Thyroid hormone suppressive therapy for thyroid nodules and benign goiter

INTRODUCTION — The efficacy of thyroid hormone suppressive therapy in euthyroid patients with solitary benign thyroid nodules or sporadic nontoxic multinodular goiters is controversial. Most studies have shown that few thyroid nodules regress in patients taking thyroid hormone. However, suppressive therapy does appear to interfere with goitrogenesis in many patients, and it has been proposed that it could reduce the risk of thyroid oncogenesis, as well. A 2016 survey of members of the American College of Physicians, American Academy of Family Practice, and the Endocrine Society found that 24.5 percent of respondents used thyroid hormone suppressive therapy, including 14 percent of endocrinologists [1]. It is therefore important to review the evidence.

This topic will review potential benefits of thyroid hormone suppressive therapy in patients with benign nodules or goiter. The risks of thyroid hormone suppressive therapy, the overall approach to the evaluation and treatment of patients with goiter and with thyroid nodules, as well as the use of thyroid hormone suppressive therapy in thyroid cancer are discussed separately. (See "Subclinical hyperthyroidism in nonpregnant adults", section on 'Potential consequences of subclinical hyperthyroidism' and "Clinical presentation and evaluation of goiter in adults" and "Diagnostic approach to and treatment of thyroid nodules" and "Differentiated thyroid cancer: Overview of management", section on 'Thyroid hormone suppression'.)

PATHOPHYSIOLOGY — Suppression of thyroid-stimulating hormone (TSH) secretion in normal subjects by the administration of thyroid hormone results in thyroid atrophy [2]. Although the pathogenesis of thyroid nodules and sporadic nontoxic multinodular goiters is poorly understood, TSH is presumed to be necessary if not sufficient, and therefore, suppression of TSH secretion might be expected to result in a decrease in nodule or goiter size or at least prevent further enlargement.

The importance of TSH in goiter formation varies with the cause of the goiter. For example, in patients with iodine deficiency or chronic autoimmune (Hashimoto's) thyroiditis, an increase in TSH secretion is the predominant cause of goiter. In contrast, most patients with thyroid nodules or sporadic nontoxic multinodular goiters have normal serum TSH concentrations. In them, particularly those with nontoxic multinodular goiters, the thyroid enlargement is probably caused by several growth factors (including TSH) that act over time on thyroid follicular cells that have different synthetic and growth potentials. The result is diffuse and later multinodular thyroid enlargement; some nodules eventually become autonomous [3], and others may undergo cystic degeneration.

Because thyroid hormone is presumed to reduce goiter size by reducing TSH secretion, suppressive therapy would be expected to be ineffective in patients in whom serum TSH concentrations were already subnormal due to autonomous thyroid hormone production.

NONTOXIC GOITER — In the absence of a history of childhood head and neck irradiation, we do not routinely treat euthyroid goitrous patients from areas of iodine sufficiency with levothyroxine (T4). The American Thyroid Association (ATA) also does not recommend suppression therapy of benign thyroid nodules in iodine-sufficient populations owing to concern that the risks of suppressive therapy, especially in older patients, outweigh its benefits [4]. T4 suppressive therapy was previously commonly used for goiter, but its use has declined since the 1990s primarily due to concerns regarding the long-term side effects from the induction of subclinical or overt hyperthyroidism, such as reduced bone density and increased risk of atrial fibrillation. (See "Subclinical hyperthyroidism in nonpregnant adults".)

However, in iodine-deficient patients or selected younger patients who are concerned about growth of their goiter, a trial of T4 aiming either for minimal TSH suppression or a low-normal TSH is a reasonable intervention pending further studies, especially those that assess the efficacy of suppressing serum TSH into the low-normal range. (See 'TSH goal' below.)

Thyroid hormone suppressive therapy is effective in reducing goiter volume and preventing the development of new nodules in some patients, particularly in patients from regions of the world with borderline or low iodine intake [5-7]. (See 'Efficacy' below.)

