Clinical Endocrinology (2000) 52, 471 -477
Thyroid suppression test with L-thyroxineand
[99 mTc] pertechnetate
Celso D. Ratnos*, Denise E. Zantut-Wittmann,t
Marcos A. Tambascia,t Ligia AssumpqBo,t
Elba C. S. C. Etchebehere* and
Edwaldo E. Camargo*
*Divisionof Nuclear Medicine, Department of Radiology,
and t Division of Endocrinology, Department of Internal
Medicine, School of Medical Sciences, Campinas State
University, Campinas, Brazil
(Received 16 March 1999; returned for revision 3 April 1999;
finally revised 1 June 1999; accepted 28 September 1999)
Summary
OBJECTIVE The thyroid suppression test is still used
in some centres as an adjunt in the dlagnosls of
autonomous functioning thyroid nodules. With the
purpose of minimizing the disadvantages of the ori-
ginal T3 suppression test, we have evaluated the
efficacy of a method using L-thyroxine as TSH sup-
pression agent and [ss"'Tc] pertechnetate as radio-
pharmaceutical.
DESIGN Open nonrandomized prospective study
MATERIALS AND METHODS A control group of 15
normal volunteers (11 males, 4 females; 21-35
years, mean 26-4 years) and a patient group of 20
patients (18 females, 2 males: 27-83 years, mean 53.6
years) divided into 4 subgroups, were studied: 7
patients with autonomous functioning nontoxic nod-
ules, 3 with autonomous functioning toxic nodules, 7
with Graves disease and 3 with nonautoimmune dif-
fuse toxic goitre. Baseline thyroid uptake and imaging
were begun 20 minutes after an intravenous injection
of 370 MBq (10mCi) of [""'Tc] pertechnetate. This
was followed by a single daily intake of 2pg/kg of
L-thyroxine, for 10 days. Thyroid imaging and uptake
were then repeated.
RESULTS In the control group [sQmTc]pertechnetate
uptake after L-thyroxine suppression had a mean
reduction of 75.8 ? 7.69% (5847%) in comparison to
the baseline level. All subjects were euthyroid by
Correspondence: Dr Celso Dario Ramos, Division of Nuclear
Medicine, Department of Radiology, School of Medical Sciences,
Campinas State University, PO Box 61 1 1 , 13083-970 Campinas-SP,
Brazil. Fax: + 55 19 252 6826
E-mail: cdramos@mn-d.com
0 2000 Blackwell Science Ltd
clinical and laboratory criteria and none complained
of side-effects, despite significant suppression of
TSH levels. In the patient group, thyroid uptake after
suppression decreased in 10 patients (maximum
reduction 39%), was unchanged In 2 patients and
increased in the remaining 8 patients.
CONCLUSION The method described was efficient for
demonstration of autonomous thyroid tissue, since
none of the patients showed significant reduction of
thyroid uptake after L-thyroxine suppression com-
pared with the control group. This test was as effec-
tive as the original T3 suppression test, but more
convenient to the patient: no side-effects, ease of
hormonal intake, low dosimetry and short stay in the
nuclear medicine laboratory.
The original thyroid suppression test consisted of a measure-
ment of thyroid uptake with [I3'I] iodide before and 7-10 days
after oral administration of 75- 100 pg of hiiodotironine (T3).
Usually, in a positive test, thyroid uptake decreased by more
than 50% of the baseline level. Initially, the most important
indications for this test consisted of distinguishing euthyroid
from borderline hyperthyroid patients, the diagnosis of
autonomous functioning nodules and some patients with
Graves disease. With an autonomous functioning thyroid
tissue there was no significant reduction of thyroid uptake
after T3 intake (Werner & Spooner, 1955; Hamburger, 1971).
With the ultra-sensitive tests for TSH and free T4 (fT4)
measurement to distinguish euthyroid from hyperthyroid
individuals, the need for a thyroid suppression test declined.
However, it is still used as an adjunct in the diagnosis of
autonomousfunctioning thyroid nodules (Cavalieri & McDougall,
1996).
There are two disadvantages with the original test: the use of
T3 as a TSH suppressor hormone, and the use of [I3'I] iodide
for thyroid imaging and uptake.
In the past, T3 was the hormone of choice for treatment of
hypothyroid patients. However, because of its short biological
half-life (1 day) and fast absorption, its plasma concentration
changes abruptly during the day, even when the daily dose is
fractionated into 3-4 intakes (Brent & Larsen, 1996). For some
time now, T3 has been replaced by L-thyroxine for hormonal
treatment, with several advantages: longer biological half-life
(7 days) which allows one single daily dose, easy intestinal
absorption, reliable serum level measurements, and very little
471
472 C.D. Ramos et al.
serum level changes between daily intakes (Kaufman et al.,
1991).
Thyroid studies with ["'I] iodide have some disadvantages
such as high radiation dose to the gland and poor quality images
with conventional scintillation cameras. Thyroid studies with
