Nonsurgical Approaches to the Management of Thyroid Nodules

Sebastiano Filetti; Cosimo Durante; Massimo Torlontano


Nat Clin Pract Endocrinol Metab. 2006;2(7):384-394. 

In This Article

Thyroid-hormone-suppressive Therapy

Thyroid-hormone-suppressive therapy with levothyroxine was preferred by over 40% of clinicians for treatment of solitary thyroid nodules. Over 50% of clinicians considered TSH suppression to be the treatment of choice for multinodular goiters.[7,8,9,10] The latter finding is surprising, since there is very little published evidence of the efficacy of this approach, and its use is not recommended in any of the currently accepted treatment guidelines.[16,17]

It is widely agreed that levothyroxine-induced suppression of TSH secretion shrinks thyroid nodules by preventing TSH's growth-promoting effect on thyroid cells. Thyrocyte growth, however, can also be promoted by insulin-like growth factors, and by other growth factors;[31] furthermore, the effects of TSH suppression on gene expression in nodular thyroid tissue are different from those observed in the corresponding normal tissue.[32] Finally, the degree of TSH suppression required to produce the putative therapeutic effect should be better defined, and this issue is becoming more and more pressing in light of our increasing awareness of the possible adverse effects of long-term thyroid-hormone-suppressive therapy.[33,34]

It is important to recall that reduction in nodule volume is a surrogate endpoint that does not necessarily correlate with the patient's well-being. Assuming that nodule shrinkage is necessary or at least beneficial in some cases, conflicting results have emerged. Many trials have been nonrandomized or lack controls, and have a wide variation in the number of patients and types of nodules studied, target levels of TSH suppression and treatment duration, and methods used for assessing nodule dimensions (palpation versus ultrasonography). There is also considerable variation in the degree of volume reduction used to define therapeutic efficacy.

A meta-analysis[35] of six randomized, controlled clinical trials[36,37,38,39,40,41] demonstrated a significant benefit with levothyroxine treatment in one study;[39] whereas, in another, the results of treatment were clearly negative.[36] On the average, the effects of levothyroxine failed to reach statistical significance: 22% of all levothyroxine-treated patients showed nodule shrinkage of more than 50%, as opposed to 10% of those in the placebo or control groups, and treatment was found to carry a relative risk of volume reduction of only 1.9 (95% CI 0.95–3.81).

More-significant differences emerged from a multicenter, randomized, double-blind, placebo-controlled trial.[42] After 18 months of follow-up, patients treated with levothyroxine displayed significantly greater reductions in nodule volumes than placebo-treated controls did (P = 0.01), and the percentage of responders (volume reductions ≥50%) was also higher in the treated group (26.6% versus 16.9%; P = 0.04). Thyroid-hormone-suppressive therapy was also effective in preventing the development of new nodules.[42,43]

A subset of benign thyroid nodules do respond to thyroid-hormone-suppressive therapy.[35] Unfortunately, markers for this subset have yet to be defined; however, cystic nodules are not responsive to levothyroxine therapy.[44] By contrast, thyroid-hormone-suppressive therapy was found to be effective in patients with solid nodules.[39,42] Other nodule characteristics associated with responsiveness to levothyroxine therapy are a recent diagnosis,[45] relatively small volumes (<10 ml,[45] <2.5 ml,[46] or <1.5 ml[26]), and an abundance of colloid in FNAs.[45] Of note, thyroid nodules rapidly return to their pretreatment size after discontinuation of therapy.[13] This observation, obviously, implies the necessity for long-term administration of levothyroxine.

It is known, however, that prolonged thyroid-hormone-suppressive therapy induces a state of subclinical hyperthyroidism, defined as an undetectable serum TSH concentration together with normal serum levels of free T3 and free T4. This condition can be the source of unpleasant symptoms as well as more serious adverse effects involving the cardiovascular system (elevated heart rate; supraventricular arrhythmias, particularly atrial fibrillation, increased left ventricular mass; increased cardiac contractility; and impaired diastolic function).[33,34,47] All are potential risk factors for cardiovascular mortality and morbidity in elderly patients with subclinical hyperthyroidism.[48] As for the effects of levothyroxine on bone metabolism, two meta-analyses reported a significant loss of BMD among postmenopausal women but not among premenopausal women;[49,50] nevertheless, there is inadequate evidence that this loss of BMD leads to adverse clinical outcomes (i.e. increased fracture risk).[33,51]

The degree of TSH suppression that can be tolerated without adverse effects is also unclear. Overall, for patients whose serum TSH was in the range 0.10–0.45 mIU/l (normal range, commonly 0.4–4.0 mIU/l), the evidence of cardiovascular risk was rated as insufficient.[33] By contrast, there was fair-to-good evidence for increased cardiac manifestations among patients with serum TSH levels below 0.10 mIU/l, although the evidence for bone alterations in these patients was less impressive (fair-to-insufficient).[33]

It has been suggested that levothyroxine should be given at doses that reduce rather than abolish TSH secretion.[52] In a placebo-controlled, randomized, crossover trial, low-level and high-level suppression of TSH (target levels 0.40–0.60 mIU/l versus <0.01 mIU/l) proved to be equally effective in reducing thyroid nodule size.

Although levothyroxine can produce volume reductions in a subset of nodules, its use is inappropriate in certain groups of patients, such as those over 60 years of age. Benign thyroid nodules in this age-group are generally characterized by very slow growth, or no growth at all. Elderly patients and postmenopausal women in particular are also at increased risk for the potential adverse effects of hormone suppression. Levothyroxine is most likely to be effective for small, recently diagnosed nodules that are predominantly solid and contain an abundance of colloid.[26,35,42,44,45,46] In this case, one indication for treatment could be to prevent growth and the appearance of new nodules;[42,43] however, further studies are necessary to demonstrate the validity of this approach in a long term trial. Thus, routine thyroid-hormone-suppressive therapy is not recommended for benign thyroid nodules.[16]


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