The evaluation and management of nontoxic goiter is reviewed in detail separately. (See "Clinical presentation and evaluation of goiter in adults".)

Efficacy — In randomized control trials, thyroid hormone (thyroxine; T4) suppression can interfere with the process of goitrogenesis (goiter growth and new nodule formation). Only some goiters respond, while others grow despite T4 treatment [5,8]. Treatment must be continued or goitrogenesis resumes [5]. As examples:

●In a double-blind trial, 78 patients with nontoxic goiter (average thyroid volume 53 mL) were randomly assigned T4 or placebo for nine months and then followed for an additional nine months [5]. Thyroid volume, as assessed by ultrasonography, decreased in a greater proportion of patients in the T4 group (58 versus 5 percent) (figure 1). In the responders, the mean decrease in thyroid volume was 25 percent. Over half the patients in the T4 group developed thyrotoxic symptoms during the trial, and goiter growth resumed in this group after therapy was discontinued.

●In another trial from an iodine-deficient region of Italy, 71 premenopausal women with benign, nontoxic, multinodular thyroid disease (mean thyroid volume 15 mL) were randomly assigned T4 (2 mcg/kg) or no treatment [6]. Compared with baseline values, treatment with T4 for one year significantly reduced mean thyroid volume (15.6 to 10.6 mL), mean dominant nodule volume (1.8 to 0.8 mL), and the number of nodules greater than 5 mm (0.8 to 0.4). In contrast, those parameters significantly increased from baseline in controls (14.8 to 20.0 mL, 1.2 to 2.5 mL, and 0.7 to 1.5, respectively).

TSH goal — It is possible that the benefits of T4 therapy do not require suppression to subnormal serum TSH concentrations. In one trial, 49 patients from Istanbul (a city with reported adequate iodine intake) with solitary thyroid nodules were randomly assigned to receive high-dose (serum TSH <0.01 mU/L) or low-dose (serum TSH 0.4 to 0.6 mU/L) T4 therapy [9]. High- and low-dose T4 therapy were equally effective in reducing nodule volume (36 and 45 percent reduction in nodule size in the high- and low-dose groups, respectively).

In another trial of T4 therapy, 1024 patients with mild to moderate iodine deficiency and one or more thyroid nodules were randomly assigned to T4 (goal TSH 0.2 to 0.8 mU/L), iodine (150 mcg, ie, the amount of iodine present in most multivitamins in the United States), T4 plus iodine, or placebo [7]. After one year, mean thyroid nodule volume decreased in all groups (-12.1, -9.0, -21.6, and -5.2 percent, respectively). Treatment with T4 plus iodine was significantly superior to placebo, T4, and iodine alone. Individual changes in thyroid nodule volume were variable. Decreases of more than 50 percent were seen in 7.6, 9.5, 11.3, and 8.5 percent of the nodules in the T4, iodine, T4 plus iodine, and placebo groups, respectively [7]. Thus, maintaining TSH in the lower end of or just below the normal range (rather than below 0.01 mU/L) appears to be efficacious. It is possible that this strategy will mitigate the adverse effects of T4 suppressive therapy. This concept requires further study.

Special populations

Irradiated patients — External radiation exposure during childhood (therapeutic radiation as part of cancer therapy, radiation for nonmalignant conditions, exposure from nuclear power plants [Chernobyl, Fukushima]) increases thyroid tumorigenesis. There are few data to determine the efficacy of thyroid hormone suppressive therapy in reducing nodular thyroid growth in this population [10,11]. In a nonrandomized study of 632 adults who were treated prior to age 16 with conventional radiation for nonmalignant conditions and who subsequently had benign thyroid nodules removed surgically, patients who were treated with thyroid hormone had a lower incidence of recurrent nodules than those who were not (14 versus 34 percent; relative risk [RR] 0.69, 95% CI 0.47-1.01) [12]. (See "Radiation-induced thyroid disease".)