[123X]iodide have also some disadvantages such as limited
availability and high cost.
On the other hand, technetium-99 m in the chemical form of
pertechnetateis consideredby many as the radiopharmaceutical
of choice for thyroid scintigraphy, due to its lower radiation
dose to the thyroid and good quality images. The physical
half-life of only 6 h of technetium-99 m and the short stay of
[w"'Tc] pertechnetate in the thyroid gland are factors that
permit sequential studies at short time intervals (Reschini et al.,
1993).
With the purpose of minimizing the disadvantages of the
original thyroid suppression test with T3, the efficacy of a
method using L-thyroxine as TSH suppression agent and [" y c ]
pertechnetate as the radiopharmaceutical, has been evaluated.
Materials and methods
Control group and patients
Thuty-five subjects, 15 normal volunteers and 20 patients with
thyroid disease, divided into control group and patient group,
were studied.
The study protocol was approved by the Ethics Committee
on Human Investigation, School of Medical Sciences, Campinas
State University. All subjects gave written informed consent
prior to the study.
The control group consisted of 11 males and 4 females, with
ages ranging from 21 to 35 years (mean 26.4 years), all
euthyroid by clinical and laboratory criteria (Table 1).
The patient group consisted of 18 females and 2 males with
autonomous thyroid disease, with ages ranging from 27 to 83
years (mean age 53.6 years), divided into 4 subgroups:
0 seven patients with autonomous functioning nontoxic
nodules (AF'NTN);
0 three patients with autonomous functioning toxic nodules
(");
0 seven patients with Graves' disease (GD), but clinically
euthyroid and with active disease by laboratory criteria;
0 three patients with nonautoimmune diffuse toxic goitre
(DTG).
Laboratory assessment of thyroid function was performed in all
subjects by measuring serum f14 (or total T4) and TSH levels
(ultra-sensitive TSH assay) (fluorometric enzyme immune
assay, Dade Behring Inc., Miami, FL, USA). In the control
group, additional serum f l 4 and TSH levels were obtained after
L-thyroxine administration. In the patient group, serum
antithyroperoxidase antibody (TpOAb) and antithyroglobulin
antibody (TgAb) (enzyme immunoassay, GenBio, San Diego,
CA, USA) were also measured.
Among the patients, 4 were on methimazole and had normal
serum ff4levels: 1 with autonomous functioning toxic nodule,
1 with diffuse toxic goitre and 2 with Graves' disease.
Study design
For the baseline study, all subjects were placed on a diet
without iodme-rich food for two weeks. Thyroid imaging and
uptake were performed 20minutes after an intravenous
injection of [99mTc]pertechnetate. This was followed by the
oral administration of 2 pgkg of L-thyroxine, as a single daily
dose, in the fasting condition, for 10 days, Thyroid imaging and
uptake were repeated on day 11. In the control group,
L-thyroxine intake was begun 24 h after the baseline study.
The mean time interval between the baseline and after
suppression thyroid uptake measurements was 2.8 months in
the patient group. During this period, except for the 10days that
preceded the second test, all patients were free of medication,
excluding the 4 patients who needed metimazole.
Method
Images were acquired 20 minutes after an intravenous injection
r9'
of 370 MBq (10 mCi) of "Tc] pertechnetate on a scintillation
camera (Elscint SPX6) equipped with a low energy high
resolution collimator, using a 128 x 128 matrix and zoom 2. For
the uptake measurement, images of the syringe before and after
injection for 2 s each and an image of the anterior neck for
100OOO counts, were obtained. Additional images of the neck,
for evaluation of the gland, were obtained in the anterior and
30' anterior oblique views. These images were acquired for
either 180s or 200 000 counts.
An image of the injection site was obtained to detect possible
extravazation of the radiopharmaceutical, which would invalidate
the thyroid uptake measurement.
The method used for measuring thyroid uptake was based on
the technique described by Maisey et al. (1973).Thyroid uptake
was calculated from the images acquired on the scintillation
camera and processed with a dedicated nuclear medicine
computer. The thyroid gland was delineated from a circular
'master' region of interest (ROI) which included the entire
thyroid gland; then, the computer programme automatically
detected the outer borders of the gland. A second ROI was
automatically drawn below the gland for calculation of the
background radiation.
The normal range of [wmTc] pertechnetate thyroid uptake
previously determined in our laboratory in a group of 40 normal
volunteers using the same method was 0.36% to 1.6%.
0 2000 Blackwell Science Ltd, Clinical Endocrinology, 52,471-477
 Thyroid suppression test 473

