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STUDIES ON DUAL
HORMONE REPLACEMENT
Interpretation of this
information is best left to medical professionals trained to do so, as
there may be factors the layman is unaware of that make any conclusions
we draw from reading these abstracts misleading or erroneous. Please
talk to your doctor if you have any questions.
T
Endocrine Clinic, Royal Infirmary, Edinburgh, UK.
The first treatment
for hypothyroidism introduced at the end of the 19th century was animal
thyroid extract which contained both T3and T4.
Because of variable potency it was widely replaced by synthetic T4
from the 1960s in high doses of 200-400 ug daily to compensate for the
lack of T3. The development of TSH assays showed that a dose
of T4 of 100-150 ug daily was usually adequate to restore
serum TSH to normal. Because a suppressed serum TSH has been shown to be
a risk factor for osteoporosis, atrial fibrillation, and most recently
for excess cardiovascular mortality, there is a consensus that the
correct treatment of hypothyroidism is a dose of thyroxine which
restores euthyroidism and maintains both T4 and TSH in their
respective reference ranges. However, a significant minority of patients
only achieve the desired sense of well-being if serum TSH is suppressed.
Furthermore, patients rendered hypothyroid following treatment of
thyrotoxicosis and taking a dose of T4 which maintains a
normal TSH, gain more weight than those who do not become hypothyroid.
Studies in hypothyroid rats suggest that it is only possible to restore
universal tissue euthyroidism using a combination of T3and T4.
In patients in whom long-term T4 therapy was substituted by
the equivalent combination of T3 and T4 scored
better in a variety of neuropsychological tests. It would appear that
the treatment of hypothyroidism is about to come full circle.
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N Engl J Med 1999 Feb 11;340(6):424-9
Effects of thyroxine as compared with thyroxine plus triiodothyronine
in patients with hypothyroidism.
Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr.
Institute of Endocrinology, Kaunas Medical University, Lithuania.
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
microg of the usual dose of thyroxine was replaced by 12.5 microg 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 (T3) for thyroxine (T4) may improve mood and
neuropsychological function; this finding suggests a specific effect of
the triiodothyronine (T3) normally secreted by the thyroid gland.
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Endocrine 2002 Jul;18(2):129-33
Thyroxine vs thyroxine plus triiodothyronine in treatment of
hypothyroidism after thyroidectomy for Graves' disease.
Bunevicius R, Jakubonien N, Jurkevicius R, Cernicat J, Lasas L,
Prange AJ Jr.
Institute of Endocrinology, Clinic of the Kaunas Medical University,
Lithuania.
It was recently demonstrated that treatment with levorotatory thyroxine
(T4) plus triiodothyronine (T3) compared with treatment with T4 alone
improves psychologic functioning in hypothyroid patients with thyroid
cancer or autoimmune thyroiditis. In the present double-blind crossover
study, we again compared the effects of combined thyroid replacement vs
monotherapy on psychologic function, endocrine function, cardiovascular
function, and body composition. The patients were women who were
hypothyroid after thyroidectomy for Graves' disease. The substitution of
10 microg of T3 for 50 microg of T4 caused a statistically significant
decrease in free T4 concentration but no significant change in T3 or
thyroid-stimulating hormone concentration. Symptoms of hypothyroidism
and of hyperthyroidism tended to decrease on a standard symptom scale
after combined treatment. With combined hormone replacement, mental
state tended to improve on some mood scales but not on cognitive tests.
We found alterations in left ventricular diastolic function but no
change in body composition after the combined treatment regimen. These
preliminary findings in a small group of patients with Graves' disease
are consistent with earlier findings that thyroid replacement with T4-T3
combination improves mental functioning.
Int J Neuropsychopharmacol 2000 Jun;3(2):167-174
J Endocrinol Invest 2002 Feb;25(2):106-9
Mental improvement after replacement therapy with thyroxine plus
triiodothyronine: relationship to cause of hypothyroidism.
