Clinical Endocrinology (1992) 36, 25-28
Suppressive therapy with levothyroxine for solitary thyroid nodules J. L. Reverter’, A. Lucas’, 1. Salinas’, L. Audit, M. FozS and A. Sanmarti’ ‘Endocrinology Section, tHormonal Laboratory, $Internal Medicine Service, Hospital Universitari ‘Germans Trias i Pujol’, Badalona, Spain (Received 9 May 1991; returned for revision 5 June 1991; finally revised 18 July 1991; accepted 6 August 1997)
Summary OBJECTIVE To evaluate the effect of treatment wlth TSH
suppressive dose of levothyroxine in patients wlth benign thyroid nodules. DESIGN Prospectlve randomlzed study. Group A ( n = 20) patients recelved ievothyroxine and group 3 ( n =20) patlentsdid not. The dose of levothyroxlne was adjustedto obtain an effective suppression of TSH. A clinical, analytical and morphologlcal (with ultrasound) review was performed every 3 months. The mean+SD follow-up perlod was 10.6f2.2 months. PATIENTS Forty euthyrold women wlth solitary thyroid nodule on palpation, cold on scintlgraphy and cytologically benlgn without contraindicationpartlcipated. MEASUREMENTS At entry: biochemical and hormonal parameters, thyroid sclntigraphy and thyroid ultrasonography. Every 3 months additlonal determinations of thyroid hormones and TSH levels were carried out, if necessary, to verify effective TSH suppression. Every 6 months thyroid ultrasound imaging was performed. RESULTS Patients were euthyrold at entry into the study. The mean dose of ievothyroxine necessary to obtain TSH suppresslon was 2.82f0.6 pglkglday. No significant modification in the thyroid nodule diameter (mean fSD 2.6 f1.2 vs 2.5k 1.2cm) or in the thyroid nodule volume (10.3f11.9vs 10.1 f 12.2ml) were observed In group A. In group B the results were similar (24i 0.9 vs 2.7f1.8cm and 9.2f6.4vs 9.2k 9.5ml, respectively). No dlfferences were found in either group in the number of nodules that reduced significantly their volume (four and three, respectively). CONCLUSIONS The suppressivetherapy with levothyroxine Correspondence: Dr Anna Sanmarti Sala, Hospital Universitari de Badalona ‘Germans Trias i Pujol’, Seccio d’Endocrinologia, Cra. de Canyet, sjn, 08916 Badalona, Barcelona, Catalonia, Spain.
was not enectlve In reducing nodule sizes in patlents with solltary benign thyrold nodules.
Benign nodular thyroid disease is a frequent entity. Clinically palpable thyroid nodules (TN) are present in 4 7 % of the general population (Van Herle et af., 1982; Christensen et al., 1984; Rojeski & Gharib, 1985; Gharib et al., 1987) and ultrasound and necropsy studies show them in about 50% of individuals aged up to 50 (Horlocker et al., 1986; Burrow, 1989). The aetiology of the disorder is complex and a dominant role in its pathogenesis has been attributed to thyrotrophin (TSH) (Goretzki, 1989; Studer, 1989). The purpose of thyroxine (T4) administration in patients with TN is to reduce TSH secretion. T4 therapy in a TSH suppressive dose has been widely used in order to reduce the size of TN but its efficacy remains controversial. Although most prospective studies have shown that such treatment leads to a reduction in TN, the trials were not randomized and group-controlled, nor was the effect of treatment evaluated by objective methods such as ultrasonography. Furthermore, there was no evidence of TSH suppression, the follow-up was not long enough, and different benign thyroid diseases were mixed (Astwood er al., 1960; Lamberg et al., 1960; Schneeberg et al., 1962; Greenspan, 1974; Shimaoka & Sokal, 1974; Thomas Jr et al., 1976; Liechty et al., 1977; Burrow et al., 1978; Hansen et al., 1979; Blum & Rotschild, 1980; Getaz, 1980; Molitch et al., 1984; Gharib et al., 1987; Burrow, 1989; Morita et al., 1989; Berghout et al., 1990). We describe here a prospective randomized trial to study the efficacy of suppressive T4 treatment in patients with benign solitary TN. We used a sensitive ultrasonic technique to measure the TN size (Spencer et al., 1977; Scheible et al., 1979; Hansen et al., 1979; Ashcraft & Van Herle, 1981a, b; James & Charbonneau, 1985) and an ultrasensitive immunoradiometric assay to determine TSH levels (Klee & Hay, 1987). Patients and methods
We studied 40 euthyroid females with a solitary TN on palpation. Patients were admitted to the study only if their TN was single on palpation, if it was shown to be ‘cold’ and single by pertechnate-99m thyroid scanning, and proved to be benign by fine-needle aspiration biopsy (colloid goitre). Patients with multiple nodules by palpation or by scintigra25
