When should levothyroxine (thyroid hormone replacement medication) therapy be initiated in patients with hypothyroidism?

When to Initiate Levothyroxine Therapy

Initiate levothyroxine immediately for overt hypothyroidism (elevated TSH with low free T4), and for subclinical hypothyroidism with TSH >10 mIU/L regardless of symptoms. 1

Overt Hypothyroidism

• Start levothyroxine without delay when TSH is elevated AND free T4 is below the reference range (typically <10.3 pmol/L or <0.8 ng/dL). 2, 1
• This represents primary hypothyroidism requiring immediate treatment to prevent cardiovascular dysfunction, adverse lipid profiles, and quality of life deterioration. 1
• Confirm the diagnosis with repeat testing if the patient is clinically stable, but do not delay treatment in symptomatic patients. 1

Subclinical Hypothyroidism: TSH-Based Algorithm

TSH >10 mIU/L with Normal Free T4

• Initiate levothyroxine therapy regardless of age or symptoms. 1, 3, 4
• This threshold carries approximately 5% annual risk of progression to overt hypothyroidism. 1
• Treatment may improve symptoms and lower LDL cholesterol, though mortality benefit remains unproven. 1
• The evidence quality is rated as "fair" by expert panels, but the potential benefits outweigh risks of therapy. 1

TSH 4.5-10 mIU/L with Normal Free T4

Do not routinely treat, but consider treatment in these specific situations: 1, 3, 4

• Symptomatic patients with fatigue, weight gain, cold intolerance, or constipation—offer a 3-4 month trial of levothyroxine with clear evaluation of benefit. 2, 1
• Women who are pregnant or planning pregnancy—treat at any TSH elevation to prevent preeclampsia, low birth weight, and neurodevelopmental effects in offspring. 1, 5, 3
• Positive anti-TPO antibodies—these patients have 4.3% annual progression risk versus 2.6% in antibody-negative individuals. 2, 1
• Presence of goiter or infertility. 3

For asymptomatic patients without these features, monitor TSH every 6-12 months instead of treating. 1

Critical Confirmation Steps Before Treatment

• Repeat TSH measurement after 3-6 weeks along with free T4, as 30-60% of elevated TSH levels normalize spontaneously. 1, 4, 6
• Never initiate treatment based on a single elevated TSH value—transient thyroiditis in recovery phase commonly causes temporary TSH elevation. 1
• Measure both TSH and free T4 to distinguish subclinical hypothyroidism (normal free T4) from overt hypothyroidism (low free T4). 1

Special Populations Requiring Modified Approach

Pregnant Women

• Treat hypothyroidism of any magnitude immediately—maternal hypothyroidism is associated with spontaneous abortion, gestational hypertension, preeclampsia, stillbirth, premature delivery, and impaired fetal neurocognitive development. 5, 3
• Monitor TSH levels throughout pregnancy as levothyroxine requirements typically increase 25-50% above pre-pregnancy doses. 1, 5
• Return to pre-pregnancy dose immediately after delivery. 5

Elderly Patients (>70 Years)

• For TSH >10 mIU/L, treat with caution using lower starting doses (25-50 mcg/day). 1, 4
• For TSH 4.5-10 mIU/L in patients >80-85 years, adopt a wait-and-see strategy—limited evidence suggests treatment should probably be avoided in this age group. 3, 4
• Elderly patients with coronary disease face increased risk of cardiac decompensation, angina, or arrhythmias even with therapeutic levothyroxine doses. 1

Patients with Cardiac Disease

• Start at lower doses (25-50 mcg/day) regardless of age to avoid exacerbating cardiac symptoms. 1, 6
• Titrate slowly using 12.5 mcg increments rather than 25 mcg increments. 1

Patients on Immunotherapy

• Consider treatment even for mild TSH elevation (4.5-10 mIU/L) if fatigue or other hypothyroid symptoms are present, as thyroid dysfunction occurs in 6-9% with anti-PD-1/PD-L1 therapy and 16% with combination immunotherapy. 1
• Continue immunotherapy in most cases—thyroid dysfunction rarely requires treatment interruption. 1

When NOT to Initiate Levothyroxine

• Do not treat during acute illness or hospitalization—TSH can be transiently suppressed or elevated, and 30-60% of abnormal values normalize after recovery. 1
• Do not treat based on symptoms alone with normal TSH and free T4—non-specific symptoms like fatigue are commonly misattributed to thyroid dysfunction. 6
• Never start levothyroxine before ruling out adrenal insufficiency in patients with suspected central hypothyroidism or hypophysitis—this can precipitate adrenal crisis. 1

Initial Dosing Considerations

Young Patients (<70 Years) Without Cardiac Disease

• Start with full replacement dose of approximately 1.6 mcg/kg/day. 1, 3
• This rapidly normalizes thyroid function and prevents complications. 1

Elderly or Cardiac Patients

• Start with 25-50 mcg/day and titrate gradually every 6-8 weeks. 1, 4, 6
• Monitor closely for cardiac symptoms, particularly atrial fibrillation. 1

Patients with Long-Standing Severe Hypothyroidism

• Start at low doses even in younger patients to avoid cardiac complications from rapid metabolic changes. 3

Monitoring After Initiation

• Recheck TSH and free T4 in 6-8 weeks after starting therapy or any dose adjustment. 1, 4
• Target TSH within the reference range (0.5-4.5 mIU/L) with normal free T4 for primary hypothyroidism. 1, 3
• Once stable, monitor TSH every 6-12 months or sooner if symptoms change. 1, 4

Common Pitfalls to Avoid

• Overtreatment occurs in 14-21% of treated patients and increases risk for atrial fibrillation, osteoporosis, fractures, abnormal cardiac output, and ventricular hypertrophy. 1
• Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, significantly increasing morbidity risks. 1
• Failing to recognize transient hypothyroidism leads to unnecessary lifelong treatment—always confirm persistent elevation before committing to long-term therapy. 1
• Attributing non-specific symptoms to slightly elevated TSH (4.5-10 mIU/L) leads to unnecessary treatment—randomized trials found no symptom improvement with levothyroxine in this range. 2, 1