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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 11 4928-4934
Copyright © 2002 by The Endocrine Society

Original Article

Effects of Thyroid-Stimulating Hormone Suppression with Levothyroxine in Reducing the Volume of Solitary Thyroid Nodules and Improving Extranodular Nonpalpable Changes: A Randomized, Double-Blind, Placebo-Controlled Trial by the French Thyroid Research Group

Jean-Louis Wémeau, Philippe Caron, Claire Schvartz, Jean-Louis Schlienger, Jacques Orgiazzi, Cécile Cousty and Virginie Vlaeminck-Guillem FOR THE FRENCH THYROID RESEARCH GROUP

Clinique Marc Linquette, Centre Hospitalier Régional et Universitaire de Lille (J.-L.W., V.V.-G.), F-59037 Lille cedex, France; Hôpital de Rangueil, Centre Hospitalier Universitaire de Toulouse (P.C.), F-31403 Toulouse, France; Institut Jean-Godinot (C.S.), F-51056 Reims, France; Centre Hospitalier Universitaire Hautepierre (J.-L.S.), F-67098 Strasbourg, France; and Centre Hospitalier Lyon Sud, Pierre-Bénite (J.O.), F-69495 Lyon (C.C.), France

Address all correspondence and requests for reprints to: Jean-Louis Wémeau, M.D., Clinique Marc Linquette, Centre Hospitalier Régional et Universitaire de Lille, 6 rue du Prof. Laguesse, F-59037 Lille cedex, France. E-mail: jl-wemeau{at}chru-lille.fr.

Abstract

The efficacy of suppressing TSH secretion with levothyroxine (L-T4) in reducing solitary thyroid nodule growth is still controversial. In this prospective multicenter, randomized, double-blind, placebo-controlled trial, 123 patients with a single palpable benign nodule were included and randomly allocated to an 18-month treatment with L-T4 or placebo. Individual dose was adjusted to allow a serum TSH level below 0.3 mIU/liter. Clinical and ultrasonographic nodule characteristics were assessed before treatment and 3, 6, 12, and 18 months thereafter.

The largest mean nodule size assessed on palpation and largest volume, assessed by ultrasonography, decreased in the L-T4 group and increased slightly in the placebo group [size, -3.5 ± 7 mm vs. +0.5 ± 6 mm (P = 0.006); volume, -0.36 ± 1.71 ml vs. +0.62 ± 3.67 ml (P = 0.01), respectively]. The proportion of clinically relevant volume reduction (>=50%) rose significantly in the L-T4 group [26.6% vs. 16.9% (P = 0.04)]. The proportion of patients with a reduced number of infraclinical additional nodules was significantly higher in the L-T4 group [9.4% vs. 0 (P = 0.04)].

It is concluded from this study that suppressive L-T4 therapy is effective in reducing solitary thyroid nodule volume and improving infraclinical extranodular changes.

THYROID NODULES ARE a common clinical dilemma for which physicians and surgeons are often asked to make a diagnostic or management decision (1). Clinically visible nodules are present in 4–7% of the general adult population (2, 3, 4). Autopsy (5), surgery (6), and ultrasound studies (7) have revealed discrete nodules in up to 50% of individuals. The efficacy of levothyroxine (L-T4) in reducing thyroid nodule size remains controversial. The purpose of L-T4 administration was originally to reduce the growth-promoting effect of TSH (8, 9, 10). However, during the last 15 yr, several authors have undermined this concept by failing to prove the efficacy of L-T4 (11, 12, 13, 14). Others believe that nodules should be left to regress spontaneously (15, 16, 17). Concern was also expressed about the risk-benefit ratio of L-T4 administration (17, 18). Nevertheless, general clinical experience, controlled studies (12, 19), as well as a recent meta-analysis (20) and a study using the so-called quantitative research synthesis (21) indicate that at least some nodules shrink under L-T4. Furthermore, negative studies may have been hampered by imprecise definition of the nodules, insufficient L-T4 dosage or duration of treatment, or insufficiently restrictive inclusion criteria. Many previous trials were not randomized or placebo-controlled. Finally, little information is available on factors predictive of nodule shrinkage as well as on the possible beneficial effect of L-T4 treatment on extranodular nonpalpable changes.

