The rationale for thyroid-stimulating hormone suppression is based on evidence that thyroid-stimulating hormone is the main stimulator of thyroid function and growth [1-3]. Indications for suppression of thyroid-stimulating hormone that we found in the literature search are listed in Table 1. By definition, thyroxine suppressive therapy is a dose of thyroxine sufficient to suppress pituitary thyroid-stimulating hormone secretion to concentrations that are below the lower limits of normal [2, 3]. Highly sensitive thyroid-stimulating hormone assays reliably distinguish euthyroid states from subclinical hyperthyroid states and can therefore be used to judge the appropriate doses of thyroxine required for replacement and suppressive therapy. Although the optimal level of thyroid-stimulating hormone suppression has not been defined, complete suppression of serum thyroid-stimulating hormone concentrations to less than 0.1 mIU/L is probably unnecessary in patients with benign thyroid disease [4].

We review these evolving concepts and controversies and offer recommendations for thyroxine suppressive therapy. We do not discuss thyroxine therapy in patients who have already been treated for thyroid cancer.

Methods

Top Methods Author & Article Info References

We reviewed relevant articles published in major English-language medical journals from 1986 to December 1996. We included studies that addressed thyroid nodule assessment by fine-needle aspiration biopsy and treatment by thyroid-stimulating hormone suppression. To locate articles, we searched the MEDLINE database by using the keywords thyroid nodule, benign nodular goiter, solitary or single nodule, nodular thyroid, thyroxine suppression, thyrotropin suppression, and thyroid hormone suppressive therapy. We also used articles from our personal files.

Data Synthesis

Indications for Thyroxine Suppressive Therapy

Identification of Benign Nodules: Detection and Incidence of Thyroid Nodules

The term nodular thyroid disease, which encompasses single and multiple palpable and impalpable nodules, is more descriptive and accurate than the current terms solitary thyroid nodule and multinodular thyroid gland and clearly indicates that proper studies must be performed to establish the correct morphologic diagnosis. Table 2 lists some conditions that cause thyroid nodules. According to physical examination, a solitary nodule is a discrete localized enlargement of the thyroid. Multiple nodules in an enlarged gland suggest a multinodular goiter. However, many patients in whom physical examination indicates a solitary nodule actually have a multinodular goiter. For example, one study [5] reported that of 151 patients who were initially thought to have a solitary nodule on physical examination, 73 had multiple nodules on ultrasonography, most of which were smaller than 1 to 1.5 cm in diameter.

Solitary palpable thyroid nodules are found in 4% to 7% of the adult population in North America [6-8]. The frequency of these nodules increases throughout life, especially in women, persons who reside in iodine-deficient regions, and persons who were exposed to ionizing radiation in infancy or childhood [4, 9]. When the thyroid gland is studied intensively, even more nodules are found: Thirty percent to 50% of persons have nodules at autopsy or on ultrasonography, but only a few nodules prove to be cancerous [10]. From a clinical viewpoint, fewer than 5% of palpable thyroid nodules are malignant: The incidence of thyroid cancer is about four new cases per 100 000 persons each year in the United States [4, 7, 11].

Although a multinodular gland is often considered less likely than a gland with a solitary nodule to be malignant, this is not true. In a study of 5637 patients, Belfiore and colleagues [12] found that the frequency of thyroid cancer was 4.1% in nodules judged to be solitary and 4.7% in nodules judged to be multiple by palpation. This concurs with the observations of McCall and colleagues [13], who also found no difference in the frequency of cancer between patients with solitary and patients with multiple thyroid nodules confirmed by histologic examination. The clinical significance of impalpable nodules seen on ultrasonography or other imaging techniques varies greatly from patient to patient, but the distinction between a solitary thyroid nodule and a multinodular goiter is not as clear as previously thought [14].

Tan and Gharib [15] recently reviewed the clinical importance of incidentally discovered thyroid nodules (incidentalomas). Most incidentalomas are small (<1.5 cm) and are discovered during imaging studies of the neck in patients with problems other than thyroid disease. The prevalence of incidentalomas is 13% to 50%, depending on the population studied and the care with which the thyroid gland is examined. The disparity between the high prevalence of serendipitously discovered thyroid lesions and the low frequency of clinically apparent malignant disease in the general population suggests that most incidentalomas are benign [6, 8]. However, some must be malignant, because all cancers-even aggressive ones-begin as impalpable lesions. Moreover, some patients with thyroid cancer have local and distant metastases at the time of diagnosis but no palpable thyroid abnormalities. Incidentalomas should therefore not be ignored entirely; they should be followed carefully but not treated with thyroxine, as suggested by some researchers [1]. Good evidence shows that tumor diameter is related closely to outcome in patients with differentiated thyroid cancer and that tumors smaller than 1.5 cm that are confined to the thyroid gland are unlikely to cause death [14]. Accordingly, it is prudent to perform fine-needle aspiration biopsy when the impalpable nodule is larger than 1.5 cm and to monitor other nodules without therapy, obtain one ultrasonogram at 6 to 12 months, and perform neck palpation for a few years. Thyroid ultrasonography should be reserved for a patient with a palpably abnormal thyroid gland; it should not be done in an asymptomatic person with a palpably normal thyroid gland.

