What to do with a patient on Tri Lo Milli (norgestimate and ethinyl estradiol) with elevated thyroxine levels but normal Thyroid-Stimulating Hormone (TSH) levels?

Elevated Thyroxine with Normal TSH in Patients on Oral Contraceptives

In a patient taking Tri Lo Milli (norgestimate and ethinyl estradiol) with elevated total thyroxine but normal TSH, no treatment is needed—this represents a benign increase in thyroid binding proteins caused by estrogen, not true thyroid dysfunction. 1

Understanding the Mechanism

• Ethinyl estradiol in oral contraceptives increases thyroxine binding capacity (TBC) and total T4 levels while maintaining normal free T4 and TSH levels 1
• This effect occurs because estrogen stimulates hepatic production of thyroid-binding globulin (TBG), which binds more thyroid hormone but does not affect the metabolically active free hormone fraction 1
• The pituitary responds only to free thyroid hormone levels, which remain normal, explaining why TSH stays within the reference range 1

Diagnostic Confirmation Algorithm

Measure free T4 (not total T4) to confirm true thyroid status:

• If free T4 is normal with normal TSH, this confirms the diagnosis of estrogen-induced TBG elevation—no further workup or treatment needed 2
• If free T4 is also elevated with normal TSH, consider rare conditions like thyroid hormone resistance or TSH-secreting pituitary adenoma 3
• TSH remains the most sensitive screening test with >98% sensitivity and >92% specificity for thyroid dysfunction 4

Critical Pitfalls to Avoid

• Never treat based on total T4 alone in patients taking estrogen-containing medications—always check free T4 to distinguish true thyroid dysfunction from binding protein alterations 2, 1
• Do not confuse this benign finding with subclinical hyperthyroidism, which would show suppressed TSH (<0.1 mIU/L), not normal TSH 5
• Avoid unnecessary thyroid imaging or additional testing when free T4 and TSH are both normal 2

When to Reassess

• Recheck thyroid function only if symptoms of thyroid dysfunction develop (palpitations, tremor, heat intolerance, weight loss, or conversely: fatigue, cold intolerance, weight gain) 4
• If the patient discontinues oral contraceptives, total T4 and TBC will normalize within 4 months without intervention 1
• For asymptomatic patients with normal TSH and free T4, routine screening intervals are not required 4

Special Considerations

• This same pattern occurs with pregnancy, where estrogen similarly elevates TBG—free T4 and TSH remain the appropriate tests for monitoring thyroid function 2
• Medications like amiodarone, heparin, and intercurrent illness can also cause discordant thyroid function tests and should be considered in the differential 2
• In the rare scenario where both free T4 and TSH are elevated, screen for thyroid hormone resistance (family history, goiter without hyperthyroid symptoms) versus TSH-secreting adenoma (requires pituitary imaging) 3