Brought to you by Mary Shomon Your Thyroid Guide
Letter from Sidney Wolfe, MD, of Public Citizen to Mary Shomon
For background, read:
Note from Mary: The following is text of a letter dated September 4, 2003 that was sent to me by Public Citizen as a Microsoft Word attachment to an email, received by me on September 5, 2003. See my point-by-point response to this letter at
Mary Shomon's Letter to Public Citizen/Sidney Wolfe, MD -- September 5, 2003
Mary: This is only a partial response to your letter. Betty Blount, the volunteer nurse who answers some
of Public Citizen's consumer mail has not been in town and we need to talk with her about the concerns
you raised about statements in her letter to you. When we have, we will get back to you
again.
Sincerely,
Sidney M. Wolfe, MD
Director, Public Citizen's Health Research Group
DATE: September 4, 2003
RE: RESPONSE TO MARY SHOMON
1. The major issue is the consistency of response to treatment that patients and physicians have a right
to expect when thyroid replacement therapy is prescribed. There have been some problems with the
manufacturing of final finished l-thyroxine dosage forms in the past, for example, changing excipients
without prior notification of the FDA by manufacturers that led to recalls.
As of June 2001, two levothyroxine products had been approved: UNITHROID, manufactured by Jerome
Stevens Pharmaceuticals, on August 21, 2000, and LEVOXYL, manufactured by Jones Pharma. There
are now other products with approved New Drug Applications.
2. Shoman [sic] finds fault with the American Thyroid Association' support of l-thyroxine products
neglecting the independence of the Medical Letter and the early editions of the AMA Drug Evaluations.
Shomon offers only anecdote in response "... ask the hundreds of thousands of patients who switched
from synthetic thyroxine to Armour Thyroid ... " She says as much that her evidence in
anecdotal.
We are well aware of the "Synthroid Affair" and have written about it extensively in Worst Pills, Best
Pills News.
3. Shoman [sic] asks how we know about thyroid hormone and weight loss doctors. There is an
extensive history of the inappropriate use of thyroid hormones alone and in combination with other drugs
from Congressional hearings that are publically [sic] available. This is why there is a box warning on
all thyroid products.
4. Shoman [sic] makes the following statement :"The fact that the vast majority of those overweight
patients diagnosed with hypothyroidism will leave their doctor's office with a prescription for
levothyroxine - not Armour Thyroid -- seems to have eluded "Worst Pills."
If the hypothyroidism is correctly diagnosed this would be appropriate therapy and it did not elude us and
we are glad Shomon appears to agree.
5. Shoman [sic] cites the February 2000 issue of the Archives of Internal Medicine and a cross-sectional
study of participants in a statewide health fair in Colorado from 1995 She makes this statement about the
study:
"The study found that among patients taking thyroid medication (the vast majority taking levothyroxine),
only 60% were within the normal range of TSH. The fact that forty percent of patients, a number that
translates to millions of Americans, are taking thyroid hormone - the overwhelming majority taking
levothyroxine -- and are still not in TSH range indicates that either vast numbers of doctors do not know
how to properly prescribe levothyroxine, or it may not be as effective as its manufacturers and supporters
claim."
This last implication is hardly supportable from the results of a cross-sectional survey.
6. Shoman [sic] mentions a New England Journal Medicine study or studies but gives no citation and makes this statement:
And you and your colleagues should also review several back issues of the New England Journal of
Medicine, which reported on studies that found that the majority of thyroid patients do not feel well on
levothyroxine (which contains only a synthetic version of one thyroid hormone, T4). Rather, these
patients felt better and had fewer symptoms with the addition of a second hormone, T3. While the New
England Journal articles may be a surprise to "Worst Pills, Best Pills," they are no surprise to the
practitioners and patients who use Armour Thyroid (which contains both T4 and T3).
