What is the recommended initial levothyroxine (synthetic thyroxine) dose and titration schedule for a healthy non‑pregnant adult, for an elderly patient (≥65 years) with coronary artery disease, heart failure, or atrial fibrillation, and for a pregnant woman, and how should thyroid‑stimulating hormone (TSH) and free thyroxine (free T4) be monitored during dose adjustments?

Levothyroxine Dosing Strategy

Initial Dosing for Healthy Non-Pregnant Adults

For healthy adults under 65 years without cardiac disease, start levothyroxine at the full replacement dose of 1.6 mcg/kg/day, taken on an empty stomach 30–60 minutes before breakfast. 1, 2, 3

• This approach rapidly normalizes thyroid function and prevents the cardiovascular dysfunction, adverse lipid profiles, and quality-of-life deterioration associated with prolonged hypothyroidism 1
• The full replacement dose can be initiated immediately in younger patients without cardiac comorbidities because the risk of unmasking cardiac ischemia is minimal 1, 4
• Dosages greater than 200 mcg/day are seldom required; inadequate response to doses exceeding 300 mcg/day suggests poor compliance, malabsorption, or drug interactions 2

Dose Titration Schedule

• Recheck TSH and free T4 at 6–8 weeks after initiating therapy, as this interval is required to reach steady-state levothyroxine concentrations 1, 2, 3
• Adjust the dose by 12.5–25 mcg increments every 6–8 weeks based on TSH results until the target TSH of 0.5–4.5 mIU/L is achieved 1, 5, 2
• Once the TSH normalizes, monitor every 6–12 months or sooner if symptoms change 1, 3
• Free T4 measurement helps interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize than free T4 1

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Initial Dosing for Elderly Patients (≥65 Years) with Cardiac Disease

For patients ≥65 years or those with coronary artery disease, heart failure, or atrial fibrillation, start levothyroxine at a low dose of 25–50 mcg/day and titrate gradually to avoid precipitating myocardial infarction, heart failure, or life-threatening arrhythmias. 1, 2, 4, 3, 6

• Rapid normalization of thyroid hormone levels can unmask or worsen cardiac ischemia in patients with underlying coronary disease 1
• Starting at 50 mcg in a patient with recent cardiac events carries unacceptable risk of precipitating acute coronary syndrome or arrhythmias 1
• Elderly patients with coronary disease are at increased risk of cardiac decompensation even with therapeutic levothyroxine doses 1

Dose Titration Schedule for Cardiac Patients

• Increase the dose by 12.5 mcg increments every 6–8 weeks based on TSH and free T4 results 1, 5, 2
• Use smaller increments (12.5 mcg) rather than 25 mcg to minimize cardiovascular risk 1, 5
• Recheck TSH and free T4 at 6–8 weeks after each dose adjustment 1, 2
• Assess for new or worsening angina, palpitations, dyspnea, or arrhythmias at each follow-up visit 1
• Target TSH of 0.5–4.5 mIU/L, though slightly higher targets (up to 5–6 mIU/L) may be acceptable in very elderly patients to avoid overtreatment risks 1
• Once stabilized, monitor TSH every 6–12 months 1, 3

Critical Safety Considerations

• Obtain an ECG to screen for baseline arrhythmias before initiating therapy in patients with cardiac disease 1
• Monitor closely for signs of cardiac decompensation, including worsening heart failure symptoms or blood pressure changes 1
• Never start at full replacement dose in elderly patients with cardiac disease, as this can precipitate myocardial infarction, heart failure, or fatal arrhythmias 1

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Initial Dosing for Pregnant Women

For pregnant women with newly diagnosed hypothyroidism, initiate levothyroxine immediately at 1.6 mcg/kg/day for overt hypothyroidism (TSH ≥10 mIU/L) or at weight-based dosing tailored to TSH severity for subclinical hypothyroidism. 1, 7, 6

Specific Dosing by TSH Level in Pregnancy

• TSH ≤4.2 mIU/L (subclinical hypothyroidism): Start at 1.20 mcg/kg/day 7
• TSH >4.2–10 mIU/L (subclinical hypothyroidism): Start at 1.42 mcg/kg/day 7
• TSH >10 mIU/L or low free T4 (overt hypothyroidism): Start at 2.33 mcg/kg/day 7

For Pre-Existing Hypothyroidism in Pregnancy

Women with pre-existing hypothyroidism should increase their levothyroxine dose by 25–50% immediately upon pregnancy confirmation. 1, 2, 6

• Levothyroxine requirements typically increase by 25–50% during pregnancy in women with pre-existing hypothyroidism 1, 2
• A practical approach is to take one extra dose twice per week (i.e., nine doses per week instead of seven) 6
• Measure TSH and free T4 as soon as pregnancy is confirmed and at minimum once per trimester 1, 2

TSH Targets in Pregnancy

• First trimester: TSH <2.5 mIU/L 1, 7, 6
• Second and third trimesters: TSH ≤3.0 mIU/L 1, 7