External radiation exposure for malignancy during childhood also increases the risk of hypothyroidism [13,14]. All patients with hypothyroidism require treatment with T4 (see "Treatment of primary hypothyroidism in adults"). However, whether irradiated euthyroid patients with one or more thyroid nodules or multinodular goiter benefit from T4 suppressive therapy is uncertain. In the absence of contraindications (such as atrial arrhythmia, ischemic heart disease, or osteoporosis), some UpToDate experts treat euthyroid patients with benign thyroid nodules and a history of external radiation exposure in childhood, aiming for a low-normal or minimally subnormal serum TSH concentration. Other experts, however, would not treat such euthyroid patients, unless the serum TSH was in the upper part of the normal range (ie, >3.0 mU/L).

Suppressive therapy after surgery for nontoxic goiter — The apparent efficacy of thyroid hormone therapy for suppression of nontoxic goiter led to its use to prevent goiter recurrence after partial thyroidectomy [15-17]. Two randomized trials showed a trend toward fewer recurrences with T4 therapy (15 versus 22 percent and 21 versus 35 percent) that were not statistically significant [18,19].

Hashimoto's thyroiditis — Thyroid hormone is particularly efficacious in reducing goiter size when thyroid enlargement is due to an elevated serum TSH concentration in patients with hypothyroidism due to Hashimoto's thyroiditis. However, even euthyroid goitrous patients with Hashimoto's thyroiditis may respond to suppressive therapy with T4 [20].

Oncogenesis in goiter — A potential benefit of T4 suppressive therapy is a reduction in the risk of thyroid cancer. The risk of thyroid cancer in patients with thyroid nodules increases with increasing serum TSH concentrations [21]. In a retrospective analysis of patients with nodular goiter, the prevalence of papillary thyroid cancer was significantly reduced in 7859 patients with nodular goiter taking T4 compared with 20,055 patients not taking T4 (3.2 versus 5.1 percent) [22]. These data suggest that suppressive therapy might reduce oncogenesis in goiter [22]. This hypothesis is still speculative, and additional data are required. The use of T4 suppression therapy to reduce tumor growth and recurrence in patients with differentiated thyroid cancer is reviewed separately. (See "Differentiated thyroid cancer: Overview of management".)

SOLITARY NODULES — Thyroid hormone suppressive therapy is effective in reducing nodule volume and preventing the development of new nodules in some patients, particularly those patients from regions of the world with borderline or low iodine intake. In iodine-sufficient regions, only 17 to 25 percent of patients with a solitary nodule will have a decrease in nodule size (more than 50 percent) as a result of T4 treatment [8,23-25]. Furthermore, in some patients, solitary nodules regress spontaneously.

In view of the small percentage of thyroid nodules that regress after T4 treatment, the modest responses, and the potential adverse risks (atrial arrhythmias and reduced bone density) of thyroid hormone suppressive therapy, we do not suggest the routine use of thyroid hormone suppressive therapy for solitary palpable thyroid nodules in areas of iodine sufficiency. This is consistent with American Thyroid Association (ATA) guidelines [26]. However, in iodine-deficient regions, a trial of T4 aiming for low-normal or minimally subnormal TSH concentrations appears to be a reasonable intervention, pending further studies that assess the efficacy of suppressing serum TSH into the low normal range [9,27]. (See 'TSH goal' above.)

Data on the impact of thyroid hormone suppressive therapy for solitary nodules are conflicting, as illustrated by the results of several randomized trials [8,9,23,28-36] and the following meta-analyses:

●A meta-analysis of six trials (346 patients) showed that patients randomly assigned to suppressive thyroid hormone therapy for longer than six months were more likely to have a reduction in nodule volume by more than 50 percent, but this was not statistically significant (relative risk [RR] 1.90, 95% CI 0.95-3.81) [24]. The meta-analysis was limited by heterogeneity in the study results.

