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A major criticism of most studies is the lack of physiological combination therapies.

It has been proposed that: “the ideal substitution therapy for hypothyroidism might be a combination of T4 and T3 in a carefully determined ratio and in a form in which T3 is slowly absorbed in a time-release form” (15).

Setting: The study was performed at a university hospital.

Design and Subjects: This was a cross-sectional study in 33 healthy individuals with 24-h blood sampling (TSH in 33 and FT4 and FT3 in 29 individuals) and cosinor analysis.

In rats there is a circadian rhythm in tissue levels of T with an increase in the level at night that relates to an increase in tissue type II 5′-deiodinase activity (10).

This probably relates to the physiology of thyroid hormones, the small sample sizes studied, and the variety of assays used for thyroid hormone measurements. The failure of change in free thyroid hormones in response to the nighttime increase in TSH was found by one group to relate to the secretion of differentially glycosylated TSH with reduced bioactivity at night (9).

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The increase in TSH after metoclopramide was related to changes in both thyroid hormones (TSH: T may improve quality of life for hypothyroid patients (13), there has been considerable debate as to the actual benefits.

Despite a large number of studies, there is no conclusive evidence that combination therapy with T improves efficacy of therapy or health-related quality of life (14).

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