Table 1 Control group data before and after L-thyroxyne suppression test

[w”Tc] pertechnetate uptake (%) TSH (mUfl) Free T4 (pmolll

Age
Patient Sex (years) Baseline Suppression A Baseline Suppression Baseline Suppression Side-effects

1 M 27 0.46 0.06 - 87 0.3 0.06 11.1 15.4

2 F 21 1 a7 0.38 - 78 1.6 0.2 12.9 19.3
3 F 26 0.63 0.12 -81 2.0 0.8 12.9 23.2
4 M 21 0.59 0-13 - 78 1.8 0.8 14.2 20.6
5 M 26 0.64 0.18 - 72 0.5 0.007 19.3 34-7
6 F 25 1 -2 0-33 - 73 1*4 0.1 12.9 19.3
7 M 26 1-0 0.34 - 66 1*2 0.09 17.2 24.1
8 F 35 0.84 0.15 - 82 2.2 0.06 11.6 22.7
9 M 25 1.1 0.32 - 71 1.8 0.3 18-0 24.4
10 M 32 0-49 0-12 - 76 0-5 0.2 14.2 27.0
11 M 26 0.44 0.06 - 86 1-2 0.2 14.8 23.2
12 M 25 0.45 0.10 - 78 0.6 0.1 12.9 23-2
13 M 27 1 -2 0.36 - 70 2.9 0.4 112.0* 148*0*
14 M 30 0.72 0.30 - 58 1.1 0-3 122*3* 158*3*
15 M 24 0-37 0.07 - 81 1 *5 0.2 115*8* 178-9*

*Total T4(normal range 60-154 nmoyl); Free T4 (normal range 9.5-27.0 pmoM); TSH (normal range 0.38-6-15 mUfl); [Tc-99m] pertechnetate
uptake (normal range 0.36-1.6%)