Bunevicius R, Prange AJ.
We treated 26 hypothyroid women - 11 with autoimmune thyroiditis and 15
who had been treated for thyroid cancer - with their usual dose of
thyroxine (T4) or with a regimen in which 50 &mgr;g of T4 had been
replaced by 12.5 &mgr;g of triiodothyronine (T3). Patients were first
randomly assigned to one regimen for 5 wk and then to a second regimen
for an additional 5 wk. The substitution of T3 for a portion of T4
caused expected changes in concentrations of thyroid hormones and
thyroid-stimulating hormone (TSH). After combined hormone treatment
there were clear improvements in both cognition and mood, the latter
changes being greater. The patients who had been treated for thyroid
cancer showed more mental improvement than the women with autoimmune
thyroiditis, perhaps because they were more dependent on exogenous
hormone. Some mood improvements correlated positively with changes in
TSH while others correlated negatively with changes in free T4.
Br Med J (Clin Res Ed) 1984 Mar 3;288(6418):693-5
Total and free thyroid hormone concentrations in patients receiving
maintenance replacement treatment with thyroxine.
Pearce CJ, Himsworth RL.
Total and free serum concentrations of thyroxine and triiodothyronine
were measured in 122 subjects with hypothyroidism who were clinically
well while receiving conventional replacement treatment with thyroxine.
In a third of patients concentrations of total and free thyroxine were
raised, often considerably; nevertheless concentrations of total and
free triiodothyronine were usually normal. Though significant
correlations were obtained between total triiodothyronine concentrations
and total thyroxine concentrations (p less than 0.001) and between the
triiodothyronine concentrations and free thyroxine concentrations (p
less than 0.001) the slope of the line of the regression equation
describing these correlations was small, hence large increases in both
total and free thyroxine concentrations were accompanied by only modest
increases in total and free triiodothyronine concentrations. The
presence of total or free thyroxine concentrations above normal in
patients taking thyroxine (T4) therefore are not necessarily of clinical
consequence. In the assessment of adequacy of replacement treatment with
thyroxine (T4) the most logical combination of in vitro thyroid function test
results may be a normal thyrotrophin (TSH) concentration and normal free
triiodothyronine (T3) concentration.
Levothyroxine therapy and serum free thyroxine and free
triiodothyronine concentrations.
Woeber KA.
Department of Medicine, University of California, San Francisco/Mount
Zion, San Francisco 94143-1640, USA. woeber@itsa.ucsf.edu
Although the normal thyroid gland secretes both levothyroxine (L-T4) and
levotriiodothyronine (L-T3), normalization of serum TSH with
L-T4-replacement therapy alone in hypothyroidism is generally believed
to result in a normal serum L-T3 and to reflect a euthyroid state.
However several recent studies suggest that this may not be the case.
Accordingly, the relationship between serum free L-T4 and free L-T3 was
examined in 20 normal individuals (group A) and in 53 patients with
chronic autoimmune thyroiditis, 18 with normal TSH on no
L-T4-replacement (group B), and 35 with normal TSH on L-T4-replacement
therapy for hypothyroidism (group C). Data were analyzed by applying a
one-way analysis of variance with correction for multiple comparisons.
Serum TSH values were very similar among the 3 groups. In groups A and
B, mean serum free T4 and free T3 were very similar. In group C, the
mean free T4 (16+/-2 pmol/l) was significantly higher than the values in
groups A (14+/-1) and B (14+/-2) (p<0.001) and the mean free T3 lower
(4.0+/-0.5 pmol/l vs 4.2+/-0.5, NS and 4.4+/-0.5, p<0.02). Consequently,
the mean molar ratio of free T4 to free T3 was significantly higher in
group C than the ratios in groups A and B (p<0.0001), despite very
similar TSH values. These findings indicate that in hypothyroid patients
L-T4-replacement, that is sufficient to maintain a normal serum TSH, is
accompanied by a serum free T4 that is higher than that in untreated
euthyroid patients or normal individuals and may not result in an
appropriately normal serum free T3 concentration.
