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Clinical Studies |
Endocrine Research Unit, Division of Endocrinology, Mayo Foundation and Clinic (S.K.G.G.), Rochester, Minnesota 55905; and the Departments of Chemical Pathology (R.R.C.), Endocrinology (J.N.F., D.P.C., C.M.F.) and Cardiology (N.A.L.), Wellington Hospital, and the Departments of Pathology (H.C.F.) and Public Health (G.L.P.), Wellington School of Medicine, Wellington, New Zealand
Address all correspondence and requests for reprints to: Dr. Stefan Grebe, Dept. of Pathology, Wellington School of Medicine, Wellington, New Zealand. E-mail: grebs{at}wnmeds.ac.nz
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Abstract |
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Compared with daily administration, the mean serum TSH before the administration of weekly T4 was higher (weekly, 6.61; daily, 3.92 µIU/mL; P < 0.0001), and the mean FT4 (weekly, 0.98; daily, 1.35 ng/dL; P < 0.01) and FT3 (weekly, 208; daily, 242 pg/dL; P < 0.01) were lower. A minimally elevated serum total cholesterol during weekly administration (weekly, 246.8; daily, 232.6 mg/dL; P < 0.03) was the only evidence of hypothyroidism at the tissue level.
Compared with daily administration, the mean peak FT4 following weekly administration of T4 was significantly higher (weekly, 2.71; daily, 1.59 ng/dL; P < 0.0001), as was the mean peak FT3 level (weekly, 285; daily, 246 pg/dL; P < 0.01). None of the tissue markers of thyroid hormone effect changed compared to daily T4, and there was no evidence of treatment toxicity, including cardiac toxicity.
During weekly T4 administration, autoregulatory mechanisms maintain near-euthyroidism. For complete biochemical euthyroidism a slightly larger dose than 7 times the normal daily dose may be required.
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Introduction |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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During the 1960s through early 1980s, studies demonstrated that single doses of T4 up to 3 mg are well tolerated (9, 10, 11, 12, 13). However, peripheral thyroid hormone measurements were largely limited to total serum T4 and T3 (11, 12, 13), although one study included radioactive iodide uptake, protein-bound iodine, T3-resin uptake, and free T4 (FT4) in some patients (9). Sensitive TSH assays were not available, but two studies measured TRH-stimulated TSH responses (12, 13). No study measured free T3 (FT3). Although all studies commented to some degree on patient symptomatology, and one study measured total serum cholesterol (9), none assessed patient symptoms and thyroid hormone effects at the tissue level in a systematic or comprehensive fashion.
We, therefore, believed that the neither efficacy or safety of once weekly T4 therapy was established and decided to determine this using current thyroid function tests and measurements of the tissue effects of thyroid hormone. The aim of the study was to determine whether 7 times the daily dose of T4 administered once weekly was as safe and efficacious as the usual daily dose for maintenance therapy in hypothyroid subjects.
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Experimental Subjects |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Statistical power analysis
We used a randomized cross-over design for our study, thus achieving at least 4 times the statistical power of a comparably sized group comparative trial. We estimated that we needed 12 or more patients to achieve 80% power at the 0.05 significance level for detecting differences between daily and weekly treatment of 10–60% in the mean values of the tests performed. In addition, we ensured that the sample size was sufficient to detect a 10% difference in mean corrected systolic time intervals between the two treatments.
Patients
Fourteen patients were initially enrolled, and 12 subjects completed the study; 1 subject did not commence the study, and another patient developed chest pain of uncertain origin while receiving her normal daily T4 therapy and was withdrawn before entry into the weekly treatment phase.
Two subjects were male, and 10 were female. The mean age of the study
subjects was 50.8 (SD = 14.5) yr. All subjects suffered
from confirmed primary hypothyroidism, as evidenced by a clearly
elevated serum TSH at the time of diagnosis (
20 µIU/mL) and at
least 1 unsuccessful trial of T4 withdrawal
thereafter. At the time of enrollment all had been receiving
T4 replacement therapy at a stable dose for the
least 3 months.