Results Of the 7 patients with Graves’ disease, 4 had hormone levels

slightly elevated, 3 with ff4 of 28.2, 39.1 and 30.5 pmolfl and
Table 1 displays the results in the control group. All subjects in
one with a total T4 of 158 nmoy1. In the remaining 3 patients,
the control group were clinically euthyroid. Baseline serum
I T 4 was within normal limits. Six patients had positive ”PO
levels of total T4 (60-154 nmol/l), f f 4 (9.5-27.Opmoy1) and
and Tg antibodies; they were negative in the remaining patient,
TSH (0.38-6.15 mU/l) were aLl within normal limits. Baseline
whose diagnosis of Graves’ disease was confirmed by
[99 mTc] pertechnetate thyroid uptake ranged from 0.37% to
exophthalmos.
1.7%. All subjects remained clinically euthyroid throughout the
In the 3 patients with DTG, f f 4 levels were 16.0, 56.6 and
investigation and denied side-effects. After 10 days of oral L-
62.7 pmol/l, TSH was below 0.01 mU/l and TFQ and Tg
thyroxine, f f 4 ranged from 15.4 to 34.7 pmoyl, total T4 from
antibodies were negative.
148 to 179 nmolfl, TSH from 0.007 to 0.8 mUA; [99mTc]
There were no significant changes in the images of patients
pertechnetate uptake ranged from 0.06% to 0.38%, which
with AFTN, Graves disease and DTG after suppression.
corresponded to a mean reduction of 75.8 ? 7.69% (58-87%)
Baseline [99mTc]pertechnetate uptake in the patient group
from the baseline level (Table 1, Fig. 1).
ranged from 0.76 to 12% (mean 3.0%). After 10 days of L-
Table 2 displays the results in the patient group. Of the 7
thyroxine intake the uptake ranged from 0.49 to 10% (mean
patients with AFNTN, 2 had TSH levels below 0.01 mUfl and
2.8%): decreased in 10 patients, was unchanged in 2 patients
in the remaining 5, TSH ranged from 0.02 to 0.54 mU/l. TPOAb
and increased in the remaining 8 patients (maximum reduction
and TgAb were negative in all patients. Baseline thyroid
39%). There were no side-effects reported during L-thyroxine
imaging showed 6 single nodules and 1 functioning multi-
intake.
nodular goitre. In 2 patients there was suppression of the normal
thyroid tissue. In the remaining 5 patients the extra-nodular
thyroid tissue was faintly visualized and further suppressed
Discussion
after the suppression test (Fig. 2).
In 3 patients with AFTN, ff4levels were 38.6,31.7 and 11.1 Human and animal studies have demonstrated that about 80%
pmoy1. TSH levels were below 0.01 mU/l and TPO and Tg of serum T3, the most potent thyroid hormone, originates in
antibodies were negative. Baseline thyroid imaging demon- peripheral tissues as a result of deiodination of thyroxine, which
strated complete suppression of extra-nodular thyroid tissue, is considered a pro-hormone (Braverman ef al., 1970; Toft,
with a single nodule in 2 patients and a multinodular goitre in 1994). Therefore, T3 should be the drug of choice as hormone
the other. replacement in hypothyroid patients. Indeed, in the past, T3 was

0 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 471-477

474 C.D. Ramos eta/.

Table 2 patient group data before and after L-thyroxine suppression test

[99mTc]Pertechnetate uptake (95) Baseline Baseline TPOAbl Image

Age TSH freeT4 TgAb beforelafter
Pt Sex (years) Disease Baseline Suppression A (mull) (pmolll) suppression Observation
-
1 F 53 AF" 0.93 1.4 50 <0.01 20.5 -1- SNISN
2 F 72 AFNTN 1.6 1.3 - 19 0.18 27.0 -1- SN PISN +
3 F 47 AFNTN 2.3 1.4 - 39 0.31 13.2 -1- SNISN
4 F 68 AFNTN 0.76 0.71 -7 <0.01 14.2 4- SN P/SN +
5 F 40 AF" 1.O 1.1 10 0.06 17.1 -1- MN P/MN +
6 F 65 AF" 0.73 0.49 - 33 0.54 14.2 -1- SN P/SN +
7 F 41 AFNTN 1.1 1.6 45 0.02 13.0 -/- SN P/SN +
8 F 27 AETN 4.7 3.7 - 21 <0.01 38.6 -1- SN/SN
9 F 67 AFI" 2.1 2.4 14 co.01 31.7 -1- SNISN
10 F 66 m 1.3 1.5 13 < 0.01 11.1 -1- M N m MMI
11 M 41 GD 3.3 4.7 42 <0.01 28.2 +- DGlDG
12 F 47 GD 5.7 5.7 0 <0.01 39.1 +I+ DGlDG
13 M 66 GD 0.79 0.79 0 <0.01 21.0 +I+ DGlDG 'Relapse after 8 months
14 F 83 GD 12 10 - 17 < 0.01 8.2 +- DGIDG MMI
15 F 34 GD 8.8 8.3 -6 <0.01 30.5 +- DGlDG MMI
16 F 38 GD 1.4 1.5 7 <0.01 19.2 -1- DGlDG Relapse after 10 months,
ophtalmopathy
17 F 27 GD 5.3 3.9 - 26 0.01 155.3* +- DOG
18 F 44 DTG 1.8 2-4 33 <0.01 62.7 -I- DGlDG
19 F 63 DTG 1.6 1.5 -6 <0.01 56.6 -1- DGlDG
20 F 70 DTG 2.1 1.5 - 29 <0.01 16.0 -1- DGlDG MMI