Med J Aust
2001 Feb 5;174(3):141-3
What is the optimal treatment for hypothyroidism?
Walsh JP, Stuckey BG.
Department of Endocrinology and Diabetes, Sir Charles Gairdner
Hospital, Perth, WA. john.walsh@health.wa.gov.au
Standard treatment of primary hypothyroidism is with thyroxine, with
the aim of relieving symptoms and bringing the serum TSH
(thyroid-stimulating hormone) concentration to within the reference
range. Recent research suggests that in some patients symptoms of
hypothyroidism persist despite standard thyroxine replacement therapy.
The optimal treatment of these patients is not known. Adjusting the
thyroxine dose until the serum TSH concentration is in the lower part
of the reference range (eg, 0.3-2.0 mU/L) may be beneficial. Animal
studies and a single small clinical trial suggest that a combination
of thyroxine and T3 (triiodothyronine), rather than thyroxine alone,
may be required for optimal thyroid replacement therapy. Further
research is needed to determine why some patients appear to have a
suboptimal response to thyroxine, and whether combined thyroxine/T3
treatment is preferable to thyroxine alone in these patients.
Tidsskr Nor
Laegeforen 2002 Apr 10;122(9):935-7
[Treatment of hypothyroidism]
Haug E.
Hormonlaboratoriet Aker universitetssykehus 0514 Oslo. egil.haug@ioks.uio.no
BACKGROUND: Hypothyroidism is a common disease with a prevalence of
5-6% in women and 1-2% in men. Primary hypothyroidism is the most
common form (> 98%) autoimmune thyroiditis and thyroid destruction
caused by radio-iodine treatment or thyroidectomy are the most common
causes. MATERIALS AND METHODS: On the basis of relevant literature, an
overview of diagnostic criteria and guidelines for treatment is
presented. RESULTS AND INTERPRETATION: An elevated TSH and a low free
thyroxine level are diagnostic for primary hypothyroidism. The
presence of anti-TPO antibodies indicates an autoimmune thyroiditis as
the cause. In patients with non-thyroidal illness, a range of test
abnormalities may be observed, making the interpretation of the test
results difficult. Thyroxine is the preferred treatment of
hypothyroidism. The therapeutic goal is to achieve a TSH level between
0.5-1.5 mIU/l. Most patients will then have thyroxine values in the
upper 1/3 of the reference range, some will have elevated thyroxine
values. If necessary, the thyroxine dose can be increased to give a
TSH level between 0.2 and 1.0 mIU/l. In patients not satisfactorily
treated with thyroxine alone, treatment with thyroxine combined with
triiodothyronine may be tried. A diagnosis made on clinical grounds
must always be verified biochemically before thyroxine treatment is
started. The present literature does not support the treatment of
patients complaining of "symptoms of hypothyroidism" such as
tiredness, lethargy, weight gain and intolerance to cold, provided
that their thyroid function tests are normal.
Metabolism
1984 Mar;33(3):215-8
Is it necessary to adjust the replacement dose of thyroid hormone
to the season in patients with hypothyroidism?
Hamada N, Ohno M, Morii H, Jaeduk N, Yamakawa J, Inaba M, Ikeda S,
Wada M.
Hypothalamo-pituitary-thyroid activity varies with the temperature of
the environment; we therefore measured variables involved with thyroid
function in summer and winter in normal controls and in patients with
primary hypothyroidism. All seven patients had impalpable thyroid
glands and had received a set replacement dose of thyroxine for over a
year. In the patients, serum T3 and FT4 levels were slightly but
significantly lower in winter, and TSH levels and delta TSH at 30
minutes in the TRH tests were significantly higher. In the controls,
there were no significant differences between summer and winter in
these values. These findings suggest that the dose required for
replacement of thyroid hormone in patients with hypothyroidism may be
higher in winter than in summer.