I believe the citation for this study if N Engl J Med 1999;340:424-9. (attached at the end of this
email)
The study involved 33 patients with chronic autoimmune thyroiditis or thyroid cancer treated by near total
thyroidectomy. The patients did not receive natural thyroid supplementation they received synthetic
thyroxine (levothyroxine) plus T-3. Shamon [sic] appears to be advocating synthetic thyroid hormones
produced by Berlin Chemie, Berlin, Germany
The second study is an editorial in the same issue of the N Engl J Med, Volume 340:468-470. The
author of the editorial concludes:
"Finally, it should not be forgotten that the majority of patients taking a dose of thyroxine that satisfies
the recommendations of the American Thyroid Association have no complaints about their medication."
Effects of Thyroxine as Compared with Thyroxine plus Triiodothyronine in Patients with
Hypothyroidism
Robertas Buneviius, M.D., Ph.D., Gintautas Kaanaviius, M.D., Ph.D., Rimas alinkeviius, M.D., and
Arthur J. Prange, M.D.
ABSTRACT
Background Patients with hypothyroidism are usually treated with thyroxine (levothyroxine) only,
although both thyroxine and triiodothyronine are secreted by the normal thyroid gland. Whether thyroid
secretion of triiodothyronine is physiologically important is unknown.
Methods We compared the effects of thyroxine alone with those of thyroxine plus triiodothyronine
(liothyronine) in 33 patients with hypothyroidism. Each patient was studied for two five-week periods.
During one period, the patient received his or her usual dose of thyroxine. During the other, the patient
received a regimen in which 50 µg of the usual dose of thyroxine was replaced by 12.5 µg of
triiodothyronine. The order in which each patient received the two treatments was randomized.
Biochemical, physiologic, and psychological tests were performed at the end of each treatment period.
Results The patients had lower serum free and total thyroxine concentrations and higher serum total
triiodothyronine concentrations after treatment with thyroxine plus triiodothyronine than after thyroxine
alone, whereas the serum thyrotropin concentrations were similar after both treatments. Among 17 scores
on tests of cognitive performance and assessments of mood, 6 were better or closer to normal after
treatment with thyroxine plus triiodothyronine. Similarly, among 15 visual-analogue scales used to
indicate mood and physical status, the results for 10 were significantly better after treatment with
thyroxine plus triiodothyronine. The pulse rate and serum sex hormone-binding globulin concentrations
were slightly higher after treatment with thyroxine plus triiodothyronine, but blood pressure, serum lipid
concentrations, and the results of neurophysiologic tests were similar after the two treatments.
Conclusions In patients with hypothyroidism, partial substitution of triiodothyronine for thyroxine may
improve mood and neuropsychological function; this finding suggests a specific effect of the
triiodothyronine normally secreted by the thyroid gland.
--------------------------------------------------------------------------------
There are two thyroid hormones, thyroxine and triiodothyronine. The daily production of thyroxine is
about 100 µg, all produced by the thyroid gland. The daily production of triiodothyronine is about 30
µg, of which about 20 percent is produced by the thyroid gland and 80 percent by deiodination of
thyroxine in extrathyroidal tissues.1 Not all tissues that need thyroid hormone are equally able to convert
thyroxine to triiodothyronine, the active form of the hormone.2 Nevertheless, most patients with
hypothyroidism are treated only with thyroxine (levothyroxine). Although this treatment is effective, some
patients with hypothyroidism treated with thyroxine are not entirely well.3 This observation, plus the
existence of differences in the rate of conversion of thyroxine to triiodothyronine in different tissues,2
prompted us to compare the effects of thyroxine alone with those of thyroxine plus triiodothyronine
(liothyronine) on thyroid hormone actions in the brain, pituitary gland, and other organs in patients with
hypothyroidism.
Methods
Patients
We invited patients with chronic autoimmune thyroiditis or thyroid cancer treated by near-total
thyroidectomy who received care at the Institute of Endocrinology of Kaunas Medical University in
Kaunas, Lithuania, to participate in the study if they were totally, or nearly totally, dependent on
exogenous thyroxine. The patients with chronic autoimmune thyroiditis were receiving replacement
therapy with thyroxine, and the patients with cancer were receiving thyroxine as suppressive therapy.
