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The Journal of Clinical Endocrinology & Metabolism 88(10):4540 – 4542
Copyright © 2003 by The Endocrine Society
doi: 10.1210/jc.2003-031436
Editorial: In Search of the Impossible Dream? Thyroid
Hormone Replacement Therapy That Treats All
Symptoms in All Hypothyroid Patients
We tell our patients, “It’s really quite simple, your thyroid
is not working (or has been removed or destroyed by our
treatment). The tablet contains the natural hormone that your
body cannot make. Don’t worry, you’ll be fine.” For many of
our patients, T4 therapy resolves their symptoms and they
are fine. For some, however, this therapy remains unsatisfactory, with the persistence of specific symptoms or a failure
to regain a normal sense of well-being.
It is unclear how many patients fail to achieve satisfactory
results, because dissatisfied patients are more likely to be
referred or to seek advice from other physicians. A survey
conducted in Bristol, United Kingdom, attempted to determine the degree of dissatisfaction with T4 therapy (1).
Records obtained from general practitioners’ offices were
used to create a roster of patients taking T4 and an equal
number of controls. Two survey instruments, a well-established one related to feelings of general well-being and a
second one containing questions related to the symptoms
associated with hypothyroidism, were administered. Patients on T4 scored worse on both surveys. For the thyroidspecific survey, 48.6% of the 397 responding patients with a
recent normal TSH and 35.0% of the 551 responding controls
had scores indicating dissatisfaction with their health status.
In other words, an excess of about 13 in every 100 patients
had symptoms that might, in some way, be related to their
T4 therapy.
Why is this? One proposed explanation with support from
both clinical and basic research, is that the thyroid produces
both T4 and T3, whereas we use T4 alone for treatment. In a
study performed in Kaunas, Lithuania, 33 hypothyroid patients felt better and performed better, according to their
scores on standardized tests, when 12.5 ␮g of T3 was given
to replace 50 ␮g of their usual T4 dose (2). Lending credence
to this clinical observation are studies in rats that show that
in thyroidectomized rats, normal tissue levels of T4 and T3
cannot be achieved by an infusion of T4 alone, but require an
infusion of T4 and T3 (3, 4). Only the combined treatment with
T4 and T3 ensures euthyroidism of the thyroidectomized rat,
although cerebral cortical T3 tissue concentrations are normal
over a wide range of T4 doses and a wide range of serum T4
concentrations.
With a problem as important as this and an explanation as
straightforward as this, why was the initial T3-substitution
study met with so much reserve? As discussed below, the
study had a number of limitations. However, another reason
may be that we have the preconceived conviction that there
are other explanations and do not feel the need for additional
ones. First, many hypothyroid patients receive or, because of
variable compliance, take insufficient or excessive doses of T4
(5). Second, many hypothyroid patients are relatively young,
and T4 may be the only medication that they take. Thus, it is
understandable that they might ascribe a variety of symptoms to their medication. Third, it is generally thought that
some patients feel better when they are slightly hyperthyroid
(6). It is often difficult to reduce the dose of T4 in patients who
have been overreplaced for a prolonged period of time, because they develop low energy and other symptoms. Finally,
because symptoms such as fatigue, constipation, and difficulty losing weight are common in the general population,
it would be expected that they would occur in some hypothyroid patients even after appropriate thyroid hormone
replacement.
In this issue of JCEM, Walsh et al. (7) report on their
attempt to replicate the Kaunas study in a group of patients
from Western Australia using a similar design, a blinded,
crossover study with randomization of the order of the treatments, and Sawka et al. (8) report a comparison of T4 plus T3
vs. T4 alone, using a different study design, a randomized
double-blinded trial with two patient groups in Hamilton,
Ontario. Both studies used a variety of standardized instruments to measure psychological status, including quality of
life, thyroid symptoms, and cognitive function. In contrast to
the findings from Kaunas, the results of a series of primary
and subgroup analyses indicate that T3 substitution is no
better, and in some comparisons, worse, than T4 alone.
What are the strengths and weaknesses of the three studies
and what factors could explain the different results? Because
the Kaunas investigation can be looked upon as a pilot study,
it may be understandable that power calculations were not
performed at the outset. We must assume, however, that the
study size was predetermined and not extended during the
study until positive observations were made. Because many
measurements were made, another concern is that no mention is made of correcting the statistical tests for multiple
endpoints. However, many of the endpoints were statistically significant in the positive direction, making it unlikely
that the findings arose by chance.
Several cogent concerns have been raised about the Kaunas study. The patients were heterogeneous. One of the participants in the study was overtly hypothyroid, and three had
marked depression (9). About half were taking T4 for hypothyroidism arising from thyroid cancer treatment, and about
half of these had fully suppressed TSH levels. In a post hoc
analysis (9), 11 patients with autoimmune thyroiditis had less
mental improvement than 15 thyroid cancer patients. The
average baseline dose of T4, 175 ␮g/d, was high. Because the
amount of T3 was fixed at 12.5 ␮g/d, the T3/T4 ratio varied
according to the baseline dose of T4. T3 was given once a day,
resulting in a large diurnal variation. T3 levels were measured near the peak of the administered dose. There was no
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Kaplan et al. • Editorial
washout period between the two doses, and the duration of
treatment was short (5 wk).
