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Article 1
ECED/699/7.3.2007/Macmillan
Twenty-four Hour Hormone Profiles of TSH, Free T3
and Free T4 in Hypothyroid Patients on Combined T3/
T4 Therapy
Authors
P. Saravanan1, H. Siddique2, D. J. Simmons1, R. Greenwood3, C. M. Dayan1
Affiliations
1
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol
Department of Endocrinology, Bristol Royal Infirmary, Bristol, UK
3
Research and Development Support Unit, Bristol Royal Infirmary, Bristol, UK
2
Key words
䉴 24-hour profile
䊉
䉴 thyroxine
䊉
䉴 triiodothyronine
䊉
䉴 diurnal variation
䊉
䉴 hypothyroidism
䊉
received
䊏. 䊏. 䊏
first decision 䊏. 䊏. 䊏
accepted
䊏. 䊏. 䊏
Bibiliography
DOI 10.1055/s-2007-973071
Exp Clin Endocrinol Diabetes
2007; 00: 1–7
© J. A. Barth Verlag in
Georg Thieme Verlag KG ·
Stuttgart · New York ·
ISSN 0947-7349
Correspondence
C. M. Dayan
Henry Wellcome Laboratories
for Integrative Neuroscience
and Endocrinology · Dorothy
Hodgkin Building · University of
Bristol · Whitson St · Bristol BS1
3NY · UK
Tel.: + 44/117/92 82 271
Fax: + 44/117/92 84 081
[email protected]
Abstract
&
The benefits of using thyroxine (T4) plus triiodothyronine (T3) in combination in thyroid
hormone replacement are unproven but many
individuals continue to be treated with this
regime. When T3 is used alone for hypothyroidism, it results in wide fluctuations of thyroid hormone levels. However, only limited data
exists on combined T3/T4 therapy. In this study,
we have compared 24-hour profiles of thyroid
stimulating hormone (TSH), free T4 (fT4) and
free T3 (fT3) and cardiovascular parameters in
10 hypothyroid patients who had been on once
daily combined T3/T4 therapy for more than 3
months with 10 patients on T4 alone. Twenty
patients, who were part of a larger study, investigating the long-term benefits of combined T3/T4
therapy, were recruited into this sub-study. Over
Introduction
&
Even after 100 years of discovery, thyroid hormone replacement still remains controversial
(Cooper, 2003; Wartofsky, 2004). Development
of sensitive TSH assays in the 1980s, resulted in
dose reductions for many individuals as clinicians titrated the thyroxine dose to achieve TSH
in the “reference range”. Since this time, an
increasing number of patients express dissatisfaction with their thyroid hormone replacement
despite apparently physiological levels of replacement (Saravanan et al., 2002; Walsh, 2002). In
1999, a widely publicised study by Bunevicius et
al (Bunevicius et al., 1999) renewed interest in
combination replacement with Thyroxine (T4)
and Triiodothyronine (T3). Seven other studies
on combined T3/T4 therapy have been published
since 1999. Five showed no benefit (Clyde et al.,
Financial support: Southwest National Health Service Research and Development, UK.
24-hours, 12 samples were taken for thyroid
hormones. Their 24-hour pulse and BP is also
monitored on a separate occasion. On T4 alone, a
modest 16 % rise in fT4 with no change in fT3 was
seen in the first 4-hours post-dose. In contrast,
on combined treatment, fT3 levels showed a
marked rise of 42 % within the first 4-hours postdose (T3/T4:T4 = 6.24: 4.63 mU/L, p < 0.001). Mean
exposure to fT3 calculated by area under the
curve (AUC) was higher (T3/T4:T4 = 1148:1062,
p < 0.0001) on T3. Circadian rhythm of TSH was
maintained on both treatments. No difference in
pulse or blood pressure over the 24-hours was
seen between the groups. Our data suggests that
despite chronic combined T3/T4 therapy, wide
peak-to-trough variation in fT3 levels persists.
Although no immediate cardiovascular effects
were seen, the long-term consequences for
patients on combined therapy are unknown.