Identification of Benign Nodules: Is Thyroxine Therapy Superior to Fine-Needle Aspiration Biopsy?

The use of short-term thyroxine suppressive therapy has been suggested as a diagnostic tool: Nodules that shrink with thyroxine therapy are considered benign [2, 4, 6]. However, the presence of thyroid-stimulating hormone receptors in malignant thyroid tissue suggests that this tissue may respond to thyroxine suppressive therapy, and, in fact, 13% to 15% of cancers decrease in size with thyroxine therapy [2, 4]. Failure to respond does not imply the presence of malignancy [2, 16].

On the other hand, the high accuracy of fine-needle aspiration biopsy has been confirmed by numerous recent reviews [4, 7, 8, 17-20]. In a review of more than 18 000 biopsies performed at seven institutions, Gharib and Goellner [18] found fine-needle aspiration biopsy to have a sensitivity of 83%, a specificity of 92%, and an overall accuracy of 95%. Although the results of fine-needle aspiration of nodules smaller than 1 cm in diameter should be interpreted with caution [8], cytologic diagnosis of incidentalomas under ultrasonographic guidance [15] and of irradiated nodules [18, 21] is reliable and accurate. For example, an analysis of the efficacy of fine-needle aspiration biopsy in patients from the Chernobyl area showed a sensitivity for identification of a neoplasm of 98%, a specificity of 99%, and positive predictive values of 98% for thyroid neoplasia and 95% for thyroid cancer [22].

For these reasons, fine-needle aspiration biopsy is considered superior to thyroxine therapy for distinguishing benign nodules from malignant palpable nodules, impalpable nodules, or radiated nodules.

Shrinking Benign Nodules To Minimize Risk for False-Negative Biopsy Results

A major concern of physicians and patients is a false-negative result on fine-needle aspiration biopsy caused by sampling error (that is, an erroneous diagnosis of benign disease). To minimize this problem, some authors recommend thyroxine suppressive therapy for biopsy-proven benign nodules to separate nodules that respond to therapy from those that do not; the latter are more likely to be malignant [3, 16]. The rate of false-negative results has varied from 1% to 10% in series of fine-needle aspiration biopsy; however, in centers with adequate experience with fine-needle aspiration biopsy, rates of false-negative results are less than 2% [18-20]. We think that fine-needle aspiration biopsy, when properly done, is an accurate and reliable procedure that does not require verification with thyroxine suppressive therapy.

Two studies searched for thyroid cancer in patients with benign cytologic results. Boey and colleagues [23] followed 365 patients with benign results on fine-needle aspiration biopsy for a mean of 30 months; only 2 patients had cancer, suggesting a false-negative rate of 0.6%. Of interest, nodules spontaneously disappeared in 46% of patients an average of 13 months after fine-needle aspiration biopsy. In another study, 439 patients with benign aspirates were followed for 6.1 years; cancer was discovered in only 3 patients, for a false-negative rate of 0.7% [24].

We conclude that fine-needle aspiration biopsy is reliable. In experienced hands, the false-negative rate is acceptably low, provided that cytologically benign nodules do not grow during follow-up. Therefore, administering thyroxine suppressive therapy for cytologically benign nodules to avoid sampling error seems redundant.

Shrinking Nodules for Cosmetic Reasons or To Avoid Surgery

Early studies of thyroid hormone therapy for nodular goiters, undertaken for cosmetic reasons or to avoid diagnostic and therapeutic surgery, showed moderate or complete response to therapy. However, a critical examination of trials of thyroid-stimulating hormone suppression published between 1950 and 1980 revealed many methodologic flaws [2]. For example, nodule type was not defined; measurements of nodule size and changes in nodule size were imprecise; response was poorly defined; thyroid-stimulating hormone suppression was not documented; a heterogeneous group of patients with goiters that were diffuse, nodular, or sporadic or were caused by iodine deficiency were included in most studies; and only a few studies were controlled. As a result, the reported success rates of suppressive therapy ranged from 0% to 60% [6]. More recent reviews on the subject have addressed some of these shortcomings [2, 3, 8, 17, 25].

