When should levothyroxine therapy be initiated in a patient with hypothyroidism based on thyroid‑stimulating hormone level, free thyroxine, symptoms, age, cardiac disease, and pregnancy status?

When to Start Thyroid Medications

Initiate levothyroxine immediately for any patient with overt hypothyroidism (elevated TSH with low free T4), TSH persistently >10 mIU/L regardless of free T4, or any TSH elevation in pregnant women or those planning pregnancy. 1

Treatment Algorithm Based on TSH and Clinical Context

Immediate Treatment Required

Overt Hypothyroidism:

• Start levothyroxine without delay when TSH is elevated AND free T4 is below the reference range 1
• This prevents cardiovascular dysfunction, adverse lipid profiles, and quality of life deterioration 1
• Confirm diagnosis with repeat testing is NOT needed when free T4 is clearly low 1

TSH >10 mIU/L with Normal Free T4:

• Initiate levothyroxine regardless of symptoms or age (in adults <80-85 years) 1
• This threshold carries approximately 5% annual risk of progression to overt hypothyroidism 1, 2
• Associated with cardiac dysfunction (delayed relaxation, abnormal cardiac output) and adverse lipid profiles 1
• Treatment may improve symptoms and lower LDL cholesterol 1

Pregnancy or Planning Pregnancy:

• Treat ANY TSH elevation immediately, targeting TSH <2.5 mIU/L in first trimester 1, 2
• Untreated hypothyroidism increases risk of preeclampsia, low birth weight, and neurodevelopmental effects in offspring 1
• Women with pre-existing hypothyroidism require 25-50% dose increase immediately upon pregnancy confirmation 1

Confirm Before Treating (TSH 4.5-10 mIU/L with Normal Free T4)

Confirmation Step:

• Repeat TSH and free T4 after 3-6 weeks before initiating therapy 1
• 30-60% of initially elevated TSH values normalize spontaneously 1
• Do NOT treat based on single elevated TSH value 1

Consider Treatment in Specific Situations:

• Symptomatic patients with fatigue, weight gain, cold intolerance, or constipation: offer 3-4 month trial with clear evaluation of benefit 1
• Positive anti-TPO antibodies: 4.3% annual progression risk vs 2.6% in antibody-negative patients 1, 2
• Goiter or infertility 2
• Age <70 years with symptoms 1

Do NOT Routinely Treat:

• Asymptomatic patients with TSH 4.5-10 mIU/L and normal free T4 1
• Randomized controlled trials show no symptomatic benefit 1
• Monitor thyroid function tests every 6-12 months instead 1

Special Populations Requiring Modified Approach

Elderly Patients (>70 years):

• Start with lower dose: 25-50 mcg/day 1
• Titrate gradually to avoid cardiac complications 1
• Consider avoiding treatment in those >85 years with TSH ≤10 mIU/L 2
• TSH reference range shifts upward with age (upper limit reaches 7.5 mIU/L in patients >80) 1

Cardiac Disease:

• Start at 25-50 mcg/day regardless of age 3, 1
• Rapid normalization can unmask or worsen cardiac ischemia 1
• Increase by 12.5-25 mcg every 6-8 weeks 1
• Never start at full replacement dose—can precipitate MI, heart failure, or fatal arrhythmias 1

Patients on Immune Checkpoint Inhibitors:

• Consider treatment even for subclinical hypothyroidism if fatigue or other complaints present 3, 1
• Thyroid dysfunction occurs in 6-9% with anti-PD-1/PD-L1 therapy, 16-20% with combination immunotherapy 3, 1
• Continue immunotherapy in most cases—thyroid dysfunction rarely requires treatment interruption 3, 1

Critical Safety Considerations Before Starting Levothyroxine

Rule Out Adrenal Insufficiency:

• ALWAYS check morning cortisol and ACTH before initiating levothyroxine in suspected central hypothyroidism or hypophysitis 3, 1
• Starting thyroid hormone before corticosteroids can precipitate life-threatening adrenal crisis 3, 1
• If adrenal insufficiency present, start hydrocortisone at least 1 week BEFORE levothyroxine 3, 1
• This is particularly important in patients with autoimmune hypothyroidism (increased risk of concurrent Addison's disease) 1

Exclude Transient Causes:

• Recent iodine exposure (CT contrast) can transiently affect thyroid function 3, 1
• Recovery phase from severe illness or thyroiditis 1
• Recent levothyroxine dose adjustments 1
• Certain medications 1

Initial Dosing Strategy

Young Patients (<70 years) Without Cardiac Disease:

• Full replacement dose: approximately 1.6 mcg/kg/day 1
• Can start with calculated full dose 2

Elderly (>70 years) OR Cardiac Disease OR Multiple Comorbidities:

• Start low: 25-50 mcg/day 3, 1
• Titrate by 12.5-25 mcg every 6-8 weeks 1

Long-Standing Severe Hypothyroidism:

• Start at low dose even in young patients 2
• Gradual titration to avoid cardiac complications 2

Monitoring After Initiation

Initial Phase:

• Recheck TSH and free T4 every 6-8 weeks after any dose adjustment 1, 4
• This represents time needed to reach steady-state 1, 4
• Target TSH: 0.5-4.5 mIU/L with normal free T4 1

Maintenance Phase:

• Once stable, repeat TSH every 6-12 months 1
• Or sooner if symptoms change 1

Pregnancy:

• Check TSH every 4 weeks until stable, then minimum once per trimester 1
• Target TSH <2.5 mIU/L in first trimester 1

Common Pitfalls to Avoid

Do NOT treat based on single elevated TSH without confirmation 1

• 30-60% normalize spontaneously 1

Never start thyroid hormone before ruling out adrenal insufficiency in central hypothyroidism 3, 1

• Can precipitate adrenal crisis 3, 1

Avoid overtreatment 1

• Approximately 25% of patients unintentionally maintained with suppressed TSH 1
• TSH <0.1 mIU/L increases risk of atrial fibrillation, osteoporosis, fractures, cardiovascular mortality 1

Do not assume hypothyroidism is permanent without reassessment 1

• Consider transient thyroiditis, especially in recovery phase 1

Avoid starting full replacement dose in elderly or cardiac patients 1

• Can precipitate cardiac complications 1