Abstract
In the “modern” era, in keeping with the growing emphasis on DTC, there are three actual or potential additions to the thyroid pharmacopeia. These are recombinant human thyrotropin (rhTSH); a host of relatively new drugs targeting the oncogenic and signaling kinases that, when mutated, promote thyroid cancer (1); and thyroid hormone analogues with “certain metabolic and organ-specific actions” (2). The first, rhTSH, is now routinely used in the management of thyroid cancer. Except for vandetanib for progressive metastatic medullary thyroid carcinoma, tyrosine kinase inhibitors are still being developed or are in Phase I–III clinical trials. Some others may be approved for clinical use; their side effects should be even more challenging than the adverse effects of antithyroid drugs. Finally, the thyroid hormone analogues with metabolic effects that do enter clinical practice (for lowering cholesterol, for example) will be prescribed by many primary care providers and specialists, not only endocrinologists.
In this issue of Thyroid, Allen et al. (3) describe the effects of a small molecule (SM) thyrotropin receptor (TSHR) agonist on cAMP production by HEK-EM293 cells into which mutant TSHRs were introduced. This study continues a series of papers on the TSHR from this group (4 –16), starting with the first report in 2006 of a SM TSHR agonist (12,14). Notably, in addition to discovering TSHR agonistic properties in a series of compounds, they recently reported the first SM TSHR antagonist (7). In addition to SM TSHR agonists and antagonists, proteins with TSHR agonist and antagonist activities have also been described, the most prominent of which is rhTSH itself. Superagonist TSH analogs have been developed by Szkuklinski, Weintraub, and colleagues (17), and monoclonal antibodies acting as TSHR agonist and antagonists have been prepared by the group of Rees Smith and Sanders (18 –20).
When will TSHR agonists and antagonists be available for clinical use? The question is moot as far as TSHR agonists are concerned because rhTSH, a potent TSHR agonist, was approved almost 13 years ago (21). Even were this not so, the more interesting part of the question might be “When will TSHR antagonists be available for clinical use?” This is because TSHR antagonists have a wider range of potential clinical uses than TSHR agonists. Whereas TSHR agonists have actual or potential use in thyroid cancer and multinodular goiter (21), there are rationales for using TSHR antagonists in simple and nodular goiter, DTC, Graves' disease, human chorionic gonadotropin (HCG)-induced hyperthyroidism, TSH-secreting pituitary tumors, and thyroid hormone resistance.
Strictly speaking, “TSHR antagonist” refers to agents that inhibit ligand-induced activation of the TSHR. This activation, in turn, triggers signaling cascades, the best established of which are mediated by adenylyl cyclase and Gq. Even in the absence of TSH or other agonists, there is some basal signaling activity of the TSHR. Inverse TSHR agonists inhibit this basal activity (6). Inverse TSHR agonists might be useful to treat thyroid diseases associated with activation of the TSHR despite suppressed serum TSH concentrations.
The pathogenesis of simple and nodular goiter is likely multifactorial. The usefulness of thyroid hormones, LT4 and triiodothyronine (T3), in treating these conditions is debatable. Insofar as they are effective, they probably work by inhibiting TSH secretion, in turn reducing TSH-induced activation of the TSHR, a potent stimulus to thyroid growth. In addition to questions regarding their utility, thyroid hormones have the disadvantage that, along with suppressing TSH secretion, there is the unavoidable induction of thyrotoxicosis. TSHR antagonists would not have this shortcoming. Their potential utility would vary from patient to patient, depending on the levels of circulating TSH. In long-standing nodular goiter, TSH levels often decline as evolution to toxic multinodular goiter occurs. In these patients inverse TSHR agonists might suppress thyroid growth and function.
DTC is treated by thyroidectomy and often, RAI ablation of residual thyroid tissue. LT4 treatment is universally recommended thereafter to treat hypothyroidism. According to the revised American Thyroid Association management guidelines for thyroid nodules and DTC, LT4 should also be given to suppress endogenous TSH in patients with persistent disease and in those who are clinically and biochemically free of disease but who originally presented with high-risk disease (22). Even for the low-risk categories of DTC, the guidelines recommend that serum TSH be maintained in the low normal range (22). Unfortunately, subclinical thyrotoxicosis (subTOX) is an inevitable consequence of using suppressive doses of LT4 to treat DTC. TSHR antagonists should, in theory, be as effective as TSH suppression in treating DTC. Their use might permit TSH to be maintained within the normal range in all ablated patients with DTC. In patients with cardiac disease, or others more susceptible to the consequences of subTOX, indications for their use would be even stronger. Rationales for using inverse TSHR agonists in DTC probably exist, but no doubt are more complex than for using TSHR antagonists. Inverse TSH agonists should be studied in experimental models of DTC and eventually, if appropriate, in patients with DTC.