2003; Escobar-Morreale et al., 2005; Sawka et al.,
2003; Siegmund et al., 2004; Walsh et al., 2003),
one showed patient preference for combined
T3/T4 replacement (Appelhof et al., 2005) and
our own study suggested only a limited, possible
short-term benefit (Saravanan et al., 2005). However, combined T3/T4 therapy is still widely used
(Blanchard, 2004; Woliner, 2003).
Careful pharmacokinetic studies performed
nearly 30 years ago showed that T3 if used as
monotherapy for hypothyroidism, should be
given at least three times a day to have a smooth
24-Hour profile of T3 (Saberi and Utiger, 1974).
They also showed that thyroid hormone levels
were stable over the 24-hour period on once
daily T4 monotherapy. However, there is only
one published report on the fluctuations in T3
levels on combined T3/T4 therapy (Hennemann
et al., 2004). In this report, Hennemann et al.
showed a peak in T3 levels 2–4 hours after dosing
in subjects treated for 6 weeks but observations
Saravanan P et al. Thyroid Hormone Profiles on Combined T3/T4 … Exp Clin Endocrinol Diabetes 2007; 00: 1–7
2 Article
were not continued for the full 24-hour period and the duration
of increased T3 exposure over this period was not fully defined.
In addition, chronic exposure to high T3 levels over longer periods of time may alter deiodinase expression (Bianco et al., 2002;
Saravanan et al., 2005). If wide diurnal fluctuations in T3 levels
persist on long-term once daily combined T3/T4 therapy, sample
timing in relation to dose remains essential for the correct interpretation of thyroid function test results. Furthermore, wide
diurnal variation in T3 levels may have adverse effects, particularly on the cardiovascular system. Here we report the results of
24-hour hormone profiles on 10 individuals (and 10 controls)
after treatment with a combination of T3 and T4 for more than 3
months, as well as cardiovascular parameter changes over the
24-hour period.
Subjects and Methods
&
Subjects
WATTS (Weston Area T3/T4 Study) was a double blind randomised trial of 697 patients, designed to investigate the benefits of combined T3/T4 therapy versus T4 therapy alone, over a
period of 12 months. Patients entering this study were aged
between 18 and 75 years, on ≥ 100 g of thyroxine and biochemically euthyroid (TSH in the laboratory reference range) for at
least 3 months prior to entering the study. For detailed inclusion
and exclusion criteria see Saravanan et al (Saravanan et al.,
2005). At study entry, all patients had their thyroxine dose
reduced by 50 g and replaced either by an identical tablet containing either 50 g of thyroxine (placebo – T4 alone) or 10 g of
T3 (T3/T4 group). For the current study, 10 patients on T4 alone
and 10 patients on combined therapy (T3/T4) were randomly
selected by the trial pharmacist, who was not in direct contact
with the patients. This enabled the patients and the investigators to remain blinded. The patients had been on their study
medication for a minimum period of 3 months at the time of
investigation. 7 patients in the T4 alone group and 8 in the T3/T4
group were on thyroxine for primary hypothyroidism. The rest
were on thyroxine after having radioactive iodine treatment for
thyrotoxicosis.
Methods
&
All patients were given written and verbal instructions to take
all their study medication at 8. 00 am for a week prior to their
24-hour profile. On the day of the study, baseline blood sample
was taken at 8.00 am and subjects then took their study medication under supervision. Eleven more blood samples were collected at 0900, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400,
0600 and 0800 hrs over the next 24-hours. Patients were ambulatory with normal daily activity although strenuous exercise
was avoided. Subjects slept between 2200 hrs and 0600 hrs and
the final blood sample was collected at 0800 hrs on the following day.
Eleven patients (T3/T4:T4 = 6:5) not on beta blocking or antihypertensive drugs attended on a second occasion for monitoring of their 24-hour ambulatory blood pressure (BP) and pulse
rate. Similar instructions were given prior to their attendance
and the monitor was attached to the patients immediately after
taking their study medication. Thyroid function was monitored
for the first 6 hours (5 samples at 0, 1, 2, 4, 6 hours post-dose).