In the past decade, several researchers who used sensitive determinations of thyroid-stimulating hormone concentrations and ultrasonography published results of thyroxine suppressive therapy for solitary and multinodular glands [26-37]. Four studies were nonrandomized trials of thyroxine suppressive therapy in patients with nodular thyroid glands (Table 3) [26-29]. These studies included a total of 310 patients, 206 of whom had solitary thyroid nodules. The duration of treatment ranged from 3 to 8 months. Response rates, defined as a decrease greater than 50% in nodule or goiter size, ranged from 27% to 56%. The highest rates occurred in patients from an iodine-deficient region [27].

The remaining eight studies [30-37] were randomized, controlled trials of thyroxine suppressive therapy that examined solitary nodules or multinodular goiters (Table 4). These studies included 491 patients (246 patients treated with thyroxine and 209 controls); only four trials were placebo controlled, and the remainder of the controls received no treatment. Study duration ranged from 6 to 21 months. Most studies used sensitive thyroid-stimulating hormone assays to verify suppression.

Five studies [30, 31, 34, 35, 37] found no significant differences in the degree of nodule suppression in treatment and control groups. Of note, the responses in treatment groups (measured in millimeters of nodule shrinkage) were significant compared with baseline measurement but were not significant when compared with the changes that occurred spontaneously in the untreated groups. In the study by Papini and colleagues [35], for example, palpation but not ultrasonography showed a significant reduction in nodule size. La Rosa and colleagues [36] found that nodule size was significantly (P = 0.004) more reduced in patients who received thyroxine than in controls, but only in patients with nodules smaller than about 2.5 cm. A more recent study by La Rosa and colleagues [38] suggests that nodule response may depend on the underlying cytologic characteristics: Although only 33% of all nodules were substantially reduced (>50%) in size by thyroid hormone therapy, 62% of colloid nodules and 57% of small degenerative nodules but none of the hyperplastic or fibrotic nodules showed this response to therapy.

These studies indicate that, in general, patients with benign nodules benefit little from thyroxine therapy, that nodule size often decreases spontaneously and nodules often disappear, and that palpable shrinkage of the surrounding tissue but not the nodule may be erroneously interpreted as nodule response to suppression by thyroxine. Some authors suggest that a subset of patients (probably <20%) may respond to thyroxine suppressive therapy. Characteristics that increase the likelihood of response include small, solid colloid nodules with unsuppressed serum thyroid-stimulating hormone [4, 36].

It is generally agreed that nodules or nodular glands with a cytologic diagnosis of lymphocytic thyroiditis (Hashimoto thyroiditis) should be treated with thyroxine [3]. However, little evidence supports this practice (unless the thyroid-stimulating hormone level is increased), and even less evidence shows that thyroxine therapy affects the underlying process responsible for thyroid nodules. Most nodules, however, are solid colloid (a palpable nodule of an impalpable multinodular colloid goiter) or solid cystic (of variable pathologic origin) and seem not to respond to suppressive therapy.

Prevention of Further Growth of Existing Nodules

We found few studies that evaluated the natural history of thyroid nodules or the effect of suppressive therapy on long-term nodule growth. Most nodules change little over the short term, although they can grow, shrink, or even spontaneously disappear [8]. Burch [4] pointed out that "the rate of spontaneous nodule regression has ranged from 0% to 35% in untreated arms of randomized placebo-controlled trials." In five recent studies of a total of 154 patients with colloid nodules (most of which were hypofunctional on radioisotope scanning) followed prospectively without thyroxine therapy, 34 (22%) had substantial reductions ( 50%) in nodule size or volume in 6 months to 3 years [30, 31, 34-36]. It is now clear that nodule size does spontaneously change, and only controlled, long-term studies would provide information on the effects of thyroxine in preventing growth of nodules. We found no such studies.