The French Thyroid Research Group therefore undertook a multicenter, prospective, randomized, double-blind, placebo-controlled trial to assess the efficacy of TSH-suppressing L-T4 therapy in reducing the volume of solitary benign thyroid nodules and in modifying perinodular thyroid tissue.

Patients and Methods

Study design

This study was a multicenter, randomized, double-blind, placebo-controlled clinical trial designed to establish whether or not the administration of L-T4 reduces the volume of thyroid nodules found to be solitary by clinical examination. We enrolled patients when they had a single palpable nodule proven to be benign by fine-needle aspiration biopsy and they were identified less than 1 yr before the study began. The following were excluded from the study: patients with more than one palpable nodule, and patients with a history of cardiovascular disease, osteoporosis, previous thyroid surgery, neck irradiation, and/or thyroiditis. Also excluded were patients with abnormal serum thyroid hormone or TSH levels, circulating autoantibodies, patients who had nodules with a cystic component exceeding 20%, and patients with hot nodules and suppression of surrounding tissue at thyroid imaging. No patient included was taking any medication. Only patients aged from 18–55 yr were enrolled. All patients were from France, an area in which median urinary iodine excretion (8 µg/100 ml) suggests a quite sufficient iodine supply (22).

Nodule size, location, shape (oval or round), consistency, and boundaries were carefully recorded. Nodule size was measured by high-frequency ultrasonography. Thyroid scanning was performed. We also measured the following in all patients: serum levels of free T3 (fT3) and free T4 (fT4; radioimmunometric assays), TSH (immunochemoluminometric assays), and antithyroglobulin, antithyroperoxidase, and anti-TSH receptor antibodies (hemagglutination or solid immunoradiometric assays). Patients were then randomly allocated to the L-T4 treatment or placebo group using a table of random numbers, without stratification according to site. Oral L-T4 was given at an initial dose of 2.5 µg/kg body weight per day, to be taken in a single dose in the morning. The dose was individually adjusted after the first 4 wk, to maintain serum TSH levels below normal values (<0.3 mIU/liter). Both L-T4 and placebo were administered as externally identical tablets.

Patients were seen after 3, 6, 12, and 18 months of L-T4 treatment. At each visit, they were assessed by the same physician for weight, blood pressure, heart rate, nodule palpation, and signs and symptoms of thyrotoxicosis. ß-Blocker prescription was allowed if a patient complained of tachycardia (bisoprolol, 5–10 mg/d). Compliance with therapy was individually checked by careful questioning of the patient and measurement of serum TSH levels. Serum thyroid hormones were measured at each visit and additionally when L-T4 dose had been changed. Ultrasonography was repeated at 6, 12, and 18 months, and the ultrasonography examiner had no access to previous findings about the nodule, TSH levels during the study, or the treatment code. Fine-needle aspiration biopsy was repeated at 12 months. All patients admitted to the study had given informed consent to the protocol, which was approved by our institutional Ethics Committee.

Ultrasonography

High-resolution ultrasonography imaging was performed with a commercially available real-time instrument (10 MHz). The maximal diameter of the palpable nodule was measured in three planes. Patients with nodules larger than 3 cm in any dimension were excluded, because such nodules could not be accurately measured. The sonographic characteristics of the nodule were recorded to determine whether the internal contents were cystic, solid, or mixed, or whether peripheral halo (hypoechogenic pad surrounding the nodule) or calcifications were present. The ultrasonography examiner also mentioned the presence of other nonpalpable thyroid nodules, and extranodular nonpalpable changes were defined as the presence of at least one additional nonpalpable nodule. The volume of the palpable nodule was calculated according to the spherical ellipsoid formula: volume (ml) = {pi}/6 x AP (cm) x width (cm) x length (cm), where AP is the anteroposterior diameter (23). The dimensions of the thyroid lobes homolateral and contralateral to the palpable nodule were also measured in three planes. In all patients, ultrasound examinations were carried out before fine-needle aspiration biopsies (24).

Fine-needle aspiration biopsy

Direct or ultrasonography-guided fine-needle aspiration biopsies were performed by a trained cytologist or clinician according to the recommended techniques (25). Several samples of each nodule were obtained, and smears were prepared on microscopic slides, immediately fixed in 95% ethyl alcohol while still wet, and stained by the Papanicolaou method (25).

