How do you properly test cortisol levels in a female patient of reproductive age with a pre-existing thyroid condition using the NuvaRing (etonogestrel/ethinyl estradiol)?

Testing Cortisol in Patients Using NuvaRing

In patients using NuvaRing, measure free cortisol index (serum cortisol divided by cortisol-binding globulin) rather than total cortisol alone, as the ethinyl estradiol component significantly elevates cortisol-binding globulin (CBG) levels, leading to falsely elevated total cortisol measurements that do not reflect true adrenal function. 1, 2

Why Standard Cortisol Testing is Inadequate

• NuvaRing releases 15 μg ethinyl estradiol daily, which stimulates hepatic production of CBG 3, 1
• Total cortisol levels can increase dramatically (up to 50-61 mcg/dL) in women using estrogen-containing contraceptives due to elevated CBG, despite normal free (biologically active) cortisol 2
• CBG levels can rise from normal range (1.7-3.1 mg/dL) to as high as 6.4 mg/dL with estrogen-containing contraceptives 2
• The vaginal ring causes significantly less CBG elevation compared to oral contraceptives (30 μg ethinyl estradiol), but the effect is still clinically relevant 1

Recommended Testing Approach

Morning (8 AM) blood draw should include:

• Total serum cortisol 4, 5
• Cortisol-binding globulin (CBG) 1, 2
• Calculate free cortisol index (FCI) = serum cortisol ÷ CBG 6
• ACTH level (to distinguish primary from secondary adrenal insufficiency) 4, 5

Additional confirmatory tests if FCI is abnormal:

• 24-hour urinary free cortisol (not affected by CBG elevation) 5, 2
• ACTH stimulation test using peak FCI rather than peak total cortisol for interpretation 6
• Consider late-night salivary cortisol to assess circadian rhythm 5

Critical Interpretation Guidelines

• Do not use total cortisol values alone - they will be falsely elevated and misleading 2, 6
• Peak FCI less than mean -3 SD of healthy controls on ACTH stimulation indicates true adrenal insufficiency 6
• On ACTH stimulation testing, up to 11% of patients may have subnormal peak FCI despite seemingly adequate total cortisol responses 6
• 24-hour urinary free cortisol remains normal or only slightly elevated (when corrected for creatinine) even when total serum cortisol is extremely high 2

Special Considerations for Thyroid Disease

In patients with pre-existing thyroid conditions, additional complexity exists:

• Hyperthyroidism can independently affect cortisol metabolism, increasing both production and clearance 7, 6
• Hypothyroidism increases cortisol half-life and decreases metabolic clearance, potentially elevating total cortisol 7
• Measure TSH and free T4 concurrently with cortisol assessment 3, 4
• Never initiate thyroid hormone replacement before addressing adrenal insufficiency, as this can precipitate adrenal crisis 4
• In hyperthyroid patients, plasma ACTH and FCI may be elevated despite normal adrenal reserves 6

Alternative Testing Strategy

If unable to measure CBG:

• Discontinue NuvaRing for 2 months and retest total cortisol 2
• CBG levels typically normalize within 2 months of stopping estrogen-containing contraceptives 2
• However, this approach delays diagnosis and may not be practical for patients requiring contraception

Common Pitfalls to Avoid

• Misdiagnosing Cushing's syndrome based on elevated total cortisol alone in NuvaRing users 2
• Using total cortisol to monitor adequacy of hydrocortisone replacement in patients continuing NuvaRing 3
• Failing to account for thyroid disease effects on cortisol metabolism when both conditions coexist 7, 6
• Interpreting ACTH stimulation tests using total cortisol cutoffs (e.g., 18 μg/dL) rather than FCI in estrogen users 6