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Original Studies |
Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcellos 2350/2030, 90035–003 - Porto Alegre, RS, Brazil
Address all correspondence and requests for reprints to: Flávio Zelmanovitz, Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcellos 2350/2030, Porto Alegre - 90035–003 - RS, Brazil.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Concerns about the risk-benefit ratio of suppressive T4 treatment were raised because it was associated with a decrease in bone mineral density (BMD) (11) and unwanted effects on the heart (12).
The aim of this study was to analyze the effect of suppressive doses of T4 on the volume of benign STN and BMD. Furthermore, meta-analyses were performed to examine the quantitative synthesis of data from similar designed controlled trials.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study was a randomized double-blind placebo-controlled clinical trial. The criterion standard was a reduction of nodule volume, at ultrasonography, to less than 50% of the baseline value. Fifty-one consecutive clinically euthyroid patients (3 males, 23, 39 and 40 yr-old; 48 females, age range: 19–73 yr) with an STN, attending the Endocrine Division, were included. The inclusion criteria were the presence of an STN (at ultrasonography), hypofunctioning (at 131I scintigraphy), and benign cytological findings. Patients with cystic or mixed (cystic component > 20%) nodules, Hashimoto’s thyroiditis (positive antithyroid antibodies or compatible cytopathological findings), or previous neck surgery were excluded, as were those who were pregnant or had cardiovascular disease or any other contraindication for the use of suppressive T4 therapy. The patients were randomly allocated to receive T4 treatment or identical placebo pills. The initial T4 dose was 2.5–3.0 µg/kg·day, adjusted after 1.5 months to obtain a serum TSH less than 0.3 µIU/mL or a TSH, after TRH stimulation, less than 2.0 µIU/mL. The mean T4 dose was 2.73 ± 0.32 µg/kg body weight·day. Patients were seen at 0, 1.5, 3, 6, and 12 months. At each visit, the patients were examined for body weight, thyrotoxicosis features, and nodule size. The ultrasound, T4, TSH, and thyroglobulin examinations were repeated after 3, 6, and 12 months of treatment. BMD was measured at the lumbar spine and femur before and after 1 yr of treatment.
Clinical trial methods
Serum TSH (Delfia human TSH), T3, and T4 (Coat-a-Count), antimicrosomal and antithyroglobulin antibodies (Sera-Tek), and thyroglobulin (DPC) were measured. Normals: TSH, 0.3–3.8 µIU/mL; T3, 86–187 ng/dL; T4, 4.5–12.5 µg/dL; antimicrosomal and antithyroglobulin antibodies, less than 1/100; and thyroglobulin, 0–52 ng/mL. When TSH was undetectable, a 0.03 µIU/mL value (lower detection limit) was attributed. The TRH test was performed with TRH (200 µg) IV bolus and TSH measured at 20 min.
High-resolution ultrasound imaging was performed with a real-time
instrument (Toshiba Sonolayer VSSA-100A) with a linear
transducer of 7.5 MHz. All examinations were done by the same
radiologist, who had no access to the patients’ data or group
assignment. The coefficient of variation for repeated measurements, in
a series of seven triplicate scans in a period of less than 1 month,
was 5.7%. Thyroid scans were obtained on both transverse and
longitudinal planes. The maximal diameter on the three possible planes
was recorded. The internal contents of the nodules were described as
solid or mixed. The nodule volume (mL) was calculated according to the
spherical ellipsoid formula: 
x anteroposterior diameter (cm) x
width (cm) x length (cm)/6.
Thyroid scintigraphy was performed 24 h after the ingestion of 2.96 Mbq of 131I using a rectilinear scanner. Fine-needle aspiration biopsy was performed according to Soderstrom’s technique (13). BMD values (g/cm3) were measured by dual-energy x-ray absortiometry (Lunar DPX, Lunar Corp., WI) at the lumbar spine (L2-L4), femoral neck, Ward’s triangle, and trochanter. The measurement precision is 1% for the spine and 2% for the femur. The female patients were analyzed according to their menopausal status. The protocol was approved by the Ethics Committee of the hospital, and all patients gave written informed consent.
Clinical trial statistical analysis
Comparisons between treatment and placebo groups were based on a
two-tailed Student’s t test, Fisher Scientific International, Inc.’s exact test or 
-square test for
differences in proportions. Comparisons between data from the same
group were based on a two-tailed Student’s t test or ANOVA
for more than two repeated tests. Results for continuous measures were
reported as mean ± SD and range. Confidence intervals
(CI) of 95% were used to establish significance.