ECED/699/7.3.2007/Macmillan
Patients’ BP and pulse rate were monitored at the following
intervals: half-hourly for the first 6 hours post-dose, hourly for
the next 8 hours and then 2 hourly (at night time) until the following morning. Patients returned home after the first 6 hours
and were advised to avoid strenuous exercise and take rest for at
least 5 min before and during each BP measurement.
The study was approved by the 2 local human research ethics
committees (United Bristol Healthcare Trust & Southmead Hospital, Bristol, UK). All subjects gave written consent prior to
entering both the main WATTS and the 24-hour profile study.
Biochemical analyses
All the blood samples were stored overnight at 4˚C and then centrifuged. The serum was then stored below − 70˚C for later analysis. All the samples were analysed for TSH (Rapid quantitative
immunometric assay, Diagnostic Product Corporation, Los Angeles, USA), fT4 (Quantitative competitive immunoassay, Diagnostic Product Corporation, Los Angeles, USA) and fT3 levels (Electro
Chemiluminescence quantitative immunoassay, Elecsys system
1010 kit, Roche diagnostics, Mannheim, Germany). The laboratory reference ranges for these tests are TSH: 0.3–4.0 mU/L, fT4:
10.0–24.0 pmol/L and fT3: 2.8–7.1 pmol/L.
Blood pressure and Pulse rate monitoring
The 24-hour BP and pulse were recorded by an ambulatory
blood pressure monitor TM-2421, A&D Co Ltd, Saitama, Japan
Statistical methods
Unpaired t-tests were used to detect the differences in the mean
values of thyroid function parameters between the two groups.
Mann-Whitney U test was used to detect the differences in the
median TSH. TSH values of < 0.01 were analysed as 0.01. The area
under the curve for the fT3 values were calculated individually
for each patient by means of the linear trapezoid rule and the
difference between the groups was analysed by unpaired t-test.
Un-paired t-tests were used to detect the differences in the
mean values of BP and Pulse rate.
Results
&
The T4 dose at the entry to WATTS was similar between the 2
sub-groups although there were differences in sex ratio and
mean ages between the two groups (Table 1).
Baseline values
Baseline mean fT3 levels were similar between the 2 groups
(T3/T4:T4 = 4.38:4. 69 pmol/L, p = 0.208; range – T3/T4:T4 = 3.5–
5.2: 4.1–5.6) but the baseline mean fT4 was lower (T3/T4:
T4 = 12.05:17.9 pmol/L, p = 0.0001) and median TSH was higher
(T3/T4:T4 = 3.5:0.7 mU/L, range – T3/T4:T4 = < 0.01,15.3: < 0.01,2.7,
p < 0.001) as a result of T3 substitution (Table 1).
24-hour variation in free T3 and free T4 values
In patients on T4 alone, a modest 16 % rise in fT4 levels peaking
2–4 hours post dose was seen, with higher levels for 12–16 hours
(䊉䉴 Figs. 1 and 2). No rise (indeed a slight fall) in fT3 levels was
seen. However, in the T3/T4 group mean fT3 levels showed a
marked 42 % rise within the first 4 hours of medication ingestion, remaining above baseline for 16 hours and higher than the
T4 alone group for 22 hours (䊉䉴 Figs. 1 and 2). The mean fT3 levels at 4 hours post-dose (T3/T4:T4 = 6.24:4.63 pmol/L, p = 0.0007)
Saravanan P et al. Thyroid Hormone Profiles on Combined T3/T4 … Exp Clin Endocrinol Diabetes 2007; 00: 1–7