Thyroid scanning

Thyroid scans were performed after pertechnetate-99m iv administration. Nodules were classified as follows, according to the activity recorded in the region of the nodule: nonfunctional, if only background activity was seen; hypofunctional, if isotope activity was equal to or less than that of the surrounding parenchyma; and functional, if isotope activity was increased with no suppression of the surrounding parenchyma.

Statistical analysis

According to previous reports, a reduction of 0.5 ml in nodule volume could be expected after 6 months of suppressive L-T4 treatment. We considered therapy successful when it induced a 0.75-ml reduction in nodule volume after 18 months of suppressive L-T4 treatment. Given a type I error of 0.05 (two-sided) and a power of 0.9, we estimated the necessary sample size to be 127 patients in each group. Considering that about 10% of patients might not complete the protocol, the total sample size necessary was estimated at 300.

Analyses were completed on an intention-to-treat basis. Results for continuous measures are expressed as means ± SD. All comparisons between the L-T4 and placebo groups were based on two-tailed, two-sample t tests for quantitative variables, except for skewed variables that were analyzed using the Wilcoxon rank-sum test. The {chi}2 and Fisher exact tests were used to calculate differences between proportions.

Results

Pretreatment findings

Despite an expected total sample of 300 patients, patient recruitment was difficult, and it was stopped after 135 informed patients had been enrolled at 25 study centers. In all, 123 patients (91%) were available for evaluation of the main judgment criteria, i.e. variations in nodule volume. Sixty-four of these 123 patients were randomly assigned to the L-T4 group, and 59 to the placebo group. All patients were clinically and biologically euthyroid on entry into the study. At baseline, there were no apparent differences between the distribution of demographic or other characteristics between the two groups (Table 1Go).


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  		Table 1. Initial clinical, biological, and thyroid nodule characteristics in patients given L-T4 or placebo

 
Of the 123 patients included, 106 (86%) completed the 18-month protocol, and 17 did not. In the L-T4 group, 4 patients were treated for 6 months, 2 for 12 months, and 58 for 18 months. In the placebo group, 2 patients complied with the procedure for 6 months, 9 for 12 months, and 48 for 18 months. Six of the 17 patients who did not complete the protocol spontaneously decided to withdraw from the study. Of the remaining 11, 2 patients receiving L-T4 treatment dropped out (one developed iatrogenic thyrotoxicosis and required dose reduction, and the other requested thyroidectomy because of nodule growth). The 9 other patients, who were in the placebo group, dropped out for the following reasons: 5 underwent hemithyroidectomy because of a suspect fine-needle aspiration biopsy at 12 months (papillary carcinoma in 1 patient), 1 patient refused further treatment at 12 months because of nodule pain, 1 patient decided to have surgery at 6 months for a benign follicular adenoma, 1 patient was diagnosed as having myeloproliferative syndrome at 1 month, and 1 patient was diagnosed at 10 months as having hyperthyroidism and Graves’ disease. The characteristics of the patients who dropped out and of their nodules were similar to those of the patients who completed the study (data not shown).

Treatment tolerance and patient compliance

Compliance with treatment was good in all patients studied, according to patient self-reporting, clinical examination, and laboratory. Compliance was also evaluated by systematically getting tablet packaging back. In all patients receiving L-T4, the serum TSH level was less than 0.3 mIU/liter after 3, 6, and 12 months of treatment (Table 2Go). However, at 18 months, mean TSH level was 0.38 ± 0.66 mIU/liter, suggesting mild lack of compliance at the end of the study. In this group, the mean dose of L-T4 necessary to obtain effective TSH suppression without hyperthyroidism was 2.24 ± 0.45 µg/kg·d. A significant difference was observed in TSH levels in the L-T4 and placebo groups at the end of the study (Table 3Go). Although in the average, fT3 levels were not significantly different, the difference between the average fT4 levels also reached statistical significance (Table 3Go). Furthermore, at the end of the study, ultrasonography showed significant differences between the two groups as regards the mean size and volume of the thyroid lobe contralateral to the palpable nodule (Table 3Go). The mean size and volume of the ipsilateral lobe also decreased, although not significantly.


