How long should the NuvaRing (etonogestrel/ethinyl estradiol vaginal contraceptive ring) be discontinued before obtaining a serum total cortisol measurement?

Discontinue NuvaRing for 6 Weeks Before Cortisol Testing

NuvaRing should be discontinued for 6 weeks before obtaining a serum cortisol measurement to avoid false-positive results caused by estrogen-induced elevation of cortisol-binding globulin (CBG). 1

Why This Matters

The ethinyl estradiol component in NuvaRing significantly increases CBG levels in the circulation, which artificially elevates total serum cortisol measurements without actually increasing free (biologically active) cortisol. This creates a major pitfall in cortisol testing:

• Estrogens increase CBG concentration, causing serum assays that measure total cortisol to show falsely elevated values 1
• False-positive rates reach 50% in women taking oral contraceptive pills when performing dexamethasone suppression tests 1
• The same mechanism applies to all estrogen-containing contraceptives, including vaginal rings like NuvaRing [2-2]

The 6-Week Washout Period

The Endocrine Society's Clinical Practice Guideline for diagnosing Cushing's syndrome explicitly states: "Wherever possible, estrogen-containing drugs should be withdrawn for 6 wk before testing or retesting" 1. This recommendation is based on the time required for CBG levels to normalize after estrogen withdrawal.

Recent case evidence supports this concern—one patient on norgestimate-ethinyl estradiol showed extreme hypercortisolemia (50-61 mcg/dL) that decreased to 26 mcg/dL after holding the contraceptive for 2 months, with CBG dropping from 6.4 to 3.8 mg/dL 3. This demonstrates that modern low-dose contraceptives can still cause marked CBG elevation.

Clinical Algorithm

For accurate cortisol testing in NuvaRing users:

1. Remove the ring immediately when cortisol testing is planned
2. Wait 6 weeks before obtaining serum cortisol measurements
3. Use barrier contraception (condoms, spermicide) during this washout period
4. Consider alternative testing if waiting is not feasible:
   • Salivary cortisol (less affected by CBG changes)
   • 24-hour urine free cortisol (measures unbound cortisol, though still somewhat affected)

Important Caveats

• Do not test while on NuvaRing unless you're prepared to interpret artificially elevated results and potentially repeat testing after discontinuation
• The free cortisol index (total cortisol/CBG ratio) may remain normal even when total cortisol is elevated, but this requires measuring both values simultaneously 3
• Assay method matters: HPLC and LC-MS/MS methods have lower normal ranges than immunoassays, but all measure total cortisol and are affected by CBG elevation 1
• Document contraceptive use in the medical record when ordering cortisol tests, as this is a frequently overlooked cause of spurious results

The 6-week discontinuation period is critical for obtaining accurate cortisol measurements and avoiding unnecessary workup for suspected hypercortisolism.