Graves' disease, TSH-induced hyperthyroidism, and HCG-induced hyperthyroidism are the most logical candidates for TSHR antagonist therapy because they all are characterized by ligand-induced activation of the TSHR. The most optimistic prediction is that TSHR antagonists would become the primary therapy for Graves' disease, replacing RAI, thyroidectomy, and antithyroid drugs. This seems an extreme viewpoint because, for many patients, it would involve lifelong drug therapy. More appealing would be to reserve prolonged TSHR antagonist therapy for those Graves' disease patients who are most likely to achieve remission. The problem of identifying such patients has been studied by many groups. Interest in solving this problem would be even greater if more options for nonablative control of hyperthyroidism in Graves' disease, as might be provided by TSHR antagonists, were available. In this context, Neumann et al. (11) recently described an SM TSHR antagonist that inhibited the TSHR activation induced by sera from patients with Graves' disease.
None of the currently available treatments for hyperthyroidism are ideal for quickly achieving a euthyroid state. For some therapies there is a lag in their onset of action (23), others are highly invasive and require preparation of the patient with β blockers and iodides (24), and others acutely suppress thyroid secretion of T4 and T3, but the effect is sometimes incomplete and usually not sustained (25). Therefore one of the strongest indications for TSHR antagonist therapy would be in patients with thyroid storm or those in whom rapid control of thyrotoxicosis is essential.
HCG is a weak TSHR agonist. High serum concentrations of HCG are associated with varying degrees of thyrotoxicosis in women with gestational trophoblastic disease and rarely, in nonpregnant women and men with choriocarcinoma (26). TSHR antagonists would be logical considerations in these patients. On the other hand, concerns about toxicity and the relatively benign nature of disorders such as transient thyrotoxicosis of pregnancy would probably limit their use in most pregnant women.
With possible rare exceptions (27), TSH induced hyperthyroidism in the absence of thyroid hormone resistance (THR) is almost always due to TSH-secreting pituitary tumors. These tumors are often large and locally aggressive, though a few TSH-secreting microadenomas have been described (28). TSHR antagonists might be useful in selected patients with hyperthyroidism due to TSH-secreting tumors.
THR is not generally considered a cause of hyperthyroidism, but there are a few patients whose resistance to thyroid hormone appears to be greatest at the pituitary level as judged by a predominance of thyrotoxic symptoms. TSHR antagonists might be beneficial in these patients. Moreover, in almost all patients with THR, TSHR antagonists in combination with replacement doses of LT4 should prevent goiter formation.
Serum TSH concentrations are suppressed in patients with gain of function mutations of the TSHR, most of which are somatic (autonomous toxic thyroid adenomas, rare patients with follicular thyroid carcinoma) but some are germline (familial non-autoimmune hyperthyroidism) or neomutations (sporadic toxic thyroid hyperplasia) (Thyroid Disease Manager accessed July 3, 2011, at
It is evident that suitable TSHR antagonists and inverse TSHR agonists would be useful in a spectrum of thyroid diseases, invigorating the treatment of non-neoplastic disorders and likely improving the outcome of DTC even more. It is less likely they would be advantageous for treating undifferentiated thyroid carcinoma. As with any new drug, the two most important considerations are safety and efficacy. Much of the literature in this field does not yet focus on the possibility of toxic reactions to TSHR antagonists and reverse agonists. These could be due to toxic actions unrelated to effects on the TSHR or to overlapping effects on other G protein–coupled receptors in various organs. TSH receptors are found in many extrathyroidal tissues including bone, fat cells, and cells of the immune system (6). Inappropriate blocking of these extrathyroidal TSH receptors could have unintended consequences, particularly if blocking occurred for an extended period. It is too early to tell if TSHR antagonists or inverse agonists will become available for clinical use, or when this is likely to occur. The studies to date appear promising, but much work remains, including defining the toxicology profile of these agents.