●A meta-analysis of nine trials (609 patients) concluded that thyroid hormone suppression was more likely than placebo or no treatment to reduce nodule volume >50 percent (response rate 22 versus 10 percent; RR 1.88, 95% CI 1.18-3.01) [37]. However, long-term treatment appeared to be less effective, and regrowth was likely after cessation of thyroid hormone.

The trials included in the meta-analyses enrolled patients with solitary thyroid nodules and ultrasonographic evaluation of nodule volume. Appropriate suppression of TSH was documented by measurement of serum TSH or by thyrotropin-releasing hormone (TRH) stimulation test.

In one of the trials in the meta-analysis, 49 patients with solitary thyroid nodules were randomly assigned to receive high-dose (serum TSH <0.01 mU/L) or low-dose (serum TSH 0.4 to 0.6 mU/L) T4 therapy [9]. High- and low-dose T4 therapy were equally effective in reducing nodule volume (36 and 45 percent reduction in nodule size in the high- and low-dose groups, respectively). The term "levothyroxine nonsuppressive therapy" was suggested to describe the effects of levothyroxine on thyroid nodule growth when the goal is to reduce TSH into the low-normal range [27]. In one nonrandomized trial from Italy, administering levothyroxine in a dose that achieved a TSH of 0.5 to 0.8 mU/L resulted in a slower rate of nodule growth, with significant differences between levothyroxine-treated and untreated patients after four years [27]. The potential benefits and side effects of this approach require further investigation.

The majority of the trials in the meta-analyses were of relatively short duration (6 to 18 months) [23,24,37]. In one of the trials with longer follow-up, a five-year trial from an iodine-sufficient area of Italy in which 83 patients were randomly assigned to receive T4 or no treatment, nodule volume (measured by ultrasonography) decreased in only a small subset of T4-treated patients (those with complete TSH suppression) [36]. After five years, however, fewer patients receiving T4 suppressive therapy developed new sonographically detected nodules (7.5 versus 28.5 percent).

In another of the trials included in the meta-analyses, the characteristics of patients with nodules more likely to respond to suppressive therapy were [35]:

●Abundant colloid on biopsy

●Degenerative changes if the nodules were small (<2.4 mL in volume or <1.7 cm in diameter)

●Absence of hyperplastic or fibrotic changes

Oncogenesis in follicular neoplasms — The risk of thyroid cancer in patients with thyroid nodules increases with increasing serum TSH concentrations [21]. Treatment with T4 therapy in a dose adjusted to reduce TSH into the low-normal range (levothyroxine nonsuppressive therapy) may reduce the risk of thyroid cancer. As an example, in a preliminary retrospective report of levothyroxine nonsuppressive therapy in 532 patients undergoing surgery for indeterminate thyroid nodules (Bethesda III or Bethesda IV cytology), there was a lower rate of malignancy in Bethesda IV nodules (suspicious for a follicular neoplasm) in patients who were taking nonsuppressive doses of levothyroxine for at least two years to reduce nodule growth [38]. Exclusion criteria included thyroid autoimmunity, nodules >4 cm, thyroid malignancy elsewhere in the gland, radiation exposure or treatment, and a positive family history of cancer. Unfortunately, nodule size was not reported in this study. Since capsular and vascular invasion (the markers of a follicular cancer) is positively associated with size in follicular neoplasms and levothyroxine may reduce growth of thyroid nodules even when TSH is in the normal range ("levothyroxine nonsuppressive therapy"), these preliminary data suggest a reduction in oncogenesis with levothyroxine. (See 'Oncogenesis in goiter' above.)

