signs of radiculopathy.
• Signs of Cushing's syndrome: Buffalo hump, moon facies, hypertension, abdominal striae, easy bruising 1.

Imaging and Specialized Testing

• Lower extremity Doppler ultrasound: If vascular etiology suspected.
• Lumbar spine MRI: If radiculopathy or central neurologic cause suspected.
• Nerve conduction studies/EMG: If peripheral neuropathy suspected 4.

Common Pitfalls to Avoid

• Assuming leg pain is directly caused by PCOS: PCOS does not directly cause bilateral leg pain, but creates metabolic risk factors for conditions that do 1, 5.
• Overlooking metabolic screening: All women with PCOS require metabolic evaluation regardless of body weight, as insulin resistance occurs independently of BMI 3, 5.
• Missing rare but treatable causes: Polycythemia vera can present as bilateral leg pain and is treatable with venesection 2.
• Ignoring lifestyle factors: Excessive exercise patterns can cause various musculoskeletal complications in PCOS patients attempting weight management 1, 6.

Algorithmic Approach

1. Initial laboratory screen: CBC, fasting glucose with 2-hour OGTT, lipid panel, TSH, prolactin 1, 3.
2. Physical examination focus: BMI, waist-to-hip ratio, acanthosis nigricans, vascular examination, neurologic examination 1, 3.
3. If metabolic abnormalities present: Pursue diabetic neuropathy workup with nerve conduction studies.
4. If vascular signs present: Order lower extremity Doppler ultrasound.
5. If neurologic deficits present: Consider lumbar spine MRI and EMG/nerve conduction studies 4.
6. If polycythemia on CBC: Evaluate for polycythemia vera 2.
7. If Cushingoid features present: Perform dexamethasone suppression test 1, 3.