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  		Table 2. Levels of TSH in the L-T4 group at each measurement point

 

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  		Table 3. Mean variations in the clinical, biological, and ultrasonographic characteristics of patients with a solitary thyroid nodule after 18 months of treatment with L-T4 or placebo

 
Variations in heart rate and blood pressure (systolic and diastolic) were not different in the two groups (Table 3Go). Although the proportion of patients requiring at least one dose of ß-blocker during the study was larger in the L-T4 group than the placebo group, the difference did not reach significance (Table 3Go). One patient in each group developed severe hyperthyroidism requiring withdrawal from the study. Subsequently, the patient in the placebo group proved to have underlying Graves’ disease.

Nodule response to treatment

The maximal dimensions of the nodule, as assessed by palpation and ultrasonography, were compared in the two groups before and at the end of the study. In the L-T4 group, the mean maximal nodule diameter measured by palpation before treatment was not different from that in the placebo group (19 ± 5 vs. 20 ± 5 mm). At the end of the study, a significant decrease in the size of the largest nodules, as assessed by palpation, was observed in the L-T4 group (mean change, -3.5 ± 7 mm), whereas in the placebo group nodule size increased by a mean +0.5 ± 6 mm (Table 4Go). The change in the largest size of the nodule was significantly different in the two groups (P = 0.006). It was also different, although not significantly (-1.25 ± 5.57 mm vs. +0.44 ± 6.9 mm; P = 0.07), when nodule diameter was assessed by ultrasonography (Table 4Go).


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  		Table 4. Mean changes in solitary thyroid nodule size and volume after 18 months of L-T4 or placebo treatment

 
Nodule volume assessed ultrasonographically was also used to compare responses to therapy (Table 4Go). In the L-T4 group, compared with the initial value (2.76 ± 2.47 ml), a clear decrease was observed as soon as the sixth month (2.30 ± 2.01 ml), whereas no clear change was noted in the placebo group (3.50 ± 2.95 and 3.62 ± 3.24 ml, respectively). At the end of the study, the decrease in nodule volume was confirmed in the L-T4 group (mean change, -0.36 ± 1.71 ml). However, in the placebo group, nodule volume increased (mean change, +0.62 ± 3.67 ml). The change in volume was significantly different in the two groups (P = 0.01).

On the basis of the nodule volume recorded at the end of L-T4 therapy, the 123 patients were classified as responders (>=50% decrease), partial responders (>=20% to 50%), and nonresponders (<20%). As shown in Fig. 1Go, there were 17 responders among the 64 patients given L-T4 (26.6%), and 10 responders among the 59 patients receiving placebo (16.9%). The proportions of responders, partial responders, and nonresponders were significantly different in the two groups (P = 0.04).



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  		Figure 1. Distribution of clinically relevant reductions in thyroid nodule volume in patients given L-T4 and those given placebo. Significantly different distribution in the L-T4 and placebo groups (P = 0.04, {chi}2 test). Responders, volume reduction >= 50%; partial responders, 20% <= volume reduction < 50%; nonresponders, volume reduction < 20%.

 
Factors predictive of nodule shrinkage

In managing patients with a solitary thyroid nodule, it would be helpful to identify the nodules likely to shrink. We therefore attempted to define clinical, biological, ultrasonographic, or scintiscan characteristics predictive of nodule shrinkage. Using regression analysis, we failed to correlate shrinkage with any of the following characteristics: age, sex, nodule shape and location on palpation, pretreatment TSH and fT4 levels, and ultrasonographic nodule characteristics such as size, presence, or absence of perinodular halo, echotexture, and nodule function shown by thyroid scan imaging. However, we did find that nodule shrinkage was related to the initial nodule volume as assessed ultrasonographically, i.e. the larger the pretreatment nodule volume, the larger the reduction in that volume. We checked that when adjusted for pretreatment volume, the effect of L-T4 on the nodule volume was still significantly different from that of placebo (P = 0.03).