In a recent report from Japan, Kuma and colleagues [39] followed 140 untreated patients with single nodules for 10 to 30 years (average, 15 years). At follow-up evaluation, which included both palpation and ultrasonography, the researchers found that nodules had decreased in size in 74 patients (53%), remained the same in 47 patients (34%), and had increased in size in 19 patients (14%). In 42 patients (30%) in whom nodules completely disappeared, the nodules had been predominantly cystic by ultrasonography. Initial examination had not included ultrasonography; fine-needle aspiration biopsy had been used to identify cystic or solid nodules. Among the 19 patients with growing nodules, 5 (26%) had a malignant condition at surgery. In another report from the same group [40], 134 patients in whom cytology showed benign nodules were followed for 9 to 11 years; only 1 patient (0.7%) ultimately had papillary thyroid carcinoma. A striking finding was that nodules were no longer palpable at the end of follow-up in 30% of patients and had decreased in size in another 13%.

Although more data are needed, we can reach some conclusions from the existing information. Long-term follow-up of untreated patients with thyroid nodules reveals that 50% of nodules spontaneously decrease in size or disappear, 30% remain the same, and less than 20% increase in size. Nodules that decrease in size are often cystic, whereas those that increase in size should be considered possibly malignant. For the latter, biopsy should be done again or the nodule should be excised. Benign colloid nodules and nodules caused by chronic thyroiditis do not undergo malignant transformation. However, follicular adenomas that yield indeterminate cytologic results (follicular neoplasms) have a propensity to become malignant [7]; in most clinics, nodules that yield such cytologic results are excised. Some clinicians prefer thyroxine suppressive therapy for nodules that yield indeterminate cytologic results. We do not advocate this practice because short-term thyroxine therapy is safe only if the nodule disappears totally [7]. Furthermore, cytologic diagnosis of follicular neoplasm carries a 10% to 20% risk for malignancy, which is best treated surgically [7, 8].

Prevention of Nodules after Head and Neck Irradiation

Irradiation of the head and neck, particularly in infants and children, is a risk factor for benign and malignant thyroid disease. The frequency with which thyroid nodules develop depends on the patient's age at the time of radiation therapy, the radiation dose, the duration of follow-up, genetic factors, and iodine intake [4, 6, 11]. Benign and malignant tumors may appear within 3 years after radiation exposure; the incidence is 2% annually thereafter and reaches a cumulative peak between 15 and 30 years. Radiation-associated cancers are characterized by multicentricity-55% in one report [21]. Most of these tumors are papillary cancers, and up to 20% of them are tiny microfoci (1 to 5 mm) of clinically unimportant carcinomas [7, 21]. Although it is possible that foci of cancer are present in areas that are separate from an isolated nodule, the management of irradiated and nonirradiated benign nodules does not differ.

Controversy surrounds the evaluation and management of a patient with irradiated thyroid. In the past, some authorities have recommended suppressive therapy for patients with a history of irradiation, even if the thyroid gland was palpably normal, in the hope of preventing a malignant thyroid condition [41]. DeGroot [21] reviewed this topic and concluded that suppressive therapy is of no value in preventing the development of new nodules, benign or malignant, in an irradiated thyroid. In an irradiated patient with a single nodule detected by palpation, management decisions should be based on results of fine-needle aspiration biopsy. Fine-needle aspiration biopsy is as reliable in an irradiated thyroid as in a nonirradiated thyroid [1, 7, 21]. However, the presence of multiple nodules raises the problem of sampling bias in a gland already prone to developing cancer, making fine-needle aspiration biopsy less reliable. Thyroid imaging provides no additional useful information. Because thyroxine suppressive therapy does not reliably identify malignant thyroid disease, we agree with DeGroot that near-total thyroidectomy is usually advisable for multinodular goiters that develop after radiation exposure.

Management of adults who develop impalpable thyroid nodules after radiation exposure during childhood was reviewed in a decision analysis by Stockwell and colleagues [42], who recommended careful follow-up without additional studies or therapy and further evaluation only if palpable nodules develop. Fogelfeld and colleagues [43] conducted a randomized study of thyroxine suppressive therapy in previously irradiated patients who had undergone subtotal thyroidectomy for benign nodules. In this study, 511 patients were followed for 11 years after surgery; benign thyroid nodules developed in 8.4% of treated patients and 35.8% of controls, a difference that was highly statistically significant. The frequency of malignancy during the same study period was similar in both groups.

Should patients with a history of radiation therapy be treated with thyroxine? Conflicting data make a recommendation difficult. It seems reasonable to observe patients with normal thyroid detected by palpation without giving thyroxine and to treat patients undergoing thyroidectomy with thyroxine.

Prevention of Nodule Recurrence after Surgery for Nodular Goiters

For many years, standard practice was to treat all patients who had undergone partial thyroidectomy for benign nodular thyroid disease with lifelong thyroxine therapy to prevent regenerative goiters [3, 25]. However, the recurrence rates ranged from 0% to 3% within 1 year to 19% at 16 years after surgery, depending on the extent of excision and the duration of follow-up [2].

