Drug Profile

Thyroid hormone replacement therapy is prescribed for patients who do not produce any or enough thyroid hormone — most importantly, thyroxine.

Free T4 is the active form of thyroxine used by the body. T4 production is induced by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland, a pea-sized structure in the brain.

Underactive thyroid (hypothyroidism), a common disorder that occurs when the thyroid gland does not make enough thyroid hormone to meet the body’s needs, is classified into two types. The first, overt hypothyroidism, is characterized by low blood levels of free T4 and high levels of TSH (the normal blood TSH level range is approximately 0.4 to 4.0 milli-international units/liter [mIU/L]). It usually is associated with nonspecific symptoms that decrease quality of life, such as cold sensitivity, dry skin, constipation, fatigue, muscle cramps, voice changes and weight gain. Other symptoms may include anxiety and depression, forgetfulness, slowed thinking and weak muscles.

The second type, subclinical hypothyroidism, is a mild form of underactive thyroid in which the levels of free T4 are within the normal range but TSH levels are elevated. Patients with subclinical hypothyroidism may not experience any of the symptoms associated with overt hypothyroidism. Therefore, the condition usually is diagnosed solely based on the results of thyroid function tests. Progression of subclinical hypothyroidism to overt hypothyroidism, if it occurs, is usually slow and variable.[1]

Clinical practice guidelines for overt hypothyroidism consistently recommend thyroid-hormone therapy to restore thyroid-hormone levels to normal.[2] This can help prevent complications such as heart disease and infertility, as well as poor brain development in children.

Recent guidelines for subclinical hypothyroidism recommend against using thyroid-hormone therapy in most adults over age 30 with or without mild-to-moderate symptoms of subclinical hypothyroidism (one exception is adult patients with very high TSH levels [above 20 mIU/L]).[3] This is because recent evidence shows no clinical benefits for levothyroxine therapy in such patients in terms of improving quality of life or thyroid-related symptoms. Furthermore, there is no strong evidence that treatment with levothyroxine is beneficial for reducing the risk of death or cardiovascular complications in subclinical hypothyroidism patients.[4]

Among the thyroid hormone replacement drugs, levothyroxine has been the preferred product for decades.[5],[6],[7] This pure, synthetic product produces the same activity as the natural hormone. It has the most reliable and uniform potency and is easier to monitor.[8] The starting dose depends on patient factors, such as age, weight, use of other medications and the presence of heart disease. Extra caution to avoid overdosing is needed for the elderly and patients with heart disease.

The dose of thyroid hormone replacement drugs initially is adjusted every four to six weeks, based on thyroid blood test results along with patient symptoms, until an optimal steady (maintenance) dose is reached. Once a stable effective dose is achieved, thyroid blood tests should be checked annually.[9]

Liothyronine is the synthetic version of the most active thyroid hormone (T3).[10] It is almost totally absorbed within four hours after oral intake, resulting in a sudden high drug level in the blood, which can lead to more adverse effects than seen with levothyroxine.[11] But liothyronine drug levels then fall off rapidly within hours, which means that levels of the drug in the blood do not remain steady throughout the day. This makes it necessary to take multiple daily doses to maintain the drug’s effect.[12] Another concern about taking this drug is that the body no longer naturally regulates the conversion of T4 to T3 according to its needs. The American Thyroid Association does not recommend the use of this drug to treat hypothyroidism. We have classified this drug as Limited Use. We do not recommend it for the maintenance (long-term) treatment of hypothyroidism.

Liotrix contains a combination of levothyroxine and liothyronine. Because it contains much more liothyronine than is naturally produced in the body, this drug is subject to the same problems as liothyronine-only treatment. Therefore, we do not recommend this drug as maintenance therapy for hypothyroidism and classify it as Limited Use.

Thyroid hormone treatment is not approved by the Food and Drug Administration (FDA) for weight loss. Unscrupulous diet doctors have prescribed thyroid hormone in combination with digitalis, amphetamines and diuretics, at times with fatal results.

Although low and high thyroid hormone levels can lead to infertility, some doctors prescribe thyroid hormone replacement drugs to women with infertility who have normal thyroid hormone levels. However, thyroid hormone replacement drugs are not approved by the FDA for treating infertility.

Potential for prescription-filling errors

Thyroid hormone replacement drugs come in a wide range of strengths, expressed as milligrams (mg) or micrograms (µg), which can be confusing. Compared with other drugs, thyroid hormone replacement drugs are more prone to errors in filling prescriptions. For example, 125 µg is the same as 0.125 mg. Errors may be made if leading zeros are missing or decimal points misplaced. Errors also may occur due to poor handwriting or unclear abbreviations.

Physicians are encouraged to print prescriptions for these drugs and to specify the strength in micrograms or state the strength in both milligrams and micrograms. Pharmacies should have computer alerts for doses over 200 µg.[13],[14]

Drug stability and potency

Evidence shows significant stability and potency problems with levothyroxine products. These products also fail to maintain potency through their expiration dates. Further, the amount of active ingredient can vary in tablets from the same manufacturer with the same labeled dosage strength. Such variations in drug potency present actual safety and effectiveness concerns.

Some endocrinologists were concerned in the early 2000s about differences in the potency of levothyroxine products over time. As a result, the FDA in 2007 established new requirements for all levothyroxine products to ensure that they remain stable over their entire shelf lives.[12] The agency also concluded that approved generic products are as effective as brand-name products. However, the American Thyroid Association still advises patients to use the same brand or generic formulation throughout treatment and to have thyroid function tests checked after any change in drug formulation.[11]

Levothyroxine is unstable in the presence of light, high temperature, air and humidity. Subpotent tablets (tablets with too little levothyroxine) will not be effective in controlling the symptoms of low thyroid hormone production (hypothyroid).

Patients who receive superpotent tablets (tablets that have too much levothyroxine) can experience adverse effects from overtreatment (see below).

Adverse effects

The adverse effects of thyroid hormone replacement drugs usually are caused by overtreatment, which results in symptoms of hyperthyroidism (overactive thyroid).

Cardiovascular complications (irregular heartbeat, chest pain or even heart attack) are the most serious adverse effects.[15] Osteoporosis (bone loss) also can occur if high doses are taken for a long time, increasing the risk of fractures. Other adverse effects include rapid heart rate, palpitations, tremors, anxiety, sweating and weight loss.

People who are older or who have heart problems or myxedema (boggy swelling of the face, hands and, occasionally, legs caused by hypothyroidism) should be started on low doses of thyroid hormone replacement therapy, which can then be increased gradually if necessary.[16]

Studies show...

An article was published in the British Medical Journal in April 2011 discussing the outcome of a study conducted to investigate the association of levothyroxine with an increased risk of fractures in patients. The authors of the study found that, based on the dose of levothyroxine used in treatment, patients 70 years and older experienced an increased risk of fractures. According to the article, the increased risk of fractures observed in this population (70 years and older) was a “dose-response” relationship.[17]

In February 2021, the Journal of the American Medical Association Network Open published results of a randomized, placebo-controlled clinical trial showing that levothyroxine did not improve the symptoms of depression when used in older patients with a mild form of underactive thyroid called subclinical hypothyroidism.[18]