The Western Australia study, an attempt to replicate the
Kaunas findings but using 10 ␮g instead of 12.5 ␮g of T3 for
50 ␮g of T4, avoids many of these problems. First, it is larger
than the one from Kaunas, 101 vs. 33 patients. It is notable that
the number of subjects was determined by power calculations for the principal outcome analyses. Without this preplanning, negative findings, such as those observed in this
case, would not be as convincing. However, the reported
power calculations were made at the outset of the study,
based on certain assumptions about the variance of the measurements. Ideally, when a study is completed, these assumptions should be checked with the actual observations,
and power should be calculated again. The patients in this
study were more homogeneous, but not completely so, and
the treatments were given for 10 wk, compared with 5 wk in
the Kaunas study. The study avoided the problem of including patients being treated for thyroid cancer with supraphysiological T4 doses, but it included about equal numbers
of patients assessed to be satisfied and not satisfied with their
T4 therapy. This distinction was made by one observer, not
by the patients, by criteria that are not presented. Also, the
inclusion of such a high fraction of patients who were classified as not satisfied suggests that the recruitment methods
encouraged such patients to participate. The authors also
included measurements of thyroid hormone action in peripheral tissues. Of most concern to the integrity of the findings is that the average TSH level was higher after T3 substitution. The authors, realizing that these factors could affect
the findings, either before (satisfaction classification) or after
(TSH levels) the study, performed subgroup analyses that
confirm and strengthen their conclusion. However, when
subgroup analyses are performed, it is almost certain that the
power will be reduced. Decreased statistical power may not
occur if the variance of the observations decreases, but it is
best to calculate and report this in quantitative terms.
The Ontario study had a relatively homogeneous population of T4-treated subjects with noniatrogenic primary hypothyroidism, but specifically selected patients with depressive symptoms not severe enough to meet criteria for major
depression. In the T4 ⫹ T3 group, a T3 dose of 12.5 ␮g twice
a day was substituted for half of the prestudy T4 dose, and
the T3 dose was adjusted in an unspecified manner to maintain normal TSH levels by an investigator who had no contact
with the patients or those performing the psychological tests.
The study duration was 15 wk. No significant differences
between the groups were found in any of the subscales of test
instruments used to access mood, depression, and general
health status.
Although the Ontario study had only a few more subjects
than the Kaunas study, the Ontario selection criteria presumably increased the likelihood of detecting psychological
benefit from combining T3 with T4. However, no power analysis was performed, several subjects in both groups did not
complete the study, and there was a substantial placebo
effect, with significant improvement in symptoms in both
groups during the study. Also, between-patient variability
would make a therapeutic difference harder to detect than a
study in which patients can be their own controls.
J Clin Endocrinol Metab, October 2003, 88(10):4540 – 4542 4541
In view of the results of the Western Australia study, the
Ontario study, and the post hoc analysis of the Kaunas study,
evidence is fading that adding T3 to T4 is beneficial in the
long-term treatment of hypothyroid patients with autoimmune thyroiditis. In addition, the possible long-term risks of
elevated or fluctuating T3 levels have not been evaluated. We
do not believe that the current evidence supports the use of
T3 for these patients, who are probably the largest group of
hypothyroid patients. The Kaunas study raises the question
of whether patients who have had near-total thyroid ablation
might respond differently, but the findings of this short-term
pilot study of a small group of patients, analyzed post hoc, are
also insufficient to justify adopting a new long-term treatment regimen.
More needs to be done to understand why some patients
do not feel completely well on what, according to current
standards, is adequate thyroid hormone replacement. First,
careful cross-sectional and/or case-control epidemiological
studies are needed to develop a standardized definition of
cases, determine their prevalence, and generate testable hypotheses. Second, efforts should continue to identify molecular measurements that indicate, directly or as surrogate
markers, whether tissue levels of thyroid hormone are
normal.
Third, additional clinical studies with the following characteristics are needed: 1) The study population should be
homogeneous. Although this may prevent generalizing the
findings, the current uncertainties necessitate starting in this
way. 2) The sample size should be large enough to assure that
either positive or negative findings can be accepted with
confidence. The principal psychological, physiological, and
molecular endpoints should be selected with care, and the
analysis should take into account the effects of multiple testing. 3) If practical, a random order, double-blind crossover
design should be used. 4) In studies to test T3, sustained
release preparations, if available, or divided doses should be
used. Consideration needs to be given to the implications of
a fixed vs. variable T4/T3 ratio in combination therapy, both
in regard to study design and therapeutic effect. 5) TSH
should be monitored dynamically and study medications
adjusted according to the results, to maintain normal serum
TSH concentrations.
Michael M. Kaplan, David H. Sarne, and Arthur B.
Schneider
Associated Endocrinologists and Departments of
Medicine and Nuclear Medicine, William Beaumont
Hospital (M.M.K), Royal Oak, Michigan 48073; and
University of Illinois at Chicago, Section of
Endocrinology and Metabolism (D.H.S, A.B.S.),
Chicago, Illinois 60612
Acknowledgments
Received August 14, 2003. Accepted August 14, 2003.
Address all correspondence and requests for reprints to: Michael M.
Kaplan, M.D., Associated Endocrinologists, 6900 Orchard Lake Road,
Suite 203, West Bloomfield, Michigan 48322. E-mail: mmkallegro@
comcast.net.
This work was supported in part by National Cancer Institute Grant
CA-21518 (to A.B.S.).
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J Clin Endocrinol Metab, October 2003, 88(10):4540 – 4542
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