The mean daily T4 dose was 1.6 µg (SD = 0.35 µg)/kg BW. At the time of their original diagnoses, all patients had received standard instructions regarding T4 administration, including taking T4 separate from other medications and food.
The causes of hypothyroidism were autoimmune thyroiditis in five patients, radioiodine ablation in three patients, subtotal thyroidectomy in two patients, and undetermined in two patients. No patient suffered from severe medical illness, pituitary disease, untreated metabolic bone disease or osteoporosis, liver disease, cardiac disease, or known abnormalities of thyroid hormone metabolism and thyroid hormone protein binding or was taking medications known to interfere with thyroid function or thyroid hormone measurement.
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Materials and Methods |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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At trial entry, subjects were randomly assigned either to
continue with their usual daily maintenance dose of
T4 or to take 7 times the usual daily dose once
weekly, beginning on day 1 of the trial. Figure 1
summarizes the trial design. Three patients receiving other medications
in addition to T4 continued to take these in the
usual manner and dose during the duration of the trial, and all
patients were instructed not to change their normal daily habits
(including diet and exercise) during the trial period.
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On the days of testing patients attended the Department of Endocrinology, Wellington Hospital, between 0800–0900 h fasting. On arrival they underwent baseline testing (0 h), which comprised a standardized questionnaire concerning thyroid-related symptoms during the previous week, self-assessment of well-being during the previous week using a visual analog scale, echocardiographic measurement of systolic time intervals, blood sampling for serum thyroid function tests, and measurement of a variety of serum analytes used as tissue markers of thyroid hormone effects. Depending on the treatment period, the subjects then took either their daily or weekly dose of T4. Further blood samples were taken after 1, 2, 4, 8, and 24 h. Patients were permitted to eat after the 4-h testing. At 8 h, the echocardiogram was repeated. Patients receiving weekly treatment underwent an additional echocardiogram at 24 h (the 24 h echocardiogram was omitted in patients receiving daily treatment, because it was assumed to be equivalent to the baseline). The questionnaire and self-rated scale of well-being were readministered to all subjects at 24 h. All testing at 24 h was performed after an overnight fast and, for the patients receiving daily treatment, before T4 was taken.
Details of the testing procedures are summarized in Fig. 1
. The details
of the symptom questionnaire are given in Table 1. For
self-assessment of well-being, a previously validated visual analog
scale was used (14). On this scale patients rated their well-being over
the preceding week or 24 h on a 100-mm line, with the left end
corresponding to "worst ever" (0 mm) and the right end to "best
ever" (100 mm).
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Serum assays
Thyroid function tests consisted of serum FT4, FT3, TSH (all measured on the Corning ACS-180+ automated immunoanalyzer, Scianz Corp., Auckland, New Zealand), rT3 (measured by RIA, Biodata, Milan, Italy), and serum T4-binding globulin [TBG; using an immunoradiometric assay (IRMA), Corning Medical, Midland, MI]. The functional sensitivity of the TSH assay is 0.03 µIU/mL.
As general indicators of thyroid hormone effects at the tissue level, the following, previously validated, parameters (15, 16, 17) were used: sex hormone-binding globulin (by IRMA, Orion Diagnostics, Finland); total cholesterol, high density lipoprotein (HDL), and triglycerides (Hitachi 717 multianalyzer, Boehringer Mannheim, Auckland, New Zealand); and apolipoprotein a (APOa; immunoturbidimetric method, Hitachi 717). Low density lipoprotein (LDL) was calculated from HDL cholesterol and triglyceride concentrations.
To monitor the effects of thyroid hormone on the liver (17, 18, 19, 20, 21),
aspartate aminotransferase, alanine aminotransferase, and
-glutamyltransferase were measured with a Hitachi 717
multianalyzer.
Serum osteocalcin and alkaline phosphatase were used as markers of the influence of thyroid hormones on bone turnover (22, 23, 24) and were measured with an IRMA (Nichols Institute, San Juan Capistrano, CA) and a Hitachi 717 multianalyzer, respectively.
