Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial

Abstract

Objectives To determine whether thyroxine treatment is effective in patients with symptoms of hypothyroidism but with thyroid function tests within the reference range, and to investigate the effect of thyroxine treatment on psychological and physical wellbeing in healthy participants. Design Randomised double blind placebo controlled crossover trial. Setting Outpatient clinic in a general hospital. Participants 25 patients with symptoms of hypothyroidism who had thyroid function tests within the reference range, and 19 controls. Methods Participants were given thyroxine 100 g or placebo to take once a day for 12 weeks. Washout period was six weeks. They were then given the other to take once a day for 12 weeks. All participants were assessed physiologically and psychologically at baseline and on completion of each phase. Main outcome measures Thyroid function tests, measures of cognitive function and of psychological and physical wellbeing. Results 22 patients and 19 healthy controls completed the study. At baseline, patients' scores on 9 out of 15 psychological measures were impaired when compared with controls. Patients showed a significantly greater response to placebo than controls in 3 out of 15 psychological measures. Healthy participants had significantly lower scores for vitality when taking thyroxine compared to placebo (mean (SD) 60 (17) v 73 (16), P < 0.01). However, patients' scores from psychological tests when taking thyroxine were no different from those when taking placebo except for a poorer performance on one visual reproduction test when taking thyroxine. Serum concentrations of free thyroxine increased and those of thyroid stimulating hormone decreased in patients and controls while they were taking thyroxine, confirming compliance with treatment. Although serum concentrations of free triiodothyronine increased in patients and controls taking thyroxine, the difference between the response to placebo and to thyroxine was significant only in the controls. ConclusionsThyroxine was no more effective than placebo in improving cognitive function and psychological wellbeing in patients with symptoms of hypothyroidism but thyroid function tests within the reference range. Thyroxine did not improve cognitive function and psychological wellbeing in healthy participants.

Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects

“…Walsh et al varied LT4 doses in a blinded fashion in LT4 treated subjects to achieve low-normal or high-normal TSH levels and did not find any effects on hypothyroid symptoms, quality of life, or cognitive function, although executive function was only tested with the Trail-Making Test (28). Pollock et al administered LT4 or placebo in a blinded fashion to euthyroid (non-LT4 treated) subjects who had hypothyroid-type symptoms, as well as asymptomatic controls, and found no improvement in psychological measures in either group, although cognitive tests were not done (50).…”

Are neuropsychological changes relevant in subclinical hypothyroidism?

“…Those authors found small alterations associated with age, with no relation between the complaints and the cognitive alterations. On the other hand, Pollock et al (14) reported cognitive deficits in 9 out of 15 measurements performed. Those differences may be related to the samples used in different studies.…”

“…In two studies, the control group comprised patients with thyroid disease (12,16). Two others (11,14) used healthy controls, and another (13) used the parameters of the Italian population. We used a homogeneous control group from the same hospital environment, meeting the same inclusion criteria, which had neither thyroid disease nor antithyroid antibodies.…”

Appropriateness of prescribing thyroxine in primary care

“…4 However, in a random double blind controlled trial in patients with symptoms of hypothyroidism but without documented hypothyroidism, thyroxine had no greater effect than placebo. 7 NICE clinical knowledge summary cites those symptoms with greatest discriminatory ability between people with hypothyroidism and those who are euthyroid as constipation, hoarse or deep voice, feeling cold, puffy eyes and weak muscles. 4 In our patient group there was documented improvement in symptoms after prescription of thyroxine in 24%.…”