What is the appropriate timing and initiation of levothyroxine (T4) and other medications in patients with hypothyroidism and hyperthyroidism?

When and How to Start Medications in Hypothyroidism and Hyperthyroidism

Hypothyroidism: When to Start Levothyroxine

Start levothyroxine immediately for TSH >10 mIU/L regardless of symptoms, for any TSH elevation with low free T4, or for symptomatic patients with any degree of TSH elevation. 1

Confirmation Before Treatment

• Confirm elevated TSH with repeat testing after 3-6 weeks, as 30-60% of high TSH levels normalize spontaneously 1
• Measure both TSH and free T4 to distinguish subclinical hypothyroidism (normal free T4) from overt hypothyroidism (low free T4) 1
• Check anti-TPO antibodies to identify autoimmune etiology, which predicts 4.3% annual progression risk versus 2.6% in antibody-negative patients 1

Treatment Thresholds by TSH Level

TSH >10 mIU/L:

• Initiate levothyroxine regardless of symptoms or free T4 level 1
• This threshold carries approximately 5% annual risk of progression to overt hypothyroidism 1
• Treatment may improve symptoms and lower LDL cholesterol 1

TSH 4.5-10 mIU/L (Subclinical Hypothyroidism):

• Do NOT routinely treat; instead monitor TSH every 6-12 months 1
• Consider treatment trial for symptomatic patients with fatigue, weight gain, cold intolerance, or constipation 1
• Treat if positive anti-TPO antibodies present (higher progression risk) 1
• Treat if pregnant or planning pregnancy at any TSH elevation 1, 2

How to Start Levothyroxine

Initial Dosing:

For patients <70 years without cardiac disease:

• Start at full replacement dose of approximately 1.6 mcg/kg/day 1, 2
• This rapidly normalizes thyroid function and reduces need for multiple dose adjustments 3

For patients >70 years OR with cardiac disease/multiple comorbidities:

• Start at 25-50 mcg/day and titrate gradually 1, 2
• Smaller increments (12.5 mcg) prevent cardiac complications including angina, arrhythmias, or myocardial infarction 1, 3

Critical Safety Consideration:

• Always rule out concurrent adrenal insufficiency before starting levothyroxine, especially in suspected central hypothyroidism, as thyroid hormone can precipitate life-threatening adrenal crisis 1, 2
• Start corticosteroids at least 1 week before levothyroxine if adrenal insufficiency is present 1

Monitoring and Dose Adjustment

Initial Titration Phase:

• Recheck TSH and free T4 every 6-8 weeks after any dose change 1, 4
• Adjust dose by 12.5-25 mcg increments based on patient age and cardiac status 1
• Target TSH within reference range (0.5-4.5 mIU/L) with normal free T4 1

Maintenance Phase:

• Once stable, monitor TSH every 6-12 months or when symptoms change 1
• Approximately 25% of patients are unintentionally overtreated with fully suppressed TSH, increasing risks for atrial fibrillation, osteoporosis, and fractures 1

Special Populations

Pregnant Women:

• Treat at any TSH elevation due to risks of preeclampsia, low birth weight, and fetal neurodevelopmental effects 1, 2
• For pre-existing hypothyroidism: increase pre-pregnancy dose by 25-50% immediately upon pregnancy confirmation 2
• For new-onset hypothyroidism with TSH ≥10 mIU/L: start 1.6 mcg/kg/day 2
• Monitor TSH every 4 weeks until stable, then at minimum once per trimester 2
• Target TSH <2.5 mIU/L in first trimester 1
• Return to pre-pregnancy dose immediately after delivery 2

Elderly Patients:

• TSH reference ranges shift upward with age; 12% of persons aged 80+ have TSH >4.5 mIU/L without thyroid disease 1
• Target TSH 0.5-4.5 mIU/L, though slightly higher targets may be acceptable in very elderly patients 1
• Monitor closely for atrial fibrillation, the most common arrhythmia with levothyroxine overtreatment in elderly 2

Patients on Immune Checkpoint Inhibitors:

• Thyroid dysfunction occurs in 6-9% with anti-PD-1/PD-L1 therapy and 16% with combination immunotherapy 1
• Consider treatment even for subclinical hypothyroidism if fatigue or other symptoms present 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, 4

Hyperthyroidism: When to Reduce or Stop Levothyroxine

Immediately reduce levothyroxine dose if TSH <0.1 mIU/L, as this indicates iatrogenic hyperthyroidism with serious cardiovascular and bone risks. 1

Assessment of Suppressed TSH

First determine indication for thyroid hormone therapy:

• Review whether patient has thyroid cancer requiring TSH suppression versus primary hypothyroidism 1
• For thyroid cancer patients, consult endocrinologist to confirm target TSH level 1

Dose Reduction Strategy

For TSH <0.1 mIU/L (severe suppression):

• Decrease levothyroxine by 25-50 mcg immediately 1
• This level significantly increases risk of atrial fibrillation (5-fold in patients ≥45 years), osteoporosis, fractures, and cardiovascular mortality 1

For TSH 0.1-0.45 mIU/L (moderate suppression):

• Decrease levothyroxine by 12.5-25 mcg, particularly if in lower part of range or in elderly/cardiac patients 1
• Recheck TSH and free T4 in 6-8 weeks 1

For patients with atrial fibrillation, cardiac disease, or serious medical conditions:

• Consider repeating testing within 2 weeks rather than waiting 6-8 weeks 1
• More aggressive dose reduction may be warranted 1

Risks of Prolonged TSH Suppression

Cardiovascular complications:

• 2.8-fold increased risk of atrial fibrillation over 2 years 1
• Increased heart rate, cardiac output, and potential ventricular hypertrophy 1
• Higher cardiovascular mortality rates 1

Bone health complications:

• Significant bone mineral density loss in postmenopausal women 1
• Increased hip and spine fractures in women >65 years with TSH ≤0.1 mIU/L 1
• Patients with chronically suppressed TSH should ensure adequate calcium (1200 mg/day) and vitamin D (1000 units/day) intake 1

Target TSH Levels by Indication

Primary hypothyroidism without thyroid cancer:

• Target TSH 0.5-4.5 mIU/L with normal free T4 1

Thyroid cancer patients (targets vary by risk stratification):

• Low-risk with excellent response: TSH 0.5-2 mIU/L 1
• Intermediate-to-high risk with biochemical incomplete response: TSH 0.1-0.5 mIU/L 1
• Structural incomplete response: TSH <0.1 mIU/L 1

Common Pitfalls to Avoid

• Never treat based on single elevated TSH without confirmation testing 1
• Never start thyroid hormone before ruling out adrenal insufficiency in suspected central hypothyroidism 1, 2
• Avoid excessive dose increases that could lead to iatrogenic hyperthyroidism 1
• Do not adjust doses more frequently than every 6-8 weeks before reaching steady state 1
• Recognize transient hypothyroidism (recovery from thyroiditis, acute illness) that may not require lifelong treatment 1, 5
• Do not overlook medication interactions: iron, calcium, and antacids reduce levothyroxine absorption and should be taken at least 4 hours apart 1