SUGGESTED APPROACH — Uncertainty and controversy remain regarding the efficacy, risks, and benefits of thyroid hormone suppressive therapy for thyroid nodules and benign goiter. Because T4-suppressive therapy results (by definition) in subclinical hyperthyroidism, treated patients are at increased risk for atrial fibrillation, other cardiac abnormalities, or reduced bone density. The use of T4 suppression has, therefore, dramatically declined. Since 1996, the American Thyroid Association (ATA) guidelines have not recommended thyroid hormone suppressive therapy for benign thyroid nodules and nodular goiter in iodine sufficient populations. (See "Subclinical hyperthyroidism in nonpregnant adults" and "Bone disease with hyperthyroidism and thyroid hormone therapy".)

Since only 17 to 25 percent of nodules regress and the degree of regression is modest, we do not suggest T4 suppression for solitary or dominant thyroid nodules. We do not routinely use T4 suppression for patients with nodular goiter. However, in select patients (history of external radiation exposure during childhood, iodine-deficient region, and younger patients with growing diffuse or nodular goiter who are concerned about growth of their goiter), a trial of T4 aiming either for minimal TSH suppression or a low-normal TSH is a reasonable intervention, pending further studies, especially those that assess the efficacy of suppressing serum TSH into the low-normal range, which would mitigate the adverse effects of treatment.

Speculation that suppressive therapy may reduce the risk of oncogenesis as well as goitrogenesis may result in reconsideration of T4 suppression for more patients with goiter, especially if efficacy can be demonstrated when TSH is suppressed into the low-normal range. Suppressive therapy is not useful if the TSH is already subnormal.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thyroid nodules and cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Thyroid nodules (The Basics)" and "Patient education: Hyperthyroidism (overactive thyroid) (The Basics)")

●Beyond the Basics topics (see "Patient education: Thyroid nodules (Beyond the Basics)" and "Patient education: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient education: Antithyroid drugs (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Thyroxine (T4) suppression interferes with goitrogenesis (goiter growth and new nodule formation). Only some goiters respond, while others grow despite T4 treatment. Treatment must be continued or goitrogenesis resumes. (See 'Nontoxic goiter' above.)

●T4 suppression may also interfere with oncogenesis in nodular goiter. (See 'Oncogenesis in goiter' above.)

●In iodine-sufficient regions, 17 to 25 percent of patients with a solitary (or dominant) thyroid nodule will have a modest decrease in nodule size (>50 percent) as a result of T4 suppression therapy. In some patients, solitary nodules regress spontaneously. (See 'Solitary nodules' above.)

●Because T4-suppressive therapy results (by definition) in subclinical hyperthyroidism, treated patients are at increased risk for atrial fibrillation, other cardiac abnormalities, and/or reduced bone density. The American Thyroid Association (ATA) guidelines recommend against T4-suppressive therapy because the risks outweigh the advantages. (See "Subclinical hyperthyroidism in nonpregnant adults" and "Bone disease with hyperthyroidism and thyroid hormone therapy".)

●For most euthyroid patients with diffuse or nodular goiter, we suggest not routinely treating with T4 suppression therapy (Grade 2C). However, in selected patients (iodine deficient, history of childhood neck radiation, younger patients with growing diffuse or nodular goiter who are concerned about growth of their goiter), a trial of T4 aiming either for minimal thyroid-stimulating hormone (TSH) suppression or a low-normal TSH is a reasonable intervention. Suppressive therapy is not useful if the TSH is already subnormal. (See 'Suggested approach' above.)

●For euthyroid patients with solitary nodules living in iodine-sufficient regions of the world, we suggest not treating with T4 suppressive therapy (Grade 2B). However, in iodine-deficient regions, a trial of T4 aiming for low-normal or minimally subnormal TSH concentrations may be a reasonable alternative. (See 'Solitary nodules' above and 'Suggested approach' above.)

●The use of thyroid hormone suppressive therapy for prevention of recurrence in patients with differentiated thyroid cancer is reviewed separately. (See "Differentiated thyroid cancer: Overview of management", section on 'Thyroid hormone suppression'.)