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ECED/699/7.3.2007/Macmillan
Baseline Characteristics
Table 1
Group
Age (yrs)
Number of
Number of
Pre WATTS T4
Females
primary Hypo
dose (mcg)
Baseline Values
fT3 (pmol/L)
fT4 (pmol/L)
MedianTSH
(mU/L)
T4 Alone
(n = 10)
T3/T4 (n = 10)
62.39
4
7
127.5
4.69
17.9
0.7
54.29
7
8
126.25
4.38
12.05
3.5
Figure 1 a–c Mean values for free
T3 (a), free T4 (b) and TSH (c) over the
24-hour period. Error bars show standard
errors (SEM) for each value. (Normal
ranges: Free T3: 2.8–7.1 pmol/L; Free T4:
10.0–24.0 pmol/L; TSH: 0.3–4.0 mU/L)
FT3 - Normal Range
(pmol/L)
Mean FT3 Values
6.80
6.00
5.20
T3 /T4
T4 Alone
4.40
3.60
2.80
0.00
4.00
a
20.00
24.00
Mean Free T4 values
24.00
FT4 - Normal Range
(pmol/L)
8.00
12.00
16.00
Hours Post - Dose
22.00
20.00
18.00
T3/T4
T4 Alone
16.00
14.00
12.00
10.00
0.00
4.00
b
7.0
8.00
12.00
16.00
Hours Post - Dose
Mean TSH Values
20.00
24.00
TSH (mU/L)
6.0
5.0
4.0
T3/T4
T4 Alone
3.0
2.0
1.0
0.0
0.00
c
4.00
8.00
12.00
16.00
Hours Post - Dose
20.00
as well as the overall area under the curve (AUC) were significantly higher in the T3/T4 group than the T4 alone (AUC: T3/T4:
T4 = 1148:1062, p < 0.0001). 3 patients in T3/T4 group but none
in the T4 alone had fT3 levels above the laboratory reference
range at some time over the 24-hour period. However these
higher levels lasted only for a maximum of 2 hours.
24.00
rhythm with a nocturnal rise persisted in both groups (䊉䉴 Figs.
1c, 2c). 3 patients in the T3/T4 group and none in the T4 alone
had a mean TSH higher than the lab normal range. One patient
in the T3/T4 and 2 in the T4 alone had a suppressed TSH level
throughout the 24-hour period.
Pulse and BP changes
TSH values
Despite greater T3 exposure in the T3/T4 group, this appeared
not to alter the pattern of TSH secretion. A similar circadian
In the patients who attended for cardiovascular parameter analysis (n = 11, T3/T4:T4 = 6:5), no difference was apparent in the
24-hour variation of the BP and pulse rate between the 2 groups
Saravanan P et al. Thyroid Hormone Profiles on Combined T3/T4 … Exp Clin Endocrinol Diabetes 2007; 00: 1–7
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ECED/699/7.3.2007/Macmillan
Mean % Change - Free T3
Figure 2 a–c Mean values for the percentage
change from baseline (time = 0) in free T3 (a), free
T4 (b) and TSH (c) over the 24 h period. Error bars
show standard errors (SEM) for each value.
50
40
% Change
30
20
T3/ T4
T4 Alone
10
0
-10
-20
0.00
4.00
a
8.00
12.00
16.00
Hours Post - Dose
20.00
24.00
Mean % Change - Free T4
20
% Change
15
10
T3/ T4
T4 Alone
5
0
-5
-10
0.00
4.00
b
8.00
12.00
16.00
Hours Post - Dose
Mean % Change - TSH
20.00
24.00
30
20
% Change
10
0
T3/ T4
T4 Alone
-10
-20
-30
-40
0.00
c
4.00
8.00
12.00
16.00
Hours Post - Dose
20.00
(Table 2 and 䊉䉴 Fig. 3). No post-dosing peak in heart rate or blood
pressure that differed between the groups was discernable and
both groups showed similar night-time falls in cardiovascular
parameters. Thyroid function tests taken on this occasion for the
first 6 hours showed similar changes to those seen at the first
visit (䊉䉴 Fig. 4).