Clinical Endocrinology (1992) 36
26 J. L. Reverter et al.
Table 1 Clinical and
hormonal initial data
Age (years)
Nodule characteristics Maximal diameter (an) Volume (ml)
Hormonal data TSH (mIU/I) (0.145) T4 (nmol/l) (58.0-161.2) T3 (nmol/l) (1-35-2.7) Free T4 @mol/l)(84-25.8)
Group A (n = 20)
Group B (n= 20)
40.10 f8.20
39.45 12.80
2.6 k 1.2 10.3f 11.9
2.8 f0.9 9.2f6.4
1.1 k0.8
1.1 f 0 . 4 108.4 f 14.2 1.7 k0.5 15.5 f2.6
107.1f16.8 1.8f0.3 15.5 f3.9
+
Values shown are mean +SD.
frequency real-time ultrasound (7 MHz frequency) producing a rectangular image with a 3 x 4 cm field of view. The axial and lateral resolution capabilities are 0.3 and 0.1 cm, respectively. The ultrasound examiner identified the TN size and sonographic characteristics of the nodule and described other eventual nonpalpable nodules. The TN volume was calculated according to the spherical ellipsoid formula (volume (ml)=ix x AP (cm) x width (cm) x length (cm), where AP is the anteroposterior diameter). A response to treatment was thus defined as in previous studies (Gharib et al., 1987; Morita et al., 1989), as a decrease of T N volume greater than 50% at the end of the follow-up.
Statistical analysis
phy, cytological findings suggestive of a neoplastic process, Hashimoto’s thyroiditis, pregnancy and/or any contraindication for levothyroxine (LT4) treatment, were excluded. Patients were randomly allocated in two groups to LT4 treatment or no treatment using a table of random numbers. In group A, 20 women received 100 pg/day of levothyroxine (LT4) for 2 weeks and 200 pg/day thereafter. This dose was modified to get a correct TSH suppression (TSH < 0.1 mIU/l by IRMA; see below). The mean dose necessary to obtain this effective TSH suppression without hyperthyroidism was 2-82k0.6 pg/kg body weight/day. The 20 patients allocated in group B did not receive treatment. Groups A and B were similar for clinical and hormonal data and nodule characteristics (Table 1). Patients were seen at 0,3,6,9 and 12 months. At each visit, the patient was assessed by the same physician for weight, blood pressure, heart rate, nodule size on palpation, and signs and symptoms of thyrotoxicosis. Plasma thyroid hormones and TSH were measured at 0,3,6, 9 and 12months with additional tests in patients in whom the LT4 dose had been changed. Ultrasonography and fineneedle aspiration biopsy were performed initially and every 6 months and/or at the end of the follow-up if patients did not complete the second 6-month period. The mean & SD followup period of group A was 10-65 2.25 months (6-12 months) from the TSH suppression achievement. In this group, six patients dropped out of the trial (three patients desired the surgical treatment for aesthetic reasons at 6,7 and 8 months, respectively and three patients abandoned treatment at 6, 8 and 10 months, respectively). All the group B patients completed the study. Plasma T3, T4 and free T4 levels were measured by RIA (total T3 and T4 from Diagnostic Products Corporation and free T4 from Behringwerke) and TSH by IRMA (Behringwerke). T N size was measured by ultrasonography using high-
*
Results for continuous measures are expressed as mean& standard deviation. The two-tailed, two-sample t-test and chi-squared test for differences in the proportions were used for comparisons between the groups.
