What is thyroxine (levothyroxine), and how is it used to treat hypothyroidism?

What is Thyroxine (Levothyroxine)?

Thyroxine (levothyroxine) is a synthetic form of the thyroid hormone T4 that serves as the standard first-line treatment for hypothyroidism of any cause, working as a replacement therapy to restore normal thyroid hormone levels in the body. 1

Mechanism and Function

• Levothyroxine is a synthetic levoisomer of thyroxine (T4), one of the two main hormones produced by the thyroid gland 2
• T4 functions primarily as a prohormone that is converted in the body to the more biologically active triiodothyronine (T3), which binds to nuclear thyroid hormone receptors at the cellular level 2, 3
• Only free (unbound) thyroxine is biologically active, though most plasma thyroxine is bound to transport proteins 2
• The conversion of T4 to T3 allows the body to maintain its reservoir of active thyroid hormone, which is why T4 monotherapy can effectively treat hypothyroidism 4

Primary Indications

Levothyroxine is FDA-approved for two main indications: 1

• Hypothyroidism replacement therapy: For primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism in adults and pediatric patients, including neonates 1
• TSH suppression therapy: As an adjunct to surgery and radioiodine therapy in managing thyrotropin-dependent well-differentiated thyroid cancer 1

How It Treats Hypothyroidism

• Levothyroxine normalizes thyroid-stimulating hormone (TSH) levels while restoring the body's T3 reservoir, addressing the metabolic slowing that causes hypothyroid symptoms 5, 4
• Treatment prevents serious complications of untreated hypothyroidism, including heart failure, myxedema coma (which has up to 30% mortality), cardiovascular events, and reproductive health issues 6
• Proper dosing improves clinical manifestations such as fatigue (present in 68-83% of hypothyroid patients), weight gain (24-59%), cognitive issues (45-48%), and menstrual irregularities (approximately 23%) 6

Dosing Principles

• The therapeutic dose depends on residual thyroid secretion, patient weight, and treatment purpose 2
• For patients under 70 years without cardiac disease, the full replacement dose is approximately 1.6 mcg/kg/day 5
• For patients over 70 years or with cardiac disease/multiple comorbidities, start with 25-50 mcg/day and titrate gradually to avoid cardiac complications 5, 6
• Initial dose titration is not recommended during postoperative replacement therapy or in pregnant women with hypothyroidism 2

Administration Requirements

• Levothyroxine must be taken as a single daily dose on an empty stomach, one-half to one hour before breakfast with a full glass of water to ensure proper absorption and avoid choking 1, 2
• Administer at least 4 hours before or after drugs that interfere with absorption (such as calcium, iron supplements, or antacids that increase gastric pH) 1, 2
• Avoid administration with foods that decrease absorption, such as soybean-based infant formula 1

Monitoring and Safety

• TSH should be monitored every 6-8 weeks while titrating the dose, then every 6-12 months once stable to avoid both undertreatment and overtreatment 5, 7, 6
• Approximately 25% of patients on levothyroxine are unintentionally maintained on doses high enough to suppress TSH completely, increasing risks for atrial fibrillation, osteoporosis, fractures, and cardiac complications 5, 7
• Properly managed levothyroxine treatment is safe with minimal adverse effects when appropriately dosed 2

Critical Limitations and Warnings

• Levothyroxine should NOT be used for treatment of obesity or weight loss - the FDA includes a boxed warning that larger doses may produce serious or life-threatening toxicity, particularly when combined with sympathomimetic amines used for weight loss 1
• Not indicated for suppression of benign thyroid nodules or nontoxic diffuse goiter in iodine-sufficient patients, as overtreatment may induce hyperthyroidism 1
• Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis 1
• Levothyroxine has a narrow therapeutic index - both underdosage (causing subclinical hypothyroidism) and excessive dosage (causing subclinical hyperthyroidism) are associated with adverse symptoms and must be avoided 8

Why Levothyroxine Monotherapy Remains Standard

• Levothyroxine alone remains the treatment of choice despite the thyroid gland naturally secreting both T4 and T3, because T4 is effectively converted to T3 in the body 3
• While some studies showed potential benefits of combined T4+T3 therapy on mood and quality of life, clear advantages have not been consistently demonstrated, and the preference for combination therapy must be balanced against potential adverse events 3
• Combination therapy with T4+T3 can be considered on a trial basis only for patients who remain symptomatic despite adequate T4 monotherapy 4