Introduction

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The classic symptoms of hypothyroidism are wide ranging and non-specific, therefore biochemical testing has become the cornerstone of diagnosis in patients for whom there is a clinical suspicion of thyroid dysfunction. However, recent anecdotal evidence has suggested there may be some clinical benefit in giving thyroxine to patients with symptoms of hypothyroidism who have thyroid function tests within the reference range.^1-3 After a series of reports in our local newspaper suggesting that such patients benefited from thyroxine therapy we treated two patients empirically with thyroxine, and they both reported symptomatic relief.⁴

To investigate this further, we conducted a double blind placebo controlled crossover trial of thyroxine in patients who had symptoms of hypothyroidism but whose thyroid function tests were within the reference range. A group of controls, who were similar in age and sex to the patient group, took part in a parallel trial. The same protocol was used for controls and patients to test the clinical belief that thyroxine treatment would have an effect on wellbeing even in participants without symptoms of hypothyroidism. We assessed response to thyroxine by using a battery of biochemical, physical, and psychological tests.

	Methods

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Participants
Patients were required to have had at least three of the following symptoms for six months: tiredness, lethargy, weight gain or inability to lose weight, intolerance to cold, hair loss, or dry skin or hair. We recruited patients either by referral from their general practitioner or hospital clinician, or through an article, published in a local newspaper, which described the trial and asked for volunteers. Controls were healthy volunteers recruited by personal contact with the investigators. All participants were required to have no current medical disorder, no history of thyroid disease, and recent thyroid function tests within the reference range.

Study protocol
The study was a randomised double blind placebo controlled crossover trial. The two treatment periods of twelve weeks each were separated by a washout period of six weeks. Half of the participants were given thyroxine for the first treatment period and placebo for the second treatment period; half were given placebo first and thyroxine second. The first 20 participants received the treatment in 100 µg capsules; thereafter 100 µg tablets were supplied. In each case a visually identical placebo was used. A 14 week supply of tablets, to be taken once a day, was provided for each phase and participants were asked to bring the remaining tablets to their assessment to assess compliance.

Evaluation
Serum thyroid stimulating hormone, free thyroxine, free triiodothyronine, cholesterol, and prolactin were measured at each visit. At baseline, serum ferritin and antithyroid peroxidase antibodies were measured and a thyrotrophin releasing hormone test was performed. Physiological and psychological assessments were performed at baseline and on completion of each phase.

Biochemical measurements
Serum thyroid stimulating hormone, free thyroxine, cholesterol, and prolactin were analysed at the time the blood was collected. All blood samples were stored at -80°C and free triiodothyronine, ferritin, and antithyroid peroxidase antibodies were analysed in single batches to minimise interassay variation. Serum thyroid stimulating hormone, free thyroxine, free triiodothyronine, prolactin, and ferritin were measured by fluorescent microparticle enhanced immunoassay (Abbott Laboratories Ltd, Maidenhead, UK). An increment in thyroid stimulating hormone of >25 mU/l constituted an abnormal result in the thyrotrophin releasing hormone test. Antithyroid peroxidase antibodies were measured by a solid phase chemiluminescent enzyme immunoassay (DPC, Llanberis, UK). Cholesterol was measured on a multichannel discrete analyser (Olympus Diagnostica, Hamburg, Germany) using a cholesterol oxidase method (Randox Laboratories Ltd, Co. Antrim, UK). Interassay coefficients of variation were <15% for thyroid stimulating hormone, <9% for free thyroxine, <8.5% for free triiodothyronine, <6% for prolactin, and <2% for cholesterol.

Physical and psychological evaluation
We recorded supine blood pressure and pulse of participants using a Criticare (CE1023, Waukesha, WI, USA) non-invasive blood pressure monitor after they had rested for five minutes. We measured their weight on SECA scales (Hamburg, Germany).

Statistical methods
Baseline characteristics were summarised by means (SD) or counts and percentages as appropriate. For each variable, participants were grouped into their sequence group (thyroxine-placebo or placebo-thyroxine) to create data summaries in relation to treatment.

