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This is the first issue of a newsletter which will
be quarterly, designed for the endocrine community and those others
interested in thyroid diseases. It is sponsored by Theramed Corporation,
but the views to be contained within each issue will be those of
the authors and the editor only. We would certainly seek input and
articles from those in the endocrine community, although the decision
to publish will be in the hands of the editor only. Some of the
topics to be discussed will undoubtedly be controversial, and we
would invite comments and letters following the publication of these
articles. It is certainly the intent of the editor to select those
topics of current interest and controversy in the hope that this
will engender further interaction and discussion. We certainly await
with great interest the reaction of our reading audience to the
type of newsletter which we expect to produce.
While, therefore, we expect that the pages of the newsletter will
often be filled with topical and somewhat controversial topics,
the thrust of this newsletter will be based on solid, factual, scientific
information and will be on the controversial side. Empirical and
unproven ideas will receive short shrift in these pages. We look
forward to hearing suggestions for improvement or modifications
as we go along.
Robert Volpé, MD, FRCP(C),
MACP
Editor
The Wellesley Hospital, 160 Wellesley Street East,
Room 112D, Jones Building, Toronto, Ontario M4Y 1J3 (416) 926-7777
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Quarterly Issue # 1
APRIL 2000
Is the Addition of Tri-iodothyronine
(T3) to Thyroxine (T4) Therapy of Value in the Management of Hypothyroidism?
In the past, hypothyroidism has been treated with iodine, extracts
of defatted animal thyroids, as well as thyroid hormones, thyroxine
(T4) and tri-iodothyronine (T3), either alone or in combination.
For the past three decades, however, the management of hypothyroidism
has almost universally consisted of the use of T4 alone in doses
of about 1.6 ug/kg for adults and slightly higher doses for children.
Since the majority of our patients respond well to this therapy
and since it is well known that T4 is converted to T3 both peripherally
and centrally by the enzymes, 5’-deiodinase 1 and 5’-deiodinase
2, what would be the rationale of adding T3 to T4 in the treatment
of hypothyroidism?
A firm answer to the above question is not available. Some observations
and recent evidence does support the need to re-examine whether
T4 and T3 would have any value in the management of hypothyroidism.
Under physiological conditions, the thyroid gland secretes not only
T4 (in amounts of 100 to 130 ug/d)(1) but also a small amount of
T3 (2 to 6 ug/d)(1). The T3 secreted directly from the thyroid gland
represents about 20% of daily production of T3. Does the small amount
of T3 directly produced by the thyroid have any relevance physiologically,
compared to the far larger amounts produced by the peripheral conversion
of T4 to T3? Escobar(2,3,4) et al have demonstrated that the only
way to ensure the normal physiological ratio of T3 to T4 in the
brains of thyroidectomized rats is to administer both T3 and T4
simultaneously. In a series of studies, Escobar and colleagues first
demonstrated that none of 10 different concentrations of T4 administered
to thyroidectomized rats could produce euthyroidism in all tissues(3).
The cerebral cortex and the cerebellum were the only tissues that
did not demonstrate a significant elevation in T3 levels despite
very high levels of T4. This supports the notion that the brain
maintains a narrow range of T3 levels. It also suggests that when
T4 is given alone at doses high enough to normalize thyrotrophin
(TSH) levels, brain T3 may be normal but brain T4 may be substantially
higher than in the euthyroid state. More recently, Escobar’s
group (4) treated thyroidectomized rats with either placebo, T4
alone, or T4 plus T3 at different dosage levels in combination.
They noted that normalization of brain T3 occurred at relatively
low dosages of T4 alone, but these doses were not sufficient to
produce euthyroidism in all tissues, whereas the only treatment
that led to normalization of both T3 and T4 in all tissues was a
combination of both T4 plus T3.
Mood disturbance is one of the most common symptoms of hypothyroidism.
Jaeshcke(5) found that 61% of subjects with overt hypothyroidism
reported feeling frustrated and depressed. Cleare(6,7) demonstrated
reduced serotonergic responses in hypothyroid patients. Hence, the
depression associated with hypothyroidism may be a function of reduced
central nervous system serotonergic function. Although T4 predictably
normalizes TSH levels, there are few data regarding the ability
of T4 to normalize the neuropsychiatric symptoms of hypothyroidism.
One small study(8) examined T4-treated hypothyroid patients with
major depression who had failed to respond to antidepressant medication.
All were adequately replaced with T4 and had normal TSH levels.
When 25 ug/d of T3 was administered, 89% demonstrated clinical improvement.
Studies looking at combined use of T4 and T3 in hypothyroidism go
back almost three decades(9,10). Smith et al(10) examined a group
of hypothyroid patients treated with either 200 ug or 300 ug of
T4 per day. The patients were given, in a random order, either their
usual dose of T4 for a 2-month period or a T4 plus T3 combination
in a 4:1 ratio; that is, 160 ug of T4 and 40 ug of T3 or 240 ug
of T4 plus 60 ug of T3. When polled, 20% of subject preferred the
combination, 30% preferred T4 alone, and 50% had no preference.