Meta-analyses
The medical literature (from January 1985 to December 1997) was searched for papers in Medline that examined the issue of suppressive treatment with T4 for STN. The criteria for inclusion were: prospective, controlled clinical trials with a sufficient dose of T4 for TSH suppression, minimum follow-up of 6 months, and STN volume monitored by ultrasonography.
The number of patients allocated to treatment or control groups whose nodule volume decreased at least 50% were analyzed by the DerSimonian and Laird method (14). This method takes into account the variance between and within the studies, and the 95% CI are thus expanded when heterogeneity exists (15). A Q test was used to examine heterogeneity (14). The same procedure was used to analyze the nodules’ tendency to grow in the treatment and control groups. A significant variation in the nodule volume was defined as a change greater than 50% of baseline value. The data were presented as absolute percentage differences with 95% CI. All data processing for the cumulative meta-analysis was performed in Excel (Microsoft Corp.).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fifty-one euthyroid patients were admitted to the study, and all
presented a cytological diagnosis of colloid goiter. Twenty-four of the
51 patients were randomly assigned to the T4 group and 27
to the placebo group. Three patients in each group had no follow-up
after receiving initial orientations. The two groups were similar for
clinical and hormonal data and nodule characteristics (Table 1
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). All patients presented
complete TSH suppression at 1.5 months, even after TRH stimulation
(0.28 ± 0.46 µIU/mL). Suppressed TSH values were maintained
thereafter in 86% (18/21) of the patients, reflecting the compliance
with treatment. Only three patients (14%) had occasional nonsuppressed
values. The T3 levels did not change significantly.
Thyroglobulin levels decreased at the end of the study. None of the
patients in the T4 group developed side-effects requiring
withdrawal from the study. There was no change in the thyroid hormone,
TSH, or thyroglobulin levels in the placebo group (Table 3); and all patients presented normal TSH
response after stimulation with TRH (11.6 ± 6.7 µIU/mL). Body
weight did not change in the T4 (65.1 ± 12.3
vs. 65.1 ± 12.2 kg) or in the placebo group (64.2
± 9.1 vs. 65.7 ± 9.4 kg).
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and 3). Six (28.6%) of 21 patients in the T4 group and 2 (8.3%) of 24 in the placebo group decreased their volumes more than 50% at the end of the study period, as compared with baseline values. This difference was not significant (P = 0.12). In treated patients, the nodules were no longer detectable in 3 cases, or presented reductions between 50 and 80% in another 3 patients. No difference was observed in the proportion of patients who increased thyroid nodule volume more than 50% in T4 (2/21; 9.5%) or placebo groups (4/24; 16.7%) by the end of the study.
There were no significant differences in age (41.0 ± 6.0 vs. 45.6 ± 10.6 yr), gender (1/5 vs. 1/14 male/female ratio), baseline nodule volume (9.3 ± 12.2 vs. 15.9 ± 11.8 cm3), time since nodule diagnosis (70 ± 92 vs. 52 ± 69 months), baseline thyroglobulin concentrations (33 ± 32 vs. 47 ± 35 ng/mL), thyroglobulin reduction during therapy (-19 ± 66% vs. -32 ± 36%), baseline TSH (1.13 ± 0.67 vs. 0.99 ± 0.83 µIU/mL), or T4 (9.2 ± 2.0 vs. 9.4 ± 1.9 µg/dL) levels between patients with and without significant decrease in STN volume in the T4 group.
Complete BMD data, at baseline and after 1 yr, were obtained in 16
female patients (46.7 ± 9.5 yr) in the T4 group;
there were 10 premenopausal women (41.1 ± 4.3 yr) and 6
postmenopausal women (58.3 ± 5.2 yr). In the placebo group, the
same data were obtained in 19 female patients (43.4 ± 13.9 yr).
There were 12 premenopausal women (35.8 ± 9.9 yr) and 7
postmenopausal women (56.6 ± 7.4 yr). BMD density did not differ
between the groups or subgroups at baseline or after 1 yr of treatment,
and there was no difference between initial and final measurements in
both groups and subgroups (Tables 2 and 3).
Meta-analyses
The clinical trial described in this study and six other trials (5, 6, 7, 8, 9, 10) were identified and selected for the cumulative meta-analyses. Two hundred forty-two patients (18 males, 224 females, mean age: 42.5 yr) were assigned to T4 treatment and 171 patients (13 males, 158 females, mean age 42.7 yr) to the control group. The duration of follow-up ranged from 6–24 months, and the T4 suppressive dose varied from 1.7–3 µg/kg·day.