Patients with other serious medical illnesses were excluded.
Thirty-five patients were enrolled, and 33 completed the study: 31 women and 2 men, with a mean
(±SD) age of 46±13 years (Table 1). Sixteen patients had chronic autoimmune thyroiditis, and 17 had
thyroid cancer. The mean dose of thyroxine at base line was 175±53 µg per day; the range was from
100 µg per day (five patients) to 300 µg per day (two patients). The mean duration of treatment was
73±72 months. In all patients the dosage had been stable for at least three months. The mean score on
the Hamilton Rating Scale for Depression (the 21-item "long" version) was 9.8±5.4, on a scale from
0 (indicating no depression) to 69 (the maximal theoretical score).4 Four women had major depression,
as defined and diagnosed by standard instruments.5,6 One patient withdrew from the study because she
became pregnant, and another because of anxiety. The study was approved by the institutional review
board of Kaunas Medical University, and all patients gave written informed consent.
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Table 1. Base-Line Characteristics of the Study Patients.
Study Protocol
Patients took their usual dose of thyroxine through the first day of the study. On this day each patient was
assigned, according to a prearranged randomization schedule, either to receive thyroxine alone for five
weeks, then thyroxine plus triiodothyronine for five weeks, or to receive thyroxine plus triiodothyronine
for five weeks, then thyroxine alone for five weeks. The thyroxine (Berlin-Chemie, Berlin, Germany)
was given as 50-µg tablets at each patient's usual total dose, but 50 µg of the dose of thyroxine was
replaced by a capsule. These capsules contained either 50 µg of thyroxine or 12.5 µg of
triiodothyronine (Berlin-Chemie), depending on the assigned treatment. They were prepared by a
pharmacist and were identical in appearance. If, for example, a patient had been treated with 200 µg of
thyroxine per day, he or she was instructed to take 150 µg of the usual thyroxine tablets plus one capsule
each morning. If the patient had been assigned to receive thyroxine alone, the capsule contained 50 µg
of thyroxine; if the patient had been assigned to receive thyroxine plus triiodothyronine, the capsule
contained 12.5 µg of triiodothyronine. Patients took the medications once daily, half an hour before
breakfast.
At the end of each five-week period, the patients were given another batch of tablets and capsules. Only
the pharmacist knew which capsules had been dispensed. At the end of each treatment phase, all patients,
when asked, said that they had taken their medications as instructed, but remaining pills were not
counted.
Evaluations
The patients were systematically studied on the last day of each five-week treatment period. They reported
to the clinic at about 9 a.m., having omitted breakfast but having taken their thyroid hormone about two
hours earlier. Venous blood was taken for measurements of serum thyrotropin, thyroid hormones,
cholesterol, triglycerides, and sex hormone-binding globulin.7 Physiologic tests were performed.
Assessments were made of cognitive function and psychological state. Each patient had the same examiner
for whatever variable was being measured at each session, and the examiners were unaware of the
patients' treatment assignments.
Biochemical Measurements
Serum samples were frozen, allowing the samples from all the patients to be analyzed at the same time
for each variable. Serum thyrotropin was measured by immunoradiometric assay with kits obtained from
Orion Diagnostica (Espoo, Finland), with a sensitivity of 0.05 µU per milliliter. Serum free and total
thyroxine and triiodothyronine were measured with radioimmunoassay kits (Orion Diagnostica). Serum
total cholesterol and triglycerides were measured by enzymatic colorimetric methods (Sera-Pak
Cholesterol Fast Color kit and Sera-Pak Triglycerides Fast Color kit, Bayer, Tarrytown, N.Y.). Serum
sex hormone-binding globulin was measured with immunoenzymometric assay kits (Medix Biochemica,
Kauniainen, Finland). The intraassay variation ranged from 3 to 6 percent.
Physiologic Measurements
Cardiovascular System
The pulse rate was recorded after the patient had been supine for five minutes. Blood pressure was
measured in the sitting position. Electrocardiography was performed at both sessions, and all the results
were normal.
