T4 (Levothyroxine/Synthroid) for Thyroid Replacement & Metabolic Support — Weight & Metabolism
Pro-hormone thyroid replacement. FDA-approved first-line for hypothyroidism. Converted to active T3 peripherally. Narrow therapeutic index.
Overview
Levothyroxine sodium (T4, brand names Synthroid, Levoxyl, Tirosint) is the synthetic form of thyroxine, the primary thyroid hormone produced by the thyroid gland. Levothyroxine is the most prescribed medication in the United States, with over 100 million prescriptions annually, and is the FDA-approved first-line treatment for hypothyroidism of any etiology. T4 functions as a pro-hormone — it is converted to the biologically active triiodothyronine (T3) by type 1 and type 2 deiodinase enzymes (DIO1, DIO2) in peripheral tissues including the liver, kidneys, and skeletal muscle. Approximately 80% of circulating T3 is derived from peripheral T4 deiodination, with only 20% produced directly by the thyroid gland. Levothyroxine has a long elimination half-life of 6-7 days, providing extremely stable plasma levels with once-daily dosing and a wide therapeutic window compared to T3. Standard replacement dosing is 1.6 mcg/kg/day for complete replacement, with typical doses ranging from 50-200 mcg/day adjusted based on TSH levels. In performance-enhancement contexts, T4 is less commonly abused than T3 because its effects depend on peripheral conversion to T3, which is subject to regulatory mechanisms. The body can partially compensate for excess T4 by reducing deiodinase activity, providing a degree of physiological buffering against supraphysiological effects. However, chronic supraphysiological T4 still carries risks of subclinical thyrotoxicosis, including atrial fibrillation, osteoporosis, and increased cardiovascular mortality. The narrow therapeutic index (despite being narrower than T3) means that brand switching and bioequivalence variations can cause clinically significant TSH fluctuations. The American Thyroid Association recommends maintaining consistent brand or formulation throughout treatment.
Indications
- FDA-approved: Primary hypothyroidism — first-line replacement therapy
- FDA-approved: Secondary (pituitary) and tertiary (hypothalamic) hypothyroidism
- FDA-approved: TSH suppression in thyroid cancer management
- FDA-approved: Myxedema coma (high-dose IV, with or without T3)
- Off-label: Combined T4/T3 therapy for hypothyroidism (controversial)
- Off-label: Adjunctive treatment of refractory depression (controversial)
- Occasionally misused for mild metabolic enhancement
Mechanism of Action
Levothyroxine absorbed primarily in jejunum and upper ileum. Bioavailability 40-80% depending on formulation and fasting state. Long half-life (6-7 days) creates extremely stable plasma levels with minimal diurnal variation
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Levothyroxine (T4/Synthroid) | 50-100 mcg/day | Once daily, empty stomach | Standard starting range; adjust based on TSH every 6-8 weeks |
| Levothyroxine (T4/Synthroid) | 100-200 mcg/day | Once daily, empty stomach | Full replacement dose (1.6 mcg/kg/day); individualized by TSH |
| Levothyroxine (T4/Synthroid) | 200-300 mcg/day | Once daily, empty stomach | TSH suppression dose for thyroid cancer — oncologist supervised |
| Levothyroxine sodium | 200-500 mcg | Once, then 50-100 mcg/day | Myxedema coma — ICU setting only |
Evidence Grade
GRADE A
Safety & Contraindications
- Narrow therapeutic index — small dose changes affect clinical outcomes
- Overreplacement causes subclinical thyrotoxicosis (suppressed TSH, normal T3/T4)
- Atrial fibrillation risk with chronic overreplacement (HR 1.6 for AF at TSH <0.1)
- Accelerated bone loss with TSH suppression — osteoporosis risk in postmenopausal women
- Increased cardiovascular mortality with chronic TSH suppression
- Must take on empty stomach 30-60 minutes before breakfast for consistent absorption
- Drug interactions: calcium, iron, PPIs, cholestyramine reduce absorption
- Brand switching can cause clinically significant TSH changes
- Contraindicated in uncorrected adrenal insufficiency
- Pregnancy requires dose increase of 25-50% — monitor TSH every 4 weeks
- Drug interactions with warfarin (potentiation), insulin (increased requirements)