When should levothyroxine therapy be initiated in patients with overt or subclinical hypothyroidism, including considerations for pregnancy, children, the elderly, and cardiovascular risk?

When to Start Levothyroxine Treatment in Hypothyroidism

Initiate levothyroxine immediately for any patient with TSH >10 mIU/L, regardless of symptoms, age, or antibody status, as this threshold carries approximately 5% annual risk of progression to overt hypothyroidism and is associated with cardiac dysfunction and adverse lipid profiles. 1

Treatment Algorithm Based on TSH Levels

TSH >10 mIU/L with Normal Free T4 (Subclinical Hypothyroidism)

• Start levothyroxine without delay in all patients, as this level represents a clear treatment threshold supported by fair-quality evidence 1, 2, 3
• Treatment may improve hypothyroid symptoms and lower LDL cholesterol, though mortality benefit has not been demonstrated 1
• The 5% annual progression risk to overt disease justifies intervention at this threshold 1, 4

TSH 4.5-10 mIU/L with Normal Free T4

Do not routinely treat asymptomatic patients in this range, as randomized controlled trials show no symptomatic benefit from levothyroxine 1

However, initiate treatment in these specific situations:

• Pregnant women or those planning pregnancy – target TSH <2.5 mIU/L in first trimester to prevent preeclampsia, low birth weight, and neurodevelopmental effects in offspring 1, 5
• Symptomatic patients with fatigue, weight gain, cold intolerance, or constipation – consider a 3-4 month therapeutic trial with clear evaluation of benefit 1
• Positive anti-TPO antibodies – these patients have 4.3% annual progression risk versus 2.6% in antibody-negative individuals 1, 3
• Goiter present – thyroid enlargement warrants treatment even with mild TSH elevation 1
• Infertility – subclinical hypothyroidism may impair fertility 3

Overt Hypothyroidism (Elevated TSH + Low Free T4)

• Start levothyroxine immediately in all cases to prevent cardiovascular dysfunction, adverse lipid profiles, and quality of life deterioration 1, 3
• Treatment is mandatory and non-negotiable in overt disease 2, 6

Critical Confirmation Steps Before Treatment

Always confirm elevated TSH with repeat testing after 3-6 weeks, as 30-60% of initially elevated values normalize spontaneously 1, 2

Measure both TSH and free T4 to distinguish subclinical (normal free T4) from overt (low free T4) hypothyroidism 1

Check anti-TPO antibodies in patients with TSH 4.5-10 mIU/L to identify autoimmune etiology and predict progression risk 1, 3

Exclude transient causes before committing to lifelong therapy:

• Recent acute illness or hospitalization 1
• Recovery phase from thyroiditis 1
• Recent iodine exposure (CT contrast) 1
• Medications (lithium, amiodarone, interferon) 1

Special Population Considerations

Pregnancy and Preconception

• Treat any TSH elevation immediately in pregnant women or those planning pregnancy 1, 5, 3
• Target TSH <2.5 mIU/L in first trimester 1
• Untreated maternal hypothyroidism increases risk of spontaneous abortion, gestational hypertension, preeclampsia, stillbirth, premature delivery, and impaired fetal neurocognitive development 5
• Levothyroxine requirements typically increase 25-50% during pregnancy 1, 5
• Return to pre-pregnancy dose immediately after delivery 5

Elderly Patients (>70 Years)

• Start at lower dose (25-50 mcg/day) regardless of TSH level to avoid unmasking cardiac ischemia or precipitating arrhythmias 1, 2, 3
• Titrate gradually by 12.5-25 mcg increments every 6-8 weeks 1
• Consider that TSH reference ranges shift upward with age – approximately 12% of persons aged ≥80 years have TSH >4.5 mIU/L without thyroid disease 1
• Exercise caution in treating elderly patients with TSH 4.5-10 mIU/L, as limited evidence suggests treatment should probably be avoided in those >85 years 3

Patients with Cardiac Disease

• Start at 25-50 mcg/day in any patient with coronary artery disease, heart failure, or atrial fibrillation, regardless of age 1, 2, 3
• Rapid normalization can unmask or worsen cardiac ischemia 1
• Titrate slowly with 12.5 mcg increments every 6-8 weeks 1
• Monitor closely for angina, palpitations, or worsening heart failure 1

