In a patient on induced‑menopause estradiol (Estrace) three times daily, iron supplement, and levothyroxine (Synthroid), must estradiol and levothyroxine be taken at least four hours apart?

Estradiol and Levothyroxine Separation

Yes, estradiol (Estrace) and levothyroxine (Synthroid) should be separated by at least 4 hours to prevent impaired thyroid hormone absorption and maintain optimal thyroid function.

The Core Interaction

Estrogen compounds, including estradiol, increase thyroxine-binding globulin (TBG) levels, which can reduce free thyroid hormone availability and necessitate levothyroxine dose adjustments. 1 In a clinical trial of menopausal women with hypothyroidism taking oral estradiol, total T4 levels increased significantly (from 5.84 to 8.41 μg/dL), and 30% of participants required levothyroxine dose increases due to clinically important TSH changes. 1

Timing Recommendations

• Levothyroxine should be taken 30-60 minutes before breakfast or at bedtime, at least 4 hours away from potentially interacting medications. 2, 3

• The 4-hour separation applies specifically to substances that sequester or bind levothyroxine, including calcium, iron, and estrogen preparations. 4, 3

• For patients taking estradiol three times daily, optimal timing would be:

  • Levothyroxine upon waking (30-60 minutes before breakfast)
  • Estradiol doses spaced throughout the day, maintaining at least 4 hours from the levothyroxine dose 2, 3

Iron Supplement Consideration

Your patient is also taking iron, which is a known levothyroxine sequestrant requiring the same 4-hour separation. 4 In a study of 19 hypothyroid patients with levothyroxine malabsorption due to calcium or iron supplements, switching to liquid levothyroxine normalized TSH levels in 95% of patients, demonstrating the significant impact of these interactions. 4

Monitoring Requirements

• TSH levels should be monitored 6-8 weeks after initiating estradiol therapy, as dose adjustments may be needed. 1

• Oral estradiol has a more pronounced effect on thyroid function than transdermal formulations, with oral administration causing significant increases in TBG (from 15.29 to 20.84 μg/mL) and requiring levothyroxine dose adjustments in 30% of patients. 1

• Transdermal estradiol causes minimal changes in thyroid function and may be preferable for patients with hypothyroidism, though it still warrants TSH monitoring. 1

Common Pitfalls to Avoid

• Do not assume that because estradiol is not listed as a "classic" levothyroxine interaction (like calcium or iron) that separation is unnecessary—the TBG-mediated effect is clinically significant. 1

• Do not rely solely on TSH values without considering total T4 levels, as estrogen increases TBG and can mask true thyroid status. 1

• Avoid taking all three medications (levothyroxine, iron, and estradiol) within the same 4-hour window, as this creates multiple competing interactions. 4, 3

• If compliance with timing becomes problematic, consider bedtime levothyroxine dosing (at least 4 hours after the last meal and medications), which has shown comparable efficacy in some studies. 2