Discussion
&
This study demonstrates that after more than 3 months on once
daily combined T3 (10 g) plus T4 therapy, subjects continue to
show wide peak-to-trough fluctuations in serum fT3 levels over
a 24-hour period. The pharmacokinetics of T3 in combination
therapy in which T3 is also being continuously generated from
T4 therefore appears similar to that of T3 alone in hypothyroid
patients and no adaptation to chronic therapy appears to occur
(Saberi and Utiger, 1974). A recent study examined pharmacokinetic changes over a more limited period (the first 9 hours postdose) and reported similar results (Hennemann et al., 2004). We
have additionally been able to observe that although excess fT3
24.00
exposure persists for 16 hours post-dose, no effect on TSH diurnal rhythm or pulse or blood pressure variation was discernible.
These observations have several important clinical implications.
Firstly, any interpretation of total or free T3 estimations on combined therapy must take into account the timing of sampling in
relation to dose. Indeed, no single value of fT3 can be used to
reflect the 24-hour profile and isolated fT3 measurements cannot be used for fine titration of T3 doses on once daily therapy.
In the study of Bunevicius et al advocating combined therapy,
fT3 levels were measured 2 hours post-dose, and as a result were
significantly higher than on T4 alone. Where pre-dose levels
were measured (Bunevicius et al., 2002; Siegmund et al., 2004;
Walsh et al., 2003) the levels are observed to be little different
from T4 alone. This can erroneously lead to the conclusion that
overall T3 exposure is similar when in fact the area under the
curve for fT3 is higher on combination therapy.
Secondly, our observations lead us to reconsider which features
of the thyroid hormone profile on replacement therapy are most
important. Despite a 42 % rise in fT3 over the first 4 hours, no
significant changes in cardiovascular parameters were apparent
Saravanan P et al. Thyroid Hormone Profiles on Combined T3/T4 … Exp Clin Endocrinol Diabetes 2007; 00: 1–7
Article 5
ECED/699/7.3.2007/Macmillan
replacement therapy and indeed a trend towards greater excursions in the 2–8 hours post-dose was seen in the T4/T3 group
(Table 2). Much larger and longer-term studies are required to
clarify this. If a slow tissue response to T3 results in an integration of the response over the 24-hour period, then the effects of
a transiently raised T3 peak may be less detrimental than that
they might appear. Intracellular T3 levels vary between tissues
and are different from serum levels because of the actions of
thyroid hormone transporters and intracellular deiodinases
(Saravanan and Dayan, 2004; Escobar-Morreale et al., 1995).
Many tissues express the D3 deioidinase which has the potential
to metabolise and inactivate T3 thereby reducing the effects of a
rapid rise in T3. On the other hand, fluctuations in serum T3 may
have important effects via the recently described non-transcriptional pathways of action of thyroid hormones (Scanlan et al.,
Percentage changes in cardiovascular parameters
Table 2
Mean % changes from
p value
baseline
Systolic BP
2–8 hours post dose
Night time (11 pm–7 am)
Diastolic BP
2–8 hours post dose
Night time (11 pm–7 am)
Pulse Rate
2–8 hours post dose
Night time (11 pm–7 am)
T4 alone
T3/T4
2.60
− 7.83
5.28
− 4.60
0.74
0.68
− 2.51
− 20.72
1.58
− 8.68
0.58
0.15
3.34
− 2.41
6.37
− 7.93
0.63
0.36
Figure 3 a–c Mean percentage change from
baseline of Blood Pressure and Pulse rate of patients
without b-blockers and anti-hypertensives
Mean % Change - Systolic BP
15
% Change
10
5
0
T3/ T4
T4 Alone
-5
-10
-15
-20
0.00
4.00
a
8.00
12.00
16.00
20.00
24.00
Hours post - dose
Mean % Change - Diastolic BP
10
% Change
0
-10
T3/ T4
T4 Alone
-20
-30
-40
0.00
4.00
b
8.00
12.00
16.00
Hours post - dose
20.00
24.00
Mean % Change - Pulse
30
% Change
20
10
T3/ T4
T4 Alone
0
-10
-20
0.00
c
4.00
8.00
12.00
16.00
20.00
24.00
Hours post - dose
and patients did not appear to notice any particular symptoms
over this period or report diurnal variation in symptoms as often
reported on hydrocortisone replacement in hypoadrenalism
(Feek et al., 1981; Scott et al., 1978). However, the numbers of
subjects in whom cardiovascular profiles were studied (T3/T4 = 6;
T4 = 5) may have been insufficient to detect small changes that
could nonetheless be clinically important over many years of
2004) with associated long-term cardiovascular consequences.