Ann
Pharmacother 2000 Oct;34(10):1142-5
Hypothyroidism and depression: a therapeutic challenge.
Rack SK, Makela EH.
Department of Behavioral Medicine and Psychiatry, School of Medicine,
West Virginia University, Morgantown 26505, USA. srack@hsc.wvu.edu
OBJECTIVE: To describe a patient with longstanding depression and
hypothyroidism who had marked mood improvement only after
triiodothyronine (T3) was added to her thyroxine (T4) replacement
therapy. CASE SUMMARY: A 50-year-old white woman had a long history of
depression and documented hypothyroidism since 1991. Despite treatment
with T4 with dosages up to 0.3 mg/d, she continued to be depressed,
have symptoms of hypothyroidism, and have a persistently elevated
thyroid-stimulating hormone concentration. Addition of a low dose of
T3 to her regimen resulted in significant mood improvement.
DISCUSSION: The relationship between hypothyroidism and depression is
well known. It is possible that this patient's long history of
depression may have been a consequence of inadequately treated
hypothyroidism, due either to poor patient compliance or resistance to
T4. Nevertheless, her depression responded to addition of a low dose
of T3 to her regimen. This case emphasizes the importance of screening
depressed patients for hypothyroidism. Her clinical course also
suggests that depression related to hypothyroidism may be more
responsive to a regimen that includes T3 rather than to replacement
with T4 alone. This is consistent with the observation that T3 is
superior to T4 as adjuvant therapy in the treatment of unipolar
depression. CONCLUSIONS: Depressed patients should be screened for
hypothyroidism. In hypothyroid patients, depression may be more
responsive to a replacement regimen that includes T3 rather than T4
alone. Therefore, inclusion of T3 in the treatment regimen may be
warranted after adequate trial with T4 alone.
Endocrinology 1996 Jun;137(6):2490-502
* The information
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medical or professional advice. It should not be used for diagnosing or
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health problems, you should consult a physician.
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Only the combined treatment with thyroxine and triiodothyronine
ensures euthyroidism in all tissues of the thyroidectomized rat.
Escobar-Morreale HF, del Rey FE, Obregon MJ, de Escobar GM.
Molecular Endocrinology Unit, Consejo Superior de Investigaciones
Cientificas, Universidad Autonoma de Madrid, Spain. hescobar@mvax.fmed.uam.es
We have recently shown that it is not possible to restore euthyroidism
completely in all tissues of thyroidectomized rats infused with T4
alone. The present study was undertaken to determine whether this is
achieved when T3 is added to the continuous sc infusion of T4.
Thyroidectomized rats were infused with placebo or T4 (0.80 and 0.90
microgram/100 g BW.day), alone or in combination with T3 (0.10, 0.15,
or 0.20 microgram/100 g BW.day). Placebo-infused intact rats served as
euthyroid controls. Plasma and 12 tissues were obtained after 12 days
of infusion. Plasma TSH and plasma and tissue T4 and T3 were
determined by RIA. Iodothyronine deiodinase activities were assayed
using cerebral cortex, pituitary, brown adipose tissue, liver, and
lung. Circulating and tissue T4 levels were normal in all the groups
infused with thyroid hormones. On the contrary, T3 in plasma and most
tissues and plasma TSH only reached normal levels when T3 was added to
the T4 infusion. The combination of 0.9 microgram T4 and 0.15
microgram T3/100 g BW.day resulted in normal T4 and T3 concentrations
in plasma and all tissues as well as normal circulating TSH and normal
or near-normal 5'-deiodinase activities. Combined replacement therapy
with T4 and T3 (in proportions similar to those secreted by the normal
rat thyroid) completely restored euthyroidism in thyroidectomized rats
at much lower doses of T4 than those needed to normalize T3 in most
tissues when T4 alone was used. If pertinent to man, these results
might well justify a change in the current therapy for hypothyroidism.
since 2004