Response of extranodular nonpalpable changes to treatment

Although according to palpation, each patient was diagnosed as having only a single nodule, 27 patients in the L-T4 group (42.2%) and 20 in the placebo group (33.9%) were found to have at least one additional nodule on ultrasonography. At the end of the study, these proportions were 40.6% (26 patients) and 47.5% (28 patients), respectively. Extranodular nonpalpable changes were classified as improved (disappearance of at least one of the additional infraclinical nodules), unchanged (no change in the number of these nodules), or worse (appearance of at least one other additional infraclinical nodule). Figure 2Go depicts the evolution of extranodular nonpalpable changes at the end of the study. The respective distributions of improvement, lack of change, and worsening were significantly different in the L-T4 and placebo groups (P = 0.04). Compared with placebo, L-T4 therapy therefore improved or arrested the evolution of extranodular nonpalpable changes.



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  		Figure 2. Distribution of changes in extranodular nonpalpable changes in patients given L-T4 and those given placebo. Significantly different distribution in the L-T4 and placebo groups (P = 0.04, Fisher exact test). Improvement, disappearance of at least one of additional infraclinical nodule; No change, no change in the number of additional infraclinical nodules; Worsening, appearance of at least one other additional infraclinical nodule.

 
Discussion

This multicenter, prospective, randomized, double-blind, placebo-controlled trial, conducted in 123 patients, shows that the mean size of a palpable thyroid nodule, as well as the mean nodule volume assessed ultrasonographically, decreased in patients treated for 18 months with TSH-suppressive L-T4 therapy, compared with the patients given placebo. We observed a clinically relevant reduction in nodule volume (>=50%) in 17 of the 64 patients receiving L-T4 and in 10 of the 59 placebo-treated patients. In addition, we showed that L-T4 therapy has a favorable effect on the development of extranodular nonpalpable changes.

The effectiveness of L-T4 in reducing the size of thyroid nodules remains controversial (1), although survey data suggested that many endocrinologists would recommend maintaining serum TSH concentrations below, or at least within the low normal range (21, 26). The effect of L-T4 treatment on thyroid nodule volume has been extensively studied. However, except for one study published in 1963 (27), the results of which are questionable because of inappropriate methodology (21), only eight trials were randomized (Table 5Go; Refs. 11, 13, 14, 19, 20, 28, 29, 30). Six of them were negative, with no beneficial effect of L-T4 therapy on nodule size (11, 14, 20, 28, 29, 30). Discrepancy between these six studies and the present one may be due to the absence of ultrasonography evaluation (28, 31), the lack of a placebo control group (14, 28), uncontrolled or inefficient TSH suppression (11, 32), insufficient treatment duration (11, 14, 20, 30), inclusion of hot or cystic nodules (11, 14), excessive dropout rate in the L-T4 group (14, 33), and/or an insufficient number of patients (20, 30). In the present study, we evaluated nodule size and volume in a double-blind manner, using high-resolution ultrasonography imaging. As many as 123 patients were given L-T4 or placebo for 18 months, and effective TSH suppression was routinely checked at each visit. Our results are in keeping with those of a recent meta-analysis and of a quantitative research synthesis showing that suppressive L-T4 therapy is effective in reducing nodule volume and impeding nodule growth (20, 21). They are also consistent with the last two randomized trials published (13, 19). These trials showed a significant decrease in nodule size or volume, as assessed by palpation and/or ultrasonography, in L-T4-treated patients compared with baseline values. However, their authors did not compare the mean changes in nodule size in the L-T4 and placebo groups, as was done in our study. This comparison enabled us to demonstrate that L-T4 is significantly more effective than placebo in reducing thyroid volume.


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  		Table 5. Summary of the randomized studies addressing the efficiency of L-T4 in reducing nodule growth

 
In fact, the relevant issue is not the average nodule shrinkage, but rather the proportion of nodules that shrink relevantly (>=50% reduction) during L-T4 therapy, compared with the substantial shrinkage reported for placebo-treated nodules (16, 21). Of the six previous randomized trials (Table 5Go), one (28) did not indicate the proportion of responders. This proportion was higher in the L-T4 groups than in the placebo or no-treatment groups in three of the five other trials (13, 19, 20), but the difference was only significant in two (13, 19). Our results clearly confirm that the proportion of responders is significantly increased by L-T4 treatment.