Echocardiography
The cardiac effects of thyroid hormone were estimated by systolic time intervals (STI) measurements, a sensitive marker of these effects (15, 25, 26, 27, 28, 29, 30). A two-dimensional echocardiogram was performed first, to exclude cardiac conditions known to interfere with STI measurements. The STI were obtained after the two-dimensional study and 15 min of rest by the method described by Tseng et al. (26), using a dual M-mode system (HP 77020AC Rev F, Hewlett-Packard, Palo Alto, CA) with a chart speed of 100 mm/s. Data were corrected for heart rate and gender (31), and a total of 10 cycles were analyzed to minimize variation due to respiration.
Data analysis
Data for TSH, FT4, and rT3 followed a log-normal distribution and were log transformed before analysis. Other noncategorical data did not need to be transformed before analysis. Statistical analysis of all data, except for the results of the symptom questionnaire, was performed using multivariate regression and ANOVA for repeated measures (32), with terms for treatment type (weekly vs. daily), treatment sequence (weekly or daily treatment first), and interactions. The Greenhouse-Geisser adjustment to degrees of freedom was used to account for the repeated measures on individuals (33). In addition, the untransformed TSH, FT4, and rT3 data were analyzed using nonparametric equivalents of the parametric statistical tests (Friedman test). The results of the symptom questionnaire were analyzed using McNemar’s test, comparing daily with weekly treatment (32). For all statistical tests, P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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All patients tolerated weekly T4 treatment
well. There were no significant differences at either 0 or 24 h
between daily and weekly treatments in the results of the questionnaire
and self-rated visual analog scale (Table 1).
Thyroid function tests
Serum thyroid hormone levels differed between weekly and daily
treatment at several time points (Fig. 2). At 0 h,
the mean values for FT3 (daily, 242; weekly, 208
pg/dL; P < 0.01), rT3 (daily,
26.75; weekly, 22 ng/dL; P < 0.01), and
FT4 (daily, 1.35; weekly, 0.98 ng/dL;
P < 0.001) were significantly lower for the group
receiving weekly therapy. For this group, FT4 was
significantly higher at all other time points (all P <
0.005), peaking at 2 h with both daily and weekly
T4 (daily, 1.6; weekly, 2.7 ng/dL).
FT3 was significantly higher with weekly than
with daily T4 at 4 h (daily, 240; weekly,
265 pg/dL; P < 0.04) and 24 h (daily, 246;
weekly, 285 pg/dL; P < 0.01).
rT3 was significantly lower with weekly compared
to daily T4 at 2 h (daily, 30.42; weekly,
26.82 ng/day; P < 0.05) and higher at 24 h
(daily, 27.8; weekly, 33.16 ng/dL; P < 0.01).
FT3 and rT3 peaked later
than FT4. This delay was more pronounced with
weekly T4. Serum TSH levels with weekly therapy
were significantly higher than those with daily treatment at all time
points (all P < 0.04), except 24 h
(P = NS). The largest difference occurred at 0 h,
with a mean serum TSH value of 3.92 µIU/mL with daily
T4 vs. 6.61 µIU/mL with weekly
T4. Serum TSH levels with weekly
T4 fell rapidly in the first hour after
T4 administration and then gradually declined to
levels similar to those with daily treatment.
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Markers of tissue effect
There were no significant differences at any time point between
daily and weekly treatment in the levels of serum sex hormone-binding
globulin, -glutamyltransferase, aspartate aminotransferase, alanine
aminotransferase, osteocalcin, alkaline phoshatase (all in Table 2), HDL, and LDL (data not shown), but total serum
cholesterol differed significantly at 0 h (P <
0.03), with the mean being 14.2 mg/dL higher during weekly therapy
(Table 2). No difference was found for serum total cholesterol
measurements at other times. APOa was subject to a sequence effect.
Consequently, as with serum TBG measurements, only the first treatment
cycle was used for analysis. No differences between groups were found
in serum APOa measurements.
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Discussion |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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At the peripheral tissue level, the effect of weekly T4 treatment did not differ from that of customary daily treatment despite differences in serum thyroid hormone levels. The only tissue marker of thyroid hormone effect to suggest hypothyroidism was total serum cholesterol at 0 h. This may have been due to statistical fluctuation. Furthermore, the observed rise was small and seemed to be caused by a rise in both HDL and LDL. It is generally believed that increased serum HDL levels may partially compensate for elevations in LDL (34). Hence, any potential adverse effect of the small rise in total serum cholesterol may have been mitigated.