Peripheral Nervous System
The sensory threshold (minimal detectable intensity of vibration) was measured with a biothesiometer
(Model PVD, Biomedical, Newbury, Ohio) applied to the tip of the fourth finger and the tip of the fourth
toe.8 The Achilles tendon reflex was measured with an electroneuromyograph (Type LT1, Medicor,
Budapest, Hungary).9
Psychological Assessment
Psychological assessment was performed according to the Diagnostic and Statistical Manual of Mental
Disorders, third edition, revised (DSM-III-R).5 Symptoms were recorded according to the Structured
Clinical Interview of the DSM-III-R for assessment of nonpsychotic disorders (Lithuanian edition).6
Cognitive functioning was assessed by three standard tests: the Digit Symbol Test,10 the Digit Span Test
of the Wechsler Adult Intelligence Scale,10 and the Visual Scanning Test.11 In the Digit Symbol Test,
a key is provided that pairs each of the numbers 1 through 9 with a nonsense symbol. Below are rows
of pairs of squares, the upper of which contains a number, the lower of which is blank. With the key
available, the subject is allowed 90 seconds to complete each pair of squares by entering the appropriate
symbol. The raw score is the number of correct entries completed in 90 seconds or until completion of
the third row, whichever occurs first. This score measures psychomotor performance. With the key
unavailable, the subject is then asked to recall which symbol matched each number. The number of pairs
correctly recalled is a measure of incidental learning. Then the subject copies 70 symbols. The less time
is required for completion, the greater the subject's psychomotor speed.
The first part of the Digit Span Test requires the subject to repeat spoken numbers with increasing
numbers of digits; it measures immediate auditory attention. The second part, which requires the subject
to repeat the numbers in reverse order, measures mental flexibility.
The Visual Scanning Test assesses distractibility and visual inattentiveness. The subject is shown a
"target" symbol and then presented with a paper with a matrix of symbols containing 60 targets. The
patient circles all the target symbols that he or she can find. The time needed to complete the test,
omissions, and errors are scored.
The Hamilton Rating Scale for Depression (21-item "long" version)4 was used to assess the severity of
depressive symptoms. Clinically important depression is associated with scores of 20 or more.
Three scales were completed by the patients: the Beck Depression Inventory,12 the Spielberger State-Trait
Anxiety Inventory,13 and the Profile of Mood States.14 The Beck Depression Inventory is a self-rating
scale of 21 items, in which scores of 10 or less indicate normal mood variation and scores of 11 or more
reflect increasing degrees of depression. The Spielberger State-Trait Anxiety Inventory is a self-rating
scale consisting of 20 items; scores below 50 are normal. The Profile of Mood States assesses affective
states. The subject rates 65 items, each pertaining to an aspect of subjective state, on a scale from 0 to
4. When the scores for combinations of items are added, values for six aspects of mood and a global
score are obtained.
Fifteen visual-analogue scales provided more detailed ratings of mood and physical symptoms by the
patients. Each scale consisted of a pair of phrases, such as "as sad as possible" and "as happy as
possible," at either end of a 100-mm line. The patient placed a mark at the point best corresponding to
his or her state at that time. Measurement of the marks from the beginning of the line generated a score.
At the completion of the study, each patient was asked which treatment (the first or the second) he or she
preferred.
Statistical Analysis
Paired t-tests were used to compare paired data from the two treatment periods. Nonpaired t-tests were
used to compare values in subgroups of patients - for example, depressed and nondepressed patients.
Results pertaining to the patients' treatment preferences were evaluated with use of McNemar's test.
Probability values were based on two-sided analyses of test results.
Results
The patients' biochemical and physiologic values after each treatment period are shown in Table 2. As
expected, the mean serum free and total thyroxine concentrations were lower and the mean serum total
triiodothyronine concentration was higher after treatment with thyroxine plus triiodothyronine than after
treatment with thyroxine alone. The mean serum thyrotropin concentrations were similar after the two
treatments. The mean serum cholesterol and triglyceride concentrations also were similar after the two
treatments, whereas the mean serum sex hormone-binding globulin concentration was significantly higher
after treatment with thyroxine plus triiodothyronine, suggesting that thyroid hormone action was greater
after treatment with thyroxine plus triiodothyronine. The mean pulse rate at rest was slightly higher after
treatment with thyroxine plus triiodothyronine, but mean blood-pressure values and neurophysiologic
findings were similar after the two treatments.