There is increasing concern (34, 35, 36) about the risk-benefit ratio of L-T4 therapy for thyroid nodule. Some authors reported bone mineral density decreases in L-T4-treated patients (18, 37) as well as undesirable effects on the heart (38, 39) and suggested that the potential benefits of L-T4 might be outweighed by the long-term potential risks, especially in postmenopausal women (40). In the present study, we did not evaluate the long-term effect of L-T4 on bone. However, the deleterious effect of L-T4 therapy remains questionable. Thus, no increase in bone fracture rate has been reported so far in any study of women treated with L-T4 (16, 36), and in a recent study (20) no change was found in the mean bone mineral density of women after 1 yr of L-T4 therapy for benign solitary thyroid nodules (TSH < 0.3 mIU/liter). Another study (41) showed a significantly increased risk for new hip and vertebral fractures in women older than 65 yr of age who had low TSH levels, but not in those with L-T4 therapy. Heart rate, blood pressure, and body weight were not significantly affected by L-T4 compared with placebo in our study, despite daily doses sufficient to suppress TSH. No other similar clinical trial has consistently demonstrated a higher risk for L-T4 than placebo or no treatment (12, 13). An interesting way of improving the risk-benefit ratio of L-T4 would be to identify a subgroup of patients whose nodules will presumably respond to this drug. Baseline thyroglobulin levels and their decrease during treatment have been advocated as useful predictors of the outcome of L-T4 therapy (42, 43), but we did not study these levels. In fact, in the present study as well as in others (13, 14), neither patient nor nodule characteristic was found to be a reliable predictor of nodule shrinkage during L-T4 treatment, except for pretreatment nodule volume (44). Taking into account these consistent observations as well as the well known natural heterogeneity of thyroid follicles (45), it is suggested that intrinsic parameters of nodule biology are in themselves likely involved in variable response to L-T4 therapy. For instance, the dependence of nodule development on growth factors different from TSH (46) might be responsible for these findings, in addition to the possible presence of mutations in the TSH receptor.

Another point of interest is the ability of L-T4 to reduce or even prevent the development of additional nodules. This question has been rarely addressed in the literature (16). Papini et al. (29) observed that L-T4-treated patients did not exhibit decreased thyroid nodule volume after 5 yr of treatment, but the nodule volume increased in the control group, in which there was a larger number of newly formed nodules. Our results suggest that L-T4 therapy is more efficient than placebo in preventing the development of additional nodules and could reduce the occurrence of nodule volume-related complaints and the number of subsequent surgical operations for multinodular goiters (47).

In conclusion, we demonstrated that 18 months of TSH-suppressive L-T4 therapy are effective in reducing the growth of solitary thyroid nodules as well as in preventing the further development of additional nodules in patients originating from an area with quite sufficient iodine supply. Clinically relevant reductions in thyroid nodule size were observed after L-T4 therapy, without significant untoward effect. Complete regression of thyroid nodules seems anecdotal, but treatment with L-T4 is worth recommending to reduce nodule size as well as to prevent further nodule growth and multinodular goiter development. Many questions remain to be answered, such as the optimal level of thyroid suppression, or the optimal duration of treatment. Further studies are also required to distinguish patients who are likely to benefit from suppressive L-T4 therapy from those who are not.

Acknowledgments

We thank Drs. Delisle, Schmitt, Muratet, Archambeaud, Winiszweski, Couturier, Lecomte, Bauters-Cardot, Boulard, Allanic, Lorcy, Decoulx, Duron, Baldet, Simon, Artus, Leclère, Lefaucheur, Lestradet, Malinski, Voitelier, Roger, Vakanas, Verier-Mine, Montpeyssen for their help in the recruitment and follow-up of patients. We are also grateful to Dr. J.-F. Cussac for ultrasonography expertise and Dr. B. Le Bealle and Mr. J.-L. Vaudo from Merck-Lipha Santé for technical assistance.

Footnotes

Computer and statistical support and L-T4 drug supply were kindly provided by Merck-Lipha Santé France.

Abbreviations: fT3, Free T3; fT4, free T4; L-T4, levothyroxine.

Received March 8, 2002.

Accepted August 14, 2002.

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