	Results

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Baseline measures
All participants had thyroid function results within the reference range, with the exception of one patient who had a concentration of thyroid stimulating hormone of 5.8 mU/l (see table A on BMJ 's website). Concentrations of the hormone in this patient, however, normalised to 4.5 mU/l when taking placebo. Other biochemical tests for the same patient were within the reference range. Three participantsthe patient described above, one control, and one patient who failed to complete the studyhad exaggerated responses to thyrotrophin releasing hormone and raised concentrations of antithyroid peroxidase antibodies (range 262-1656 U/ml). One patient and one control had raised concentrations of antithyroid peroxidase antibodies (211 U/ml and 76 U/ml, respectively) but normal thyrotrophin releasing hormone responses.

Response to thyroxine or placebo

Biochemical measures
In both groups the serum concentrations of thyroid stimulating hormone decreased and free thyroxine increased in response to thyroxine, confirming compliance with treatment. Although free triiodothyronine concentration increased in both groups when participants were taking thyroxine, the difference between the response to placebo and the response to thyroxine was only significant in the healthy group (tables 1 and 2 ). This finding was replicated by non-parametric analysis of the data. The response to thyroxine in patients with positive autoantibodies or abnormal thyrotrophin releasing hormone responses did not differ from that in other participants; numbers were too small for detailed analysis. No other significant biochemical changes were observed.

Physical health and psychological measures
We compared the differences in the scores at baseline and after placebo in participants taking placebo first. The patients showed a significant symptomatic improvement in the general health, role physical, and hospital anxiety and depression scale scores after placebo, compared with healthy participants (mean (95% confidence interval) 8 (2 to 15) v 8 (14 to 3), 25 (4 to 46) v 9 (32 to 13), and 7 (11 to 3) v 1 (2 to 0), respectively; table 3 ). We observed no changes in measures of cognitive function. There was no placebo effect with regard to psychological or cognitive function scores for the controls (table 3).

Clinical measures
No significant changes occurred in patients with respect to blood pressure, pulse rate, or weight during the study.

	Discussion

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This is the first randomised double blind placebo controlled trial of thyroxine treatment in patients who have symptoms of hypothyroidism but are biochemically euthyroid.

Biochemical results
Compliance was confirmed in both groups by the rise in free thyroxine and fall in thyroid stimulating hormone while participants were taking thyroxine. The lack of significant increase in free triiodothyronine in patients taking thyroxine might reflect impairment of the peripheral conversion of thyroxine to triiodothyronine. Although this finding requires further investigation, anecdotal evidence suggests that patients could benefit from thyroxine treatment alone.⁹

Comparison of thyroxine and placebo treatments
Psychological testing showed that patients differed from the controls at baseline. Cognitively, they scored worse on immediate and delayed verbal recall and had slower motor movements. They also perceived themselves to have poorer general health, more fatigue, increased problems with routine tasks and activities related to work, and higher levels of anxiety and depression. These findings may be consistent with a depressive illness, although no formal assessment was performed.

Numbers in the study
The small number of participants in this preliminary study means that, although there was no significant difference between placebo and thyroxine in 13 of the 14 well validated psychological tests, the power of the study may not have been sufficient to eliminate definitively a possible biological effect of thyroxine. If this was the case we would have expected to see a trend in favour of thyroxine over placebo in the test results, especially as a recent open intervention study of thyroxine (mean dose 125 µg daily) reported self assessed improvements in energy and poor memory in 80% of 139 participants.⁹ Our study showed no discernible trend (table 1).

Conclusion
We can find no support for the hypothesis that people with symptoms of hypothyroidism but thyroid function tests within the reference range benefit from treatment with 100 µg thyroxine daily. However, our results require confirmation in a larger study. The improvement noted anecdotally and in open studies may be due to the placebo effect shown in our study.

	Acknowledgments

We are grateful to the staff of the clinical biochemistry department at Stobhill Hospital for performing the biochemical analyses and to the staff of the pharmacy department for performing the randomisation and preparing the capsules. We thank Goldshield Pharmaceuticals for supplying the placebo tablets.

Contributors: MAP conceived the study and coordinated the laboratory component. MAP, EHMcL, CJGK and KMD designed the study. KMD and KM chose the cognitive function tests and questionnaires, and KM tested all participants. AS coordinated all contact with the study participants and undertook the clinical assessment of the participants at each visit. ADMcM performed the statistical analysis and provided further statistical advice. All authors were involved in writing the paper, with MAP providing coordination. EHMcL is guarantor for the study.

	Footnotes

Funding: MAP received a scientific development scholarship from the Association of Clinical Biochemists.

Competing interests: None declared.

Details of baseline measurements and scores are available on the BMJ's website

	References

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(Accepted 8 May 2001)