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Table 2. Biochemical and Physiologic Values at the End of Each Treatment Period.
cores pertaining to cognitive functioning and mood were within normal limits, except that patients
were marginally less able to recall digit-symbol pairs correctly on the Digit Symbol Test after treatment
with thyroxine alone (Table 3). Among the 17 comparisons, 6 pairs showed an advantage (P<0.05) for
treatment with thyroxine plus triiodothyronine and none for treatment with thyroxine alone.
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Table 3. Psychometric Findings at the End of Each Treatment Period.
Performance after thyroxine-plus-triiodothyronine treatment was significantly better (P<0.05)
on parts of two of the three tests of cognitive performance (Table 3). The higher scores for recall of pairs
on the Digit Symbol Test indicated better incidental learning, and the higher scores for recalling digits
in reverse order on the Digit Span Test indicated improved mental flexibility and attention.
The three self-rating mood scales pertained to depression, anxiety, or both. After
thyroxine-plus-triiodothyronine treatment, the patients tended to be less depressed (shown by lower scores
on the Beck Depression Inventory), and their global scores and scores on the three subscales
(fatigue-inertia, depression-dejection, and anger-hostility) of the Profile of Mood States were significantly
lower (P<0.05), indicating improvement, than scores after treatment with thyroxine alone (Table 3).
Eight visual-analogue scales pertained to mood and seven to physical symptoms (Table 4). Patients scored
their mood as significantly better after thyroxine-plus-triiodothyronine treatment on seven of the eight
mood scales (P<0.04) and scored their physical symptoms as significantly improved on three of seven
scales (P<0.02). Patients reported only slight physical problems at both evaluations. Their mean
visual-analogue scores were closer to "no symptoms" than to "severe symptoms" - that is, less than 50,
the middle of each test line.
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Table 4. Results on Visual-Analogue Scales at the End of Each Treatment Period.
When asked at the end of the study whether they preferred the first or second treatment, 20
patients preferred thyroxine plus triiodothyronine, 11 had no preference, and 2 preferred thyroxine alone
(P= 0.001). The order of treatment was unrelated to preference. The two patients who preferred
thyroxine had noticed that they felt slightly "nervous" during combined treatment. The 20 patients who
preferred thyroxine plus triiodothyronine had noticed that they were more energetic, had better
concentration, and simply felt better. One woman became anxious during treatment with thyroxine plus
triiodothyronine and was withdrawn from the study.
The order of treatment did not affect the results. To determine whether triiodothyronine was more
beneficial in patients receiving either high ratios of triiodothyronine to thyroxine (i.e., those who received
lower doses of thyroxine at base line) or low ratios, we compared the results from the 20 patients who
were taking 100 to 150 µg of thyroxine at base line with those from the 13 patients who were taking 200
to 300 µg. The results were similar in the two groups. There was also no difference between the
responses of the 4 patients with depression and those of the 29 patients without depression. Finally, the
advantage of thyroxine plus triiodothyronine was not limited to only a few patients. Analysis of the
psychological variables for which combined therapy was most beneficial (Table 3 and Table 4) showed
that most patients derived at least some benefit from the addition of triiodothyronine (data not shown).