Indeed, little is currently known of the relative importance of T4
and T3 levels and their profiles in terms of long-term effects of
over-replacement such as osteoporosis and effects on the heart,
although suppressed TSH levels from excess T4 can result in
myocardial changes and significant osteoporosis even with thyroid hormone levels in the reference range (Bauer et al., 2001;
Saravanan P et al. Thyroid Hormone Profiles on Combined T3/T4 … Exp Clin Endocrinol Diabetes 2007; 00: 1–7
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Mean % change - Free T3 (V2)
80
% Change
60
40
T3/ T4
T4 Alone
20
Figure 4 a–c Mean values for the percentage
change from baseline (time = 0) in free T3 (a), free
T4 (b) and TSH (c) over the second 6-hour period
(on the day of 24-hour monitoring the BP and Pulse
rate). Error bars show standard errors (SEM) for
each value.
0
a
-20
0.00
1.00
2.00
4.00
6.00
Hours Post - Dose
Mean % Change - Free T4 (V2)
20
% Change
15
10
T3/ T4
T4 Alone
5
0
b
-5
0.00
1.00
2.00
4.00
6.00
Hours Post - Dose
Mean % Change - TSH (V2)
5
% Change
0
0.00
1.00
2.00
4.00
6.00
-5
T3/ T4
T4 Alone
-10
-15
c
-20
Hours Post - Dose
Biondi et al., 2002b; Biondi et al., 2002a; Faber and Galloe, 1994;
Sheppard et al., 2002; Uzzan et al., 1996; Walsh and Stuckey,
2001). In our study baseline TSH levels rose on T3/T4 therapy
indicating that the hypothalamus/pituitary was more sensitive
to the fall in baseline fT4 levels than to the transient rise in fT3
levels.
Finally, our observations raise the issue of the correct dosing
interval for T3 on combined T3/T4 therapy. Even though we did
not demonstrate any significant differences in the cardiovascular parameters, it would be logical to use a twice or three times
daily dosing which may achieve smoother 24-hour T3 levels that
resemble individuals with an intact thyroid axis more closely
(Busnardo et al., 1980). An alternative possibility is the formulation of a slow release T3. Hennemann et al recently showed that
their in-house “slow release” version of T3 when used with T4
gives a smoother profile than the standard T3 for at least 9 hours
post-ingestion (Hennemann et al., 2004). Such a smoother profile has the added advantage of making fine titration of T3 dose
feasible. The relative merits of these two approaches in terms of
compliance, pharmacokinetics, satisfaction with replacement
and long-term side effects remain to be determined. In addition,
the relevance of failing to replace the natural pulsatility in T4 or
T3 (Weeke and Gundersen, 1978) on thyroid hormone replacement therapy with either T4 alone or combined T3/T4 is
unknown.
In conclusion, we have confirmed that wide peak-to-trough variation in fT3 levels persist in once daily combination therapy
with T3 and T4 after more than 3 months treatment. This variation makes interpretation of thyroid function tests on combined
therapy more difficult as basal fT3 levels may underestimate
total T3 exposure and peak fT3 levels may overestimate it. Furthermore, TSH levels cannot be used to indicate overall exposure
to T3 as levels rose when T3 was substituted for T4 despite
increased T3 levels. The role of combined T3/T4 in thyroid hormone replacement remains controversial (Cooper, 2003; Wartofsky, 2004). Many practitioners continue to use this
combination (Blanchard, 2004; Woliner, 2003) and our own
results in a large population are consistent with possible benefit
in a subgroup of individuals (Saravanan et al., 2005). If a role is
confirmed for combination therapy, it will be important to
resolve the pharmokinetic issues raised by the current study in
order to achieve safe and optimal dosing.
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