Hypothyroidism is a common endocrine disease that requires timely and lifelong treatment since, if left untreated, it can contribute to hypertension, dyslipidaemia, and heart failure and induce reversible dementia and infertility, as well as neurosensory, musculoskeletal, and gastrointestinal symptoms.

There is currently no other treatment for hypothyroidism, other than providing thyroid hormone replacement. Due to its long half-life of about 7 days, in patients in the clinically euthyroid state, levothyroxine is the preferred first-line treatment for primary hypothyroidism and has been the most commonly prescribed treatment since the 1980s.

Initial Dosing

The levothyroxine dose initially required by a patient depends primarily on three factors: the amount of residual thyroid function retained by the patient, the body weight or lean body mass of the patient, and the target thyrotropin or thyroid-stimulating hormone (TSH) level to be achieved during therapy.

Additional factors such as patient age, patient sex, and menopausal status may have an influence that is generally of lesser magnitude. Other physiological factors such as pregnancy and gastrointestinal functioning may be important factors in specific patients or at specific times.

When commencing levothyroxine therapy, initial dose requirements can vary greatly from small doses such as 25–50 μg in an individual with mild or subclinical disease, where the therapy may be supplementing endogenous function, to larger doses of 88–175 μg in cases of patients with negligible endogenous thyroid function.

In keeping with this concept, the initial dose of levothyroxine in patients presenting to a clinic with primary hypothyroidism can be predicted by the patient’s TSH value prior to initiation of treatment

With respect to age, for patients who are elderly, have concomitant cardiac disease, or may have had long-standing untreated hypothyroidism, it is wise to initiate levothyroxine therapy with smaller doses such as 25–50 μg levothyroxine and incrementally increase the dose to full replacement to avoid precipitating cardiac ischaemia.

Dose Adjustment

Regardless of the method used to estimate the initial levothyroxine dose requirement, dose adjustment is frequently required. This may be due to multiple factors including limitations in the dose requirement predictions, inter-patient variation, levothyroxine absorption, or effects of concomitant medical conditions or medications.

Given the half-life of levothyroxine (approximately 1 week), reassessment of thyroid status by serum TSH levels, and free thyroxine levels if desired, is indicated after 6 weeks of therapy when the pharmacokinetic steady state is reached. If the TSH is not at the desired goal, the levothyroxine dose can be adjusted up or down.

Once the desired TSH value has been achieved, it could potentially be re-confirmed by laboratory testing in 3–6 months, and then checked on an annual basis thereafter. 

Generally, hypothyroidism may be effectively treated via a constant daily dose of levothyroxine, and, for the majority of confirmed aetiologies, this needs to be lifelong. However, in this setting, there appear to be many cases of both levothyroxine over- and under-dosing and it may be that frequent adjustments of a dose are necessary. These adjustments need to be handled with caution and take into account the many contributing factors.

In summary, it is necessary in all cases to periodically verify the need for dose adjustment and/or continuation of treatment. If there is a suspicion for levothyroxine treatment having been prescribed unnecessarily, this can be investigated via a test period incorporating 6- to 8-week therapy discontinuation, followed by TSH testing.

There are many factors encountered by patients across their life span that may be associated with an altered levothyroxine requirement. Newborns, children, and adolescents typically require higher levothyroxine doses than adults.

Examples of factors affecting the levothyroxine dose requirements of adults include pregnancy, weight changes, hormonal changes, and ageing.

Pregnancy

The dramatic increase in levothyroxine dose requirements associated with pregnancy, and the subsequent decrease in requirement post-partum are perhaps the best documented alterations in levothyroxine requirement.

Increased levothyroxine doses are required in approximately 50–85% of pregnant women, and the need for an increase occurs early in the first trimester. Requirements tend to stabilise as the patient progresses into the second and third trimester, with few changes generally being required in the third trimester.

Weight Changes and Hormonal Changes

As mentioned above, levothyroxine dose requirements are affected by body weight, ideal body weight, and lean body mass, with dose requirements increasing as these parameters increase. However, if actual body weight is used to calculate the levothyroxine requirement in obese individuals, the dose may be overestimated, with ideal body weight being a better predictor

With respect to hormonal changes, premenopausal women may require higher levothyroxine doses than postmenopausal women. Conversely, oestrogen therapy is associated with a need for higher doses of levothyroxine to maintain the same serum TSH.

Ageing

Several studies have shown that the levothyroxine dose requirement is decreased in older individuals. However, a recent study suggests that this decreased requirement may be mediated by the changes in weight that may accompany ageing. Other important considerations regarding levothyroxine doses in older individuals include bearing age-adjusted TSH reference ranges in mind and avoiding over-replacement that might potentially exacerbate other medical conditions. 

Medical Conditions

Generally speaking, although other chronic medical conditions such as cardiac disease, hepatic disease, osteoporosis, or diabetes do not directly impact levothyroxine dose requirements, some individuals with these conditions may be elderly or frail and thus extra caution may need to be exercised to avoid under- or over-dosing. One specific medical condition in which levothyroxine doses that lower serum TSH may be intentionally employed is differentiated thyroid cancer.

Patients with hypothyroidism who are hospitalised with critical illness may require higher doses of levothyroxine while hospitalised, possibly because of such factors as use of proton pump inhibitors or decreased absorption associated with enteral feeding. 

A variety of gastrointestinal conditions may be associated with decreased levothyroxine absorption and higher serum TSH levels when the condition is untreated compared with when the condition is treated. These conditions include gastritis, coeliac disease, and lactose intolerance. 

Helicobacter pylori-associated gastritis is associated with increased levothyroxine requirement, with the increased requirement resolving with treatment of the gastritis. Similarly, untreated coeliac disease is associated with a high levothyroxine requirement.

The same pattern has been demonstrated with lactose intolerance. 

Nephrotic syndrome is another medical condition associated with a need for an increased dose of levothyroxine.

Medications, Supplements, and Food

A classic example of a medication that causes an increased requirement for levothyroxine is oestrogen therapy, which is associated with increased levels of thyroxine-binding globulin.

Tyrosine kinase inhibitors can have multiple effects, including causing an increased need for levothyroxine.

Other medications such as may alter a patient’s requirement for levothyroxine

If levothyroxine is ingested along with food, its absorption can be impaired. Soy-containing foods are an example of a substance that can decrease absorption.

Calcium supplements and iron also reduce absorption and thereby increase the levothyroxine dose requirement or increase serum TSH.

Vitamin C stands alone as an example of a supplement that may actually decrease the requirement for levothyroxine by enhancing its absorption, at least in patients with gastritis.