Monitoring Schedule in Pregnancy

• Check TSH and free T4 every 4 weeks until stable, then at minimum once per trimester 1, 7
• Adjust levothyroxine dose by 12.5–25 mcg increments based on TSH results 1, 7
• Untreated or inadequately treated maternal hypothyroidism increases risk of preeclampsia, low birth weight, and permanent neurodevelopmental deficits in the child 1, 7, 6

Critical Safety Considerations in Pregnancy

• Levothyroxine monotherapy is the only treatment during pregnancy; T3 supplementation provides inadequate fetal thyroid hormone delivery 1
• Do not wait for symptoms to develop before checking TSH, as fetal harm can occur before maternal symptoms appear 1
• Avoid TSH targets >2.5 mIU/L in the first trimester, as even subclinical hypothyroidism is associated with adverse pregnancy outcomes 1

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Monitoring TSH and Free T4 During Dose Adjustments

Standard Monitoring Protocol

Recheck TSH and free T4 at 6–8 weeks after any dose adjustment, as this interval is required for levothyroxine to reach steady-state concentrations. 1, 2, 3

• The peak therapeutic effect of a given levothyroxine dose may not be attained for 4–6 weeks 2
• Adjusting doses too frequently before reaching steady state (i.e., before 6–8 weeks) is a common pitfall that leads to inappropriate dose adjustments 1
• Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 1

Target Ranges

• Primary hypothyroidism: TSH 0.5–4.5 mIU/L with normal free T4 1, 2, 3
• Secondary or tertiary hypothyroidism: Use free T4 (not TSH) to titrate dosing until the patient is clinically euthyroid and free T4 is restored to the upper half of the normal range 2

Long-Term Monitoring After Stabilization

• Once the appropriate maintenance dose is established and TSH is within the target range, monitor TSH every 6–12 months or sooner if symptoms change 1, 3
• Development of low TSH (<0.1–0.45 mIU/L) on therapy suggests overtreatment or recovery of thyroid function; reduce the dose with close follow-up 1

Special Populations Requiring Modified Monitoring

• Pregnant women: Check TSH every 4 weeks until stable, then at minimum once per trimester 1, 7
• Patients on immune checkpoint inhibitors: Monitor TSH every 4–6 weeks for the first 3 months, then every second cycle thereafter 1
• Patients with atrial fibrillation, cardiac disease, or serious medical conditions: Consider repeating testing within 2 weeks of dose adjustment rather than waiting 6–8 weeks 1

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Common Pitfalls and Caveats

Overtreatment Risks

• Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for atrial fibrillation (3–5-fold), osteoporosis, fractures, and cardiovascular mortality 1, 4, 3
• TSH suppression (<0.1 mIU/L) increases risk for atrial fibrillation and cardiac arrhythmias, especially in elderly patients, and osteoporosis and fractures, particularly in postmenopausal women 1
• If TSH falls below 0.1 mIU/L, reduce levothyroxine dose by 25–50 mcg immediately 1
• For TSH 0.1–0.45 mIU/L, decrease dose by 12.5–25 mcg, especially in elderly or cardiac patients 1

Undertreatment Risks

• Persistent hypothyroid symptoms, adverse effects on cardiovascular function, lipid metabolism, and quality of life result from inadequate levothyroxine dosing 1
• TSH >10 mIU/L indicates inadequate replacement and carries approximately 5% annual risk of progression to overt hypothyroidism 1, 3

Adrenal Insufficiency Screening

Before initiating levothyroxine in patients with suspected central hypothyroidism or concurrent adrenal insufficiency, always start corticosteroids (e.g., hydrocortisone 20 mg in the morning and 10 mg in the afternoon) for at least one week prior to levothyroxine, as thyroid hormone can precipitate life-threatening adrenal crisis. 1, 2

• Measure morning cortisol and ACTH levels before starting levothyroxine to exclude occult adrenal insufficiency 1
• Patients with autoimmune hypothyroidism have increased risk of concurrent autoimmune adrenal insufficiency (Addison's disease) 1

Transient Hypothyroidism

• Do not treat based on a single elevated TSH value, as 30–60% of elevated TSH levels normalize spontaneously on repeat testing 1, 4, 3
• Repeat TSH and free T4 after 3–6 weeks to confirm persistent elevation before initiating therapy 1, 4
• Transient causes of TSH elevation include acute illness, recent iodine exposure (e.g., CT contrast), recovery from thyroiditis, and certain medications 1

Drug and Food Interactions

• Iron, calcium supplements, and antacids reduce gastrointestinal absorption of levothyroxine; administer levothyroxine at least 4 hours apart from these agents 1, 2
• Enzyme inducers reduce levothyroxine efficacy 4
• Do not administer levothyroxine in soybean-based infant formula, as it decreases absorption 2

Age-Related Considerations

• The normal TSH reference range shifts upward with age; approximately 12% of individuals aged ≥80 years have TSH >4.5 mIU/L without underlying thyroid disease 1
• Slightly higher TSH targets (up to 5–6 mIU/L) may be acceptable in very elderly patients to avoid overtreatment risks 1