Results
Before treatment, the two groups were broadly similar (Table 1). All patients were clinically euthyroid during the follow-up period. Plasma T4 and free T4 increased significantly in group A because of the LT4 treatment (mean & SD T 4 107.1+ 1 6 . 8 171.6+43.9nmol/landfreeT4: ~~ 15.5k3.9 us 3 1.0 9.0 pmol/l; P < 0.05),plasma T3 was not modified with the treatment (T3: 1.8 k0.3 us 2.0 0.5 nmol/l; P= NS) and TSH showed a correct suppression in all cases (TSH: 1.1 kO.8 vs
Suppressive therapy with levothyroxine for solitary thyroid nodules J. L. Reverter’, A. Lucas’, 1. Salinas’, L. Audit, M. FozS and A. Sanmarti’ ‘Endocrinology Section, tHormonal Laboratory, $Internal Medicine Service, Hospital Universitari ‘Germans Trias i Pujol’, Badalona, Spain (Received 9 May 1991; returned for revision 5 June 1991; finally revised 18 July 1991; accepted 6 August 1997)
Summary OBJECTIVE To evaluate the effect of treatment wlth TSH
suppressive dose of levothyroxine in patients wlth benign thyroid nodules. DESIGN Prospectlve randomlzed study. Group A ( n = 20) patients recelved ievothyroxine and group 3 ( n =20) patlentsdid not. The dose of levothyroxlne was adjustedto obtain an effective suppression of TSH. A clinical, analytical and morphologlcal (with ultrasound) review was performed every 3 months. The mean+SD follow-up perlod was 10.6f2.2 months. PATIENTS Forty euthyrold women wlth solitary thyroid nodule on palpation, cold on scintlgraphy and cytologically benlgn without contraindicationpartlcipated. MEASUREMENTS At entry: biochemical and hormonal parameters, thyroid sclntigraphy and thyroid ultrasonography. Every 3 months additlonal determinations of thyroid hormones and TSH levels were carried out, if necessary, to verify effective TSH suppression. Every 6 months thyroid ultrasound imaging was performed. RESULTS Patients were euthyrold at entry into the study. The mean dose of ievothyroxine necessary to obtain TSH suppresslon was 2.82f0.6 pglkglday. No significant modification in the thyroid nodule diameter (mean fSD 2.6 f1.2 vs 2.5k 1.2cm) or in the thyroid nodule volume (10.3f11.9vs 10.1 f 12.2ml) were observed In group A. In group B the results were similar (24i 0.9 vs 2.7f1.8cm and 9.2f6.4vs 9.2k 9.5ml, respectively). No dlfferences were found in either group in the number of nodules that reduced significantly their volume (four and three, respectively). CONCLUSIONS The suppressivetherapy with levothyroxine Correspondence: Dr Anna Sanmarti Sala, Hospital Universitari de Badalona ‘Germans Trias i Pujol’, Seccio d’Endocrinologia, Cra. de Canyet, sjn, 08916 Badalona, Barcelona, Catalonia, Spain.
was not enectlve In reducing nodule sizes in patlents with solltary benign thyrold nodules.
Benign nodular thyroid disease is a frequent entity. Clinically palpable thyroid nodules (TN) are present in 4 7 % of the general population (Van Herle et af., 1982; Christensen et al., 1984; Rojeski & Gharib, 1985; Gharib et al., 1987) and ultrasound and necropsy studies show them in about 50% of individuals aged up to 50 (Horlocker et al., 1986; Burrow, 1989). The aetiology of the disorder is complex and a dominant role in its pathogenesis has been attributed to thyrotrophin (TSH) (Goretzki, 1989; Studer, 1989). The purpose of thyroxine (T4) administration in patients with TN is to reduce TSH secretion. T4 therapy in a TSH suppressive dose has been widely used in order to reduce the size of TN but its efficacy remains controversial. Although most prospective studies have shown that such treatment leads to a reduction in TN, the trials were not randomized and group-controlled, nor was the effect of treatment evaluated by objective methods such as ultrasonography. Furthermore, there was no evidence of TSH suppression, the follow-up was not long enough, and different benign thyroid diseases were mixed (Astwood er al., 1960; Lamberg et al., 1960; Schneeberg et al., 1962; Greenspan, 1974; Shimaoka & Sokal, 1974; Thomas Jr et al., 1976; Liechty et al., 1977; Burrow et al., 1978; Hansen et al., 1979; Blum & Rotschild, 1980; Getaz, 1980; Molitch et al., 1984; Gharib et al., 1987; Burrow, 1989; Morita et al., 1989; Berghout et al., 1990). We describe here a prospective randomized trial to study the efficacy of suppressive T4 treatment in patients with benign solitary TN. We used a sensitive ultrasonic technique to measure the TN size (Spencer et al., 1977; Scheible et al., 1979; Hansen et al., 1979; Ashcraft & Van Herle, 1981a, b; James & Charbonneau, 1985) and an ultrasensitive immunoradiometric assay to determine TSH levels (Klee & Hay, 1987). Patients and methods
We studied 40 euthyroid females with a solitary TN on palpation. Patients were admitted to the study only if their TN was single on palpation, if it was shown to be ‘cold’ and single by pertechnate-99m thyroid scanning, and proved to be benign by fine-needle aspiration biopsy (colloid goitre). Patients with multiple nodules by palpation or by scintigra25
