Effect of L-Thyroxine Administration Before Breakfast vs at Bedtime on Hypothyroidism

A Meta-Analysis

Xiao Pang; Tao Pu; Li Xu; Ru Sun


Clin Endocrinol. 2020;92(5):475-481. 

In This Article

Abstract and Introduction


Purpose: To compare the effects of L-thyroxine (L-T4) administration before breakfast and administration at bedtime on hypothyroidism.

Methods: The PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched to identify relevant articles. All prospective or randomized controlled studies (RCTs) comparing L-T4 administration before breakfast to the administration at bedtime in patients with hypothyroidism were included in the analysis.

Results: Initially, 2884 articles were retrieved from the databases, and 10 articles were included in the quantitative analysis. The effect of L-T4 administration before breakfast compared with administration at bedtime had no statistically significant association with hormone thyrotropin (TSH) (Standardized mean differences [SMD] = 0.09, 95% confidence intervals (CI): −0.12, 0.30; P = .39), or free triiodothyronine (FT3) (SMD=−0.19, 95% CI: −0.53, 0.15; P = .28) in patients with hypothyroidism. However, the result of FT4 level was favourable for L-T4 bedtime administration group (SMD=−0.27, 95% CI: −0.52, −0.02; P = .03).

Conclusion: Our meta-analysis revealed that L-T4 administration at bedtime is as effective as administration before breakfast for patients with hypothyroidism. Taking L-T4 at bedtime may be an attractive option for patients with hypothyroidism.


Hypothyroidism is resulting from a deficiency of thyroid hormones, which is common condition with potentially devastating health consequences that affect all populations worldwide.[1] Thyroid hormones are essential for growth, neuronal development, reproduction and the regulation of energy metabolism. The prevalence of hypothyroidism varies considerably across the general population, ranging between 0.2% and 5.3% in Europe,[2] 0.3% and 3.7% in the USA,[3] 11% in India4 and 17.8% in China (overt hypothyroidism: 1.1%; subclinical hypothyroidism: 16.7%).[5] Longitudinal studies from large UK cohorts report an incidence rate of spontaneous hypothyroidism of 3.5–5.0 per 1000 and 0.6–1.0 per 1000 in women and men, respectively.[6]

The clinical presentation of hypothyroidism is nonspecific and variable. Therefore, the diagnosis of hypothyroidism is based primarily on biochemical abnormalities. The pituitary hormone thyrotropin (TSH) has a complex inverse relationship with the thyroid hormones thyroxine (T4) and triiodothyronine (T3).[7] Accordingly, overt hypothyroidism is defined as serum TSH concentrations above the reference range with low free T4 (FT4) levels, while subclinical hypothyroidism is diagnosed when TSH levels are high and circulating FT4 is normal. The relationship between TSH and thyroid hormones is influenced by a number of factors, including age, smoking and thyroid peroxidase antibody status.[8]

L-thyroxine (L-T4) has been considered the standard of care for the treatment of hypothyroidism for many years. This treatment is efficacious when administered orally, has a long serum half-life that permits daily administration, and results in resolution of the signs and symptoms of hypothyroidism in the majority of patients.[9]

L-thyroxine is absorbed in the jejunum and ileum, and it is enhanced by a lower gastric pH.[10] However, there are many conditions that can interfere with L-T4 absorption, such as dietary fibre and coffee. Additionally, many drugs, such as cholestyramine, colesevelam, lanthanum, calcium carbonate, calcium citrate, calcium acetate, iron sulphate, ciprofloxacin, aluminum hydroxide, sevelamer or proton pump inhibitors (PPIs), have also been shown to interfere with L-T4 absorption.[11] Malabsorption is also reported in disorders such as atrophic gastritis, helicobacter pylori infection, inflammatory bowel disease, coeliac disease and lactose intolerance.[12]

The timing of L-T4 administration has become a hot topic in recent years. The Chinese Society of Endocrinology (CSE) recommends that L-T4 should be consistently taken 60 minutes before breakfast.[13] However, the American Thyroid Association (ATA) recommends that, if possible, L-T4 be consistently taken either 60 minutes before breakfast or at bedtime (3 or more hours after the evening meal), for optimal, consistent absorption.[9] Recently, some studies have been conducted in which the efficacy of L-T4 administration before breakfast and at bedtime were compared.[14–23] Some studies reported that the efficiency of L-T4 at bedtime was better than administration before breakfast. However, other studies showed no significant difference with bedtime vs morning intake.

To further evaluate the efficacy of L-T4 administration before breakfast and at bedtime, we performed this meta-analysis to compare the effect of two different administration timings of L-T4 for patients with hypothyroidism.