Free T4, *Total T4, TSH and [Tc-99 m] pertechnetate uptake: normal range and units as given in Table 1. A F " , autonomous functioning nontoxic
nodules; AFI",autonomous functioning toxic nodules; GD, Graves' disease; DTG, nonautoimmune diffuse toxic goitr; MMI, methimazole; TPOAb,
antithyroperoxidase antibody; TgAb, antithyroglobulin antibody. Images: MN, multinodular goitre; SN, solitary nodule; P, extra - nodular
parenchyma; DG, difuse goitre.

widely used for this purpose. However, its use has been
restricted, due to undesirable pharmacological characteristics
and some side-effects. These are caused by rapid absorption of
nearly 100% of the ingested hormone and peak serum
concentration in 2 - 4 h after oral administration. Thus, low T3
doses such as 25 pg, may lead rapidly to high serum levels, that
are not maintained constant. Also, the administration of 50-
75 p g as a single oral dose may result in serum levels as high as
9.2 -10-8 nmoyl, which are poorly tolerated especially by the
elderly (Harbert, 1996). Even if this physiological dose is
fractionated at 6 h intervals, the serum levels are widely
variable during the day (Kaufman et al., 1991).
Today the preferred drug for therapy of hypothyroidism is
synthetic L-thyroxine, due to its ease of absorption, long
biological half-life and high affinity for the transporter protein
TBG, all factors that lead to a stable serum concentration and
consequently to normalization of TSH levels. Minor changes in
the serum concentration of thyroid hormones cause large
variations in TSH levels. Therefore, normal serum levels of
TSH reflect adequate hormone replacement and physiological
action of the hormone (Atkins, 1971; Cam et al., 1988).
A thyroid suppression test using T3 was described by Werner
and Spooner (1953, at a time when synthetic L-thyroxine was
not available. Today the test is still performed as originally
described, with oral administration of T3, with undesirable
side-effects to the patient. Furthermore, from the theoretical
viewpoint, pituitary TSH suppression may not be effective and
constant with oral T3, because its serum levels change
significantly throughout the day.
L-thyroxine therefore could be administered in a safer
manner, minimizing side-effects and resulting in a stable and
reproducible TSH suppression. Despite these advantages, there
are no reports in the literature on the routine use of thyroid
suppression test with L-thyroxine.
Administration of L-thyroxine for 10 days was based on the
fact that the peak action of this hormone occurs in
approximately 10 days (Blackbwn et al., 1954; Farwell &
Braverman, 1996). In the control group, using 2 pg/kg/day of L-
thyroxine for 10 days, TSH suppression was demonstrated by
laboratory data in all individuals. As described in the literature,
the maintenance dose of L-thyroxine for patients with primary
hypothyroidism ranges from 1.6 to 1.8pgkg according to
0 2000 Blackwell Science Ltd. Clinical Endocrinology, 52, 471 -477