Between 1940 and 1980, many studies supported the efficacy of postoperative thyroid hormone therapy to prevent the development of new benign nodular thyroid disease [25]. However, these studies were uncontrolled and retrospective. Studies done since 1980 have questioned the efficacy of suppressive therapy in preventing postoperative recurrence of benign thyroid disease [44-49]. We were able to identify only four prospective randomized trials that addressed this issue (Table 5). The four studies included a total of 299 patients (132 patients treated with thyroxine and 167 controls) who had undergone lobectomy for benign goiters and were followed for 1 to 9 years [47-50]. Postoperative administration of thyroxine did not prevent the formation of new nodules in three Danish studies, whereas an Italian report comparing suppressive and replacement thyroxine doses suggested reduced nodule recurrence with thyroid-stimulating hormone suppression [50]. In the latter study, follow-up was 3 years in patients from an iodine-deficient region. In two studies [48, 50], postoperative evaluation included ultrasonography. However, the validity of two reports [47, 48] has been questioned because of the short follow-up. In the study by Bistrup and colleagues [49], 15% of the treatment group and 22% of the control group developed new nodules 9 years after 100 patients were randomly assigned to receive thyroxine or no therapy after operation; the difference was not statistically significant. The authors concluded that long-term postoperative thyroxine therapy is not efficacious.

Most recent studies failed to find thyroxine effective in prophylaxis after partial thyroidectomy for benign nodular thyroid disease. We select for treatment only patients who have hypothyroidism after surgery.

Adverse Effects of Thyroxine Suppressive Therapy

In recent years, the potential side effects of thyroxine therapy have been assessed by using newly developed, highly sensitive thyroid-stimulating hormone assays; bone mineral densitometry; and sensitive echocardiography methods. It is clear that using thyroxine to suppress thyroid-stimulating hormone secretion may have adverse effects on several target organs, particularly the skeleton and the heart.

It has been known for years that naturally occurring hyperthyroidism increases bone turnover, bone loss, and risk for fractures [51]. Surprisingly, only recently has it been suggested that suppressive doses of thyroxine may have similar detrimental effects on bone [52-56]. In a meta-analysis of studies that included 441 measurements of bone mineral density in 239 women [57], it was estimated that premenopausal women treated with thyroid hormone would lose 2.7% of their bone mass over 8.2 years, a rate that did not differ from that in normal women. Schneider and colleagues [58] showed that estrogen therapy inhibits thyroxine-induced bone loss. Thyroxine therapy that does not suppress thyroid-stimulating hormone secretion does not cause osteopenia [59, 60].

The data on the effects of thyroxine in postmenopausal women are more convincing for bone loss. Two studies [53, 54] found substantial excess bone mineral loss in postmenopausal women receiving doses of thyroxine sufficient to suppress serum thyroid-stimulating hormone concentrations. However, no data link thyroxine therapy to increased fracture rates. Although a trend toward an increased fracture rate was suggested by Leese and colleagues [61], fracture rates are difficult to measure accurately because they are low. Therefore, studies of great statistical power are required.

We conclude that replacement doses of thyroxine that result in a normal serum thyroid-stimulating hormone concentration do not cause osteoporosis, whereas doses that suppress serum thyroid-stimulating hormone to concentrations seen in hyperthyroidism may be associated with decreased bone mineral density in postmenopausal women. We advise modest suppression of serum thyroid-stimulating hormone concentrations to between 0.1 and 0.5 mIU/L for most patients and reserving suppression to concentrations less than 0.1 mIU/L for the occasional patient with an aggressive malignant thyroid condition [60, 62]. In postmenopausal women given thyroxine in doses sufficient to suppress thyroid-stimulating hormone, estrogen-replacement therapy or bisphosphonate therapy should be considered because of the salutary effects of these therapies on bone mineral density.