One of the mechanisms maintaining near euthyroidism at the tissue level might be a change in the conversion rate of T4 to T3 (5, 6). Whereas serum FT4 levels almost tripled after the ingestion of weekly T4, FT3 rose by about 25%, and rT3 rose by about 50%, suggesting preferential conversion of T4 to the metabolically inactive rT3. By contrast, at the end of the dosing interval, FT4 levels during weekly treatment were almost 30% lower than those during daily treatment, whereas FT3 levels were 15% lower, and rT3 levels were 18% lower. This indicates that at the end of weekly treatment, conversion of T4 to T3 increased, and conversion to rT3 decreased.
It could be argued that the tests of peripheral thyroid hormone effect employed were too insensitive and the number of subjects studied too small to detect subtle changes in the thyroid state. However, even in subclinical thyroid states most of the tests used are discriminatory (15, 16, 17, 20, 23, 24, 25, 26, 35). STI are shortened in patients with subclinical hyperthyroidism (25, 26) and lengthened in subclinical hypothyroidism (15, 26). All the changes observed are around 20% and within the range of the power of our study. The response of STI to changes in serum thyroid hormone levels is rapid, showing significant differences in less than 2 weeks after the onset of hypothyroidism (28, 29).
However, continuous 24-h electrocardiogram monitoring, which generally parallels echocardiographic measurements of cardiac status (36), was not performed, and therefore, we cannot exclude the possibility of asymptomatic cardiac arrhythmia as a result of weekly T4 treatment. In addition, the absence of data on thyroid function tests and tissue markers during days 2–6 after weekly treatment in our study could underestimate the toxicity of weekly treatment. According to some studies, peak conversion of T4 to T3 may not occur until 2–4 days after the ingestion of large T4 doses (37, 38), although the rise after 24 h is slight if free T3 is measured (37). However, other studies have suggested that T4 doses between 2.4–300 mg will lead to a T3 peak before 24 h (11, 39). Our data suggest that FT3 levels plateau at around 4 h (and are in the lower third of the reference range), but we did not observe a fall in mean FT3 at 24 h. Consequently, we cannot completely dismiss the possibility of toxicity between days 2–6 after weekly treatment. However, in a pilot project involving two subjects (not included in this study) sampled at 0, 1, 2, 4, 8, 24, and 72 h, FT3 values at 72 h were between peak (24 h) and nadir (0 h) values.
As we do not have firm safety data for the period between 2 and 6 days after T4 administration or any direct assessment of potentially harmful arrhythmias, we would be hesitant to use weekly T4 treatment in individuals with ischemic heart disease who may be sensitive to T4 (18). We also do not know whether weekly T4 may be suitable to suppress TSH secretion, although our data suggest that the T4 dose will have to be increased significantly above 7 times the normal daily dose to ensure suppression over a week. An increase in the weekly dose above 7 times the patient’s usual daily dose might be possible without undue risk, but further study is needed on its effects on the skeletal system (22, 23, 24) and heart (36). Finally, in some patients weekly treatment could also be hazardous if several doses are missed. Clinicians and patient must work out a schedule that minimizes such risks before switching to weekly T4 therapy.
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Acknowledgments |
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Footnotes |
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2 Supported by an Overseas Postdoctoral Fellowship grant from the
Health Research Council of New Zealand.
Received June 17, 1996.
Revised October 14, 1996.
Accepted November 27, 1996.
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References |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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-Glutamyl transpeptidase levels in
thyroid disease. Arch Intern Med. 142:79–81.This article has been cited by other articles:
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  B. Vaidya and S. H S Pearce Management of hypothyroidism in adults BMJ, July 28, 2008; 337(jul28_1): a801 - a801. [Full Text]
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 S Rangan, A A Tahrani, A F Macleod, and P K Moulik Once weekly thyroxine treatment as a strategy to treat non-compliance Postgrad. Med. J., October 1, 2007; 83(984): e3 - e3. [Abstract] [Full Text] [PDF]
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