Fig. 1 L-thyroxine suppression test in a normal volunteer
(pt 3, Table 1). a, Baseline study; b, After suppression.
Mandel et al. (1993) to 2.25 pgkg, as described by Stock et al.
(1974).In our laboratory we use, on average, 2 p g k g of sodium
L-thyroxine as a single daily dose in the fasting condition, as
hormonal replacement for hypothyroid patients. With such a
dose, tT,and TSH levels are maintained within normal limits in
these patients. For this reason, in our investigation, we used the
same dose of L-thyroxine for thyroid suppression test in normal
volunteers and patients.
The thyroid uptake reduction using L-thyroxine was greater
than that originally described with oral T3 and [I3'I] iodide
(Werner & Spooner, 1955). On the other hand, the results were
0 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 471-477
Thyroid suppression test 475
Fig. 2 L-thyroxine suppresion test in a patient with autonomous
nontoxic functioning thyroid nodule (pt 2, Table 2). a, Baseline
study; b, After suppression. Note the extra-nodular thyroid tissue
suppression. Nodule imaging persisted unchanged.
similar to those of Atkins (1971) using T3 and [99mTc]
pertechnetate as a thyroid suppression test.
[wmTc]pertechnetate uptake after suppression in the patient
group was always above the lower limit of the normal range, in
contrast to the control group, where the highest uptake was
0.38%. Therefore, there was no overlap of uptake levels after
suppression when the 2 groups were compared. Even in those
476 C.D. Ramos et al.
patients with baseline uptake within normal limits, a frequent
finding in the AFNTN subgroup, the suppression test did not
result in uptake below 0.49% or a reduction greater than 39% of
the basal level. Two patients with Graves’ disease and normal
baseline uptakes were clinically euthyroid, with no medication,
had normal fT4and suppressed TSH. After L-thyroxine, none of
them showed reduction of uptake in comparison to the baseline
level, which demonstrated that there was autonomous thyroid
tissue. In fact, after 8 and 10 months, respectively, there was
recurrence of the thyrotoxicosis, meaning that they were
euthyroid, but the disease was still active.
From the theoretical viewpoint, baseline and post-
suppression thyroid uptakes in patients with autonomous thyroid
disease should be identical, a finding in 2/20 patients. However,
we have found increased (W20) and decreased (lO/20) uptakes
after suppression, similar to the findings of Atkins (1971) using
T3 and [99”’Tc] pertechnetate. Despite the high accuracy and
reproducibility of the method used for uptake measurement
(Hurley etal., 1972; Maisey etal., 1973), minor variations in the
acquisition and data processing as well as in the patients’ diet are
to be expected, and may explain fluctuations in the uptake values.
The presence of normal extra-nodular thyroid tissue in
patients with AFNTN also may explain a partial reduction of
uptake after suppression. On the other hand, the theoretical
possibility that some sensitivity to exogenous thyroid hormone
may persist in the autonomous functioning thyroid tissue could
explain the decline of thyroid uptake, suggesting that the
thyroid tissue was not completely autonomous. Increased
thyroid uptakes could also be explained by changes in the
manifestations of the disease itself.
The method proposed in this investigation was effective in
demonstrating autonomous thyroid tissue, since all patients
with Graves’ disease, DTG or autonomous functioning nodules
showed nonsignificant uptake reduction with the L-thyroxine
suppression test. Even patients receiving antithyroid drugs had
the test performed without discontinuation of the medication,
because [w”’Tc] pertechnetate uptake is not influenced by
drugs that block hormonal synthesis (Atkins, 1971; Hays &
Wesselossky, 1973), as opposed to [1311]-or [‘2311-iodide. The
test is completed in a few minutes when [99”%] pertechnetate
is used. The use of [wmTc] pertechnetate instead of [1311] or
[1231]iodide is recommended by several authors for studying
thyroid function as well as structure (Atkins, 1971; Higgins
et al., 1973; Parker et al., 1984; Kusic et al., 1990), especially
when dosimetry, cost and availability of these radioisotopes are
taken into consideration.
In conclusion the thyroid suppression test with L-thyroxine
and [99mTc]pertechnetate was as effective as the original T3
suppression test and more convenient to the patient: no side-
effects, ease of administration,low dosimetry and short stay in
the nuclear medicine laboratory.
Acknowledgement
This investigation was supported by Fundaqb de Amparo B
Pesquisa do Estado de S o Paul0 (FAPESP), under the research
grant contract 97111012-5.
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