The proportion of patients with nodule volume decrease more than 50%
after 1 yr was higher in the T4 groups (mean: 26.5%;
range: 14.3–39.1%) than in placebo or no-treatment groups (mean:
12.3%; range: 0–20.0%) in 6 of the 7 trials, but the statistical
significance was achieved in only 2. The proportion of responders in
each group was heterogeneous according to the Q test (Q = 15.9).
In Fig. 1, the data were presented as risk
difference and 95% CI as a new meta-analysis procedure was
performed each time the results of a new trial were plotted. The
cumulative method indicated that the effect of T4 treatment
in decreasing the STN volume became statistically significant (risk
difference: 16.2%; 95% CI, 3.7–28.6%; P < 0.05)
after the data from Lima et al. (12) were included.
When the data of the present study were included in the meta-analysis,
the observed risk difference was confirmed (16.7%), and 95% CI
(5.8–27.6%) was narrowed.
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The cumulative method indicated that the T4 treatment for
preventing nodule growth became statistically significant (risk
difference: 10.2%; 95% CI: 1.8–18.6%) after the inclusion of La
Rosa et al. data (10). The addition of the present
study data confirmed the risk difference (9.7%) and decreased the CI
(95% CI: 2.0–17.4%).
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Discussion |
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The trials included in the meta-analyses were similar, regarding the design, the dose of T4 used, and the number of individuals included. However, the initial studies included patients with warm nodules, at scintigraphy (5), or cystic or mixed solid-cystic nodules (5, 6), at ultrasound. The inclusion of patients with cystic nodules may have influenced the results, because these nodules are less responsive to suppressive treatment (16). Some authors suggested that the nodules with volumes less than 10 mL (8) or 2.5 mL (10), recently diagnosed and rich in colloid at fine needle aspiration (17), are particularly susceptible to volume reduction after T4 treatment. Although the patients included in the current trial did not have cystic or warm nodules, some individuals had nodules with volumes more than 10 mL.
The data obtained in this study do not suggest any significant decrease in BMD after 1 yr of treatment with suppressive doses of T4. However, a meta-analysis of related studies, performed by Uzzan et al., demonstrated that suppressive therapy decreased the BMD in 409 postmenopausal patients after an average of 9.6 yr (11).
The treatment of benign STN is still a matter of debate. Most of the studies included in this meta-analysis were recently reviewed (18). Although systematic reviews are useful for the practicing clinician and recommended by those who criticize the practice of meta-analysis (19), the meta-analysis approach provides a more quantitative evaluation of the possible effects of the drug. Furthermore, meta-analyses are a reasonable surrogate for clinical trials, especially those of thyroid nodule treatment, which would require a large number of patients. Questions about different protocols, different end points, or variations in the quality of individual studies are important for any meta-analysis, but these differences were very narrow in the trials used in this meta-analysis (19). The possibility of publication bias is another important issue, but the data from initial studies caused impact and were published exactly because they showed no significant effect of treatment in double-blind, placebo-controlled studies using ultrasound monitoring of thyroid nodule volume.
Suppressive treatment may be useful, to prevent nodule growth and decrease the number of surgeries on benign nodules. Papini et al. (20) observed that T4-treated patients did not decrease thyroid nodule volume after 5 yr of treatment, but it increased in the control group, where there was a higher number of new nodules.
The demonstration, by this meta-analysis, of significant positive effects of suppressive T4 treatment does not imply that it should be offered to all patients. The possibility of trying the suppressive therapy for 1 yr without unwanted bone effects seems promising, but the absence of a significant decrease in thyroid nodule volume may be predicted in most patients and does not mean that the treatment was not useful in preventing nodule growth. A 1-yr trial of suppressive doses of T4 for premenopausal women and men without cardiovascular contraindications could be offered. In those patients who presented a reduction of nodule volume, the treatment could be maintained with lower doses of T4, just to obtain TSH levels around the lower normal limit. The treatment of benign STN is an open issue where no single significantly effective treatment is good enough and where the unwanted effects of T4 therapy are just being defined. Future studies are needed to identify properly those nodules that are more prone to volume reduction after suppressive treatment.
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Acknowledgments |
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Footnotes |
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2 Recipient of a CAPES scholarship.
Received May 20, 1998.
Revised July 1, 1998.
Revised July 15, 1998.
Accepted July 17, 1998.
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