Children

• Initiate levothyroxine immediately for TSH >10 mIU/L regardless of symptoms or antibody status 7
• Treat TSH 4.5-10 mIU/L if underlying Hashimoto's thyroiditis with progressive deterioration, goiter, hypothyroid symptoms, or associated conditions like Turner syndrome or Down syndrome 7
• Rapid restoration of normal T4 is essential to prevent adverse effects on cognitive development and physical growth 7, 5
• Full replacement dose is approximately 1.6 mcg/kg/day in children without cardiac disease 7
• Monitor closely during first 2 weeks for cardiac overload and arrhythmias 5

Patients on Immune Checkpoint Inhibitors

• Consider treatment even for mild TSH elevation if fatigue or hypothyroid symptoms are present 1
• Thyroid dysfunction occurs in 6-9% with anti-PD-1/PD-L1 monotherapy and 16-20% with combination immunotherapy 1
• Continue immunotherapy in most cases – thyroid dysfunction rarely requires treatment interruption 1
• Monitor TSH every 4-6 weeks for first 3 months, then every second cycle 1

Critical Safety Precautions

Rule Out Adrenal Insufficiency First

Before starting levothyroxine in suspected central hypothyroidism or hypophysitis, always assess morning cortisol and ACTH levels – initiating thyroid hormone before adequate glucocorticoid coverage can precipitate life-threatening adrenal crisis 1, 3

If adrenal insufficiency is confirmed, start hydrocortisone (20 mg morning, 10 mg afternoon) at least one week before levothyroxine 1

This is particularly important in:

• Patients with autoimmune hypothyroidism (increased risk of concurrent Addison's disease) 1
• Patients on immune checkpoint inhibitors 1
• Any patient with unexplained hypotension, hyponatremia, or hypoglycemia 1

Initial Dosing Strategy

Young Adults (<70 years) Without Cardiac Disease

• Start with full replacement dose of approximately 1.6 mcg/kg/day 1, 2
• This allows rapid normalization of thyroid function 1

Elderly or Cardiac Patients

• Start at 25-50 mcg/day 1, 2, 3
• Increase by 12.5-25 mcg every 6-8 weeks based on TSH response 1
• Smaller increments (12.5 mcg) are safer in very elderly or those with significant cardiac disease 1

Severe Long-Standing Hypothyroidism

• Start at lower dose even in younger patients to avoid precipitating cardiac complications 2
• Titrate gradually over several months 2

Monitoring Protocol

Recheck TSH and free T4 in 6-8 weeks after initiating therapy or any dose adjustment – this represents the time needed to reach steady state 1, 3

Target TSH 0.5-4.5 mIU/L for primary hypothyroidism 1, 3, 8

Once stable, monitor TSH every 6-12 months or sooner if symptoms change 1

Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 1

Common Pitfalls to Avoid

Do Not Treat Based on Single Elevated TSH

30-60% of elevated TSH values normalize spontaneously – always confirm with repeat testing before committing to lifelong therapy 1, 2

Recognize Transient Hypothyroidism

Failure to distinguish transient thyroiditis from permanent hypothyroidism leads to unnecessary lifelong treatment 1

Avoid Overtreatment

Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH 1

Overtreatment (TSH <0.1 mIU/L) increases risk of:

• Atrial fibrillation (3-5 fold increase, especially in elderly) 1, 2
• Osteoporosis and fractures (particularly in postmenopausal women) 1, 2
• Cardiovascular mortality 1
• Ventricular hypertrophy and abnormal cardiac output 1

If TSH <0.1 mIU/L: Reduce levothyroxine by 25-50 mcg immediately 1

If TSH 0.1-0.45 mIU/L: Reduce by 12.5-25 mcg, especially in elderly or cardiac patients 1

Do Not Ignore Non-Thyroidal Causes

Avoid attributing non-specific symptoms to mild TSH elevation when TSH is only slightly elevated (4.5-10 mIU/L) – watchful waiting is often more appropriate than routine prescription 2

Never Start Thyroid Hormone Before Ruling Out Adrenal Insufficiency

This is the most dangerous pitfall – can precipitate adrenal crisis and death 1, 3

When NOT to Treat

Do not treat asymptomatic patients with TSH 4.5-10 mIU/L and normal free T4 unless they fall into one of the special categories above (pregnancy, positive antibodies, goiter, infertility) 1

Monitor thyroid function every 6-12 months in untreated patients with TSH 4.5-10 mIU/L 1

Consider that treatment may be harmful in elderly patients >85 years with mild TSH elevation 3