Thyroxine given in doses sufficient to suppress serum thyroid-stimulating hormone concentrations to undetectable levels may have adverse effects on the heart [63-66]. Thyroxine has direct effects on cardiac myocyte protein synthesis, intracellular calcium handling, peripheral hemodynamics, oxygen utilization, and the sympathoadrenal system. Long-term thyroxine suppressive therapy increases the pulse rate, left ventricular mass, and frequency of atrial arrhythmias [64]. Atrial fibrillation occurs in 5% to 15% of patients with clinical or subclinical thyrotoxicosis. For example, Sawin and colleagues [67] recently found that suppressed serum thyroid-stimulating hormone concentrations in elderly, otherwise healthy persons increased the risk for atrial fibrillation threefold. Leese and colleagues [61] reported that patients younger than 65 years of age who were taking thyroxine were at slightly increased risk for ischemic heart disease; however, the incidence did not differ from that in patients not taking thyroxine. Cardiac status reverts to its pretreatment state in most patients after suppressive therapy has been discontinued. Some of the adverse effects on the heart can be reduced or eliminated by treatment with ß-adrenergic blocking agents [68].

Conclusions and Recommendations

Fine-needle aspiration biopsy has dramatically altered the management of thyroid nodules. We think that fine-needle aspiration biopsy should be performed on all patients who have palpable thyroid nodules, including patients with dominant nodules in a multinodular goiter and thyrotoxic patients with a palpable nodule. When an impalpable nodule is found by ultrasonography, fine-needle aspiration biopsy should be done if the nodule is larger than 1.5 cm, is a dominant nodule of a multinodular gland (which, as a practical matter, is usually the largest nodule), seems encapsulated (halo sign), or contains an echo pattern that is distinctly different from the surrounding thyroid nodules.

In patients with incidentalomas, the data support follow-up without thyroxine suppressive therapy or frequent use of imaging procedures unless the nodule is larger than 1.5 cm in diameter. We think that a similar strategy should be followed in patients with a previous exposure to external irradiation and a palpably normal thyroid gland.

In most centers, fine-needle aspiration biopsy is reliable, sensitive, and specific, with false-negative rates of 1% to 2%. Patients with cytologically benign nodules (75% of all satisfactory aspirates) can be followed by palpation and repeated biopsy without suppressive therapy. Benign colloid nodules do not become malignant and most either do not grow in size (30%) or shrink or disappear spontaneously (30% to 50%). The debate about suppressive therapy continues because several recent well-controlled studies failed to show the efficacy of thyroxine, whereas several other studies support its efficacy. In approximately 20% of patients or less, nodules shrink in response to thyroxine therapy; those that do are usually the smallest nodules (<2.5 cm in diameter). Whether thyroxine therapy prevents further growth of existing nodules or the emergence of new nodules is not known. Clearly, additional information is required to resolve this problem; in the meantime, we avoid suppressive therapy. In addition, the data seem to indicate that a malignant condition can be better diagnosed with fine-needle aspiration biopsy than with a trial of thyroxine.

The potential risks for osteoporosis and heart disease are not negligible when long-term suppression of thyroid-stimulating hormone with thyroxine is being considered, especially in postmenopausal women. Physicians who choose suppressive therapy should be aware of its potential side effects. Serum thyroid-stimulating hormone levels should be maintained around 0.1 to 0.5 mIU/L to minimize the side effects of therapy. In postmenopausal women, thyroxine suppressive therapy should be accompanied by estrogen therapy if peak bone mineral density is more than 2 SDs below that of age-matched controls. Bisphosphonate therapy may be useful when estrogen is contraindicated or not tolerated; however, no data are available on the use of bisphosphonates in this clinical situation. If the pretreatment serum thyroid-stimulating hormone level is less than about 0.1 mIU/L, mild subclinical hyperthyroidism may already exist and thyroxine therapy may potentiate thyrotoxicosis, especially in elderly persons.

Thyroxine therapy does not prevent the recurrence of benign nodules in patients who have undergone partial thyroidectomy and is not indicated unless the patient has hypothyroidism or a history of external irradiation. One large randomized study of patients who had previous head and neck irradiation suggested that thyroxine therapy may prevent the recurrence of new nodules after subtotal thyroidectomy for benign nodular disease [43].

We conclude that there is no certain proof that suppression of the nodular thyroid with thyroxine is beneficial in most patients and thus that its continued use should be discouraged. We believe that nodule shrinkage for its own sake, apart from the specific reasons shown in Table 1, is a surrogate outcome that may not be of clinical studies to patient or physician. Long-term controlled studies of thyroxine suppressive therapy are needed to answer some of these questions. Although there is no consensus, we believe that most endocrinologists should follow rather than suppress isolated thyroid nodules. We believe that the potential risks of long-term L-thyroxine therapy outweigh the potential benefits in most patients, especially postmenopausal women.

Dr. Mazzaferri: Division of Endocrinology, Department of Internal Medicine, The Ohio State University College of Medicine, 2 East Means Hall, 1654 Upham Drive, Columbus, OH 43210.