Not unexpectedly, the combination group had more side effects. Since
sensitive TSH measurements were not available at this time, almost
certainly all groups were over-replaced. Furthermore, the 4:1 ratio
of T4 to T3 was unphysiological. Most recently, Bunevicius and colleagues(11)
looked at 33 patients with hypothyroidism, comparing two treatment
regimes each for a five week period; one treatment arm involved
keeping the subjects on their usual dose of T4 while the second
replaced 50 ug of T4 with 12.5 ug of T3. Although this study has
been criticized for its short duration, variable ratio of T4 to
T3, and combining subject requiring T4 for replacement (hypothyroid
patients) with those requiring T4 for suppression (thyroid cancer
patients), the results were, nevertheless, very interesting. Among
17 scores on tests of cognitive performance and assessments of mood,
6 were better or closer to normal after treatment with T4 and T3.
Furthermore, among 15 visual-analogue scales used to indicate mood
and physical status, 10 were significantly better with T4 and T3.
Also, sex hormone-binding globulin levels were higher in the T4
plus T3 group. TSH levels in the two treatment arms were similar.
Because of the limited scope of Bunevicius’ study, a recommendation
that all hypothyroid patients should be treated with T3 along with
T4 cannot be made at this time. Currently, studies are underway
looking at a truly physiological replacement regimen for hypothyroidism
(T4 administered with T3 in a 15:1 ratio) with expanded end-organ
measurements. Hopefully, such studies will answer the question whether
two hormones are better than one for the treatment of hypothyroidism.
Jay Silverberg, MD, FRCPC, FACP
References:
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Pilo A, Iervasi G, Vitek F, et al: Am J Physiol
1990; 258:E715-E726
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Escobar-Morreale HF, Obregon MJ, Hernandez
A, et al: Endocrinology 1997; 138:2559-2568
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Escobar-Morreale HF, Obregon MJ, Escobar DR,
et al: J Clin Investigation 1995;96:2828-2838
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Escobar-Morreale HF, del Rey FE, Obregon MJ,
et al: Endocrinology 1996;137:2490-2502
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Jaeschke R, Guyatt G, Gerstein H, et al: J
Gen Int Med 1996;11: 744-749
-
Cleare AJ, McGregor A, Chambers SM, et al:
Neuroendocrinology 1996; 64:65-69
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Cleare AJ, McGregor A, Okeane V: Clinical Endocrinology
1995; 43: 713-719
-
Cooke RG, Joffe RT, Levitt AJ: J Clin Psych
1992; 53: 16-18
-
Taylor S, Kapur M, Adie R: BMJ 1970; 2: 270-271
-
Smith RN, Taylor SA. Massey JC: BMJ 1970; 4:
145-148
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Bunevicius R, Kazanavicius G, Zalinkevicius
R, et al:N Engl J Med 1999; 340: 424-429
************
EDITORIAL COMMENT
Dr. Silverberg has certainly set out the details of the controversy
regarding the use of adding T3 to T4 in the treatment of hypothyroidism.
It should be added, however, that in my own experience, the vast
majority of patients do very well with T4 alone, and have normal
serum levels of T3 and TSH to boot. Of course, there remains a minority
of patients who do not feel perfectly well despite normal levels
of serum T3 and TSH, when treated with Thyroxine alone. Whether
the addition of T3 to their regimen will truly add to their state
of well-being is certainly the subject of current studies. It remains
to be established whether the addition of the T3 truly represents
the ingredient that makes the difference, or whether more subtle
changes in the patient’s perceptions might be of importance.
Current studies looking at T4/T3 replacement regimens must always
be carefully controlled to ensure that there is only one variable,
and even the nature of the placebo control must be carefully evaluated.
Moreover, the question must be asked, namely why is it that most
patients given T4 alone have normal well-being, and only a minority
continue to suffer some symptoms?
************
Upcoming Events:
-
CURRENT CONCEPTSIN THE MANAGEMENTOF THYROID
NODULARDISEASE AND CANCER1-2 June 2000Mount Sinai Hospital18th
Floor Auditorium600 University AvenueToronto, OntarioSponsored
by the Depts. OfOtolaryngology, Medicine, Pathologyand Surgery,
and the Inter-departmental Division of Oncology,Faculty of Medicine,University
of TorontoCURRENT CONCEPTSIN THE MANAGEMENTOF THYROID NODULARDISEASE
AND CANCER1-2 June 2000Mount Sinai Hospital18th Floor Auditorium600
University AvenueToronto, OntarioSponsored by the Depts. OfOtolaryngology,
Medicine, Pathologyand Surgery, and the Inter-departmental Division
of Oncology,Faculty of Medicine,University of Toronto
-
ENDO 200021-24 June 2000Metro Toronto Convention
CentreThe Endocrine Society’s82nd Annual MeetingCDA/CSEMJoint
Professional Conference11-14 October 2000Halifax, NS
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Atlantic Endocrine Society11th Annual Meeting2-4
June 2000Corner Brook, NF
-
Association des Médecins Endocrinologues
du Québec18e réunion scientifique annuelle19-20
mai 2000Pointe-au-Pic, QC
If you would like to see an upcoming thyroid event
published in the next issue of Thyroid Canada, please fax the information
to Theramed Corporation at (905) 564-4776 as soon as possible.
Published with a grant from Theramed Corporation.
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