Clinical Endocrinology (1992) 36
26 J. L. Reverter et al.
Table 1 Clinical and
hormonal initial data
Age (years)
Nodule characteristics Maximal diameter (an) Volume (ml)
Hormonal data TSH (mIU/I) (0.145) T4 (nmol/l) (58.0-161.2) T3 (nmol/l) (1-35-2.7) Free T4 @mol/l)(84-25.8)
Group A (n = 20)
Group B (n= 20)
40.10 f8.20
39.45 12.80
2.6 k 1.2 10.3f 11.9
2.8 f0.9 9.2f6.4
1.1 k0.8
1.1 f 0 . 4 108.4 f 14.2 1.7 k0.5 15.5 f2.6
107.1f16.8 1.8f0.3 15.5 f3.9
+
Values shown are mean +SD.
frequency real-time ultrasound (7 MHz frequency) producing a rectangular image with a 3 x 4 cm field of view. The axial and lateral resolution capabilities are 0.3 and 0.1 cm, respectively. The ultrasound examiner identified the TN size and sonographic characteristics of the nodule and described other eventual nonpalpable nodules. The TN volume was calculated according to the spherical ellipsoid formula (volume (ml)=ix x AP (cm) x width (cm) x length (cm), where AP is the anteroposterior diameter). A response to treatment was thus defined as in previous studies (Gharib et al., 1987; Morita et al., 1989), as a decrease of T N volume greater than 50% at the end of the follow-up.
Statistical analysis
phy, cytological findings suggestive of a neoplastic process, Hashimoto’s thyroiditis, pregnancy and/or any contraindication for levothyroxine (LT4) treatment, were excluded. Patients were randomly allocated in two groups to LT4 treatment or no treatment using a table of random numbers. In group A, 20 women received 100 pg/day of levothyroxine (LT4) for 2 weeks and 200 pg/day thereafter. This dose was modified to get a correct TSH suppression (TSH < 0.1 mIU/l by IRMA; see below). The mean dose necessary to obtain this effective TSH suppression without hyperthyroidism was 2-82k0.6 pg/kg body weight/day. The 20 patients allocated in group B did not receive treatment. Groups A and B were similar for clinical and hormonal data and nodule characteristics (Table 1). Patients were seen at 0,3,6,9 and 12 months. At each visit, the patient was assessed by the same physician for weight, blood pressure, heart rate, nodule size on palpation, and signs and symptoms of thyrotoxicosis. Plasma thyroid hormones and TSH were measured at 0,3,6, 9 and 12months with additional tests in patients in whom the LT4 dose had been changed. Ultrasonography and fineneedle aspiration biopsy were performed initially and every 6 months and/or at the end of the follow-up if patients did not complete the second 6-month period. The mean & SD followup period of group A was 10-65 2.25 months (6-12 months) from the TSH suppression achievement. In this group, six patients dropped out of the trial (three patients desired the surgical treatment for aesthetic reasons at 6,7 and 8 months, respectively and three patients abandoned treatment at 6, 8 and 10 months, respectively). All the group B patients completed the study. Plasma T3, T4 and free T4 levels were measured by RIA (total T3 and T4 from Diagnostic Products Corporation and free T4 from Behringwerke) and TSH by IRMA (Behringwerke). T N size was measured by ultrasonography using high-
*
Results for continuous measures are expressed as mean& standard deviation. The two-tailed, two-sample t-test and chi-squared test for differences in the proportions were used for comparisons between the groups.
Results
Before treatment, the two groups were broadly similar (Table 1). All patients were clinically euthyroid during the follow-up period. Plasma T4 and free T4 increased significantly in group A because of the LT4 treatment (mean & SD T 4 107.1+ 1 6 . 8 171.6+43.9nmol/landfreeT4: ~~ 15.5k3.9 us 3 1.0 9.0 pmol/l; P < 0.05),plasma T3 was not modified with the treatment (T3: 1.8 k0.3 us 2.0 0.5 nmol/l; P= NS) and TSH showed a correct suppression in all cases (TSH: 1.1 kO.8 vs