Discussion
Patients with hypothyroidism benefited when 12.5 µg of triiodothyronine was substituted for 50 µg of
thyroxine in their treatment regimens. They performed better on standard neuropsychological tasks, and
their psychological state improved. The differences in most physiologic variables were slight, but in any
case, these are insensitive indicators of thyroid hormone actions. Pulse rates and serum sex
hormone-binding globulin concentrations were higher after treatment with thyroxine plus triiodothyronine,
indicating a slightly greater effect on the heart and liver.7 Serum thyroxine concentrations were lower
and triiodothyronine concentrations were higher after treatment with thyroxine plus triiodothyronine, but
serum thyrotropin concentrations, a sensitive measure of thyroid hormone action, were similar after the
two treatments. The apparent difference in physiologic responses could reflect differences in tissue uptake
of the hormones, in the conversion of thyroxine to triiodothyronine, or in thyroid hormone
receptors.15,16
The variables related to mental function for which the substitution of triiodothyronine resulted in benefit
require fuller description. On tests of cognitive performance and self-rating scales for mood, patients
scored in the normal range on 16 of 17 measures after both treatments (Table 3), but on 6 of the tests
or scales they performed or felt significantly better after receiving thyroxine plus triiodothyronine. These
results were reinforced by results on the visual-analogue scales. No test result was better after treatment
with thyroxine alone. It seems clear that treatment with thyroxine plus triiodothyronine improved the
quality of life for most patients. We think that five weeks was probably long enough for the maximal
effect of the treatments to be detected, but we cannot be sure.
Despite these results, it is clear that the substitution of triiodothyronine for a portion of regular thyroxine
therapy is not sufficient treatment for depression, because the 4 depressed patients benefited from
triiodothyronine substitution no more than the other 29 patients. Nevertheless, in depressed patients who
have normal thyroid hormone concentrations, the addition of triiodothyronine to standard
antidepressant-drug treatment can be beneficial.17
This study extends two others in which different regimens of thyroxine and triiodothyronine were
compared. In one study, in which the doses were much higher than those used in this study, the patients
preferred thyroxine alone, because it was somewhat less toxic.18 In the other, an open trial involving
nine depressed patients who were receiving thyroxine-replacement therapy but were responding poorly
to an antidepressant drug, the addition of triiodothyronine (15 to 50 µg daily) to thyroxine (rather than
the substitution of triiodothyronine) resulted in a marked decrease in depression in seven patients.19
There are at least two ways in which the use of thyroxine alone for replacement therapy might deprive
the brain of triiodothyronine. First, delivery of triiodothyronine through the circulation, the source of
about 20 percent of the triiodothyronine in the rat brain,20 is deficient to the extent that thyroid glandular
secretion is deficient unless compensated for by production in peripheral tissues. Second, circulating
thyroxine, and presumably thyroxine in the brain, will be increased, and in the brain thyroxine
down-regulates its own conversion to triiodothyronine.21 However, the two hormones are differently
bound to plasma proteins and may be differently delivered to the brain.22
The daily production of triiodothyronine by the human thyroid gland is about 6 µg23; the rate of
absorption of ingested triiodothyronine is almost 100 percent.24 Thus, the dose of triiodothyronine given
in the present study somewhat exceeded the normal glandular production. The ideal replacement regimen
when thyroid-gland function is absent or nearly absent might consist of 10 µg of triiodothyronine daily
in sustained-release form (because the hormone is rapidly absorbed and metabolized), along with enough
thyroxine to ensure euthyroidism.
We conclude that in patients with hypothyroidism, partial substitution of triiodothyronine for thyroxine
may have more salutary effects on the brain and perhaps other tissues than those of an equivalent amount
of thyroxine, as determined by their effects on thyrotropin secretion. This finding suggests that thyroidal
secretion of triiodothyronine is physiologically important.
We are indebted to Susan Silva, Ph.D., for her advice regarding the choice of psychometric tests and
statistical methods, to Mr. Robert Ekstrom for statistical assistance, and to Berlin-Chemie (Berlin,
Germany) for the supplies of thyroxine and triiodothyronine.
Source Information
From the Institute of Endocrinology, Kaunas Medical University, Kaunas, Lithuania (R.B., G.K., R.Z.);
and the Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill
(A.J.P.).
Address reprint requests to Dr. Prange at the Department of Psychiatry, School of Medicine, University
of North Carolina at Chapel Hill, Campus Box 7160, Room 254, Wing D - Medical School, Chapel Hill,
NC 27599-7160.
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